Circular RNA hsa_circ_0010729 regulates vascular endothelial cell proliferation and apoptosis by targeting the miR-186/HIF-1α axis.

PubMed

Dang, Rui-Ying; Liu, Feng-Li; Li, Yan

2017-08-19

Circular RNAs (circRNAs) are a group of non-protein-coding RNAs generated from back splicing. Emerging evidence has demonstrated its vital regulation on angiogenesis. However, the underlying mechanism responsible for circRNAs effects on vascular endothelial cells is still unclear. In the present study, we screened the expression profiles and investigated the physiological role of circRNAs in hypoxia-induced human umbilical vein endothelial cells (HUVECs). Using circRNA microarray analysis, we identified 36 circRNAs that were significantly dysregulated including 14 down-regulated circRNAs and 22 up-regulated with 2-fold change (P < 0.05). From the over-expressed circRNAs, hsa_circ_0010729 was selected as candidate circRNA and which was validated to be significantly up-regulated using RT-PCR. In loss-of-function experiments of HUVECs, hsa_circ_0010729 knockdown suppressed the proliferation and migration ability and enhanced apoptosis. Bioinformatic prediction and luciferase assay revealed that hsa_circ_0010729 and hypoxia inducible factor 1 alpha (HIF-1α) were targeted by miR-186. Validation experiments verified that hsa_circ_0010729 was co-expressed with HIF-1α, being negatively correlated with miR-186. Moreover, rescue experiments demonstrated that miR-186 inhibitor could reverse the role of hsa_circ_0010729 knockdown on HUVECs progression. Overall, the present study identifies the crucial regulation of hsa_circ_0010729 on vascular endothelial cell proliferation and apoptosis via targeting miR-186/HIF-1α axis. Copyright © 2017 Elsevier Inc. All rights reserved.

Hsa-miR-195 targets PCMT1 in hepatocellular carcinoma that increases tumor life span.

PubMed

Amer, Marwa; Elhefnawi, M; El-Ahwany, Eman; Awad, A F; Gawad, Nermen Abdel; Zada, Suher; Tawab, F M Abdel

2014-11-01

MicroRNAs are small 19-25 nucleotides which have been shown to play important roles in the regulation of gene expression in many organisms. Downregulation or accumulation of miRNAs implies either tumor suppression or oncogenic activation. In this study, differentially expressed hsa-miR-195 in hepatocellular carcinoma (HCC) was identified and analyzed. The prediction was done using a consensus approach of tools. The validation steps were done at two different levels in silico and in vitro. FGF7, GHR, PCMT1, CITED2, PEX5, PEX13, NOVA1, AXIN2, and TSPYL2 were detected with high significant (P < 0.005). These genes are involved in important pathways in cancer like MAPK signaling pathway, Jak-STAT signaling pathways, regulation of actin cytoskeleton, angiogenesis, Wnt signaling pathway, and TGF-beta signaling pathway. In vitro target validation was done for protein-L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1). The co-transfection of pmirGLO-PCMT1 and pEGP-miR-195 showed highly significant results. Firefly luciferase was detected using Lumiscensor and t test analysis was done. Firefly luciferase expression was significantly decreased (P < 0.001) in comparison to the control. The low expression of firefly luciferase validates the method of target prediction that we used in this work by working on PCMT1 as a target for miR-195. Furthermore, the rest of the predicted genes are suspected to be real targets for hsa-miR-195. These target genes control almost all the hallmarks of liver cancer which can be used as therapeutic targets in cancer treatment.

Tumor targeting profiling of hyaluronan-coated lipid based-nanoparticles

NASA Astrophysics Data System (ADS)

Mizrahy, Shoshy; Goldsmith, Meir; Leviatan-Ben-Arye, Shani; Kisin-Finfer, Einat; Redy, Orit; Srinivasan, Srimeenakshi; Shabat, Doron; Godin, Biana; Peer, Dan

2014-03-01

Hyaluronan (HA), a naturally occurring high Mw (HMw) glycosaminoglycan, has been shown to play crucial roles in cell growth, embryonic development, healing processes, inflammation, and tumor development and progression. Low Mw (LMw, <10 kDa) HA has been reported to provoke inflammatory responses, such as induction of cytokines, chemokines, reactive nitrogen species and growth factors. Herein, we prepared and characterized two types of HA coated (LMw and HMw) lipid-based targeted and stabilized nanoparticles (tsNPs) and tested their binding to tumor cells expressing the HA receptor (CD44), systemic immunotoxicity, and biodistribution in tumor bearing mice. In vitro, the Mw of the surface anchored HA had a significant influence on the affinity towards CD44 on B16F10 murine melanoma cells. LMw HA-tsNPs exhibited weak binding, while binding of tsNPs coated with HMw HA was characterized by high binding. Both types of tsNPs had no measured effect on cytokine induction in vivo following intravenous administration to healthy C57BL/6 mice suggesting no immune activation. HMw HA-tsNPs showed enhanced circulation time and tumor targeting specificity, mainly by accumulating in the tumor and its vicinity compared with LMw HA-tsNPs. Finally, we show that methotrexate (MTX), a drug commonly used in cancer chemotherapy, entrapped in HMw HA-tsNPs slowly diffused from the particles with a half-life of 13.75 days, and improved the therapeutic outcome in a murine B16F10 melanoma model compared with NPs suggesting an active cellular targeting beyond the Enhanced Permeability and Retention (EPR) effect. Taken together, these findings have major implications for the use of high molecular weight HA in nanomedicine as a selective and safe active cellular targeting moiety.Hyaluronan (HA), a naturally occurring high Mw (HMw) glycosaminoglycan, has been shown to play crucial roles in cell growth, embryonic development, healing processes, inflammation, and tumor development and progression

Preparation, Characterization, and Optimization of Folic Acid-Chitosan-Methotrexate Core-Shell Nanoparticles by Box-Behnken Design for Tumor-Targeted Drug Delivery.

PubMed

Naghibi Beidokhti, Hamid Reza; Ghaffarzadegan, Reza; Mirzakhanlouei, Sasan; Ghazizadeh, Leila; Dorkoosh, Farid Abedin

2017-01-01

The objective of this study was to investigate the combined influence of independent variables in the preparation of folic acid-chitosan-methotrexate nanoparticles (FA-Chi-MTX NPs). These NPs were designed and prepared for targeted drug delivery in tumor. The NPs of each batch were prepared by coaxial electrospray atomization method and evaluated for particle size (PS) and particle size distribution (PSD). The independent variables were selected to be concentration of FA-chitosan, ratio of shell solution flow rate to core solution flow rate, and applied voltage. The process design of experiments (DOE) was obtained with three factors in three levels by Design expert software. Box-Behnken design was used to select 15 batches of experiments randomly. The chemical structure of FA-chitosan was examined by FTIR. The NPs of each batch were collected separately, and morphologies of NPs were investigated by field emission scanning electron microscope (FE-SEM). The captured pictures of all batches were analyzed by ImageJ software. Mean PS and PSD were calculated for each batch. Polynomial equation was produced for each response. The FE-SEM results showed the mean diameter of the core-shell NPs was around 304 nm, and nearly 30% of the produced NPs are in the desirable range. Optimum formulations were selected. The validation of DOE optimization results showed errors around 2.5 and 2.3% for PS and PSD, respectively. Moreover, the feasibility of using prepared NPs to target tumor extracellular pH was shown, as drug release was greater in the pH of endosome (acidic medium). Finally, our results proved that FA-Chi-MTX NPs were active against the human epithelial cervical cancer (HeLa) cells.

Circular RNA hsa_circ_0000673 promotes hepatocellular carcinoma malignance by decreasing miR-767-3p targeting SET.

PubMed

Jiang, Weidong; Wen, Dacheng; Gong, Lulu; Wang, Yu; Liu, Zefeng; Yin, Fangying

2018-06-02

The importance of circular RNAs (circRNAs) in human cancers has gradually been acknowledged. In hepatocellular carcinoma (HCC), several circRNAs have been reported to regulate tumor growth and metastasis. However, the role of hsa_circ_0000673 in HCC remains largely unknown. In this study, we found that hsa_circ_0000673 was significantly upregulated in HCC tissues compared to adjacent non-tumor tissues. Moreover, we found that hsa_circ_0000673 knockdown markedly inhibited the proliferation and invasion of HCC cells in vitro. Besides, hsa_circ_0000673 silence led to delayed tumor growth in vivo. In terms of mechanism, we showed that hsa_circ_0000673 directly associated with miR-767-3p in HCC cells. Via inhibiting miR-767-3p, hsa_circ_0000673 promoted HCC cell proliferation and invasion. Furthermore, we demonstrated that SET was a downstream effector of hsa_circ_0000673/miR-767-3p signaling. We showed that miR-767-3p could significantly promote SET expression by sponging miR-767-3p in HCC cells. Finally, rescue assays indicated that SET expression was essential for the effects of hsa_circ_0000673/miR-767-3p signaling on HCC cell proliferation and invasion. Taken together, our findings demonstrated that hsa_circ_0000673 promoted HCC malignant behaviors via regulating miR-767-3p/SET pathway. Copyright © 2018 Elsevier Inc. All rights reserved.

Design of an Anticancer Copper(II) Prodrug Based on the Lys199 Residue of the Active Targeting Human Serum Albumin Nanoparticle Carrier.

PubMed

Gou, Yi; Zhang, Yao; Zhang, Zhenlei; Wang, Jun; Zhou, Zuping; Liang, Hong; Yang, Feng

2017-06-05

We not only modified the types and numbers of coordinated ligands in a metal agent to enhance its anticancer activity, but we also designed a metal prodrug based on the N-donor residues of the human serum albumin (HSA) IIA subdomain to improve its delivery efficiency and selectivity in vivo. However, there may be a conflict in simultaneously achieving the two goals because Lys199 and His242 in the IIA subdomain of HSA can replace its two coordinated ligands, which will decrease its anticancer activity relative to the original metal agent. Thus, to improve the delivery efficiency of the metal agent and simultaneously avoid decreasing its anticancer activity in vivo, we decided to develop an anticancer metal prodrug by regulating its pharmacophore ligand so that it would not be displaced by the Lys199 residue of the folic acid (FA)-functionalized HSA nanoparticle (NP) carrier. To this end, we first synthesized two (E)-N'-(5-chloro-2-hydroxybenzylidene)benzohydrazide Schiff base (HL) Cu(II) compounds by designing a second ligand with a different coordinating atom with Cu 2+ /Cu(L)(QL)(Br) [C1, QL = quinolone] and Cu(L)(DMF)(Br) [C2, DMF = N,N-dimethylformamide]. As revealed by the structures of the two HSA complexes, the Cu compounds bind to the hydrophobic cavity in the HSA IIA subdomain. The QL ligand of C1 is replaced by Lys199, which coordinates with Cu 2+ , whereas the DMF ligand of C2 is kept intact and His242 is replaced with Br - of C2 and coordinates with Cu 2+ . The cytotoxicity of the Cu compounds was enhanced by the FA-HSA NPs in the Bel-7402 cells approximately 2-4-fold; however, they raise the cytotoxicity levels in the normal cells in vitro, and the FA-HSA NPs did not. Importantly, the in vivo data showed that FA-HSA-C2 NPs increased selectivity and the capacity to inhibit tumor growth and were less toxic than HSA-C2 NPs and C2. Moreover, C2/HSA-C2 NPs/FA-HSA-C2 NPs induced Bel-7402 cell death by potentially multiple mechanisms.

Dioxin induces expression of hsa-miR-146b-5p in human neuroblastoma cells.

PubMed

Xu, Tuan; Xie, Heidi Q; Li, Yunping; Xia, Yingjie; Sha, Rui; Wang, Lingyun; Chen, Yangsheng; Xu, Li; Zhao, Bin

2018-01-01

Dioxin can cause a series of neural toxicological effects. MicroRNAs (miRs) play important roles in regulating nervous system function and mediating cellular responses to environmental pollutants, such as dioxin. Hsa-miR-146b-5p appears to be involved in neurodegenerative diseases and brain tumors. However, little is known about effects of dioxin on the expression of hsa-miR-146b-5p. We found that the hsa-miR-146b-5p expression and its promoter activity were significantly increased in dioxin treated SK-N-SH cells, a human-derived neuroblastoma cell line. Potential roles of hsa-miR-146b-5p in mediating neural toxicological effects of dioxin may be due to the regulation of certain target genes. We further confirmed that hsa-miR-146b-5p significantly suppressed acetylcholinesterase (AChE) activity and targeted the 3'-untranslated region of the AChE T subunit, which has been down-regulated in dioxin treated SK-N-SH cells. Functional bioinformatic analysis showed that the known and predicted target genes of hsa-miR-146b-5p were involved in some brain functions or cyto-toxicities related to known dioxin effects, including synapse transmission, in which AChE may serve as a responsive gene for mediating the effect. Copyright © 2017. Published by Elsevier B.V.

Investigation of the mycobacterial enzyme HsaD as a potential novel target for anti-tubercular agents using a fragment-based drug design approach.

PubMed

Ryan, Ali; Polycarpou, Elena; Lack, Nathan A; Evangelopoulos, Dimitrios; Sieg, Christian; Halman, Alice; Bhakta, Sanjib; Eleftheriadou, Olga; McHugh, Timothy D; Keany, Sebastian; Lowe, Edward D; Ballet, Romain; Abuhammad, Areej; Jacobs, William R; Ciulli, Alessio; Sim, Edith

2017-07-01

With the emergence of extensively drug-resistant tuberculosis, there is a need for new anti-tubercular drugs that work through novel mechanisms of action. The meta cleavage product hydrolase, HsaD, has been demonstrated to be critical for the survival of Mycobacterium tuberculosis in macrophages and is encoded in an operon involved in cholesterol catabolism, which is identical in M. tuberculosis and M. bovis BCG. We generated a mutant strain of M. bovis BCG with a deletion of hsaD and tested its growth on cholesterol. Using a fragment based approach, over 1000 compounds were screened by a combination of differential scanning fluorimetry, NMR spectroscopy and enzymatic assay with pure recombinant HsaD to identify potential inhibitors. We used enzymological and structural studies to investigate derivatives of the inhibitors identified and to test their effects on growth of M. bovis BCG and M. tuberculosis. The hsaD deleted strain was unable to grow on cholesterol as sole carbon source but did grow on glucose. Of seven chemically distinct 'hits' from the library, two chemical classes of fragments were found to bind in the vicinity of the active site of HsaD by X-ray crystallography. The compounds also inhibited growth of M. tuberculosis on cholesterol. The most potent inhibitor of HsaD was also found to be the best inhibitor of mycobacterial growth on cholesterol-supplemented minimal medium. We propose that HsaD is a novel therapeutic target, which should be fully exploited in order to design and discover new anti-tubercular drugs. This article is part of a themed section on Drug Metabolism and Antibiotic Resistance in Micro-organisms. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.14/issuetoc. © 2017 The British Pharmacological Society.

[Preparation of ASODN-protamine-HSA-PLGA nanoparticles and initial evaluation of their nucleus targeting property in vitro].

PubMed

Zhang, Yi; Yuan, Li; Yan, Xiao-ling; Gong, Tao; Liu, Jie; Zhang, Zhi-rong; Sun, Xun

2009-05-01

To develop a novel non-viral gene delivery system-SODN-Protamine-HSA-PLGA (ASODN-P/H-PLGA-NP) and investigate its nucleus targeting potential in vitro. ASODN-P/H-PLGA-NP was prepared by mixing the protamine sulfate and HSA. Then the PLGA nanoparticles were prepared using double-emulsion evaporation technique, followed by addition of ASODN to the prepared P/H complex. The morphology of ASODN-P/H-PLGA-NP was observed by transmission electron microscopy. The diameter, PDI, and surface charge of ASODN-P/H-PLGA-NP were measured by photo correlation spectroscopy (PCS). The encapsulation efficiency of ASODN was determined by double step method. The cytotoxicity of ASODN-P/H-PLGA-NP was investigated by MTT assays. The ability to enter the squamouse carcinoma: Hep-2 cell line and its nucleus targeting property were observed by confocal laser scanning microscope. The average diameter, PDI, zeta potential, and encapsulation efficiency of ASODN-P/H-PLGA-NP were 128 nm, 0.234, -23.3 mV, and 78.45%, respectively. ASODN-P/H-PLGA-NP could protect the ASODN from the shear force in the ultrasound process during preparation. ASODN-P/H-PLGA-NP couldenter Hep-2 cells and have certain level of nucleus targeting property. ASODN-P/H-PLGA-NP can be prepared easily with small particle sizes and low cytotoxicity, which might be employed as a good non-viral vector for applications in ASODN delivery to nucleus.

Piezo channels and GsMTx4: Two milestones in our understanding of excitatory mechanosensitive channels and their role in pathology.

PubMed

Suchyna, Thomas M

2017-11-01

Discovery of Piezo channels and the reporting of their sensitivity to the inhibitor GsMTx4 were important milestones in the study of non-selective cationic mechanosensitive channels (MSCs) in normal physiology and pathogenesis. GsMTx4 had been used for years to investigate the functional role of cationic MSCs, especially in muscle tissue, but with little understanding of its target or inhibitory mechanism. The sensitivity of Piezo channels to bilayer stress and its robust mechanosensitivity when expressed in heterologous systems were keys to determining GsMTx4's mechanism of action. However, questions remain regarding Piezo's role in muscle function due to the non-selective nature of GsMTx4 inhibition toward membrane mechanoenzymes and the implication of MCS channel types by genetic knockdown. Evidence supporting Piezo like activity, at least in the developmental stages of muscle, is presented. While the MSC targets of GsMTx4 in muscle pathology are unclear, its muscle protective effects are clearly demonstrated in two recent in situ studies on normal cardiomyocytes and dystrophic skeletal muscle. The muscle protective function may be due to the combined effect of GsMTx4's inhibitory action on cationic MSCs like Piezo and TRP, and its potentiation of repolarizing K + selective MSCs like K2P and SAKCa. Paradoxically, the potent in vitro action of GsMTx4 on many physiological functions seems to conflict with its lack of in situ side-effects on normal animal physiology. Future investigations into cytoskeletal control of sarcolemma mechanics and the suspected inclusion of MSCs in membrane micro/nano sized domains with distinct mechanical properties will aide our understanding of this dichotomy. Published by Elsevier Ltd.

Alteration of methotrexate binding to human serum albumin induced by oxidative stress. Spectroscopic comparative study

NASA Astrophysics Data System (ADS)

Maciążek-Jurczyk, M.; Sułkowska, A.; Równicka-Zubik, J.

2016-01-01

Changes of oxidative modified albumin conformation by comparison of non-modified (HSA) and modified (oHSA) human serum albumin absorption spectra, Red Edge Excitation Shift (REES) effect and fluorescence synchronous spectra were investigated. Studies of absorption spectra indicated that changes in the value of absorbance associated with spectral changes in the region from 200 to 250 nm involve structural alterations related to variations in peptide backbone conformation. Analysis of the REES effect allowed for the observation of changes caused by oxidation in the region of the hydrophobic pocket containing the tryptophanyl residue. Synchronous fluorescence spectroscopy confirmed changes of the position of the tryptophanyl and tyrosil residues fluorescent band. Effect of oxidative stress on binding of methotrexate (MTX) was investigated by spectrofluorescence, UV-VIS and 1HNMR spectroscopy. MTX caused the fluorescence quenching of non-modified (HSA) and modified (oHSA) human serum albumin molecule. The values of binding constants, Hill's coefficients and a number of binding sites in the protein molecule in the high affinity binding site were calculated for the binary MTX-HSA and MTX-oHSA systems. For these systems, qualitative analysis in the low affinity binding sites was performed with the use of the 1HNMR technique.

Tumor targeting profiling of hyaluronan-coated lipid based-nanoparticles.

PubMed

Mizrahy, Shoshy; Goldsmith, Meir; Leviatan-Ben-Arye, Shani; Kisin-Finfer, Einat; Redy, Orit; Srinivasan, Srimeenakshi; Shabat, Doron; Godin, Biana; Peer, Dan

2014-04-07

Hyaluronan (HA), a naturally occurring high Mw (HMw) glycosaminoglycan, has been shown to play crucial roles in cell growth, embryonic development, healing processes, inflammation, and tumor development and progression. Low Mw (LMw, <10 kDa) HA has been reported to provoke inflammatory responses, such as induction of cytokines, chemokines, reactive nitrogen species and growth factors. Herein, we prepared and characterized two types of HA coated (LMw and HMw) lipid-based targeted and stabilized nanoparticles (tsNPs) and tested their binding to tumor cells expressing the HA receptor (CD44), systemic immunotoxicity, and biodistribution in tumor bearing mice. In vitro, the Mw of the surface anchored HA had a significant influence on the affinity towards CD44 on B16F10 murine melanoma cells. LMw HA-tsNPs exhibited weak binding, while binding of tsNPs coated with HMw HA was characterized by high binding. Both types of tsNPs had no measured effect on cytokine induction in vivo following intravenous administration to healthy C57BL/6 mice suggesting no immune activation. HMw HA-tsNPs showed enhanced circulation time and tumor targeting specificity, mainly by accumulating in the tumor and its vicinity compared with LMw HA-tsNPs. Finally, we show that methotrexate (MTX), a drug commonly used in cancer chemotherapy, entrapped in HMw HA-tsNPs slowly diffused from the particles with a half-life of 13.75 days, and improved the therapeutic outcome in a murine B16F10 melanoma model compared with NPs suggesting an active cellular targeting beyond the Enhanced Permeability and Retention (EPR) effect. Taken together, these findings have major implications for the use of high molecular weight HA in nanomedicine as a selective and safe active cellular targeting moiety.

Circular RNA hsa_circ_0016788 regulates hepatocellular carcinoma tumorigenesis through miR-486/CDK4 pathway.

PubMed

Guan, Zheng; Tan, Jing; Gao, Wei; Li, Xin; Yang, Yuandong; Li, Xiaogang; Li, Yingchao; Wang, Qiang

2018-06-19

Recent studies have revealed that circular RNAs (circRNAs) play important roles in the tumorigenesis of human cancer, including hepatocellular carcinoma (HCC). In present study, we screen the circular RNA expression profiles in HCC tissue and investigate the molecular roles on HCC tumorigenesis. Human circRNA microarray analysis showed there were total 1,245 differently expressed circular RNAs, including 756 up-regulated circRNAs and 489 down-regulated circRNAs, in three pairs of HCC tissue and adjacent normal tissue. Hsa_circ_0016788 was identified to be up-regulated in both HCC tissue and cell lines. Loss-of-functional experiments in vivo and vitro revealed that hsa_circ_0016788 silencing inhibited the proliferation, invasion and promoted the apoptosis in vitro, and inhibited the tumor growth in vivo. Bioinformatics tools and luciferase reporter assay validated that miR-486 targeted hsa_circ_0016788 and CDK4 accompanying with negatively correlated expression, suggesting the hsa_circ_0016788/miR-486/CDK4 pathway. Receiver operating characteristic (ROC) curve showed that hsa_circ_0016788 had high diagnostic value (AUC = 0.851). In summary, results reveal the role of hsa_circ_0016788/miR-486/CDK4 in HCC tumorigenesis, providing a novel therapeutic target for HCC. © 2018 Wiley Periodicals, Inc.

Downregulated circular RNA hsa_circ_0001649 regulates proliferation, migration and invasion in cholangiocarcinoma cells.

PubMed

Xu, Yi; Yao, Yue; Zhong, Xiangyu; Leng, Kaiming; Qin, Wei; Qu, Lijun; Cui, Yunfu; Jiang, Xingming

2018-02-05

Cholangiocarcinoma (CCA) is one of the most aggressive malignancies with increasing worldwide incidence and is characterized by unfavorable prognosis due to its early invasive characteristics and poor response to chemotherapy or radiotherapy. Accumulating evidence has indicated that aberrantly expressed circular RNAs (circRNAs) are involved in cancer development and progression. However, their clinical values and biological roles in CCA remain unclear. Hsa_circ_0001649, a novel cancer-related circRNA, has been previously reported to be downregulated in hepatocellular carcinoma and gastric cancer. In the present study, qRT-PCR was carried out to measure the expression of hsa_circ_0001649 in CCA tissue samples and cell lines, and the correlation between hsa_circ_0001649 expression and clinicopathologic features was analyzed. The biological functions of hsa_circ_0001649 in CCA cells were evaluated both in vitro and in vivo. As a result, hsa_circ_0001649 was aberrantly downregulated in CCA tissues and cells, and this downregulation was associated with tumor size and differentiation grade in CCA. In addition, hsa_circ_0001649 overexpression caused tumor suppressive effects via inhibiting cell proliferation, migration and invasion; inducing cell apoptosis in KMBC and Huh-28 cells. On the contrary, silencing of hsa_circ_0001649 caused the opposite phenotypes. Furthermore, tumor xenograft study confirmed the in vitro results. Collectively, our findings suggest that hsa_circ_0001649 might be a rational CCA-related therapeutic target. Copyright © 2018 Elsevier Inc. All rights reserved.

In vitro antitumor activity of methotrexate via pH-sensitive chitosan nanoparticles.

PubMed

Nogueira, Daniele Rubert; Tavano, Lorena; Mitjans, Montserrat; Pérez, Lourdes; Infante, M Rosa; Vinardell, M Pilar

2013-04-01

Nanoparticles with pH-sensitive behavior may enhance the success of chemotherapy in many cancers by efficient intracellular drug delivery. Here, we investigated the effect of a bioactive surfactant with pH-sensitive properties on the antitumor activity and intracellular behavior of methotrexate-loaded chitosan nanoparticles (MTX-CS-NPs). NPs were prepared using a modified ionotropic complexation process, in which was included the surfactant derived from N(α),N(ε)-dioctanoyl lysine with an inorganic lithium counterion. The pH-sensitive behavior of NPs allowed accelerated release of MTX in an acidic medium, as well as membrane-lytic pH-dependent activity, which facilitated the cytosolic delivery of endocytosed materials. Moreover, our results clearly proved that MTX-CS-NPs were more active against the tumor HeLa and MCF-7 cell lines than the free drug. The feasibilty of using NPs to target acidic tumor extracellular pH was also shown, as cytotoxicity against cancer cells was greater in a mildly acidic environment. Finally, the combined physicochemical and pH-sensitive properties of NPs generally allowed the entrapped drug to induce greater cell cycle arrest and apoptotic effects. Therefore, our overall results suggest that pH-sensitive MTX-CS-NPs could be potentially useful as a carrier system for tumor and intracellular drug delivery in cancer therapy. Copyright © 2013 Elsevier Ltd. All rights reserved.

Preparation and in vitro characterization of gallic acid-loaded human serum albumin nanoparticles

NASA Astrophysics Data System (ADS)

Mohammad-Beigi, Hossein; Shojaosadati, Seyed Abbas; Morshedi, Dina; Arpanaei, Ayyoob; Marvian, Amir Tayaranian

2015-04-01

Gallic acid (GA), as an antioxidant and antiparkinson agent, was loaded onto cationic human serum albumin nanoparticles (HSA NPs). Polyethylenimine (PEI)-coated HSA (PEI-HSA) NPs were prepared using three different methods: (I) coating negatively charged HSA NPs with positively charged PEI through attractive electrostatic interactions, (II) coating HSA NPs with PEI via covalent amide bond formation using N-(3-dimethylaminopropyl)- N-ethylcarbodiimide hydrochloride, and (III) coating HSA NPs with PEI via covalent bonding using glutaraldehyde for linking amine groups of PEI and amine groups of albumin NPs. Method II was selected since it resulted in a higher shift in the zeta potential value (mV) and less zeta potential value deviation, and also less size polydispersity. GA was loaded by adsorption onto the surface of PEI-HSA NPs of two different sizes: 117 ± 2.9 nm (PEI-P1) and 180 ± 3.1 nm (PEI-P2) NPs. Both GA-entrapment and GA-loading efficiencies increased slightly with the increasing size of NPs, and were affected intensely by the mass ratio of GA to PEI-HSA NPs. Free radical scavenging of GA was quantified based on the 2,2-diphenyl-1-picrylhydrazyl method. The obtained results showed that GA remains active during the preparation of GA-loaded PEI-HSA NPs. The cytotoxicities of HSA, PEI-HSA, and GA-loaded PEI-HSA NPs on the PC-12 cells, as the neuroendocrine cell line, were measured. Our results indicate that positively charged PEI-HSA NPs are good candidates for efficient and safe delivery of GA to the brain.

The circular RNA of peripheral blood mononuclear cells: Hsa_circ_0005836 as a new diagnostic biomarker and therapeutic target of active pulmonary tuberculosis.

PubMed

Zhuang, Ze-Gang; Zhang, Jun-Ai; Luo, Hou-Long; Liu, Gan-Bin; Lu, Yuan-Bin; Ge, Nan-Hai; Zheng, Bi-Ying; Li, Rui Xi; Chen, Chen; Wang, Xin; Liu, Yu-Qing; Liu, Feng-Hui; Zhou, Yong; Cai, Xiao-Zhen; Chen, Zheng W; Xu, Jun-Fa

2017-10-01

It has been reported that circular RNA (circRNA) is associated with human cancer. However, few studies have been reported in active pulmonary tuberculosis (APTB). The global circRNA expression was detected in the peripheral blood mononuclear cells (PBMCs) of APTB patients (n=5) and health controls (HC) (n=5) by using high-throughput sequencing. According to the systematical bioinformatics analysis, the basic content of circRNAs and their fold changes in the two groups were calculated. We selected 6 significant differentially expressed circRNAs, hsa_circ_0005836, hsa_circ_0009128, hsa_circ_0003519, hsa_circ_0023956, hsa_circ_0078768, and hsa_circ_0088452 and validated the expression in PBMCs from APTB (n=10) and HC (n=10) by real-time quantitative reverse transcription-polymerase chain reactions (qRT-PCRs). Further, the verification of these specific circRNAs (hsa_circ_0005836 and hsa_circ_0009128) between APTB (n=34) and HC (n=30) in PBMCs was also conducted by qRT-PCRs. The RNA-seq data showed the significant differential expression of the 523 circRNAs between the APTB and HC groups (199 circRNAs were significantly up-regulated and 324 circRNAs were down-regulated). Hsa_circ_0005836 and hsa_circ_0009128 expression was significantly down-regulated in the PBMCs of APTB (P<0.05) in the samples of APTB compared to HC in our study. The gene ontology based enrichment analysis of the circRNA-miRNA-mRNAs network showed that cellular catabolic process (P=7.10E-08), regulation of metabolic process (P=2.10E-06), catalytic activity (P=3.67E-08), protein binding (P=1.71E-07), cell part (P=3.46E-06), intracellular part (P=1.71E-07), and intracellular (P=3.67E-08) were recognized in the comparisons between APTB and HC. Based on KEGG analysis, HTLV-I infection, regulation of actin cytoskeleton, neurotrophin signaling pathway and mTOR signaling pathway were relevant during tuberculosis bacillus infection. We found for the first time that hsa_circ_0005836 and hsa_circ_0009128 were

Increased circular RNA hsa_circ_0012673 acts as a sponge of miR-22 to promote lung adenocarcinoma proliferation.

PubMed

Wang, Xiyong; Zhu, Xiaoli; Zhang, Hongming; Wei, Shuzhen; Chen, Yan; Chen, Yang; Wang, Fei; Fan, Xiaobo; Han, Shuhua; Wu, Guoqiu

2018-02-19

Recent reports have indicated that circular RNA (circRNA) may regulate Lung adenocarcinoma (LAC) development. Our previous studies showed that hsa_circ_0012673 was up-regulated in a circRNA microarray. However, its expression level in LAC has not been verified, and the underlying molecular mechanisms in LAC are unknown. In this study, we found that the expression of hsa_circ_0012673 was up-regulated in LAC tissues compared to pair-matched adjacent non-tumor tissues (P = 0.0079), and that the expression level was associated with tumour size (P = 0.015). Furthermore, hsa_circ_0012673 was primarily localized in the cytoplasm and promoted cell proliferation of LAC cells by sponging miR-22, which targeted erb-b2 receptor tyrosine kinase 3 (ErbB3) in LAC. Hsa_circ_0012673 promotes LAC proliferation by suppressing miR-22, which targets ErbB3. Copyright © 2018 Elsevier Inc. All rights reserved.

Methotrexate Nanoparticles Prepared with Codendrimer from Polyamidoamine (PAMAM) and Oligoethylene Glycols (OEG) Dendrons: Antitumor Efficacy in Vitro and in Vivo

NASA Astrophysics Data System (ADS)

Zhao, Yanna; Guo, Yifei; Li, Ran; Wang, Ting; Han, Meihua; Zhu, Chunyan; Wang, Xiangtao

2016-07-01

The novel methotrexate-loaded nanoparticles (MTX/PGD NPs) prepared with amphiphilic codendrimer PGD from polyamidoamine and oligothylene glycol dendrons were obtained via antisolvent precipitation method augmented by ultrasonication. Based on the excellent hydrophility of PGD, the drug-loaded nanoparticles could be investigated easily with the high drug-loading content (~85.2%, w/w). The MTX/PGD NPs possessed spherical morphology, nanoscaled particle size (approximately 182.4 nm), and narrow particle size distribution. Release of MTX from MTX/PGD NPs showed a sustained release manner and completed within 48 h. Hemolytic evaluation indicated MTX/PGD NPs presented good blood compatibility, and the cytotoxicity of nanoparticles against breast cancer cells in vitro, biodistribution in tumor tissue, and antitumor efficacy in vivo were enhanced significantly compared to MTX injection. According to the higher drug-loading content, enhanced antitumor efficacy, and appropriate particle size, MTX/PGD NPs as the drug delivery systems could have potential application for cancer chemotherapy in clinic.

Methotrexate Nanoparticles Prepared with Codendrimer from Polyamidoamine (PAMAM) and Oligoethylene Glycols (OEG) Dendrons: Antitumor Efficacy in Vitro and in Vivo

PubMed Central

Zhao, Yanna; Guo, Yifei; Li, Ran; Wang, Ting; Han, Meihua; Zhu, Chunyan; Wang, Xiangtao

2016-01-01

The novel methotrexate-loaded nanoparticles (MTX/PGD NPs) prepared with amphiphilic codendrimer PGD from polyamidoamine and oligothylene glycol dendrons were obtained via antisolvent precipitation method augmented by ultrasonication. Based on the excellent hydrophility of PGD, the drug-loaded nanoparticles could be investigated easily with the high drug-loading content (~85.2%, w/w). The MTX/PGD NPs possessed spherical morphology, nanoscaled particle size (approximately 182.4 nm), and narrow particle size distribution. Release of MTX from MTX/PGD NPs showed a sustained release manner and completed within 48 h. Hemolytic evaluation indicated MTX/PGD NPs presented good blood compatibility, and the cytotoxicity of nanoparticles against breast cancer cells in vitro, biodistribution in tumor tissue, and antitumor efficacy in vivo were enhanced significantly compared to MTX injection. According to the higher drug-loading content, enhanced antitumor efficacy, and appropriate particle size, MTX/PGD NPs as the drug delivery systems could have potential application for cancer chemotherapy in clinic. PMID:27388443

Self-assembled albumin nanoparticles as a nanocarrier for aclacinomycin A

NASA Astrophysics Data System (ADS)

Gong, Guangming; Liu, Wenya; Wang, Shudong

2016-11-01

This study aimed to reduce the cytotoxicity and improve the targeting of aclacinomycin (ACM) by covalently coupling it with amino-oxyacetic acid (AOA) to generate an active intermediate, AOA-ACM. AOA-ACM was conjugated with self-assembled human serum albumin (HSA) nanoparticles constructed using tris(2-carboxyethyl)phosphine (TCEP) as disulfide bond breaking molecules in an ‘opening stage-intermediate-closing stage’ route, in which the hydrophobic interaction, interchange of sulfhydryl and hydrogen bond may be the key factors in the assembling process. Conjugation between ACM and albumin nanoparticles was found to occur at an ACM ketone site using 1H-NMR and 13C-NMR matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass analysis indicated that the drug loading efficiency of ACM conjugated with HSA nanoparticles (NPs-ACM) was 7.4% (molar ratio = 6:1). The release of NPs-ACM was pH dependent. In vivo studies indicated that NPs-ACM exhibited fourfold higher tumor targeting capability on S180-tumor-bearing mice compared with the free ACM (p < 0.05). The cytotoxictiy and cardiotoxicity of NPs-ACM was reduced compared with the free ACM. Albumin carrier altered the blood pharmacokinetics and distribution of ACM. Hence, the NPs-ACM prodrug is ideal tumor targeting drug carriers for ACM, and the easy approach developed in this study for active intermediate and prodrug preparation can be applied to other pharmacological substances containing ketone groups. The method of preparing HSA-blank nanoparticles through TCEP reduction could be adopted to improve the water solubility of lipophilic drugs and their tumor-targeting specificity by fabricating HSA-lipophilic drug nanoparticles.

Self-assembled albumin nanoparticles as a nanocarrier for aclacinomycin A.

PubMed

Gong, Guangming; Liu, Wenya; Wang, Shudong

2016-11-18

This study aimed to reduce the cytotoxicity and improve the targeting of aclacinomycin (ACM) by covalently coupling it with amino-oxyacetic acid (AOA) to generate an active intermediate, AOA-ACM. AOA-ACM was conjugated with self-assembled human serum albumin (HSA) nanoparticles constructed using tris(2-carboxyethyl)phosphine (TCEP) as disulfide bond breaking molecules in an 'opening stage-intermediate-closing stage' route, in which the hydrophobic interaction, interchange of sulfhydryl and hydrogen bond may be the key factors in the assembling process. Conjugation between ACM and albumin nanoparticles was found to occur at an ACM ketone site using 1 H-NMR and 13 C-NMR matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass analysis indicated that the drug loading efficiency of ACM conjugated with HSA nanoparticles (NPs-ACM) was 7.4% (molar ratio = 6:1). The release of NPs-ACM was pH dependent. In vivo studies indicated that NPs-ACM exhibited fourfold higher tumor targeting capability on S180-tumor-bearing mice compared with the free ACM (p < 0.05). The cytotoxictiy and cardiotoxicity of NPs-ACM was reduced compared with the free ACM. Albumin carrier altered the blood pharmacokinetics and distribution of ACM. Hence, the NPs-ACM prodrug is ideal tumor targeting drug carriers for ACM, and the easy approach developed in this study for active intermediate and prodrug preparation can be applied to other pharmacological substances containing ketone groups. The method of preparing HSA-blank nanoparticles through TCEP reduction could be adopted to improve the water solubility of lipophilic drugs and their tumor-targeting specificity by fabricating HSA-lipophilic drug nanoparticles.

Interface potential sensing from adsorption of human serum albumin (HSA) on carbon nanotube (CNT) monitored by zero current potentiometry for HSA determination.

PubMed

Wang, Huan; Wu, Yi; Song, Jun-Feng

2015-10-15

In this work, the adsorption of human serum albumin (HSA) on the bare multiwall carbon nanotube (MWNT) was investigated by a new electrochemical method, termed as zero current potentiometry. For this, a MWNT strip was prepared by directly adhering MWNTs on the transparent adhesive tape surface. Moreover, when HSA adsorbed onto MWNT at the MWNT/solution interface, an interface potential Ψ yielded. The interface potential Ψ as the zero current potential Ezcp simply related to it was monitored by zero current potentiometry. The relationship between the zero current potential Ezcp, the HSA concentration and others was established in simple stoichiometric relation. Based on this, both the adsorption of HSA on MWNT and the HSA determination can be studied. For the HSA determination, the theoretic conclusion consisted with experimental results. The zero current potential Ezcp was proportional to the HSA concentration in the range of 2.8 × 10(-8) - 3.4 × 10(-7)M with the limit of detection 2 × 10(-8)M. The linear regression equation was Ezcp/V (vs, SCE) = (0.159 ± 0.01) + (0.358 ± 0.02) × 10(6)CHSA (µM). This determination was fast, high sensitive and good selective. Copyright © 2015 Elsevier B.V. All rights reserved.

Overexpressing circular RNA hsa_circ_0002052 impairs osteosarcoma progression via inhibiting Wnt/β-catenin pathway by regulating miR-1205/APC2 axis.

PubMed

Wu, Zhen; Shi, Wangping; Jiang, Chendi

2018-08-25

Circular RNAs (circRNAs) are a novel class of noncoding RNAs, whose importance in cancer has been gradually acknowledged. However, the functions of circRNAs in tumorigenesis have not been fully understood. In the present study, we identified a novel circRNA hsa_circ_0002052 significantly downregulated in osteosarcoma (OS) tissues and cell lines. Moreover, we found that hsa_circ_0002052 could act as a biomarker to indicate the prognosis of OS patients. Functionally, we showed that hsa_circ_0002052 overexpression significantly suppressed OS cell proliferation, migration and invasion while promoting apoptosis in vitro. Similarly, in vivo assay indicated that ectopic expression of hsa_circ_0002052 impaired OS cell growth. In terms of mechanism, we found that hsa_circ_0002052 inhibited miR-1205 while miR1205 targeted APC2, a negative regulator of Wnt/β-catenin signaling pathway. By releasing the inhibition of miR-1205 on APC2 expression, hsa_circ_0002052 suppressed the activation of Wnt/β-catenin signaling pathway, leading to attenuated OS progression. Taken together, our study for the first time revealed a suppressive circRNA hsa_circ_0002052 involved in OS progression. Our study suggested hsa_circ_0002052/miR-1205/APC2/Wnt/β-catenin axis might be a potential target for OS therapy. Copyright © 2018 Elsevier Inc. All rights reserved.

Self-targeted salinomycin-loaded DSPE-PEG-methotrexate nanomicelles for targeting both head and neck squamous cell carcinoma cancer cells and cancer stem cells.

PubMed

Zhu, Minhui; Chen, Shicai; Hua, Libo; Zhang, Caiyun; Chen, Mengjie; Chen, Donghui; Dong, Yinmei; Zhang, Yingying; Li, Meng; Song, Xianmin; Chen, Huaiwen; Zheng, Hongliang

2017-02-01

To target both head and neck squamous cell carcinoma (HNSCC) cells and cancer stem cells (CSCs) by salinomycin-loaded DSPE-PEG-MTX (synthesized using DSPE-PEG2000-NH2 and methotrexate) nanomicelles (M-SAL-MTX). The characterization, antitumor activity and mechanism of M-SAL-MTX were evaluated. M-SAL-MTX showed enhanced inhibitory effect toward both HNSCC CSCs and non-CSCs compared with a single treatment of methotrexate and salinomycin. In nude mice-bearing HNSCC xenografts, M-SAL-MTX suppressed tumor growth more effectively than other controls including combination of methotrexate and salinomycin. Therefore, M-SAL-MTX may provide a strategy for treating HNSCC by targeting both HNSCC CSCs and HNSCC cells.

Human Serum Albumin Nanoparticles for Use in Cancer Drug Delivery: Process Optimization and In Vitro Characterization

PubMed Central

Lomis, Nikita; Westfall, Susan; Farahdel, Leila; Malhotra, Meenakshi; Shum-Tim, Dominique; Prakash, Satya

2016-01-01

Human serum albumin nanoparticles (HSA-NPs) are widely-used drug delivery systems with applications in various diseases, like cancer. For intravenous administration of HSA-NPs, the particle size, surface charge, drug loading and in vitro release kinetics are important parameters for consideration. This study focuses on the development of stable HSA-NPs containing the anti-cancer drug paclitaxel (PTX) via the emulsion-solvent evaporation method using a high-pressure homogenizer. The key parameters for the preparation of PTX-HSA-NPs are: the starting concentrations of HSA, PTX and the organic solvent, including the homogenization pressure and its number cycles, were optimized. Results indicate a size of 143.4 ± 0.7 nm and 170.2 ± 1.4 nm with a surface charge of −5.6 ± 0.8 mV and −17.4 ± 0.5 mV for HSA-NPs and PTX-HSA-NPs (0.5 mg/mL of PTX), respectively. The yield of the PTX-HSA-NPs was ~93% with an encapsulation efficiency of ~82%. To investigate the safety and effectiveness of the PTX-HSA-NPs, an in vitro drug release and cytotoxicity assay was performed on human breast cancer cell line (MCF-7). The PTX-HSA-NPs showed dose-dependent toxicity on cells of 52%, 39.3% and 22.6% with increasing concentrations of PTX at 8, 20.2 and 31.4 μg/mL, respectively. In summary, all parameters involved in HSA-NPs’ preparation, its anticancer efficacy and scale-up are outlined in this research article. PMID:28335244

Circular RNA hsa_circ_0008039 promotes breast cancer cell proliferation and migration by regulating miR-432-5p/E2F3 axis.

PubMed

Liu, Yanhua; Lu, Cuntao; Zhou, Yizhou; Zhang, Zhihong; Sun, Li

2018-07-20

As the development of sequencing technology, more and more circular RNAs (circRNAs) are identified in human cancer tissues. Increasing evidences imply circRNAs are important regulators in tumor progression. Nevertheless, how circRNAs participate in breast cancer development and progression is not well understood. In the present study, we identified a novel circRNA hsa_circ_0008039 with upregulated expression level in breast cancer tissues. By functional experiments, we found that hsa_circ_0008039 depletion significantly suppressed the proliferation, arrested cell-cycle progression and reduced migration in breast cancer. Mechanistic investigations suggested that hsa_circ_0008039 served as a competing endogenous RNA (ceRNA) of miR-432-5p. Subsequently, E2F3 was identified as the functional target of miR-432-5p and overexpression of hsa_circ_0008039 elevated E2F3 expression in breast cancer. On the whole, our study indicated that hsa_circ_0008039 exerted oncogenic roles in breast cancer and suggested the hsa_circ_0008039/miR-432-5p/E2F3 axis might be a potential therapeutic target. Copyright © 2018 Elsevier Inc. All rights reserved.

Jointed toxicity of TiO2 NPs and Cd to rice seedlings: NPs alleviated Cd toxicity and Cd promoted NPs uptake.

PubMed

Ji, Ye; Zhou, Yun; Ma, Chuanxin; Feng, Yan; Hao, Yi; Rui, Yukui; Wu, Wenhao; Gui, Xin; Le, Van Nhan; Han, Yaning; Wang, Yingcai; Xing, Baoshan; Liu, Liming; Cao, Weidong

2017-01-01

Previous studies have reported that nanoparticles (NPs) and heavy metals are toxic to the environment. However, the jointed toxicity is not yet well understood. This study was aimed to investigate the combined toxicity of TiO 2 NPs and the heavy metal cadmium (Cd) to plants. Rice (Oryzasativa L.) was selected as the target plant. The rice seedlings were randomly separated into 12 groups and treated with CdCl 2 (0, 10 and 20 mg/L) and TiO 2 NPs (0, 10, 100 and 1000 mg/L). The plant height, biomass and root length indicated significant toxicity of Cd to the growth, but TiO 2 NPs exhibited the potential ability to alleviate the Cd toxicity. Transmission electron microscopy (TEM) and energy dispersive spectrometer (EDS) confirmed the existence of TiO 2 NPs in plants. Elemental analysis of Ti and Cd suggested that the presences of Cd significantly decreased the Ti accumulation in the rice roots in the co-exposure treatments. Interestingly, TiO 2 NPs could lower the Cd uptake and distribution in rice roots and leaves. The results of antioxidant enzyme activity, lipid peroxide as well as phytohormones varied in the different treatments. Comparing with the Cd alone treatment, the net photosynthetic rate and chlorophyll content were significantly increased in the co-exposure treatments, suggesting that TiO 2 NPs could tremendously reduce the Cd toxicity. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

The HSA in Your Future: Defined Contribution Retiree Medical Coverage.

PubMed

Towarnicky, Jack M

In 2004, when evaluating health savings account (HSA) business opportunities, I predicted: "Twenty-five years ago, no one had ever heard of 401(k); 25 years from now, everyone will have an HSA." Twelve years later, growth in HSA eligibility, participation, contributions and asset accumulations suggests we just might achieve that prediction. This article shares one plan sponsor's journey to help employees accumulate assets to fund medical costs-while employed and after retirement, It documents a 30-plus-year retiree health insurance transition from a defined benefit to a defined dollar structure and culminating in a full-replacement defined contribution structure using HSA-qualifying high-deductible health plans (HDHPs) and then redeploying/repurposing the HSA to incorporate a savings incentive for retiree medical costs.

Methotrexate Induces Apoptosis in Organ-Cultured Nasal Polyps Via the Fas Pathway.

PubMed

Heo, Kyung Wook; Park, Seong Kook; Lee, Yeo Myeong; Choe, Si Hong; Gu, Pyung Mo; Hong, Tae Ui; Hur, Dae Young

2017-05-01

Methotrexate (MTX) is very effective when used to treat chronic inflammatory diseases, and also induces apoptosis in nasal polyps (NPs). Increasing evidence suggests that Fas-Fas ligand (FasL) interactions activate multiple pathways involved in the regulation of immune and inflammatory cell functions. The aim of the present study was to identify pathways activated by Fas signaling when NPs were treated with MTX. Nasal polyps tissues were cultured using an air-liquid interface organ culture method. Cultures were maintained in the absence or presence of MTX (10 or 100 μM) for 24 hours. The authors used the reverse transcription-polymerase chain reaction method and Western blotting to identify pathways activated by Fas when NPs were treated with MTX. The Fas mRNA expression ratio was unchanged upon MTX treatment, but the FasL mRNA expression ratio was significantly higher in MTX-treated than nontreated polyps. In addition, the expression levels of the Fas and FasL proteins were significantly higher in polyps treated with both 10 and 100 μM MTX compared with nontreated polyps. Methotrexate induces apoptosis in NPs via the Fas pathway. Future studies should explore the topical use of MTX for NP control. Methotrexate may be a useful alternative steroid-sparing agent for the treatment of NPs.

Nanomedical strategy to prolong survival period, heighten cure rate, and lower systemic toxicity of S180 mice treated with MTX/MIT.

PubMed

Song, Ning; Zhao, Ming; Wang, Yuji; Hu, Xi; Wu, Jianhui; Jiang, Xueyun; Li, Shan; Cui, Chunying; Peng, Shiqi

2016-01-01

In spite of the usual combination form of methotrexate (MTX)/mitoxantrone (MIT) and various complex combination regimens of MTX/MIT with other anticancer drugs, the survival period, cure rate, and systemic toxicity still need to be improved. For this purpose, a nanostructured amino group-modified mesoporous silica nanoparticles (MSNN)-MTX/MIT was designed. In the preparation, the surface of mesoporous silica nanoparticles (MSNs) was modified with amino groups to form MSNN. The covalent modification of the amino groups on the surface of MSNN with MTX resulted in MSNN-MTX. The loading of MIT into the surface pores of MSNN-MTX produced nanostructured MSNN-MTX/MIT. Compared with the usual combination form (MTX/MIT), nanostructured MSNN-MTX/MIT increased the survival period greatly, heightened the cure rate to a great extent, and lowered the systemic toxicity of the treated S180 mice, significantly. These superior in vivo properties of nanostructured MSNN-MTX/MIT over the usual combination form (MTX/MIT) were correlated with the former selectively releasing MTX and MIT in tumor tissue and inside cancer cells in vitro. The chemical structure and the nanostructure of MSNN-MTX/MIT were characterized using infrared and differential scanning calorimeter spectra as well as transmission electron microscope images, respectively.

Nanomedical strategy to prolong survival period, heighten cure rate, and lower systemic toxicity of S180 mice treated with MTX/MIT

PubMed Central

Song, Ning; Zhao, Ming; Wang, Yuji; Hu, Xi; Wu, Jianhui; Jiang, Xueyun; Li, Shan; Cui, Chunying; Peng, Shiqi

2016-01-01

In spite of the usual combination form of methotrexate (MTX)/mitoxantrone (MIT) and various complex combination regimens of MTX/MIT with other anticancer drugs, the survival period, cure rate, and systemic toxicity still need to be improved. For this purpose, a nanostructured amino group-modified mesoporous silica nanoparticles (MSNN)−MTX/MIT was designed. In the preparation, the surface of mesoporous silica nanoparticles (MSNs) was modified with amino groups to form MSNN. The covalent modification of the amino groups on the surface of MSNN with MTX resulted in MSNN−MTX. The loading of MIT into the surface pores of MSNN−MTX produced nanostructured MSNN−MTX/MIT. Compared with the usual combination form (MTX/MIT), nanostructured MSNN−MTX/MIT increased the survival period greatly, heightened the cure rate to a great extent, and lowered the systemic toxicity of the treated S180 mice, significantly. These superior in vivo properties of nanostructured MSNN−MTX/MIT over the usual combination form (MTX/MIT) were correlated with the former selectively releasing MTX and MIT in tumor tissue and inside cancer cells in vitro. The chemical structure and the nanostructure of MSNN−MTX/MIT were characterized using infrared and differential scanning calorimeter spectra as well as transmission electron microscope images, respectively. PMID:27621591

Microarray profiles reveal that circular RNA hsa_circ_0007385 functions as an oncogene in non-small cell lung cancer tumorigenesis.

PubMed

Jiang, Ming-Ming; Mai, Zhi-Tao; Wan, Shan-Zhi; Chi, Yu-Min; Zhang, Xin; Sun, Bao-Hua; Di, Qing-Guo

2018-04-01

Circular RNAs (circRNAs) are a novel class of non-protein-coding RNA. Emerging evidence indicates that circRNAs participate in the regulation of many pathophysiological processes. This study aims to explore the expression profiles and pathological effects of circRNAs in non-small cell lung cancer (NSCLC). Human circRNAs microarray analysis was performed to screen the expression profile of circRNAs in NSCLC tissue. Expressions of circRNA and miRNA in NSCLC tissues and cells were quantified by qRTPCR. Functional experiments were performed to investigate the biological functions of circRNA, including CCK-8 assay, colony formation assay, transwell assay and xenograft in vivo assay. Human circRNAs microarray revealed a total 957 abnormally expressed circRNAs (> twofold, P < 0.05) in NSCLC tissue compared with adjacent normal tissue. In further studies, hsa_circ_0007385 was significantly up regulated in NSCLC tissue and cells. In vitro experiments with hsa_circ_0007385 knockdown resulted in significant suppression of the proliferation, migration and invasion of NSCLC cells. In vivo xenograft assay using hsa_circ_0007385 knockdown, significantly reduced tumor growth. Bioinformatics analysis and luciferase reporter assay verified the potential target miR-181, suggesting a possible regulatory pathway for hsa_circ_0007385. In summary, results suggest hsa_circ_0007385 plays a role in NSCLC tumorigenesis, providing a potential therapeutic target for NSCLC.

Circular RNA hsa_circ_0001982 Promotes Breast Cancer Cell Carcinogenesis Through Decreasing miR-143.

PubMed

Tang, Yi-Yin; Zhao, Ping; Zou, Tian-Ning; Duan, Jia-Jun; Zhi, Rong; Yang, Si-Yuan; Yang, De-Chun; Wang, Xiao-Li

2017-11-01

Circular RNAs (circRNAs) are a type of noncoding RNAs generated from back-splicing, which have been verified to mediate multiple tumorigenesis. With the development of high-throughput sequencing, massive circRNAs are discovered in tumorous tissue. However, the potential physiological effect of circRNAs in breast cancer is still unknown. The purpose of this study is to investigate the expression profile of circRNA in breast cancer tissue and explore the in-depth regulatory mechanism in breast cancer tumorigenesis. In the present study, we screened the circRNA expression profiles in breast cancer tissue using circRNA microarray analysis. Totally 1705 circRNAs were identified to be significantly aberrant. Among these dysregulated circRNAs, hsa_circ_0001982 was markedly overexpressed in breast cancer tissue and cell lines. Bioinformatics analysis predicted that miR-143 acted as target of hsa_circ_0001982, which was confirmed by Dual-luciferase reporter assay. Loss-of-function and rescue experiments revealed that hsa_circ_0001982 knockdown suppressed breast cancer cell proliferation and invasion and induced apoptosis by targeting miR-143. In summary, our study preliminarily investigates the circRNA expression in breast cancer tissue and explores the role of competing endogenous RNA (ceRNA) mechanism in the progression, providing a novel insight for breast cancer tumorigenesis.

HSA: a heuristic splice alignment tool.

PubMed

Bu, Jingde; Chi, Xuebin; Jin, Zhong

2013-01-01

RNA-Seq methodology is a revolutionary transcriptomics sequencing technology, which is the representative of Next generation Sequencing (NGS). With the high throughput sequencing of RNA-Seq, we can acquire much more information like differential expression and novel splice variants from deep sequence analysis and data mining. But the short read length brings a great challenge to alignment, especially when the reads span two or more exons. A two steps heuristic splice alignment tool is generated in this investigation. First, map raw reads to reference with unspliced aligner--BWA; second, split initial unmapped reads into three equal short reads (seeds), align each seed to the reference, filter hits, search possible split position of read and extend hits to a complete match. Compare with other splice alignment tools like SOAPsplice and Tophat2, HSA has a better performance in call rate and efficiency, but its results do not as accurate as the other software to some extent. HSA is an effective spliced aligner of RNA-Seq reads mapping, which is available at https://github.com/vlcc/HSA.

Molecular interaction of 2,4-diacetylphloroglucinol (DAPG) with human serum albumin (HSA): The spectroscopic, calorimetric and computational investigation

NASA Astrophysics Data System (ADS)

Pragna Lakshmi, T.; Mondal, Moumita; Ramadas, Krishna; Natarajan, Sakthivel

2017-08-01

Drug molecule interaction with human serum albumin (HSA) affects the distribution and elimination of the drug. The compound, 2,4-diacetylphloroglucinol (DAPG) has been known for its antimicrobial, antiviral, antihelminthic and anticancer properties. However, its interaction with HSA is not yet reported. In this study, the interaction between HSA and DAPG was investigated through steady-state fluorescence, time-resolved fluorescence (TRF), circular dichroism (CD), Fourier transform infrared (FT-IR) spectroscopy, isothermal titration calorimetry (ITC), molecular docking and molecular dynamics simulation (MDS). Fluorescence spectroscopy results showed the strong quenching of intrinsic fluorescence of HSA due to interaction with DAPG, through dynamic quenching mechanism. The compound bound to HSA with reversible and moderate affinity which explained its easy diffusion from circulatory system to target tissue. The thermodynamic parameters from fluorescence spectroscopic data clearly revealed the contribution of hydrophobic forces but, the role of hydrogen bonds was not negligible according to the ITC studies. The interaction was exothermic and spontaneous in nature. Binding with DAPG reduced the helical content of protein suggesting the unfolding of HSA. Site marker fluorescence experiments revealed the change in binding constant of DAPG in the presence of site I (warfarin) but not site II marker (ibuprofen) which confirmed that the DAPG bound to site I. ITC experiments also supported this as site I marker could not bind to HSA-DAPG complex while site II marker was accommodated in the complex. In silico studies further showed the lowest binding affinity and more stability of DAPG in site I than in site II. Thus the data presented in this study confirms the binding of DAPG to the site I of HSA which may help in further understanding of pharmacokinetic properties of DAPG.

Patterns of NPS Use and Risk Reduction in Slovenia.

PubMed

Sande, Matej; Paš, Mina; Nahtigal, Klara; Šabić, Simona

2018-01-15

The following study presents factors influencing the decision to use/not to use new psychoactive substances (NPS), various patterns of NPS use, the problems experienced by users, and the methods for reducing the risks associated with NPS use. The study seeks to provide an in-depth look into the characteristics of NPS use and support the planning of targeted interventions in the field of NPS. The study involved 19 in-depth interviews carried out with 25 individuals divided into three subsamples in order to gain insight into the various experiences of NPS users. The interviews were conducted in Slovenia between December 2013 and October 2014. The sample was obtained by using the convenience sampling and snowball sampling methods. The main pattern of NPS use determined by the study concerned synthetic cathinones, specifically 3-MMC, with binge use spanning several days being a prominent feature. The main risks involving NPS use were: mixing various drugs, inappropriate dosing, lack of information prior to use, and the use of unknown substances. Several users spoke about effective strategies for reducing risks, such as obtaining information beforehand, using one's own implements and using only small quantities of unknown substances. Conclusions/Importance: The study revealed various factors based on which users decide to use NPS. Furthermore, users reported a number of problems resulting from NPS use, while risk reduction strategies are employed to a much lesser extent. Based on the results obtained, specific intervention efforts concerning NPS use and targeting specific groups of younger users were designed.

Recombinant nanocomposites by the clinical drugs of Abraxane® and Herceptin® as sequentially dual-targeting therapeutics for breast cancer.

PubMed

Ding, Shuang; Xiong, Jian; Lei, Dan; Zhu, Xiao-Li; Zhang, Hai-Jun

2018-01-01

Breast cancer greatly threatens the health of women all over the word despite of several effective drugs. Targeted therapy for breast cancer is limited to human epidermal growth factor receptor 2 (HER2). Herceptin ® , monoclonal antibody against HER2, is now widely used in HER2(+) breast cancer. Abraxane ® , the current gold standard for paclitaxel (PTX) delivery, has shown superiority in breast cancer based on nanoparticle albumin bound technology. Despite these advances, further novel targeted therapy with more improved anti-tumor efficacy for breast cancer is still urgently needed. Here, we report the recombinant nanocomposites (NPs) composed of the above two clinical drugs of Abraxane ® and Herceptin ® (Abra/anti-HER2), which at first migrates to the tumor region through the unique targeting mechanism of human serum albumin (HSA) of Abraxane ® , and sequentially further precisely recognize the HER2(+) breast cancer cells due to Herceptin ® . The Abra/anti-HER2 NPs were fabricated by a "one-step" synthesis using EDC/NHS. In vitro analysis of cell viability, apoptosis and cell cycle revealed that Abra/anti-HER2 NPs showed more anti-tumor efficacy against HER2(+) SK-BR-3 cells than Abraxane ® at equivalent PTX concentration. In addition, in HER2(+) breast cancer xenograft model, Abra/anti-HER2 NPs significantly inhibited tumor growth with less side effects. Moreover, the properties of more precise target and delayed release of PTX were proved by NIRF imaging. Thus, our results indicate that Abra/anti-HER2 NPs could represent a next-generation sequentially dual-targeting therapeutic agent for HER2(+) breast cancer.

Hsa-miR-326 targets CCND1 and inhibits non-small cell lung cancer development

PubMed Central

Li, Shujun; Yang, Cuili; Xi, Yongyong; Wang, Liang; Zhang, Feng; Fu, Yunfeng; Li, Dejia

2016-01-01

Hsa-miRNA-326 (miR-326) has recently been discovered having anticancer efficacy in different organs. However, the role of miR-326 on non-small cell lung cancer (NSCLC) is still ambiguous. In this study, we investigated the role of miR-326 on the development of NSCLC. The results indicated that miR-326 was significantly down-regulated in primary tumor tissues and very low levels were found in NSCLC cell lines. Ectopic expression of miR-326 in NSCLC cell lines significantly suppressed cell growth as evidenced by cell viability assay, colony formation assay and BrdU staining, through inhibition of cyclin D1, cyclin D2, CDK4 and up-regulation of p57(Kip2) and p21(Waf1/Cip1). In addition, miR-326 induced apoptosis, as indicated by concomitantly with up-regulation of key apoptosis protein cleaved caspase-3, and down-regulation of anti-apoptosis protein Bcl2. Moreover, miR-326 inhibited cellular migration and invasiveness through inhibition of matrix metalloproteinases (MMP)-7 and MMP-9. Further, oncogene CCND1 was revealed to be a putative target of miR-326, which was inversely correlated with miR-326 expression in NSCLC. Taken together, our results demonstrated that miR-326 played a pivotal role on NSCLC through inhibiting cell proliferation, migration, invasion, and promoting apoptosis by targeting oncogenic CCND1. PMID:26840018

Inflamed site-specific drug delivery system based on the interaction of human serum albumin nanoparticles with myeloperoxidase in a murine model of experimental colitis.

PubMed

Iwao, Yasunori; Tomiguchi, Izumi; Domura, Ayaka; Mantaira, Yusuke; Minami, Akira; Suzuki, Takashi; Ikawa, Takashi; Kimura, Shin-Ichiro; Itai, Shigeru

2018-04-01

To develop a new strategy for inflamed site-specific drug delivery in the colon for the treatment of ulcerative colitis (UC), we leveraged on the interaction between myeloperoxidase (MPO) and human serum albumin (HSA) and prepared nanoparticles (HSA NPs) conjugated with 5-aminosalicylic acid (5-ASA). The 5-ASA-HSA NPs (nine molecules of 5-ASA per HSA molecule) were uniform particles with an average particle size of 190 nm, a zeta potential of --11.8 mV, and a polydispersity index of 0.35. This was considered a suitable particle characteristic to pass through the mucus layer and accumulate into the mucosa. The specific interaction between the 5-ASA-HSA NPs and MPO was observed using quartz crystal microbalance analysis in vitro. In addition, the 5-ASA-HSA NPs group containing one thousandth of the dose of the 5-ASA (75 μg/kg) showed significantly lower disease activity index values and colon weight/length ratios in UC model mice as similar to large amount of neat 5-ASA group (75 mg/kg), indicating that the therapeutic effect of the 5-ASA-HSA NP formulation was confirmed in vivo. Microscopic images of tissue sections of colon extracted from UC model mice demonstrated that HSA NPs and MPO were both localized in the colon, and this specific interaction between HSA NPs and MPO would be involved the in the therapeutic effect in vivo. Furthermore, in the 5-ASA and 5-ASA-HSA NPs groups, some inflammatory damage was observed in the colon, but the degree of damage was mild compared with the control and HSA NPs groups, suggesting mucosal repair and replacement with fibrous granulation tissue had occurred. Therefore, these data demonstrated that an HSA NP formulation has the potential to specifically deliver 5-ASA to an inflamed site where MPO is highly expressed. Copyright © 2018 Elsevier B.V. All rights reserved.

Hsa_circ_0001649: A circular RNA and potential novel biomarker for hepatocellular carcinoma.

PubMed

Qin, Meilin; Liu, Gang; Huo, Xisong; Tao, Xuemei; Sun, Xiaomeng; Ge, Zhouhong; Yang, Juan; Fan, Jia; Liu, Lei; Qin, Wenxin

2016-01-01

It has been shown that circular RNA (circRNA) is associated with human cancers, however, few studies have been reported in hepatocellular carcinoma (HCC). To estimate clinical values of a circular RNA, Hsa_circ_0001649, in HCC. Expression level of hsa_circ_0001649 was detected in HCC and paired adjacent liver tissues by real-time quantitative reverse transcription-polymerase chain reactions (qRT-PCRs). Differences in expression level of hsa_circ_0001649 were analyzed using the paired t-test. Tests were performed between clinical information and hsa_circ_0001649 expression level by analysis of variance (ANOVA) or welch t-test and a receiver operating characteristics (ROC) curve was established to estimate the value of hsa_circ_0001649 expression as a biomarker in HCC. hsa_circ_0001649 expression was significantly downregulated in HCC tissues (p = 0.0014) based on an analysis of 89 paired samples of HCC and adjacent liver tissues and the area under the ROC curve (AUC) was 0.63. Furthermore, hsa_circ_0001649 expression was correlated with tumor size (p = 0.045) and the occurrence of tumor embolus (p = 0.017) in HCC. We first found hsa_circ_0001649 was significantly downregulated in HCC. Our findings indicate hsa_circ_0001649 might serve as a novel potential biomarker for HCC and may function in tumorigenesis and metastasis of HCC.

Circular RNA hsa_circ_0023404 exerts an oncogenic role in cervical cancer through regulating miR-136/TFCP2/YAP pathway.

PubMed

Zhang, Jianhua; Zhao, Xinyuan; Zhang, Jin; Zheng, Xuerong; Li, Fenxia

2018-06-22

Cervical cancer (CC) is one of the most prevalent malignances among women. However, the mechanism underlying CC development remains elusive. Recently, circular RNAs (circRNAs) have been known as important regulators in tumorigenesis. Whether circRNAs are involved in CC requires to be determined. In the present study, we found that circRNA hsa_circ_0023404 was significantly upregulated in CC tissues compared to adjacent normal tissues. And its overexpression was correlated with poor prognosis in CC patients. Functionally, we showed that knockdown of hsa_circ_0023404 significantly suppressed the proliferation, arrested the cell-cycle progression and inhibited cell migration and invasion in CC. In terms of mechanism, we found that hsa_circ_0023404 acted as a sponge of miR-136 and miR-136 targeted TFCP2, which is an activator of YAP signaling pathway. We showed that hsa_circ_0023404 activated YAP pathway in CC via promoting TFCP2 expression by sponging miR-136, leading to CC development and progression. Taken together, our study for the first time demonstrated the pivot role of hsa_circ_0023404 and revealed a novel regulatory loop of hsa_circ_0023404/miR-136/TFCP2/YAP axis in CC progression. Copyright © 2018 Elsevier Inc. All rights reserved.

Gold Nanoparticle-Based Facile Detection of Human Serum Albumin and Its Application as an INHIBIT Logic Gate.

PubMed

Huang, Zhenzhen; Wang, Haonan; Yang, Wensheng

2015-05-06

In this work, a facile colorimetric method is developed for quantitative detection of human serum albumin (HSA) based on the antiaggregation effect of gold nanoparticles (Au NPs) in the presence of HSA. The citrate-capped Au NPs undergo a color change from red to blue when melamine is added as a cross-linker to induce the aggregation of the NPs. Such an aggregation is efficiently suppressed upon the adsorption of HSA on the particle surface. This method provides the advantages of simplicity and cost-efficiency for quantitative detection of HSA with a detection limit of ∼1.4 nM by monitoring the colorimetric changes of the Au NPs with UV-vis spectroscopy. In addition, this approach shows good selectivity for HSA over various amino acids, peptides, and proteins and is qualified for detection of HSA in a biological sample. Such an antiaggregation effect can be further extended to fabricate an INHIBIT logic gate by using HSA and melamine as inputs and the color changes of Au NPs as outputs, which may have application potentials in point-of-care medical diagnosis.

MicroRNAs hsa-miR-99b, hsa-miR-330, hsa-miR-126 and hsa-miR-30c: Potential Diagnostic Biomarkers in Natural Killer (NK) Cells of Patients with Chronic Fatigue Syndrome (CFS)/ Myalgic Encephalomyelitis (ME).

PubMed

Petty, Robert D; McCarthy, Neil E; Le Dieu, Rifca; Kerr, Jonathan R

2016-01-01

Chronic Fatigue Syndrome (CFS/ME) is a complex multisystem disease of unknown aetiology which causes debilitating symptoms in up to 1% of the global population. Although a large cohort of genes have been shown to exhibit altered expression in CFS/ME patients, it is currently unknown whether microRNA (miRNA) molecules which regulate gene translation contribute to disease pathogenesis. We hypothesized that changes in microRNA expression in patient leukocytes contribute to CFS/ME pathology, and may therefore represent useful diagnostic biomarkers that can be detected in the peripheral blood of CFS/ME patients. miRNA expression in peripheral blood mononuclear cells (PBMC) from CFS/ME patients and healthy controls was analysed using the Ambion Bioarray V1. miRNA demonstrating differential expression were validated by qRT-PCR and then replicated in fractionated blood leukocyte subsets from an independent patient cohort. The CFS/ME associated miRNA identified by these experiments were then transfected into primary NK cells and gene expression analyses conducted to identify their gene targets. Microarray analysis identified differential expression of 34 miRNA, all of which were up-regulated. Four of the 34 miRNA had confirmed expression changes by qRT-PCR. Fractionating PBMC samples by cell type from an independent patient cohort identified changes in miRNA expression in NK-cells, B-cells and monocytes with the most significant abnormalities occurring in NK cells. Transfecting primary NK cells with hsa-miR-99b or hsa-miR-330-3p, resulted in gene expression changes consistent with NK cell activation but diminished cytotoxicity, suggesting that defective NK cell function contributes to CFS/ME pathology. This study demonstrates altered microRNA expression in the peripheral blood mononuclear cells of CFS/ME patients, which are potential diagnostic biomarkers. The greatest degree of miRNA deregulation was identified in NK cells with targets consistent with cellular activation

MicroRNAs hsa-miR-99b, hsa-miR-330, hsa-miR-126 and hsa-miR-30c: Potential Diagnostic Biomarkers in Natural Killer (NK) Cells of Patients with Chronic Fatigue Syndrome (CFS)/ Myalgic Encephalomyelitis (ME)

PubMed Central

Petty, Robert D.; McCarthy, Neil E.; Le Dieu, Rifca; Kerr, Jonathan R.

2016-01-01

Background Chronic Fatigue Syndrome (CFS/ME) is a complex multisystem disease of unknown aetiology which causes debilitating symptoms in up to 1% of the global population. Although a large cohort of genes have been shown to exhibit altered expression in CFS/ME patients, it is currently unknown whether microRNA (miRNA) molecules which regulate gene translation contribute to disease pathogenesis. We hypothesized that changes in microRNA expression in patient leukocytes contribute to CFS/ME pathology, and may therefore represent useful diagnostic biomarkers that can be detected in the peripheral blood of CFS/ME patients. Methods miRNA expression in peripheral blood mononuclear cells (PBMC) from CFS/ME patients and healthy controls was analysed using the Ambion Bioarray V1. miRNA demonstrating differential expression were validated by qRT-PCR and then replicated in fractionated blood leukocyte subsets from an independent patient cohort. The CFS/ME associated miRNA identified by these experiments were then transfected into primary NK cells and gene expression analyses conducted to identify their gene targets. Results Microarray analysis identified differential expression of 34 miRNA, all of which were up-regulated. Four of the 34 miRNA had confirmed expression changes by qRT-PCR. Fractionating PBMC samples by cell type from an independent patient cohort identified changes in miRNA expression in NK-cells, B-cells and monocytes with the most significant abnormalities occurring in NK cells. Transfecting primary NK cells with hsa-miR-99b or hsa-miR-330-3p, resulted in gene expression changes consistent with NK cell activation but diminished cytotoxicity, suggesting that defective NK cell function contributes to CFS/ME pathology. Conclusion This study demonstrates altered microRNA expression in the peripheral blood mononuclear cells of CFS/ME patients, which are potential diagnostic biomarkers. The greatest degree of miRNA deregulation was identified in NK cells with targets

Enzyme Functionalized AuNPs and Glucometer-based Protein Detection

NASA Astrophysics Data System (ADS)

Dai, Tao; Fang, Jie; Yu, Wen; Xie, Guoming

2017-12-01

We here developed a novel method for protein detection by using protein aptamer-functionalized magnetic beads for protein recognition and invertase-functionalized AuNPs catalyze sucrose generate glucose that can be detected by a glucometer. First, the invertase and DNA probe P2 are immobilized onto the gold nanoparticles (I.P2@AuNPs). Next protein aptamer P1 are immobilized onto the streptavidin-coated Magnetic beads (P1@MB). P1 and P2 can complementary to form double-stranded DNA. When target protein presence, P1 combine with target and release I/P2@AuNPs. Then magnetic separation, take supernatant fluid and add sucrose after a period of reaction, detection of glucose concentration by glucometer, thus achieve the sensitive and selective detection of the target protein.

Design of pH-sensitive methotrexate prodrug-targeted curcumin nanoparticles for efficient dual-drug delivery and combination cancer therapy.

PubMed

Xie, Jiajiang; Fan, Zhongxiong; Li, Yang; Zhang, Yinying; Yu, Fei; Su, Guanghao; Xie, Liya; Hou, Zhenqing

2018-01-01

We designed acid-labile methotrexate (MTX) targeting prodrug self-assembling nanoparticles loaded with curcumin (CUR) drug for simultaneous delivery of multi-chemotherapeutic drugs and combination cancer therapy. A dual-acting MTX, acting as both an anticancer drug and as a tumor-targeting ligand, was coupled to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[aldehyde(polyethylene glycol)-2000] via Schiff's base reaction. The synthesized prodrug conjugate (DSPE-PEG-Imine-MTX) could be self-assembled into micellar nanoparticles (MTX-Imine-M) in aqueous solution, which encapsulated CUR into their core by hydrophobic interactions (MTX-Imine-M-CUR). The prepared MTX-Imine-M-CUR nanoparticles were composed of an inner hydrophobic DSPE/CUR core and an outside hydrophilic bishydroxyl poly (ethyleneglycol) (PEG) shell with a self-targeting MTX prodrug corona. The imine linker between 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[aldehyde(polyethyleneglycol)-2000] and MTX, as a dynamic covalent bond, was strong enough to remain intact in physiological pH, even though it is rapidly cleaved in acidic pH. The MTX-Imine-M-CUR could codeliver MTX and CUR selectively and efficiently into the cancer cells via folate receptor-mediated endocytosis followed by the rapid intracellular release of CUR and the active form of MTX via the acidity of endosomes/lysosomes. Moreover, the MTX-Imine-M-CUR resulted in significantly higher in vitro and in vivo anticancer activity than pH-insensitive DSPE-PEGAmide-MTX assembling nanoparticles loaded with CUR (MTX-Amide-M-CUR), MTX unconjugated DSPE-PEG assembling micellar nanoparticles loaded with CUR (M-CUR), combination of both free drugs, and individual free drugs. The smart system provided a simple, yet feasible, drug delivery strategy for targeted combination chemotherapy.

Downregulation of circular RNA hsa_circ_0001649 indicates poor prognosis for retinoblastoma and regulates cell proliferation and apoptosis via AKT/mTOR signaling pathway.

PubMed

Xing, Lichen; Zhang, Leiming; Feng, Yali; Cui, Zhe; Ding, Lin

2018-06-01

Retinoblastoma (RB) is the most common intraocular malignancy in infants and children with high mortality rate in developing countries. Emerging evidence demonstrated that abnormally expressed circular RNAs (circRNAs) are involved in tumorigenesis and progression in several malignancies. However, their clinical values, biological functions and mechanisms in RB has not been reported before. Recently, hsa_circ_0001649 was found to play imperative roles in cholangiocarcinoma, gastric cancer, and hepatocellular carcinoma. In the current study, qRT-PCR was performed to detect the expression of hsa_circ_0001649 in RB samples and cells. The correlations between hsa_circ_0001649 expression and clinicopathologic characteristics were further analyzed. In addition, we up-regulated hsa_circ_0001649 in Y79 cells and knocked down hsa_circ_0001649 in WERI-Rb1 cells to explore its effect on cell proliferation and apoptosis. The animal study was performed to confirm the in vitro results. Furthermore, AKT/mTOR signaling pathway was detected to clarify the molecular mechanisms of hsa_circ_0001649 exerts in RB cell growth. The results indicated that hsa_circ_0001649 was decreased in RB tissues and cells, and this downregulation was associated with larger tumor size and advanced intraocular international retinoblastoma classify (IIRC) stage in RB patients. Additionally, hsa_circ_0001649 could act as an independent prognostic predictor for overall survival in patients with RB. Moreover, hsa_circ_0001649 inhibits cell growth and promotes cell apoptosis in RB cells. AKT/mTOR signaling pathway is involved in the cell growth alteration affected by hsa_circ_0001649. Overall, hsa_circ_0001649 might be a potentially useful prognostic biomarker and therapeutic target for RB. Copyright © 2018. Published by Elsevier Masson SAS.

Circular RNA hsa_circRNA_103809 promotes lung cancer progression via facilitating ZNF121-dependent MYC expression by sequestering miR-4302.

PubMed

Liu, Wei; Ma, Weiming; Yuan, Yuan; Zhang, Youwei; Sun, Sanyuan

2018-06-12

Lung cancer characterized with malignant cell growth is the leading cause of cancer-related deaths. In recent years, several circular RNAs (circRNAs) have been reported to participate in lung cancer progression. However, the correlation between circular RNA (circRNA) and lung cancer still remains to be further investigated. In this study, we screened out a highly expressed circular RNA hsa_circRNA_103809 in lung cancer tissues. We showed hsa_circRNA_103809 could serve as a prognostic biomarker for patients with lung cancer. Furthermore, we found that hsa_circRNA_103809 knockdown significantly suppressed lung cancer cell proliferation and invasion in vitro and delayed tumor growth in vivo. In mechanism, we identified hsa_circRNA_103809 as a sponge of miR-4302 targeting ZNF121. By sequestering miR-4302, hsa_circRNA_103809 promoted the expression of ZNF121 which consequently enhanced MYC protein level in lung cancer cells. Through rescue assays, we demonstrated hsa_circRNA_103809 contributed to lung cancer cell proliferation and invasion via facilitating ZNF121-dependent MYC expression by sponging miR-4302. In conclusion, our findings illustrated a novel hsa_circRNA_103809/miR-4302/ZNF121/MYC regulatory signaling pathway in lung cancer progression. Copyright © 2018 Elsevier Inc. All rights reserved.

The Effects of Organic Solvents on the Physicochemical Properties of Human Serum Albumin Nanoparticles.

PubMed

Mohammad-Beigi, Hossein; Shojaosadati, Seyed Abbas; Morshedi, Dina; Mirzazadeh, Negar; Arpanaei, Ayyoob

2016-03-01

Recently, applications of albumin nanoparticles as drug delivery carriers have increased. Most toxicology studies have shown that surface chemistry and size of nanoparticles play an important role in biocompatibility and toxicity. The effect of desolvating agents with different chemical properties on the size of synthesized HSA NPs was investigated. Acetone, ethanol, methanol, and acetonitrile were used to synthesize HSA NPs with controllable size by desolvation method. Scanning electron microscopy (SEM), dynamic light scattering (DLS), and circular dichroism (CD) were employed to characterize produced particles. Finally, the toxicity of HSA NPs synthesized under different conditions was evaluated on PC-12 cells. The sizes of synthesized particles differed according to the different solvents used. The sizes were 275.3 nm, 155.3 nm, 100.11 nm, and 66.2 nm for acetonitrile, ethanol, acetone, and methanol, respectively. CD showed that larger NPs had more changes in the secondary structures. Finally, the toxicity monitored on the cultured PC-12 cells showed no significant toxic effect through treating with these NPs at different concentrations (0-500 μg.mL -1 ). The size of HSA NPs has a strong dependency on the desolvating agent. The mechanism in which the desolvating agent affects the size of HSA NPs is complex. Various factors such as dielectric constant, polarity, functional groups, and hydrogen bonding of the solvents have the potential to affect the size and structure of HSA NPs. CD analysis suggested that the solvent denaturing capability had a critical effect on the HSA particle size. The stronger denaturing capability of the solvent resulted in the larger HSA particle size.

Mechanism-based inhibition of HsaD: a C-C bond hydrolase essential for survival of Mycobacterium tuberculosis in macrophage.

PubMed

Ryan, Ali; Keany, Sebastian; Eleftheriadou, Olga; Ballet, Romain; Cheng, Hung-Yuan; Sim, Edith

2014-01-01

Mycobacterium tuberculosis remains the leading cause of death by a bacterial pathogen worldwide. Increasing prevalence of multidrug-resistant organisms means prioritizing identification of targets for antituberculars. 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoate hydrolase (HsaD), part of the cholesterol metabolism operon, is vital for survival within macrophage. The C-C bond hydrolase, HsaD, has a serine protease-like catalytic triad. We tested a range of serine protease and esterase inhibitors for their effects on HsaD activity. As well as providing a potential starting point for drug development, the data provides evidence for the mechanism of C-C bond hydrolysis. This screen also provides a route to initiate development of fragment-based inhibitors. © 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.

Self-Delivery Nanoparticles of Amphiphilic Methotrexate-Gemcitabine Prodrug for Synergistic Combination Chemotherapy via Effect of Deoxyribonucleotide Pools.

PubMed

Wang, Yao; Huang, Ping; Hu, Minxi; Huang, Wei; Zhu, Xinyuan; Yan, Deyue

2016-11-16

The distinct and complementary biochemical mechanisms of folic acid analog methotrexate (MTX) and cytidine analog gemcitabine (GEM) make their synergistic combination effective. Unfortunately, such a combination faces severe pharmacokinetic problems and several transportation barriers. To overcome these problems, a new strategy of amphiphilic small molecule prodrug (ASMP) is developed to improve their synergistic combination effect. The ASMP was prepared by the amidation of the hydrophilic GEM with the hydrophobic MTX at a fixed ratio. Owing to its inherent amphiphilicity, the MTX-GEM ASMP self-assembled into stable nanoparticles (ASMP-NPs) with high drug loading capacity (100%), in which the MTX and GEM could self-deliver without any carriers and release synchronously in cancer cells. In vitro studies showed that the MTX-GEM ASMP-NPs could greatly improve the synergistic combination effects by the reason of arresting more S phase of the cell cycle and reducing levels of deoxythymidine triphosphate (dTTP), deoxyadenosine triphosphate (dATP), and deoxycytidine triphosphate (dCTP). The stronger synergistic effects caused the higher cell cytotoxicity and apoptotic ratio, and circumvented the multidrug resistance (MDR) of tumor cells. Additionally, MTX-GEM ASMP-NPs could achieve the same anticancer effect with the greatly reduced dosage compared with the free drugs according to the dose-reduction index (DRI) values of MTX and GEM in MTX-GEM ASMP-NPs, which may be beneficial for reducing the side effects.

Improving the pharmacokinetic properties of biologics by fusion to an anti-HSA shark VNAR domain

PubMed Central

Müller, Mischa R.; Saunders, Kenneth; Grace, Christopher; Jin, Macy; Piche-Nicholas, Nicole; Steven, John; O’Dwyer, Ronan; Wu, Leeying; Khetemenee, Lam; Vugmeyster, Yulia; Hickling, Timothy P.; Tchistiakova, Lioudmila; Olland, Stephane; Gill, Davinder; Jensen, Allan; Barelle, Caroline J.

2012-01-01

Advances in recombinant antibody technology and protein engineering have provided the opportunity to reduce antibodies to their smallest binding domain components and have concomitantly driven the requirement for devising strategies to increase serum half-life to optimise drug exposure, thereby increasing therapeutic efficacy. In this study, we adopted an immunization route to raise picomolar affinity shark immunoglobulin new antigen receptors (IgNARs) to target human serum albumin (HSA). From our model shark species, Squalus acanthias, a phage display library encompassing the variable binding domain of IgNAR (VNAR) was constructed, screened against target, and positive clones were characterized for affinity and specificity. N-terminal and C-terminal molecular fusions of our lead hit in complex with a naïve VNAR domain were expressed, purified and exhibited the retention of high affinity binding to HSA, but also cross-selectivity to mouse, rat and monkey serum albumin both in vitro and in vivo. Furthermore, the naïve VNAR had enhanced pharmacokinetic (PK) characteristics in both N- and C-terminal orientations and when tested as a three domain construct with naïve VNAR flanking the HSA binding domain at both the N and C termini. Molecules derived from this platform technology also demonstrated the potential for clinical utility by being available via the subcutaneous route of delivery. This study thus demonstrates the first in vivo functional efficacy of a VNAR binding domain with the ability to enhance PK properties and support delivery of multifunctional therapies. PMID:23676205

Improving the pharmacokinetic properties of biologics by fusion to an anti-HSA shark VNAR domain.

PubMed

Müller, Mischa R; Saunders, Kenneth; Grace, Christopher; Jin, Macy; Piche-Nicholas, Nicole; Steven, John; O'Dwyer, Ronan; Wu, Leeying; Khetemenee, Lam; Vugmeyster, Yulia; Hickling, Timothy P; Tchistiakova, Lioudmila; Olland, Stephane; Gill, Davinder; Jensen, Allan; Barelle, Caroline J

2012-01-01

Advances in recombinant antibody technology and protein engineering have provided the opportunity to reduce antibodies to their smallest binding domain components and have concomitantly driven the requirement for devising strategies to increase serum half-life to optimise drug exposure, thereby increasing therapeutic efficacy. In this study, we adopted an immunization route to raise picomolar affinity shark immunoglobulin new antigen receptors (IgNARs) to target human serum albumin (HSA). From our model shark species, Squalus acanthias, a phage display library encompassing the variable binding domain of IgNAR (VNAR) was constructed, screened against target, and positive clones were characterized for affinity and specificity. N-terminal and C-terminal molecular fusions of our lead hit in complex with a naïve VNAR domain were expressed, purified and exhibited the retention of high affinity binding to HSA, but also cross-selectivity to mouse, rat and monkey serum albumin both in vitro and in vivo. Furthermore, the naïve VNAR had enhanced pharmacokinetic (PK) characteristics in both N- and C-terminal orientations and when tested as a three domain construct with naïve VNAR flanking the HSA binding domain at both the N and C termini. Molecules derived from this platform technology also demonstrated the potential for clinical utility by being available via the subcutaneous route of delivery. This study thus demonstrates the first in vivo functional efficacy of a VNAR binding domain with the ability to enhance PK properties and support delivery of multifunctional therapies.

The Effects of Organic Solvents on the Physicochemical Properties of Human Serum Albumin Nanoparticles

PubMed Central

Mohammad-Beigi, Hossein; Shojaosadati, Seyed Abbas; Morshedi, Dina; Mirzazadeh, Negar; Arpanaei, Ayyoob

2016-01-01

Background Recently, applications of albumin nanoparticles as drug delivery carriers have increased. Most toxicology studies have shown that surface chemistry and size of nanoparticles play an important role in biocompatibility and toxicity. Objective The effect of desolvating agents with different chemical properties on the size of synthesized HSA NPs was investigated. Materials and Methods Acetone, ethanol, methanol, and acetonitrile were used to synthesize HSA NPs with controllable size by desolvation method. Scanning electron microscopy (SEM), dynamic light scattering (DLS), and circular dichroism (CD) were employed to characterize produced particles. Finally, the toxicity of HSA NPs synthesized under different conditions was evaluated on PC-12 cells. Results The sizes of synthesized particles differed according to the different solvents used. The sizes were 275.3 nm, 155.3 nm, 100.11 nm, and 66.2 nm for acetonitrile, ethanol, acetone, and methanol, respectively. CD showed that larger NPs had more changes in the secondary structures. Finally, the toxicity monitored on the cultured PC-12 cells showed no significant toxic effect through treating with these NPs at different concentrations (0-500 μg.mL-1). Conclusions The size of HSA NPs has a strong dependency on the desolvating agent. The mechanism in which the desolvating agent affects the size of HSA NPs is complex. Various factors such as dielectric constant, polarity, functional groups, and hydrogen bonding of the solvents have the potential to affect the size and structure of HSA NPs. CD analysis suggested that the solvent denaturing capability had a critical effect on the HSA particle size. The stronger denaturing capability of the solvent resulted in the larger HSA particle size. PMID:28959317

Synthesis, characterization and target protein binding of drug-conjugated quantum dots in vitro and in living cells

NASA Astrophysics Data System (ADS)

Choi, Youngseon; Kim, Minjung; Cho, Yoojin; Yun, Eunsuk; Song, Rita

2013-02-01

Elucidation of unknown target proteins of a drug is of great importance in understanding cell biology and drug discovery. There have been extensive studies to discover and identify target proteins in the cell. Visualization of targets using drug-conjugated probes has been an important approach to gathering mechanistic information of drug action at the cellular level. As quantum dot (QD) nanocrystals have attracted much attention as a fluorescent probe in the bioimaging area, we prepared drug-conjugated QD to explore the potential of target discovery. As a model drug, we selected a well-known anticancer drug, methotrexate (MTX), which has been known to target dihydrofolate reductase (DHFR) with high affinity binding (Kd = 0.54 nM). MTX molecules were covalently attached to amino-PEG-polymer-coated QDs. Specific interactions of MTX-conjugated QDs with DHFR were identified using agarose gel electrophoresis and fluorescence microscopy. Cellular uptake of the MTX-conjugated QDs in living CHO cells was investigated with regard to their localization and distribution pattern. MTX-QD was found to be internalized into the cells via caveolae-medicated endocytosis without significant sequestration in endosomes. A colocalization experiment of the MTX-QD conjugate with antiDHFR-TAT-QD also confirmed that MTX-QD binds to the target DHFR. This study showed the potential of the drug-QD conjugate to identify or visualize drug-target interactions in the cell, which is currently of great importance in the area of drug discovery and chemical biology.

Dosing algorithm to target a predefined AUC in patients with primary central nervous system lymphoma receiving high dose methotrexate.

PubMed

Joerger, Markus; Ferreri, Andrés J M; Krähenbühl, Stephan; Schellens, Jan H M; Cerny, Thomas; Zucca, Emanuele; Huitema, Alwin D R

2012-02-01

There is no consensus regarding optimal dosing of high dose methotrexate (HDMTX) in patients with primary CNS lymphoma. Our aim was to develop a convenient dosing algorithm to target AUC(MTX) in the range between 1000 and 1100 µmol l(-1) h. A population covariate model from a pooled dataset of 131 patients receiving HDMTX was used to simulate concentration-time curves of 10,000 patients and test the efficacy of a dosing algorithm based on 24 h MTX plasma concentrations to target the prespecified AUC(MTX) . These data simulations included interindividual, interoccasion and residual unidentified variability. Patients received a total of four simulated cycles of HDMTX and adjusted MTX dosages were given for cycles two to four. The dosing algorithm proposes MTX dose adaptations ranging from +75% in patients with MTX C(24) < 0.5 µmol l(-1) up to -35% in patients with MTX C(24) > 12 µmol l(-1). The proposed dosing algorithm resulted in a marked improvement of the proportion of patients within the AUC(MTX) target between 1000 and 1100 µmol l(-1) h (11% with standard MTX dose, 35% with the adjusted dose) and a marked reduction of the interindividual variability of MTX exposure. A simple and practical dosing algorithm for HDMTX has been developed based on MTX 24 h plasma concentrations, and its potential efficacy in improving the proportion of patients within a prespecified target AUC(MTX) and reducing the interindividual variability of MTX exposure has been shown by data simulations. The clinical benefit of this dosing algorithm should be assessed in patients with primary central nervous system lymphoma (PCNSL). © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Hsa-Let-7g miRNA Targets Caspase-3 and Inhibits the Apoptosis Induced by ox-LDL in Endothelial Cells

PubMed Central

Zhang, Yefei; Chen, Naiyun; Zhang, Jihao; Tong, Yaling

2013-01-01

It has been well confirmed ox-LDL plays key roles in the development of atherosclerosis via binding to LOX-1 and inducing apoptosis in vascular endothelial cells. Recent studies have shown ox-LDL can suppress microRNA has-let-7g, which in turn inhibits the ox-LDL induced apoptosis. However, details need to be uncovered. To determine the anti-atherosclerosis effect of microRNA has-let-7g, and to evaluate the possibility of CASP3 as an anti-atherosclerotic drug target by has-let-7g, the present study determined the role of hsa-let-7g miRNA in ox-LDL induced apoptosis in the vascular endothelial cells. We found that miRNA has-let-7g was suppressed during the ox-LDL-induced apoptosis in EAhy926 endothelial cells. In addition, overexpression of has-let-7g negatively regulated apoptosis in the endothelial cells by targeting caspase-3 expression. Therefore, miRNA let-7g may play important role in endothelial apoptosis and atherosclerosis. PMID:24252910

Comprehensive two-dimensional HPLC to study the interaction of multiple components in Rheum palmatum L. with HSA by coupling a silica-bonded HSA column to a silica monolithic ODS column.

PubMed

Hu, Lianghai; Li, Xin; Feng, Shun; Kong, Liang; Su, Xingye; Chen, Xueguo; Qin, Feng; Ye, Mingliang; Zou, Hanfa

2006-04-01

A mode of comprehensive 2-D LC was developed by coupling a silica-bonded HSA column to a silica monolithic ODS column. This system combined the affinity property of the HSA column and the high-speed separation ability of the monolithic ODS column. The affinity chromatography with HSA-immobilized stationary phase was applied to study the interaction of multiple components in traditional Chinese medicines (TCMs) with HSA according to their affinity to protein in the first dimension. Then the unresolved components retained on the HSA column were further separated on the silica monolithic ODS column in the second dimension. By hyphenating the 2-D separation system to diode array detector and MS detectors, the UV and molecular weight information of the separated compounds can also be obtained. The developed separation system was applied to analysis of the extract of Rheum palmatum L., a number of low-abundant components can be separated on a single peak from the HSA column after normalization of peak heights. Six compounds were preliminarily identified according to their UV and MS spectra. It showed that this system was very useful for biological fingerprinting analysis of the components in TCMs and natural products.

Facile one-pot formulation of TRAIL-embedded paclitaxel-bound albumin nanoparticles for the treatment of pancreatic cancer.

PubMed

Min, Sun Young; Byeon, Hyeong Jun; Lee, Changkyu; Seo, Jisoo; Lee, Eun Seong; Shin, Beom Soo; Choi, Han-Gon; Lee, Kang Choon; Youn, Yu Seok

2015-10-15

Nanoparticle albumin-bound (nab™) technology is an effective way of delivering hydrophobic chemotherapeutics. We developed a one-pot/one-step formulation of paclitaxel (PTX)-bound albumin nanoparticles with embedded tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/PTX HSA-NP) for the treatment of pancreatic cancer. TRAIL/PTX HSA-NPs were fabricated using a high-pressure homogenizer at a TRAIL feeding ratio of 0.2%, 1.0%, and 2.0%. TRAIL/PTX HSA-NPs were spherical and became larger in size (170-230 nm) with increasing TRAIL amount (0.2-2.0%). The loading efficiencies of PTX were in the range of ∼86.4% and significantly low at 2.0% TRAIL (60.4%). Specifically, the inhibitory concentrations (IC50) of TRAIL (1.0 or 2.0%)/PTX HSA-NPs were >20-fold lower than that of plain PTX-HSA NP (0.032±0.06, 0.022±0.005, and 0.96±0.15 ng/ml, respectively) in pancreatic Mia Paca-2 cells. Considering TRAIL loading, bioactivity, and particle size, TRAIL(1.0%)/PTX HSA-NPs were determined as the optimal candidate for further studies. TRAIL(1.0%)/PTX HSA-NPs displayed substantially greater apoptotic activity than plain PTX HSA-NP in both FACS and TUNEL analysis. The loaded PTX and TRAIL were gradually released from the TRAIL(1.0%)/PTX HSA-NPs until ∼24 h, which is considered to be a sufficient time for delivery to the tumor tissue. TRAIL(1.0%)/PTX HSA-NP displayed markedly more antitumor efficacy than plain PTX HSA-NP in Mia Paca-2 cell-xenografted mice in terms of tumor volume (size) and weight (213.9 mm(3) and 0.18 g vs. 1126.8 mm(3) and 0.80 g, respectively). These improved in vitro and in vivo performances were due to the combined synergistic effects of PTX and TRAIL. We believe that this TRAIL/PTX HSA-NP would have potential as a novel apoptosis-based anticancer agent. Copyright © 2015 Elsevier B.V. All rights reserved.

Inorganic Nanovehicle Targets Tumor in an Orthotopic Breast Cancer Model

NASA Astrophysics Data System (ADS)

Choi, Goeun; Kwon, Oh-Joon; Oh, Yeonji; Yun, Chae-Ok; Choy, Jin-Ho

2014-03-01

The clinical efficacy of conventional chemotherapeutic agent, methotrexate (MTX), can be limited by its very short plasma half-life, the drug resistance, and the high dosage required for cancer cell suppression. In this study, a new drug delivery system is proposed to overcome such limitations. To realize such a system, MTX was intercalated into layered double hydroxides (LDHs), inorganic drug delivery vehicle, through a co-precipitation route to produce a MTX-LDH nanohybrid with an average particle size of approximately 130 nm. Biodistribution studies in mice bearing orthotopic human breast tumors revealed that the tumor-to-liver ratio of MTX in the MTX-LDH-treated-group was 6-fold higher than that of MTX-treated-one after drug treatment for 2 hr. Moreover, MTX-LDH exhibited superior targeting effect resulting in high antitumor efficacy inducing a 74.3% reduction in tumor volume compared to MTX alone, and as a consequence, significant survival benefits. Annexin-V and propidium iodine dual staining and TUNEL analysis showed that MTX-LDH induced a greater degree of apoptosis than free MTX. Taken together, our data demonstrate that a new MTX-LDH nanohybrid exhibits a superior efficacy profile and improved distribution compared to MTX alone and has the potential to enhance therapeutic efficacy via inhibition of tumor proliferation and induction of apoptosis.

Inorganic nanovehicle targets tumor in an orthotopic breast cancer model.

PubMed

Choi, Goeun; Kwon, Oh-Joon; Oh, Yeonji; Yun, Chae-Ok; Choy, Jin-Ho

2014-03-21

The clinical efficacy of conventional chemotherapeutic agent, methotrexate (MTX), can be limited by its very short plasma half-life, the drug resistance, and the high dosage required for cancer cell suppression. In this study, a new drug delivery system is proposed to overcome such limitations. To realize such a system, MTX was intercalated into layered double hydroxides (LDHs), inorganic drug delivery vehicle, through a co-precipitation route to produce a MTX-LDH nanohybrid with an average particle size of approximately 130 nm. Biodistribution studies in mice bearing orthotopic human breast tumors revealed that the tumor-to-liver ratio of MTX in the MTX-LDH-treated-group was 6-fold higher than that of MTX-treated-one after drug treatment for 2 hr. Moreover, MTX-LDH exhibited superior targeting effect resulting in high antitumor efficacy inducing a 74.3% reduction in tumor volume compared to MTX alone, and as a consequence, significant survival benefits. Annexin-V and propidium iodine dual staining and TUNEL analysis showed that MTX-LDH induced a greater degree of apoptosis than free MTX. Taken together, our data demonstrate that a new MTX-LDH nanohybrid exhibits a superior efficacy profile and improved distribution compared to MTX alone and has the potential to enhance therapeutic efficacy via inhibition of tumor proliferation and induction of apoptosis.

Towards hybrid biocompatible magnetic rHuman serum albumin-based nanoparticles: use of ultra-small (CeLn)3/4+ cation-doped maghemite nanoparticles as functional shell

NASA Astrophysics Data System (ADS)

Israel, Liron L.; Kovalenko, Elena I.; Boyko, Anna A.; Sapozhnikov, Alexander M.; Rosenberger, Ina; Kreuter, Jörg; Passoni, Lorena; Lellouche, Jean-Paul

2015-01-01

Human serum albumin (HSA) is a protein found in human blood. Over the last decade, HSA has been evaluated as a promising drug carrier. However, not being magnetic, HSA cannot be used for biomedical applications such as magnetic resonance imaging (MRI) and magnetic drug targeting. Therefore, subsequent composites building on iron oxide nanoparticles that are already used clinically as MRI contrast agents are extensively studied. Recently and in this context, innovative fully hydrophilic ultra-small CAN-stabilized maghemite ((CeLn)3/4+-γ-Fe2O3) nanoparticles have been readily fabricated. The present study discusses the design, fabrication, and characterization of a dual phase hybrid core (rHSA)-shell ((CeLn)3/4+-γ-Fe2O3 NPs) nanosystem. Quite importantly and in contrast to widely used encapsulation strategies, rHSA NP surface-attached (CeLn)3/4+-γ-Fe2O3 NPs enabled to exploit both rHSA (protein functionalities) and (CeLn)3/4+-γ-Fe2O3 NP surface functionalities (COOH and ligand L coordinative exchange) in addition to very effective MRI contrast capability due to optimal accessibility of H2O molecules with the outer magnetic phase. Resulting hybrid nanoparticles might be used as a platform modular system for therapeutic (drug delivery system) and MR diagnostic purposes.

Circular RNA hsa_circ_0000745 may serve as a diagnostic marker for gastric cancer.

PubMed

Huang, Mei; He, Yi-Ren; Liang, Li-Chuan; Huang, Qiang; Zhu, Zhi-Qiang

2017-09-14

To determine whether circular RNAs (circRNAs) are involved in pathological processes of gastric cancer (GC). Three circRNAs with differential expression in GC and colorectal cancer were randomly selected for validation by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), using 20 pairs of gastric tissues and normal tissues. Based on the predicted circRNA-miRNA network, we then focused on hsa_circ_0000745, which was found to be down-regulated in 20 GC tissues compared with normal tissues. The hsa_circ_0000745 levels were further analyzed by qRT-PCR in 60 GC tissues and paired adjacent non-tumor tissues, as well as 60 plasma samples from GC patients and 60 plasma samples from healthy controls. The associations between the levels of hsa_circ_0000745 and the clinicopathological features of GC patients were statistically assessed. A receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of hsa_circ_0000745 in GC. Hsa_circ_0000745 was down-regulated in GC tissues vs non-tumorous tissues ( P < 0.001) and in plasma samples from patients with GC vs healthy controls ( P < 0.001). The expression level of hsa_circ_0000745 in GC tissues correlated with tumor differentiation, while the expression level in plasma correlated with tumor-node-metastasis stage. The area under the ROC curve (AUC) of hsa_circ_0000745 in plasma was 0.683, suggesting good diagnostic value. Plasma hsa_circ_0000745 level combined with carcinoembryogenic antigen (CEA) level increased the AUC to 0.775. Hsa_circ_0000745 plays an important role in GC and its expression level in plasma in combination with CEA level is a promising diagnostic marker for this malignancy.

Orthogonal test design for optimization of synthesis of MTX/LDHs hybrids by ion-exchange method

NASA Astrophysics Data System (ADS)

Liu, Su-Qing; Dai, Chao-Fan; Wang, Lin; Li, Shu-Ping; Li, Xiao-Dong

2015-04-01

Based on orthogonal test design, the factors influencing the synthesis of methotrexate intercalated magnesium-aluminum layered double hydroxides (MTX/LDHs for short) by ion-exchange method, such as weight ratio of pristine LDHs to MTX (R for short), exchange temperature, time and pH value were investigated. Of the four controllable independent variables, R had the strongest effect on the crystallinity and the drug-loading capacity and the optimum synthesis conditions considered from the crystallinity and the drug-loading capacity both pointed to the same values, i.e., R=2:1, pH=9.5, temperature of 80 °C and exchange time of 3 day. The XRD diffractions indicated that high MTX content was in favor of the formation of intercalated hybrids, while low content lead to the failure of it. TEM photos indicated that the intercalated hybrids all exhibited aggregated hexagonal plates. In order to improve the morphology, two different states of pristine LDHs, i.e., powder and colloid, were chosen to prepare MTX/LDHs hybrids and the results indicated that colloid state of pristine was advantageous to obtain regular particles. The study also revealed that the properties of hybrids obtained at optimum conditions by ion-exchange were superior to that obtained from standard methods, such as co-precipitation method.

hsa_circ_0013958: a circular RNA and potential novel biomarker for lung adenocarcinoma.

PubMed

Zhu, Xiaoli; Wang, Xiyong; Wei, Shuzhen; Chen, Yan; Chen, Yang; Fan, Xiaobo; Han, Shuhua; Wu, Guoqiu

2017-07-01

Circular RNAs (circRNAs) are associated with cancer progression and metastasis, although little is known about their role in lung adenocarcinoma (LAC). In the present study, microarrays were first used to screen for tumour-specific circRNA candidates in LAC tissue. Thirty-nine circRNAs were found to be up-regulated and 20 were down-regulated (fold change > 2.0). Among them, hsa_circ_0013958 was further confirmed to be up-regulated in all of the LAC tissues, cells and plasma. In addition, hsa_circ_0013958 levels were associated with TNM stage (P = 0.009) and lymphatic metastasis (P = 0.006). The area under the receiver operating characteristic curve was 0.815 (95% confidence interval = 0.727-0.903; P < 0.001). In addition, to further illustrate the bioactivities of hsa_circ_0013958 in LAC, siRNA-mediated inhibition of hsa_circ_0013958 was performed in vitro. The results showed that hsa_circ_0013958 promoted cell proliferation and invasion and inhibited cell apoptosis in LAC. Moreover, hsa_circ_0013958 was identified as a sponge of miR-134, and thus it up-regulated oncogenic cyclin D1, which plays a pivotal role in the development of non-small cell lung cancer. In conclusion, our results suggested that hsa_circ_0013958 could be used as a potential non-invasive biomarker for the early detection and screening of LAC. © 2017 Federation of European Biochemical Societies.

Weekly vs. daily administration of oral methotrexate (MTX) for generalized plaque psoriasis: a randomized controlled clinical trial.

PubMed

Radmanesh, Mohammad; Rafiei, Behnam; Moosavi, Zahra-Beigum; Sina, Niloofar

2011-10-01

Methotrexate (MTX) treatment for psoriasis is most often administered weekly, because the drug has been considered more hepatotoxic when taken daily. However, some patients may tolerate smaller, more frequent doses better. To study the efficacy and toxicity of daily vs. weekly MTX. In a randomized controlled trial, 101 patients with generalized plaque psoriasis received oral MTX 2.5 mg daily for weeks, 4 weeks and monthly for a total of 4 months. Changes in PASI scores were classified into three categories: >75% improvement was considered significant; 25-75% moderate; and <25% poor. Sixty Group 1 patients and 81 Group 2 patients showed a significant response (P-value 0.001); 19 patients in Group 1 and 14 in Group 2 responded moderately; 22 patients in Group 1 and six patients from Group 2 responded poorly. Forty-five patients in Group 1 and 33 in Group 2 developed transient increases in liver enzymes (P-value 0.11). Nausea, headache, fatigue, and gastrointestinal upset were noted in four Group 1 patients and 30 Group 2 patients (P-value 0.0001). Nausea, vomiting, headache, and fatigue were significantly less common side effects in our patients who received MTX daily, but liver enzyme abnormalities were less common, and clinical efficacy was greater in the patients who received MTX weekly. © 2011 The International Society of Dermatology.

Human serum albumin (HSA) nanoparticles: reproducibility of preparation process and kinetics of enzymatic degradation.

PubMed

Langer, K; Anhorn, M G; Steinhauser, I; Dreis, S; Celebi, D; Schrickel, N; Faust, S; Vogel, V

2008-01-22

Nanoparticles prepared from human serum albumin (HSA) are versatile carrier systems for drug delivery and can be prepared by an established desolvation process. A reproducible process with a low batch-to-batch variability is required for transfer from the lab to an industrial production. In the present study the batch-to-batch variability of the starting material HSA on the preparation of nanoparticles was investigated. HSA can build dimers and higher aggregates because of a free thiol group present in the molecule. Therefore, the quality of different HSA batches was analysed by size exclusion chromatography (SEC) and analytical ultracentrifugation (AUC). The amount of dimerised HSA detected by SEC did not affect particle preparation. Higher aggregates of the protein detected in two batches by AUC disturbed nanoparticle formation at pH values below 8.0. At pH 8.0 and above monodisperse particles between 200 and 300 nm could be prepared with all batches, with higher pH values leading to smaller particles. Besides human derived albumin a particle preparation was also feasible based on recombinant human serum albumin (rHSA). Under comparable preparation conditions monodisperse nanoparticles could be achieved and the same effects of protein aggregates on particle formation were observed. For nanoparticulate drug delivery systems the enzymatic degradation is a crucial parameter for the release of an embedded drug. For this reason, besides the particle preparation process, particle degradation in the presence of different enzymes was studied. Under acidic conditions HSA as well as rHSA nanoparticles could be digested by pepsin and cathepsin B. At neutral pH trypsin, proteinase K, and protease were suitable for particle degradation. It could be shown that the kinetics of particle degradation was dependent on the degree of particle stabilisation. Therefore, the degree of particle stabilisation will influence drug release after cellular accumulation of HSA nanoparticles.

Structure of HsaD, a steroid-degrading hydrolase, from Mycobacterium tuberculosis

PubMed Central

Lack, Nathan; Lowe, Edward D.; Liu, Jie; Eltis, Lindsay D.; Noble, Martin E. M.; Sim, Edith; Westwood, Isaac M.

2008-01-01

Tuberculosis is a major cause of death worldwide. Understanding of the pathogenicity of Mycobacterium tuberculosis has been advanced by gene analysis and has led to the identification of genes that are important for intracellular survival in macrophages. One of these genes encodes HsaD, a meta-cleavage product (MCP) hydrolase that catalyzes the hydrolytic cleavage of a carbon–carbon bond in cholesterol metabolism. This paper describes the production of HsaD as a recombinant protein and, following crystallization, the determination of its three-dimensional structure to 2.35 Å resolution by X-ray crystallography at the Diamond Light Source in Oxfordshire, England. To the authors’ knowledge, this study constitutes the first report of a structure determined at the new synchrotron facility. The volume of the active-site cleft of the HsaD enzyme is more than double the corresponding active-site volumes of related MCP hydrolases involved in the catabolism of aromatic compounds, consistent with the specificity of HsaD for steroids such as cholesterol. Knowledge of the structure of the enzyme facilitates the design of inhibitors. PMID:18097091

Structure of HsaD, a steroid-degrading hydrolase, from Mycobacterium tuberculosis.

PubMed

Lack, Nathan; Lowe, Edward D; Liu, Jie; Eltis, Lindsay D; Noble, Martin E M; Sim, Edith; Westwood, Isaac M

2008-01-01

Tuberculosis is a major cause of death worldwide. Understanding of the pathogenicity of Mycobacterium tuberculosis has been advanced by gene analysis and has led to the identification of genes that are important for intracellular survival in macrophages. One of these genes encodes HsaD, a meta-cleavage product (MCP) hydrolase that catalyzes the hydrolytic cleavage of a carbon-carbon bond in cholesterol metabolism. This paper describes the production of HsaD as a recombinant protein and, following crystallization, the determination of its three-dimensional structure to 2.35 A resolution by X-ray crystallography at the Diamond Light Source in Oxfordshire, England. To the authors' knowledge, this study constitutes the first report of a structure determined at the new synchrotron facility. The volume of the active-site cleft of the HsaD enzyme is more than double the corresponding active-site volumes of related MCP hydrolases involved in the catabolism of aromatic compounds, consistent with the specificity of HsaD for steroids such as cholesterol. Knowledge of the structure of the enzyme facilitates the design of inhibitors.

Circular RNA hsa_circ_0008344 regulates glioblastoma cell proliferation, migration, invasion, and apoptosis.

PubMed

Zhou, Jinxu; Wang, Hongxiang; Chu, Junsheng; Huang, Qilin; Li, Guangxu; Yan, Yong; Xu, Tao; Chen, Juxiang; Wang, Yuhai

2018-04-24

Recent studies have found circular RNAs (circRNAs) involved in the biological process of cancers. However, little is known about their functional roles in glioblastoma. Human circRNA microarray analysis was performed to screen the expression profile of circRNAs in IDH1 wild-type glioblastoma tissue. The expression of hsa_circ_0008344 in glioblastoma and normal brain samples was quantified by qRT-PCR. Functional experiments were performed to investigate the biological functions of hsa_circ_0008344, including MTT assay, colony formation assay, transwell assay, and cell apoptosis assay. CircRNA microarray revealed a total of 417 abnormally expressed circRNAs (>1.5-fold, P < .05) in glioblastoma tissue compared with the adjacent normal brain. Hsa_circ_0008344, among the top differentially expressed circRNAs, was significantly upregulated in IDH1 wild-type glioblastoma. Further in vitro studies showed that knockdown of hsa_circ_0008344 suppressed glioblastoma cell proliferation, colony formation, migration, and invasion, but increased cell apoptotic rate. Hsa_circ_0008344 is upregulated in glioblastoma and may contribute to the progression of this malignancy. © 2018 Wiley Periodicals, Inc.

MicroRNA profiling reveals dysregulated microRNAs and their target gene regulatory networks in cemento-ossifying fibroma.

PubMed

Pereira, Thaís Dos Santos Fontes; Brito, João Artur Ricieri; Guimarães, André Luiz Sena; Gomes, Carolina Cavaliéri; de Lacerda, Júlio Cesar Tanos; de Castro, Wagner Henriques; Coimbra, Roney Santos; Diniz, Marina Gonçalves; Gomez, Ricardo Santiago

2018-01-01

Cemento-ossifying fibroma (COF) is a benign fibro-osseous neoplasm of uncertain pathogenesis, and its treatment results in morbidity. MicroRNAs (miRNA) are small non-coding RNAs that regulate gene expression and may represent therapeutic targets. The purpose of the study was to generate a comprehensive miRNA profile of COF compared to normal bone. Additionally, the most relevant pathways and target genes of differentially expressed miRNA were investigated by in silico analysis. Nine COF and ten normal bone samples were included in the study. miRNA profiling was carried out by using TaqMan® OpenArray® Human microRNA panel containing 754 validated human miRNAs. We identified the most relevant miRNAs target genes through the leader gene approach, using STRING and Cytoscape software. Pathways enrichment analysis was performed using DIANA-miRPath. Eleven miRNAs were downregulated (hsa-miR-95-3p, hsa-miR-141-3p, hsa-miR-205-5p, hsa-miR-223-3p, hsa-miR-31-5p, hsa-miR-944, hsa-miR-200b-3p, hsa-miR-135b-5p, hsa-miR-31-3p, hsa-miR-223-5p and hsa-miR-200c-3p), and five were upregulated (hsa-miR-181a-5p, hsa-miR-181c-5p, hsa-miR-149-5p, hsa-miR-138-5p and hsa-miR-199a-3p) in COF compared to normal bone. Eighteen common target genes were predicted, and the leader genes approach identified the following genes involved in human COF: EZH2, XIAP, MET and TGFBR1. According to the biology of bone and COF, the most relevant KEGG pathways revealed by enrichment analysis were proteoglycans in cancer, miRNAs in cancer, pathways in cancer, p53-, PI3K-Akt-, FoxO- and TGF-beta signalling pathways, which were previously found to be differentially regulated in bone neoplasms, odontogenic tumours and osteogenesis. miRNA dysregulation occurs in COF, and EZH2, XIAP, MET and TGFBR1 are potential targets for functional analysis validation. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Development and characterization of surface engineered PPI dendrimers for targeted drug delivery.

PubMed

Kaur, Avleen; Jain, Keerti; Mehra, Neelesh Kumar; Jain, N K

2017-05-01

In this study, we reported folate-conjugated polypropylene imine dendrimers (FA-PPI) as efficient carrier for model anticancer drug, methotrexate (MTX), for pH-sensitive drug release, selective targeting to cancer cells, and anticancer activity. In the in vitro drug release studies this nanoconjugate of MTX showed initial rapid release followed by gradual slow release, and the drug release was found to be pH sensitive with greater release at acidic pH. The ex vivo investigations with human breast cancer cell lines, MCF-7, showed enhanced cytotoxicity of MTX-FA-PPI with significantly enhanced intracellular uptake. The biofate of nanoconjugate was determined in Wistar rat where MTX-FA-PPI showed 37.79-fold increase in the concentration of MTX in liver after 24 h in comparison with free MTX formulation.

Folate-targeted nanoparticles show efficacy in the treatment of inflammatory arthritis

PubMed Central

Thomas, Thommey P.; Goonewardena, Sascha N.; Majoros, Istvan; Kotlyar, Alina; Cao, Zhengyi; Leroueil, Pascale R.; Baker, James R.

2011-01-01

Objective To investigate the uptake of a poly(amidoamine) dendrimer (generation 5 (G5)) nanoparticle covalently conjugated to polyvalent folic acid (FA) as the targeting ligand into macrophages, and the activity of a FA- and methotrexate-conjugated dendrimer (G5-FA-MTX) as a therapeutic for the inflammatory disease of arthritis. Methods In vitro studies were performed in macrophage cell lines and in isolated mouse macrophages to check the cellular uptake of fluorescently tagged G5-FA nanoparticles, using flow cytometry and confocal microscopy. In vivo studies were conducted in a rat model of collagen-induced arthritis to evaluate the therapeutic potential of G5-FA-MTX. Results Folate targeted dendrimer bound and internalized in a receptor-specific manner into both folate receptor β-expressing macrophage cell lines and primary mouse macrophages. The G5-FA-MTX acts as a potent anti-inflammatory agent and reduces arthritis-induced inflammatory parameters such as ankle swelling, paw volume, cartilage damage, bone resorption and body weight decrease. Conclusion The use of folate-targeted nanoparticles to specifically target MTX into macrophages may provide an effective clinical approach for anti-inflammatory therapy in rheumatoid arthritis. PMID:21618461

Interaction of flavonols with human serum albumin: a biophysical study showing structure-activity relationship and enhancement when coated on silver nanoparticles.

PubMed

Das, Pratyusa; Chaudhari, Sunil Kumar; Das, Asmita; Kundu, Somashree; Saha, Chabita

2018-04-24

Binding affinities of flavonols namely quercetin, myricetin, and kaempferol to human serum albumin (HSA) were determined fluorimetrically and the order was observed to be myricetin > quercetin > kaempferol demonstrating structure-activity relationship. Quercetin-coated silver nanoparticles (AgNPs) show higher binding affinity to HSA compared to free quercetin with binding constants 6.04 × 10 7  M -1 and 4.2 × 10 6  M -1 , respectively. Using site-specific markers it is concluded that free quercetin and that coated on AgNPs bind at different sites. Significant structural changes in circular dichroism (CD) spectra of HSA were recorded with quercetin-coated AgNPs compared to free quercetin. These results were further substantiated by time-resolved fluorescence spectroscopy where fluorescence life time of the tryptophan residue in HSA-quercetin-coated AgNPs complex decreased to 3.63 ns from 4.22 ns in HSA-quercetin complex. Isothermal calorimetric studies reveal two binding modes for quercetin-coated AgNPs and also higher binding constants compared to free quercetin. These higher binding affinities are attributed to altered properties of quercetin when coated on AgNPs enabling it to reach the binding sites other than site II where free quercetin mainly binds.

Hsa_circ_0001649: A circular RNA and potential novel biomarker for colorectal cancer.

PubMed

Ji, Wenxin; Qiu, Chunli; Wang, Mao; Mao, Ning; Wu, Shaofeng; Dai, Yinhai

2018-02-26

The circRNAs are differentially expressed in a wide range of cancers in regulating their initiation and progression, and could be used to make a diagnosis for some diseases like tumor as a new biomarker. However, the correlation and the mechanism of action between circRNAs and colorectal cancer (CRC) are still unclear. In this study, by using qRT-PCRs, we detected the expression level of hsa_circ_0001649 in tissue and serum samples from CRC patients, and the cultured cell has been detected. We found that the hsa_circ_0001649 in CRC is significantly lower than the expression level of correspondent nontumorous tissues (n = 64, P < 0.01). We also tested the HCT116 cell lines, and the similar result is observed (n = 15, P < 0.01). Moreover, we detected the serum samples obtained before and after surgery, showing significantly the expression level of hsa_circ_0001649 in the same patient is up-regulated after surgery (n = 18, P < 0.01). Besides, we analyzed the correlation between clinicopathological date and the expression level of hsa_circ_0001649, we found that hsa_circ_0001649 expression level is closely associated with pathological differentiation (P = 0.037), and the result also illustrated that the expression level of hsa_circ_0001649 is no direct correlation with age, gender, TMN stage, lymphatic metastasis, CEA, CA19-9, and CA-724 levels. The area under the receiver operating characteristic (ROC) curve was 0.857. In conclusion, this study showed that the expression level of hsa_circ_0001649 was down-regulated in CRC and could use it as a new biomarker for specific and sensitive inspection of CRC. Copyright © 2018 Elsevier Inc. All rights reserved.

The Growing Problem of New Psychoactive Substances (NPS).

PubMed

Madras, Bertha K

The term "new psychoactive substances" (NPS) can be defined as individual drugs in pure form or in complex preparations that are not scheduled under the Single Convention on Narcotic Drugs (1961) or the Convention on Psychotropic Substances (1971). NPS may be categorized by chemical structure, by psychoactive properties, by biological targets, or by source (plant, synthetic, or combined). The emergence of hundreds of NPS in the past decade is challenging for public health and drug policies globally. The novelty of NPS, their ambiguous legal status, ability to evade toxicological tests, swift adaptation to legal restrictions, global Internet marketing, and scant public knowledge of their adverse effects are among the key drivers of this twenty-first century phenomenon. Multi-disciplinary research in areas of biology, epidemiology, prevention, and web analytics are needed to develop effective responses in a domain capable of overwhelming current international conventions and national drug control policies. Ultimately, research-guided prevention education will fortify societies against this tidal wave.

Methotrexate-loaded PLGA nanobubbles for ultrasound imaging and Synergistic Targeted therapy of residual tumor during HIFU ablation.

PubMed

Zhang, Xuemei; Zheng, Yuanyi; Wang, Zhigang; Huang, Shuai; Chen, Yu; Jiang, Wei; Zhang, Hua; Ding, Mingxia; Li, Qingshu; Xiao, Xiaoqiu; Luo, Xin; Wang, Zhibiao; Qi, Hongbo

2014-06-01

High intensity focused ultrasound (HIFU) has attracted the great attention in tumor ablation due to its non-invasive, efficient and economic features. However, HIFU ablation has its intrinsic limitations for removing the residual tumor cells, thus the tumor recurrence and metastasis cannot be avoided in this case. Herein, we developed a multifunctional targeted poly(lactic-co-glycolic acid) (PLGA) nanobubbles (NBs), which not only function as an efficient ultrasound contrast agent for tumor imaging, but also a targeted anticancer drug carrier and excellent synergistic agent for enhancing the therapeutic efficiency of HIFU ablation. Methotrexate (MTX)-loaded NBs were synthesized and filled with perfluorocarbon gas subsequently using a facile but general double emulsion evaporation method. The active tumor-targeting monoclonal anti-HLA-G antibodies (mAbHLA-G) were further conjugated onto the surface of nanobubbles. The mAbHLA-G/MTX/PLGA NBs could enhance the ultrasound imaging both in vitro and in vivo, and the targeting efficiency to HLA-G overexpressing JEG-3 cells has been demonstrated. The elaborately designed mAbHLA-G/MTX/PLGA NBs can specifically target to the tumor cells both in vitro and in vivo, and their blood circulation time in vivo was much longer than non-targeted MTX/PLGA NBs. Further therapeutic evaluations showed that the targeted NBs as a synergistic agent can significantly improve the efficiency of HIFU ablation by changing the acoustic environment, and the focused ultrasound can promote the on-demand MTX release both in vitro and in vivo. The in vivo histopathology test and immunohistochemical analysis showed that the mAbHLA-G/MTX/PLGA NBs plus HIFU group presented most serious coagulative necrosis, the lowest proliferation index and the highest apoptotic index. Therefore, the successful introduction of targeted mAbHLA-G/MTX/PLGA NBs provides an excellent platform for the highly efficient, imaging-guided and non-invasive HIFU synergistic therapy

Elucidation of the Human Serum Albumin (HSA) Binding Site for the Cu-PTSM and Cu-ATSM Radiopharmaceuticals

PubMed Central

Basken, Nathan E.; Mathias, Carla J.; Green, Mark A.

2008-01-01

The Cu-PTSM (pyruvaldehyde bis(N4-methylthiosemicarbazonato)copper(II)) and Cu-ATSM (diacetyl bis(N4-methylthiosemicarbazonato)copper(II)) radiopharmaceuticals exhibit strong, species-dependent binding to human serum albumin (HSA), while Cu-ETS (ethylglyoxal bis(thiosemicarbazonato)copper(II)) appears to only exhibit non-specific binding to human and animal serum albumins. This study examines the structural basis for HSA binding of Cu-PTSM and Cu-ATSM via competition with drugs having known albumin binding sites. Warfarin, furosemide, ibuprofen, phenylbutazone, benzylpenicillin, and cephmandole were added to HSA solutions at drug:HSA mole ratios from 0 to 8:1, followed by quantification of radiopharmaceutical binding to HSA by ultrafiltration. Warfarin, a site IIA drug, progressively displaced both [64Cu]Cu-PTSM and [64Cu]Cu-ATSM from HSA. At 8:1 warfarin:HSA mole ratios, free [64Cu]Cu-PTSM and [64Cu]Cu-ATSM levels increased 300–500%. This was in contrast to solutions containing ibuprofen, a site IIIA drug; no increase in free [64Cu]Cu-PTSM or [64Cu]Cu-ATSM was observed except at high ibuprofen:HSA ratios, where secondary ibuprofen binding to the IIA site may cause modest radiopharmaceutical displacement. By contrast, and consistent with earlier findings suggesting Cu-ETS exhibits only non-specific associations, [64Cu]Cu-ETS binding to HSA was unaffected by the addition of drugs that bind in either site. We conclude that the species-dependence of Cu-PTSM and Cu-ATSM albumin binding arises from interaction(s) with the IIA site of HSA. PMID:18937368

hsa-miR-135a-1 inhibits prostate cancer cell growth and migration by targeting EGFR.

PubMed

Xu, Bin; Tao, Tao; Wang, Yiduo; Fang, Fang; Huang, Yeqing; Chen, Shuqiu; Zhu, Weidong; Chen, Ming

2016-10-01

Prostate cancer is one of the leading causes of death in men worldwide. Differentially expressed microRNAs (miRNAs) are associated with metastatic prostate cancer. However, their potential roles for affecting prostate cancer initiation and progression remain largely unknown. Here, we examined the aberrant expression profiles of miRNAs in human metastatic prostate cancer tissues. We further validated our miRNA expression data using two large, independent clinical prostate cancer datasets from the Memorial Sloan Kettering Cancer Center (MSKCC) and The Cancer Genome Atlas (TCGA). Our data support a model in which hsa-miR-135-1 acts as a potential tumor suppressor in metastatic prostate cancer. First, its downregulation was positively correlated with late TNM stage, high Gleason score, and adverse prognosis. Second, cell growth, cell cycle progression, cell migration and invasion, and xenograft tumor formation were dramatically inhibited by miR-135a overexpression. Third, in the microarray gene expression data analysis using Gene Set Enrichment Analysis (GSEA), Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis, Ingenuity Pathway Analysis (IPA), and Oncomine concept analysis, we showed that miR-135a targets multiple oncogenic pathways including epidermal growth factor receptor (EGFR), which we verified using functional experimental assays. These results help advance our understanding of the function of miRNAs in metastatic prostate cancer and provide a basis for further clinical investigation.

Different responses of Fe transporters in Caco2/HT29-MTX cocultures than in independent Caco-2 cell cultures

USDA-ARS?s Scientific Manuscript database

The human intestinal epithelium is composed of several cell types; mainly enterocytes and globet (mucin-secreting) cells. This study compares the cellular response for Fe transporters in Caco-2, HT29-MTX, and Caco-2/HT29-MTX coculture models for Fe bioavailability studies. Under culture, Caco-2 cell...

Hsa-mir-145 is the top EWS-FLI1-repressed microRNA involved in a positive feedback loop in Ewing's sarcoma.

PubMed

Ban, J; Jug, G; Mestdagh, P; Schwentner, R; Kauer, M; Aryee, D N T; Schaefer, K-L; Nakatani, F; Scotlandi, K; Reiter, M; Strunk, D; Speleman, F; Vandesompele, J; Kovar, H

2011-05-05

EWS-FLI1 is a chromosome translocation-derived chimeric transcription factor that has a central and rate-limiting role in the pathogenesis of Ewing's sarcoma. Although the EWS-FLI1 transcriptomic signature has been extensively characterized on the mRNA level, information on its impact on non-coding RNA expression is lacking. We have performed a genome-wide analysis of microRNAs affected by RNAi-mediated silencing of EWS-FLI1 in Ewing's sarcoma cell lines, and differentially expressed between primary Ewing's sarcoma and mesenchymal progenitor cells. Here, we report on the identification of hsa-mir-145 as the top EWS-FLI1-repressed microRNA. Upon knockdown of EWS-FLI1, hsa-mir-145 expression dramatically increases in all Ewing's sarcoma cell lines tested. Vice versa, ectopic expression of the microRNA in Ewing's sarcoma cell lines strongly reduced EWS-FLI1 protein, whereas transfection of an anti-mir to hsa-mir-145 increased the EWS-FLI1 levels. Reporter gene assays revealed that this modulation of EWS-FLI1 protein was mediated by the microRNA targeting the FLI1 3'-untranslated region. Mutual regulations of EWS-FLI1 and hsa-mir-145 were mirrored by an inverse correlation between their expression levels in four of the Ewing's sarcoma cell lines tested. Consistent with the role of EWS-FLI1 in Ewing's sarcoma growth regulation, forced hsa-mir-145 expression halted Ewing's sarcoma cell line growth. These results identify feedback regulation between EWS-FLI1 and hsa-mir-145 as an important component of the EWS-FLI1-mediated Ewing's sarcomagenesis that may open a new avenue to future microRNA-mediated therapy of this devastating malignant disease.

Two-gigawatt burst-mode operation of the intense microwave prototype (IMP) free-electron laser (FEL) for the microwave tokamak experiment (MTX)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Felker, B.; Allen, S.; Bell, H.

1993-10-06

The MTX explored the plasma heating effects of 140 GHz microwaves from both Gyrotrons and from the IMP FEL wiggler. The Gyrotron was long pulse length (0.5 seconds maximum) and the FEL produced short-pulse length, high-peak power, single and burst modes of 140 GHZ microwaves. Full-power operations of the IMP FEL wiggler were commenced in April of 1992 and continued into October of 1992. The Experimental Test Accelerator H (ETA-II) provided a 50-nanosecond, 6-MeV, 2--3 kAmp electron beam that was introduced co-linear into the IMP FEL with a 140 GHz Gyrotron master oscillator (MO). The FEL was able to amplifymore » the MO signal from approximately 7 kW to peaks consistently in the range of 1--2 GW. This microwave pulse was transmitted into the MTX and allowed the exploration of the linear and non-linear effects of short pulse, intense power in the MTX plasma. Single pulses were used to explore and gain operating experience in the parameter space of the IMP FEL, and finally evaluate transmission and absorption in the MTX. Single-pulse operations were repeatable. After the MTX was shut down burst-mode operations were successful at 2 kHz. This paper will describe the IMP FEL, Microwave Transmission System to MTX, the diagnostics used for calorimetric measurements, and the operations of the entire Microwave system. A discussion of correlated and uncorrelated errors that affect FEL performance will be made Linear and non-linear absorption data of the microwaves in the MTX plasma will be presented.« less

Molecular aspects of metal oxide nanoparticle (MO-NPs) mediated pharmacological effects.

PubMed

Tuli, Hardeep Singh; Kashyap, Dharambir; Bedi, Simranjeet Kaur; Kumar, Pardeep; Kumar, Gaurav; Sandhu, Sardul Singh

2015-12-15

Metal oxide nanoparticles (MO-NPs) are the multidisciplinary nano-scaled molecules which are being used in the diagnosis and treatment of the challenging diseases including cancer. Evidence suggest that antimicrobial formulations in the form of MO-NPs can be possibly used as effective antimicrobial agents. In addition, MO-NPs are known to target various cellular signaling pathways associated with apoptosis, angiogenesis, metastasis and inflammation of cancer. In combination with other chemotherapeutic/anticancer agents, MO-NPs not only increase their bioavailability and efficacy but also lower down the requirement of active dosages. To date, to our knowledge there is no single comprehensive report on cellular and molecular interactions of MO-NPs which have been well elaborated in this review. Also we highlight various action mechanisms through which MO-NPs act as antimicrobial, anticancer, antioxidant and anti-inflammatory agents. Copyright © 2015 Elsevier Inc. All rights reserved.

pH-responsive drug release and real-time fluorescence detection of porous silica nanoparticles.

PubMed

Zhang, Xu; Wang, Yamin; Zhao, Yanbao; Sun, Lei

2017-08-01

In this work, pH-sensitive "dual-switch" porous silica (pSiO 2 ) nanoparticles (NPs) were constructed for drug delivery. Poly(acrylic acid) (PAA) was grafting onto the internal and external surfaces of amino groups functionalized porous silica (pSiO 2 -NH 2 ) NPs by the amidation between the amino groups and the carboxyl groups of PAA for pH triggered drug release. The resultant pSiO 2 /PAA NPs have an average diameter of 50-60nm and high specific surface area (914m 2 ·g -1 ). To improve the loading capacity, ZnO quantum dots (QDs) were used to block the partial pores of pSiO 2 /PAA and the loading capacity reached to 28% for methotrexate (MTX) model drug. The in vitro cellular cytotoxicity test and a hemolysis assay demonstrated that the pSiO 2 /PAA/ZnO NPs were highly biocompatible and suitable to utilize as drug carriers. The MTX-loaded pSiO 2 /PAA/ZnO NPs displayed more efficient cytotoxic to HepG2 cells than free MTX. The pSiO 2 /PAA/ZnO NPs displayed low premature, pH-responsive release and pH-dependent fluorescence. Moreover, pH-dependent fluorescence enables to trace MTX release behavior. Copyright © 2017 Elsevier B.V. All rights reserved.

Surfactant-cobalt(III) complexes: The impact of hydrophobicity on interaction with HSA and DNA - insights from experimental and theoretical approach.

PubMed

Veeralakshmi, Selvakumar; Sabapathi, Gopal; Nehru, Selvan; Venuvanalingam, Ponnambalam; Arunachalam, Sankaralingam

2017-05-01

To develop surfactant-based metallodrugs, it is very important to know about their hydrophobicity, micelle forming capacity, their interaction with biomacromolecules such as proteins and nucleic acids, and biological activities. Here, diethylenetriamine (dien) and tetradecylamine ligand (TA) based surfactant-cobalt(III) complexes with single chain domain, [Co(dien)(TA)Cl 2 ]ClO 4 (1) and double chain domain [Co(dien)(TA) 2 Cl](ClO 4 ) 2 (2) were chosen to study the effect of hydrophobicity on the interaction with human serum albumin and calf thymus DNA. The obtained results showed that (i) single chain surfactant-cobalt(III) complex (1) interact with HSA and DNA via electrostatic interaction and groove binding, respectively; (ii) double chain surfactant-cobalt(III) complex (2) interact with HSA and DNA via hydrophobic interaction and partial intercalation, respectively, due to the play of hydrophobicity by single and double chain domains. Further it is noted that, double chain surfactant-cobalt(III) complex interact strongly with HSA and DNA, compared single chain surfactant-cobalt(III) complex due to their more hydrophobicity nature. DFT and molecular docking studies offer insights into the mechanism and mode of binding towards the molecular target CT-DNA and HSA. Hence, the present findings will create new avenue towards the use of hydrophobic metallodrugs for various therapeutic applications. Copyright © 2017 Elsevier B.V. All rights reserved.

Circular RNA expression profile and potential function of hsa_circ_0045272 in systemic lupus erythematosus.

PubMed

Li, Lian-Ju; Zhu, Zhi-Wei; Zhao, Wei; Tao, Sha-Sha; Li, Bao-Zhu; Xu, Shu-Zhen; Wang, Jie-Bing; Zhang, Ming-Yue; Wu, Jun; Leng, Rui-Xue; Fan, Yin-Guang; Pan, Hai-Feng; Ye, Dong-Qing

2018-04-26

Circular RNAs (circRNAs) represent as a class of non-coding RNAs which form covalently closed RNA circles, and their extensive expression and conservation in mammals are observed. CircRNAs regulate gene expression through acting as competitive endogenous RNAs (ceRNAs) and modulating gene transcription. Accumulating evidence supports the implication of circRNAs in a variety of human diseases. Yet, study exploring the role of circRNAs in systemic lupus erythematosus (SLE) is lacking. The present study measured the circRNAs expression profiles in T cells from SLE patients and healthy controls with human circRNA microarray and identified 127 differentially expressed circRNAs in SLE patients. Downregulation of hsa_circ_0045272 in SLE T cells was verified with quantitative PCR. Jurkat cells with stable hsa_circ_0045272 knockdown were generated using specific lentiviral shRNA for functional studies. Flow cytometric analysis indicated that hsa_circ_0045272 knockdown significantly upregulated the early apoptosis of Jurkat cells. Meanwhile, enzyme-linked immunosorbent assay showed that hsa_circ_0045272 knockdown significantly enhanced IL-2 production of activated Jurkat cells. ceRNAs were then predicted for hsa_circ_0045272 and the significant downregulation of two mRNAs predicted as its ceRNAs, NM_003466 (PAX8) and NM_015177 (DTX4), but not their corresponding proteins was validated. Furthermore, dual luciferase reporter assay indicated binding of hsa_circ_0045272 with hsa-miR-6127. circRNAs-mRNAs coexpression networks showed the correlation of circRNAs with mRNAs and provided additional clues to circRNA functions. Our study demonstrated the dysregulated circRNAs in SLE and revealed function of hsa_circ_0045272 in negatively regulating apoptosis and IL-2 secretion and its potential mechanism. The implication of hsa_circ_0045272 and other abnormal circRNAs in SLE merits further investigation. This article is protected by copyright. All rights reserved. This article is

Decreased expression of hsa_circ_0137287 predicts aggressive clinicopathologic characteristics in papillary thyroid carcinoma.

PubMed

Lan, Xiabin; Cao, Jun; Xu, Jiajie; Chen, Chao; Zheng, Chuanming; Wang, Jiafeng; Zhu, Xuhang; Zhu, Xin; Ge, Minghua

2018-05-22

Circular RNA (circRNA) is a new type of noncoding RNA that can serve as ideal biomarkers. Evidence has showed that circRNAs play an important role in carcinogenesis and cancer development. However, little is known about the diagnostic value of circRNAs in papillary thyroid carcinoma (PTC) as well as their associations with clinicopathologic characteristics of patients with PTC. The expression levels of hsa_circ_0137287 were detected in 120 PTC and 60 adjacent noncancerous thyroid tissues by quantitative real-time polymerase chain reaction. The relationships between the expression of hsa_circ_0137287 in PTC and the clinicopathologic factors were analyzed. Finally, receiver operating characteristic (ROC) curves were generated to assess the diagnostic value of hsa_circ_0137287 as a biomarker for PTC. The expression of hsa_circ_0137287 was significantly downregulated in PTC tissues compared with adjacent noncancerous tissues (P < .0001). Downregulation of hsa_circ_0137287 correlated with aggressive clinicopathologic characteristics of PTC such as extrathyroidal extension (P < .001), lymph node metastasis (P = .022), advanced T stage (P < .001) and larger tumor size (P < .001). The ROC curves revealed that hsa_circ_0137287 had a potential diagnostic value in predicting malignancy, extrathyroidal extension and lymph node metastasis. The area under curves were 0.8973 (95% CI = 0.8452-0.9494, P < .0001), 0.6885 (95%CI = 0.5908-0.7862, P = .0009), and 0.6691(95%CI = 0.5641-0.7742, P = .0034), respectively. Our findings suggest that hsa_circ_0137287 may serve as a novel biomarker for PTC. © 2018 Wiley Periodicals, Inc.

Hsa-miR-146a-5p modulates androgen-independent prostate cancer cells apoptosis by targeting ROCK1.

PubMed

Xu, Bin; Huang, Yeqing; Niu, Xiaobing; Tao, Tao; Jiang, Liang; Tong, Na; Chen, Shuqiu; Liu, Ning; Zhu, Weidong; Chen, Ming

2015-12-01

MicroRNAs (miRNAs) have been demonstrated playing important roles in the procession of prostate cancer cells transformation from androgen-dependence to androgen-independence. We conducted the miRNA microarray and realtime PCR analyses in both androgen-dependent (ADPC) and androgen-independent prostate cancer (AIPC) tissues. We also explored the role of hsa-miR-146a-5p (miR-146a) in MSKCC prostate cancer clinical database. Moreover, the impact of miR-146a on prostate cancer cells apoptosis were detected by Hoechst staining and fluorescence-activated cell sorter (FACS). Its target is predicted by DIANA LAB online database and the result was assumed by western blotting and luciferase assay. We demonstrated that miR-146a was down-regulated in AIPC tissues and cell lines compared to that in the ADPC tissues. In MSKCC data re-analyses, we found that miR-146a was underexpressed in metastatic prostate cancer tissues and those with Gleason score >8, moreover, low level of miR-146a represented a high biochemical relapse rate after radical prostatectomy. In the functional analyses, we transfected miR-146a mimics into CPRC cell lines and found miR-146a induced cells apoptosis. In mechanic analyses, we found that miR-146a inhibited the basal level of Rho-associated, coiled-coil containing protein kinase 1 (ROCK1) expression by targeting its 3'UTR and an inverse correlation of expression between miR-146a and ROCK1 was observed. Moreover, caspase 3 activity was stimulated by miR-146a overexpression. miR-146a has a critical role in the process of AIPC prostate cancer cells apoptosis through regulation of ROCK/Caspase 3 pathway. Targeting this pathway may be a promising therapeutic strategy for future personalized anti-cancer treatment. © 2015 Wiley Periodicals, Inc.

Polypharmacotherapy in rheumatology: 1H NMR analysis of binding of phenylbutazone and methotrexate to serum albumin

NASA Astrophysics Data System (ADS)

Maciążek-Jurczyk, M.; Sułkowska, A.; Równicka-Zubik, J.; Bojko, B.; Szkudlarek-Haśnik, A.; Knopik, M.; Sułkowski, W. W.

2011-05-01

The influence of phenylbutazone (Phe) and methotrexate (MTX) on binding of MTX and Phe to human (HSA) and bovine (BSA) serum albumin in the low-affinity binding sites is investigated. The strength and kind of interactions between serum albumin (SA) and drugs used in combination therapy were found using 1H NMR spectroscopy. A stoichiometric molar ratios for Phe-SA and MTX-SA complexes are 36:1 and 31:1, respectively. It appeared these molar ratios are higher for the ternary systems than it were in the binary ones. The presence of the additional drug (MTX or Phe) causes the increase of an affinity of albumin towards Phe and MTX. It was found that the aliphatic groups of MTX are more resistant to the influence of Phe on the MTX-SA complex than the aromatic rings. The results showed the important impact of another drug (MTX or Phe) on the affinity of SA towards Phe and MTX in the low-affinity binding sites. This work is a subsequent part of the spectroscopic study on Phe-MTX-SA interactions (Maciążek-Jurczyk, 2009 [1]).

Determinants for drug survival of methotrexate in patients with psoriasis, split according to different reasons for discontinuation: results of the prospective MTX-CAPTURE.

PubMed

Otero, M E; van den Reek, J M; Seyger, M M; van de Kerkhof, P C; Kievit, W; de Jong, E M

2017-08-01

As methotrexate (MTX) is a widely used treatment for psoriasis, it is important to gain insight into the reasons for the discontinuation of MTX and to understand the determinants for drug survival. To describe 5-year drug survival for MTX in patients with psoriasis, split according to different reasons for discontinuation, and to identify the determinants for drug survival. Data were extracted from a prospective psoriasis registry of patients treated with MTX (MTX-CAPTURE). Drug survival was analysed using Kaplan-Meier estimates and the determinants for discontinuation were analysed using Cox regression analysis. Analyses were split according to the reason for discontinuation: side-effects or ineffectiveness. We included 85 patients treated with MTX, with a maximum treatment duration of 5·2 years. The overall drug survival rates were 63%, 30% and 15% after 1, 3 and 5 years, respectively. The median survival was 1·8 years. Overall, 55 patients (65%) discontinued MTX for the following reasons: side-effects (35%), ineffectiveness (26%), combination of side-effects and ineffectiveness (13%), other reasons (16%) and 11% were lost to follow-up. The most reported side-effects were gastrointestinal symptoms, despite the use of folic acid in 99% of patients. Based on univariate analysis, a high Psoriasis Area and Severity Index score and a high score on the visual analogue scale for disease severity at baseline were possible determinants for a short drug survival. Drug survival of MTX was low with 15% of patients 'on drug' after 5 years. Side-effects alone or in combination with inadequate disease control were more important in the context of treatment discontinuation than inadequate disease control alone. © 2017 British Association of Dermatologists.

The in vitro and in vivo anti-tumor effects of MTX-Fe3O 4-PLLA-PEG-PLLA microspheres prepared by suspension-enhanced dispersion by supercritical CO2.

PubMed

Chen, AiZheng; Dang, TingTing; Wang, ShiBin; Tang, Na; Liu, YuanGang; Wu, WenGuo

2014-07-01

The in vitro and in vivo anti-tumor efficacy of methotrexate-loaded Fe3O4-poly-L-lactide-poly(ethylene glycol)-poly-L-lactide magnetic composite microspheres (MTX-Fe3O4-PLLA-PEG-PLLA MCMs, MMCMs), which were produced by co-precipitation (C) and microencapsulation (M) in a supercritical process, was evaluated at various levels: cellular, molecular, and integrated. The results at the cellular level indicate that MMCMs (M) show a better anti-proliferation activity than raw MTX and could induce morphological changes of cells undergoing apoptosis. At the molecular level, MMCMs (M) lead to a significantly higher relative mRNA expression of bax/bcl-2 and caspase-3 than MMCMs (C) at 10 μg mL(-1) (P<0.01); and the pro-caspase-3 protein expression measured by Western blot analysis also demonstrates that MMCMs (M) can effectively activate pro-caspase-3. At the integrated level, mice bearing a sarcoma-180 tumor are used; in vivo anti-tumor activity tests reveal that MMCMs (M) with magnetic induction display a much higher tumor suppression rate and lower toxicity than raw MTX. Pharmacokinetic studies show that MMCMs (M) with magnetic induction significantly increase the accumulation of MTX in the tumor tissue compared with the other treatments. These results suggest that the MMCMs (M) prepared by the SpEDS process have great potential to play a positive role in the magnetic targeted therapy field.

Methotrexate loading in chitosan nanoparticles at a novel pH: Response surface modeling, optimization and characterization.

PubMed

Hashad, Rania A; Ishak, Rania A H; Geneidi, Ahmed S; Mansour, Samar

2016-10-01

The aim of this study was to assess the feasibility of employing a novel but critical formulation pH (6.2) to encapsulate an anionic model drug (methotrexate, MTX) into chitosan(Cs)-tripolyphosphate nanoparticles(NPs). A response surface methodology using a three-level full factorial design was applied studying the effects of two independent variables namely; Cs concentration and MTX concentration. The responses investigated were the entrapment efficiency (EE%), mean hydrodynamic particle size (PS), polydispersity index (PDI) and zeta potential (ZP). In order to simultaneously optimize the series of models obtained, the desirability function approach was applied with a goal to produce high percent of MTX encapsulated into highly charged Cs-TPP NPs of homogenous optimum PS. MTX-loaded CsNPs were successfully prepared at the novel pH applied. The suggested significant models were found quadratic for EE, PS and ZP responses, while 2-factor interaction model for PDI. The optimization overlay graph showed that the maximum global desirability, D=0.856, was reached when the conditions were set at high Cs and MTX concentration. Thus, the use of such optimized conditions, at this novel pH, achieved a maximum drug EE% (73.38%) into NPs characterized by optimum PS (232.6nm), small PDI value (0.195) and highly surface charged (+18.4mV). Copyright © 2016 Elsevier B.V. All rights reserved.

Detection of hepatocellular carcinoma in transgenic mice by Gd-DTPA- and rhodamine 123-conjugated human serum albumin nanoparticles in T1 magnetic resonance imaging.

PubMed

Watcharin, Waralee; Schmithals, Christian; Pleli, Thomas; Köberle, Verena; Korkusuz, Hüdayi; Hübner, Frank; Waidmann, Oliver; Zeuzem, Stefan; Korf, Horst-Werner; Terfort, Andreas; Gelperina, Svetlana; Vogl, Thomas J; Kreuter, Jörg; Piiper, Albrecht

2015-02-10

Nanoparticle (NP)-based contrast agents that enable high resolution anatomic T1-weighted magnetic resonance imaging (MRI) offer the prospect of improving differential diagnosis of liver tumors such as hepatocellular carcinoma (HCC). In the present study, we investigated the possibility of employing novel non-toxic human serum albumin nanoparticles conjugated with Gd-DTPA and rhodamine 123 (Gd-Rho-HSA-NPs) for the detection of HCC by T1-weighted MRI. In addition, the influence of surface coating of the NPs with poloxamine 908, which alters the absorptive behavior of NPs and changes their distribution between the liver and tumor was examined. MRI of transgenic mice with endogenously formed HCCs following intravenous injection of Gd-Rho-HSA-NPs revealed a strong negative contrast of the tumors. Contrasting of the HCCs by NP-enhanced MRI required less Gd as compared to gadolinium-ethoxybenzyl-diethylenetriaminepentaacetic acid-enhanced MRI, which currently provides the most sensitive detection of HCC in patients. Immunohistochemical analyses revealed that the Gd-Rho-HSA-NPs were localized to macrophages, which were - similar to HCC in patients - fewer in number in HCC as compared to the liver tissue, which is in agreement with the negative contrasting of HCC in Gd-Rho-HSA-NP-enhanced MRI. Poloxamine-coated NPs showed lower accumulation in the tumor macrophages and caused a longer lasting enhancement of the MRI signal. These data indicate that Gd-Rho-HSA-NPs enable sensitive detection of HCC by T1-weighted MRI in mice with endogenous HCC through their uptake by macrophages. Poloxamine coating of the NPs delayed the tumor localization of the NPs. Copyright © 2014 Elsevier B.V. All rights reserved.

Novel morphology change of Au-Methotrexate conjugates: From nanochains to discrete nanoparticles.

PubMed

Wang, Wei-Yuan; Zhao, Xiu-Fen; Ju, Xiao-Han; Wang, Yu; Wang, Lin; Li, Shu-Ping; Li, Xiao-Dong

2016-12-30

A novel morphology change of Au-methotrexate (Au-MTX) conjugates that could transform from nanochains to discrete nanoparticles was achieved by a simple, one-pot, and hydrothermal growth method. Herein, MTX was used efficiently as a complex-forming agent, reducing agent, capping agent, and importantly a targeting anticancer drug. The formation mechanism suggested a similarity with the molecular imprinting technology. The Au-MTX complex induced the MTX molecules to selectively adsorb on different crystal facets of gold nanoparticles (AuNPs) and then formed gold nanospheres. Moreover, the abundantly binding MTX molecules promoted directional alignment of these gold nanospheres to further form nanochains. More interestingly, the linear structures gradually changed into discrete nanoparticles by adding different amount of ethylene diamine tetra (methylene phosphonic acid) (EDTMPA) into the initial reaction solution, which likely arose from the strong electrostatic effect of the negatively charged phosphonic acid groups. Compared with the as-prepared nanochains, the resultant discrete nanoparticles showed almost equal drug loading capacity but with higher drug release control, colloidal stability, and in vitro anticancer activity. Copyright © 2016 Elsevier B.V. All rights reserved.

Combination of UV-vis spectroscopy and chemometrics to understand protein-nanomaterial conjugate: a case study on human serum albumin and gold nanoparticles.

PubMed

Wang, Yong; Ni, Yongnian

2014-02-01

Study of the interactions between proteins and nanomaterials is of great importance for understanding of protein nanoconjugate. In this work, we choose human serum albumin (HSA) and citrate-capped gold nanoparticles (AuNPs) as a model of protein and nanomaterial, and combine UV-vis spectroscopy with multivariate curve resolution by an alternating least squares (MCR-ALS) algorithm to present a new and efficient method for comparatively comprehensive study of evolution of protein nanoconjugate. UV-vis spectroscopy coupled with MCR-ALS allows qualitative and quantitative extraction of the distribution diagrams, spectra and kinetic profiles of absorbing pure species (AuNPs and AuNPs-HSA conjugate are herein identified) and undetectable species (HSA) from spectral data. The response profiles recovered are converted into the desired thermodynamic, kinetic and structural parameters describing the protein nanoconjugate evolution. Analysis of these parameters for the system gives evidence that HSA molecules are very likely to be attached to AuNPs surface predominantly as a flat monolayer to form a stable AuNPs-HSA conjugate with a core-shell structure, and the binding process takes place mainly through electrostatic and hydrogen-bond interactions between the positively amino acid residues of HSA and the negatively carboxyl group of citrate on AuNPs surface. The results obtained are verified by transmission electron microscopy, zeta potential, circular dichroism spectroscopy and Fourier transform infrared spectroscopy, showing the potential of UV-vis spectroscopy for study of evolution of protein nanoconjugate. In parallel, concentration evolutions of pure species resolved by MCR-ALS are used to construct a sensitive spectroscopic biosensor for HSA with a linear range from 1.8 nM to 28.1 nM and a detection limit of 0.8 nM. © 2013 Published by Elsevier B.V.

Reduced expression of circRNA hsa_circ_0003159 in gastric cancer and its clinical significance.

PubMed

Tian, Mengqian; Chen, Ruoyu; Li, Tianwen; Xiao, Bingxiu

2018-03-01

Circular RNAs (circRNAs) play a crucial role in the occurrence of several diseases including cancers. However, little is known about circRNAs' diagnostic values for gastric cancer, one of the worldwide most common diseases of mortality. The hsa_circ_0003159 levels in 108 paired gastric cancer tissues and adjacent non-tumorous tissues from surgical patients with gastric cancer were first detected by real-time quantitative reverse transcription-polymerase chain reaction. Then, the relationships between hsa_circ_0003159 expression levels in gastric cancer tissues and the clinicopathological factors of patients with gastric cancer were analyzed. Finally, its diagnostic value was evaluated through the receiver operating characteristic curve. Compared with paired adjacent non-tumorous tissues, hsa_circ_0003159 expression was significantly down-regulated in gastric cancer tissues. What is more, we found that hsa_circ_0003159 expression levels were significantly negatively associated with gender, distal metastasis, and tumor-node-metastasis stage. All of the results suggest that hsa_circ_0003159 may be a potential cancer marker of patients with gastric cancer. © 2017 Wiley Periodicals, Inc.

Study on the interaction of the epilepsy drug, zonisamide with human serum albumin (HSA) by spectroscopic and molecular docking techniques

NASA Astrophysics Data System (ADS)

Shahabadi, Nahid; Khorshidi, Aref; Moghadam, Neda Hossinpour

2013-10-01

In the present investigation, an attempt has been made to study the interaction of zonisamide (ZNS) with the transport protein, human serum albumin (HSA) employing UV-Vis, fluorometric, circular dichroism (CD) and molecular docking techniques. The results indicated that binding of ZNS to HSA caused strong fluorescence quenching of HSA through static quenching mechanism, hydrogen bonds and van der Waals contacts are the major forces in the stability of protein ZNS complex and the process of the binding of ZNS with HSA was driven by enthalpy (ΔH = -193.442 kJ mol-1). The results of CD and UV-Vis spectroscopy showed that the binding of this drug to HSA induced conformational changes in HSA. Furthermore, the study of molecular docking also indicated that zonisamide could strongly bind to the site I (subdomain IIA) of HSA mainly by hydrophobic interaction and there were hydrogen bond interactions between this drug and HSA, also known as the warfarin binding site.

Methotrexate conjugated magnetic nanoparticle for targeted drug delivery and thermal therapy

NASA Astrophysics Data System (ADS)

Gupta, Jagriti; Bhargava, Parag; Bahadur, D.

2014-05-01

A simple soft chemical approach is used for the preparation of citrate functionalized iron oxide (Fe3O4) aqueous colloidal magnetic nanoparticles (CA-MNPs) of average size ˜10 nm. The CA-MNPs exhibit superparamagnetic behavior at room temperature with strong field dependent magnetic responsivity. The CA-MNPs can be conjugated with Methotrexate (MTX) drug through amide bonds between the carboxylic group on the surface of MNPs and amine group of MTX. The surface functionalization of Fe3O4 nanoparticles with citric acid and conjugation of MTX drug is evident from FTIR spectroscopy, zeta-potential measurement, and elemental and thermal analyses. From the drug release study, it has been observed that this bonding of MTX conjugated MNPs (MTX-MNPs) is cleaved by the intracellular enzymes in lysosome, and MTX is delivered largely inside target cancerous cells at lower pH, thereby reducing toxicity to normal cells. Also, it has been observed that the intercellular uptake of MTX-MNPs is higher compared to CA-MNPs. In addition, the aqueous colloidal stability, optimal magnetization, and good specific absorption rate (under external AC magnetic field) of CA-MNPs act as effective heating source for thermal therapy. Cytotoxicity study of MTX-MNPs shows the reduction of cellular viability for human cervical cancer cells (HeLa). Further, a synergistic effect of MTX-MNPs shows a more effective tumor cell death due to the combined effect of thermo-chemotherapy.

Ceramic core with polymer corona hybrid nanocarrier for the treatment of osteosarcoma with co-delivery of protein and anti-cancer drug

NASA Astrophysics Data System (ADS)

Ram Prasad, S.; Sampath Kumar, T. S.; Jayakrishnan, A.

2018-01-01

For the treatment of metastatic bone cancer, local delivery of therapeutic agents is preferred compared to systemic administration. Delivery of an anti-cancer drug and a protein that helps in bone regeneration simultaneously is a challenging approach. In this study, a nanoparticulate carrier which delivers a protein and an anti-cancer drug is reported. Bovine serum albumin (BSA) as a model protein was loaded into hydroxyapatite (HA) nanoparticles (NPs) and methotrexate (MTX) conjugated to poly(vinyl alcohol) was coated onto BSA-loaded HA NPs. Coating efficiency was in the range of 10-17 wt%. In vitro drug release showed that there was a steady increase in the release of both BSA and MTX with 76% of BSA and 88% of MTX being released in 13 days. Cytotoxicity studies of the NPs performed using human osteosarcoma (OMG-63) cell line showed the NPs were highly biocompatible and exhibited anti-proliferative activity in a concentration-dependent manner.

EphB4 as a therapeutic target in mesothelioma

PubMed Central

2013-01-01

Background Malignant pleural mesothelioma (MPM) often develops decades following exposure to asbestos. Current best therapy produces a response in only half of patients, and the median survival with this therapy remains under a year. A search for novel targets and therapeutics is underway, and recently identified targets include VEGF, Notch, and EphB4-Ephrin-B2. Each of these targets has dual activity, promoting tumor cell growth as well as tumor angiogenesis. Methods We investigated EphB4 expression in 39 human mesothelioma tissues by immunohistochemistry. Xenograft tumors established with human mesothelioma cells were treated with an EphB4 inhibitor (monomeric soluble EphB4 fused to human serum albumin, or sEphB4-HSA). The combinatorial effect of sEphB4-HSA and biologic agent was also studied. Results EphB4 was overexpressed in 72% of mesothelioma tissues evaluated, with 85% of epithelioid and 38% of sarcomatoid subtypes demonstrating overexpression. The EphB4 inhibitor sEphB4-HSA was highly active as a single agent to inhibit tumor growth, accompanied by tumor cell apoptosis and inhibition of PI3K and Src signaling. Combination of sEphB4-HSA and the anti-VEGF antibody (Bevacizumab) was superior to each agent alone and led to complete tumor regression. Conclusion EphB4 is a potential therapeutic target in mesothelioma. Clinical investigation of sEphB4-HSA as a single agent and in combination with VEGF inhibitors is warranted. PMID:23721559

Delayed Wound Healing in Heat Stable Antigen (HSA/CD24)-Deficient Mice.

PubMed

Shapira, Shiran; Ben-Amotz, Oded; Sher, Osnat; Kazanov, Dina; Mashiah, Jacob; Kraus, Sarah; Gur, Eyal; Arber, Nadir

2015-01-01

Healthy individuals rarely have problems with wound healing. Most skin lesions heal rapidly and efficiently within one to two weeks. However, many medical and surgical complications can be attributed to deficiencies in wound repair. Open wounds have lost the barrier that protects tissues from bacterial invasion and allows the escape of vital fluids. Without expeditious healing, infections become more frequent. The CD24 gene encodes a heavily-glycosylated cell surface protein anchored to the membrane by phosphatidylinositol. CD24 plays an important role in the adaptive immune response and controls an important genetic checkpoint for homeostasis and autoimmune diseases in both mice and humans. We have previously shown that overexpression of CD24 results in increased proliferation and migration rates. To examine the role of CD24 in the wound healing process. An excisional model of wound healing was used and delayed wound healing was studied in genetically modified heat stable antigen (HSA/CD24)-deficient mice (HSA-/-) compared to wild-type (WT) mice. Large full-thickness skin wounds, excised on the back of mice, exhibited a significant delay in the formation of granulation tissue, and in wound closure when compared to their WTHSA+/+ littermates. Wounds were histologically analyzed and scored, based on the degree of cellular invasion, granulation tissue formation, vascularity, and re-epithelialization. Additionally, in stitched wounds, the HSA-/- mice failed to maintain their stitches; they did not hold and fell already 24 hours, revealing erythematous wound fields. Re-expression of HSA, delivered by lentivirus, restored the normal healing phenotype, within 24 hours post-injury, and even improved the healing in WT, and in BalbC mice. Delayed wound-healing in the absence of HSA/CD24 suggests that CD24 plays an important role in this process. Increased expression of CD24, even in the normal state, may be used to enhance wound repair.

Fluorometric immunoassay for human serum albumin based on its inhibitory effect on the immunoaggregation of quantum dots with silver nanoparticles

NASA Astrophysics Data System (ADS)

Marukhyan, Seda S.; Gasparyan, Vardan K.

2017-02-01

Quantitative determination of HSA was conducted by competitive immunoassay. Inhibition of aggregation of antibody conjugated quantum dots (QD) with albumin conjugated silver nanoparticles (AgNPs) in the presence of HSA was conducted. If antibody-loaded CdSe QDs aggregate with HSA-coated silver nanoparticles the distance between the two kinds of nanoparticles will be reduced enough to cause fluorescence resonance energy transfer (FRET). In this case the yellow fluorescence of the Ab-QDs is quenched. However if HSA (antigen) is added to the Ab-QDs their surface will be blocked and they cannot aggregate any longer with the HSA-AgNPs. Hence, fluorescence will not be quenched. The drop of the intensity of fluorescence (peaking at 570 nm) is inversely correlated with the concentration of HSA in the sample. The method allows to determine HSA in the 30-600 ng·mL-1 concentration range.

New insight into protein-nanomaterial interactions with UV-visible spectroscopy and chemometrics: human serum albumin and silver nanoparticles.

PubMed

Wang, Yong; Ni, Yongnian

2014-01-21

In recent years, great efforts have focused on the exploration and fabrication of protein nanoconjugates due to potential applications in many fields including bioanalytical science, biosensors, biocatalysis, biofuel cells and bio-based nanodevices. An important aspect of our understanding of protein nanoconjugates is to quantitatively understand how proteins interact with nanomaterials. In this report, human serum albumin (HSA) and citrate-coated silver nanoparticles (AgNPs) are selected as a case study of protein-nanomaterial interactions. UV-visible spectroscopy together with multivariate curve resolution by alternating least squares (MCR-ALS) algorithm is first exploited for the detailed study of AgNPs-HSA interactions. Introduction of the chemometrics tool allows extracting the kinetic profiles, spectra and distribution diagrams of two major absorbing pure species (AgNPs and AgNPs-HSA conjugate). These resolved profiles are then analysed to give the thermodynamic, kinetic and structural information of HSA binding to AgNPs. Transmission electron microscopy, circular dichroism spectroscopy and Fourier transform infrared spectroscopy are used to further characterize the complex system. Moreover, a sensitive spectroscopic biosensor for HSA is fabricated with the MCR-ALS resolved concentration of absorbing pure species. It is found that the linear range for the HSA nanosensor was from 1.9 nM to 45.0 nM with a detection limit of 0.9 nM. It is believed that the proposed method will play an important role in the fabrication and optimization of a robust nanobiosensor or cross-reactive sensors array for the detection and identification of biocomponents.

Smart human serum albumin-indocyanine green nanoparticles generated by programmed assembly for dual-modal imaging-guided cancer synergistic phototherapy.

PubMed

Sheng, Zonghai; Hu, Dehong; Zheng, Mingbin; Zhao, Pengfei; Liu, Huilong; Gao, Duyang; Gong, Ping; Gao, Guanhui; Zhang, Pengfei; Ma, Yifan; Cai, Lintao

2014-12-23

Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is a light-activated local treatment modality that is under intensive preclinical and clinical investigations for cancer. To enhance the treatment efficiency of phototherapy and reduce the light-associated side effects, it is highly desirable to improve drug accumulation and precision guided phototherapy for efficient conversion of the absorbed light energy to reactive oxygen species (ROS) and local hyperthermia. In the present study, a programmed assembly strategy was developed for the preparation of human serum albumin (HSA)-indocyanine green (ICG) nanoparticles (HSA-ICG NPs) by intermolecular disulfide conjugations. This study indicated that HSA-ICG NPs had a high accumulation with tumor-to-normal tissue ratio of 36.12±5.12 at 24 h and a long-term retention with more than 7 days in 4T1 tumor-bearing mice, where the tumor and its margin, normal tissue were clearly identified via ICG-based in vivo near-infrared (NIR) fluorescence and photoacoustic dual-modal imaging and spectrum-resolved technology. Meanwhile, HSA-ICG NPs efficiently induced ROS and local hyperthermia simultaneously for synergetic PDT/PTT treatments under a single NIR laser irradiation. After an intravenous injection of HSA-ICG NPs followed by imaging-guided precision phototherapy (808 nm, 0.8 W/cm2 for 5 min), the tumor was completely suppressed, no tumor recurrence and treatments-induced toxicity were observed. The results suggest that HSA-ICG NPs generated by programmed assembly as smart theranostic nanoplatforms are highly potential for imaging-guided cancer phototherapy with PDT/PTT synergistic effects.

A wireless and sensitive detection of octachlorostyrene using modified AuNPs as signal-amplifying tags.

PubMed

Chen, Lan; Li, Jiezhen; ThanhThuy, T Tran; Zhou, Liping; Huang, Chen'an; Yuan, Lijuan; Cai, Qingyun

2014-02-15

A wireless, remote query octachlorostyrene (OCS) biosensor was fabricated by coating a mass-sensitive magnetoelastic ribbon with anti-OCS antibody. In response to a time-varying magnetic field, the magnetoelastic sensor mechanically vibrates at a characteristic resonance frequency which inversely depends on the sensor mass loading. As the magnetoelastic film is magnetostrictive itself, the vibrations launch magnetic flux that can be remotely detected using a pickup coil. Au nanoparticles (NPs) were used to amplify the mass loading. In a sample solution containing OCS target and OCS-modified AuNPs (OCS-AuNPs), both OCS and OCS-AuNPs react with the anti-OCS antibody immobilized on the sensor surface in a competition mode. The bound OCS-AuNPs amount is inversely proportional to the OCS target concentration. The reduction of bound OCS-AuNPs induced by free OCS results in significant change in mass loading, which amplifies the responses. The biosensor demonstrates a linear shift in resonance frequency with OCS concentration between 7.4 μM and 9 nM, with a detection limit of 2.8 nM. © 2013 Published by Elsevier B.V.

Production and characterization of monoclonal antibodies (mAbs) against human serum albumin (HSA) for the development of an immunoaffinity system with oriented anti-HSA mAbs as immobilized ligand.

PubMed

Rajak, Poonam; Vijayalakshmi, M A; Jayaprakash, N S

2013-05-05

Proteins present in human serum are of immense importance in the field of biomarker discovery. But, the presence of high-abundant proteins like albumin makes the analysis more challenging because of masking effect on low-abundant proteins. Therefore, removal of albumin using highly specific monoclonal antibodies (mAbs) can potentiate the discovery of low-abundant proteins. In the present study, mAbs against human serum albumin (HSA) were developed and integrated in to an immunoaffinity based system for specific removal of albumin from the serum. Hybridomas were obtained by fusion of Sp2/0 mouse myeloma cells with spleen cells from the mouse immunized with HSA. Five clones (AHSA1-5) producing mAbs specific to HSA were established and characterized by enzyme linked immunosorbent assay (ELISA) and immunoblotting for specificity, sensitivity and affinity in terms of antigen binding. The mAbs were able to bind to both native albumin as well as its glycated isoform. Reactivity of mAbs with different mammalian sera was tested. The affinity constant of the mAbs ranged from 10(8) to 10(9)M(-1). An approach based on oriented immobilization was followed to immobilize purified anti-HSA mAbs on hydrazine activated agarose gel and the dynamic binding capacity of the column was determined. Copyright © 2013 Elsevier B.V. All rights reserved.

Circular RNA hsa_circ_0003575 regulates oxLDL induced vascular endothelial cells proliferation and angiogenesis.

PubMed

Li, Chen-Ye; Ma, Lan; Yu, Bo

2017-11-01

Circular RNAs (circRNAs) are a novel class of RNAs generated from back-splicing and characterized by covalently closed continuous loops. Recently, circRNAs have recently shown large regulation on cardiovascular system, including atherosclerosis. The present study aims to investigate the circRNA expression profile and identify their roles on vascular endothelial cells induced by oxLDL. Human circRNA microarray analysis revealed that total 943 differently expressed circRNAs were screened with 2 fold change. Hsa_circ_0003575 was validated to be significantly up-regulated in oxLDL induced HUVECs. Loss-of-function experiments indicated that hsa_circ_0003575 silencing promoted the proliferation and angiogenesis ability of HUVECs. Bioinformatics online programs predicted the potential circRNA-miRNA-mRNA network for hsa_circ_0003575. In summary, circRNA microarray analysis reveals the expression profiles of HUVECs and verifies the role of hsa_circ_0003575 on HUVECs, providing a therapeutic strategy for vascular endothelial cell injury of atherosclerosis. Copyright © 2017. Published by Elsevier Masson SAS.

Overexpression of hsa-miR-125a-5p enhances proliferation, migration and invasion of head and neck squamous cell carcinoma cell lines by upregulating C-C chemokine receptor type 7.

PubMed

Jin, Shan; Liu, Min-Da; Wu, Hong; Pang, Pai; Wang, Song; Li, Zhen-Ning; Sun, Chang-Fu; Liu, Fa-Yu

2018-06-01

Head and neck squamous cell carcinoma (HNSCC) is usually diagnosed accompanied by lymph node metastasis. C-C chemokine receptor type 7 (CCR7) is associated with the invasion and metastasis of tumors in HNSCC through various signaling pathways. The role of hsa-miR-125a-5p in HNSCC remains unclear. The present study was performed to investigate the association between hsa-miR-125a-5p and CCR7 in HNSCC. Reverse transcription-quantitative polymerase chain reaction was applied to analyze the expression of hsa-miR-125a-5p in clinical samples. Cell Counting Kit-8, Transwell and wound healing assays were used to detect cell proliferation, invasion, and metastasis, respectively, following overexpression of hsa-miR-125a-5p. Changes in protein expression of CCR7 were observed using western blotting. In the survival analysis, Student's t-tests and log rank tests were performed to analyze the association between the expression of hsa-miR-125a-5p, and HNSCC according to the Cancer Genome Atlas database. The expression of hsa-miR-125a-5p was identified to be significantly lower in cancer tissue compared with the corresponding adjacent normal tissues in clinical samples (P=0.038). The results of western blotting indicated that there was a positive regulatory association between hsa-miR-125a-5p and CCR7. Furthermore, overexpression of hsa-miR-125a-5p significantly enhanced the ability of cell proliferation, migration and invasion in HNSCC, with upregulation of CCR7. The results of survival analysis revealed that patients in the low expression group of hsa-miR-125a-5p tended to have longer survival times compared with the high expression group (P=0.045). Altogether, the data raised the possibility that hsa-miR-125a-5p has a significant role in promoting cancer in HNSCC, which may provide a basis for the treatment of HNSCC in molecular targeted therapy. Further studies are required to ascertain the role of hsa-miR-125a-5p in other HNSCC cell lines and in vivo .

Immunogencity of HSA-L7/L12 (Brucella abortus ribosomal protein) in an animal model.

PubMed

Pakzad, Iraj; Rezaee, Abbas; Rasaee, Mohammad Javad; Tabbaraee, Bahman; Delpisheh, Ali

2009-03-01

The immunogenic Brucella abortus ribosomal protein L7/L12 is a promising candidate antigen for the development of subunit vaccines against brucellosis. This study was aimed to evaluate the protection of recombinant Human Serum Albumin (HAS)-L7/L12 fusion protein in Balb/c mice. The amplified L7/L12 gene was cloned in pYHSA5 vector, pYHSA5-L7/L12 construct was transformed in Saccharomyces cerevisiae and the expressed protein from supernatant was purified by affinity chromatography. Balb/c mice were immunized in five groups by tHSA-L7/L12 fusion protein (group 1), Brucella abortus S19 (group 2), HSA (group 3), recombinant L7/L12 (group 4), PBS (group 5). ELISA to detect antibody production, LTT test to assess antigen specific lymphocyte response were conducted prior to virulent B. abortus strain 544 challenge two weeks after the last injection. Bacterial counts from spleens of immunized mice were done four weeks after challenge. In ELISA tests, the specific antibodies exhibited a dominance of immunoglobulin IgG1 over IgG2a. In addition, the tHSA-L7/L12 fusion protein and L7/L12 elicited a strong T-cell proliferative response upon restimulation in vitro with recombinant tHSA-L7/L12 and L7/L12, suggesting the induction of a cellular immunity response in vivo. However, there was no significant difference in proliferative response of L7/L12 and tHSA-L7/L12 fusion protein (p>0.05). The L7/L12 and tHSA-L7/L12 fusion protein vaccines could also induce significant protection against challenge with the virulent strain B. abortus 544 in Balb/c mice (p< or =0.05). The tHSA-L7/L12 fusion protein, similar to L7/L12 has the ability to induce antigen specific lymphocyte proliferation, stimulate humoral immunity and engender protection.

Immunohistochemical detection of a potential molecular therapeutic target for canine hemangiosarcoma

PubMed Central

ADACHI, Mami; HOSHINO, Yuki; IZUMI, Yusuke; TAKAGI, Satoshi

2015-01-01

Canine hemangiosarcoma (HSA) is a progressive malignant neoplasm of dogs for which there is currently no effective treatment. A recent study suggested that receptor tyrosine kinases (RTKs), the PI3K/Akt/m-TOR and MAPK pathways are all activated in canine and human HSA. The aim of the present study was to investigate the overexpression of these proteins by immunohistochemistry in canine splenic HSA to identify potential molecular therapeutic targets. A total of 10 splenic HSAs and two normal splenic samples surgically resected from dogs were sectioned and stained with hematoxylin and eosin for histological diagnosis or analyzed using immunohistochemistry. The expression of RTKs, c-kit, VEGFR-2 and PDGFR-2, as well as PI3K/Akt/m-TOR and MEK was higher in canine splenic HSAs compared to normal spleens. These proteins may therefore be potential therapeutic targets in canine splenic HSA. PMID:26685984

Immunohistochemical detection of a potential molecular therapeutic target for canine hemangiosarcoma.

PubMed

Adachi, Mami; Hoshino, Yuki; Izumi, Yusuke; Takagi, Satoshi

2016-05-03

Canine hemangiosarcoma (HSA) is a progressive malignant neoplasm of dogs for which there is currently no effective treatment. A recent study suggested that receptor tyrosine kinases (RTKs), the PI3K/Akt/m-TOR and MAPK pathways are all activated in canine and human HSA. The aim of the present study was to investigate the overexpression of these proteins by immunohistochemistry in canine splenic HSA to identify potential molecular therapeutic targets. A total of 10 splenic HSAs and two normal splenic samples surgically resected from dogs were sectioned and stained with hematoxylin and eosin for histological diagnosis or analyzed using immunohistochemistry. The expression of RTKs, c-kit, VEGFR-2 and PDGFR-2, as well as PI3K/Akt/m-TOR and MEK was higher in canine splenic HSAs compared to normal spleens. These proteins may therefore be potential therapeutic targets in canine splenic HSA.

Circular RNA hsa_circ_0001564 regulates osteosarcoma proliferation and apoptosis by acting miRNA sponge.

PubMed

Song, Yu-Ze; Li, Ji-Feng

2018-01-15

Circular RNAs (circRNAs) is a novel type of non-coding RNAs generated from back splicing, which has been verified to mediate multiple tumorigenesis. However, the role of circRNA in osteosarcoma is still unclear. In the present study, we preliminarily screened the circRNAs expression profiles in osteosarcoma and investigated the potential regulation mechanism. The circRNAs expression profiles in osteosarcoma were screened using circRNA microarray analysis, and results showed that there were 1152 circRNAs up-regulated and 915 circRNAs down-regulated in tumor tissue compared to adjacent tissue. Hsa_circ_0001564, located at 5q35.3 and its associated-gene symbol is CANX, was one of the significantly overexpressed circRNAs in osteosarcoma tissue, as well as in osteosarcoma cell lines. In functional experiments, hsa_circ_001564 knockdown significantly suppressed the proliferation activity, induced cell cycle arrest in G0/G1 phase, and promoted apoptosis in HOS and MG-63 cells. Subsequently, we explored the probable mechanism of hsa_circ_001564, and fortunately, bioinformatics analysis revealed that miR-29c-3p contained the complementary binding region with hsa_circ_0001564, which was confirmed by dual-luciferase reporter assay. Moreover, rescue experiments illustrated that miR-29c-3p could reverse the oncogenesis effect of hsa_circ_001564. Our study discovers that hsa_circ_0001564 acts as miR-29c-3p sponge to mediate the tumorigenicity, which could act as a potential biomarker for the osteosarcoma and provide a novel insight for competing endogenous RNAs (ceRNAs) mechanism in osteosarcoma. Copyright © 2017 Elsevier Inc. All rights reserved.

Interplay between Heat Shock Proteins HSP101 and HSA32 Prolongs Heat Acclimation Memory Posttranscriptionally in Arabidopsis1[W][OA

PubMed Central

Wu, Ting-ying; Juan, Yu-ting; Hsu, Yang-hsin; Wu, Sze-hsien; Liao, Hsiu-ting; Fung, Raymond W.M.; Charng, Yee-yung

2013-01-01

Heat acclimation improves the tolerance of organisms to severe heat stress. Our previous work showed that in Arabidopsis (Arabidopsis thaliana), the “memory” of heat acclimation treatment decayed faster in the absence of the heat-stress-associated 32-kD protein HSA32, a heat-induced protein predominantly found in plants. The HSA32 null mutant attains normal short-term acquired thermotolerance but is defective in long-term acquired thermotolerance. To further explore this phenomenon, we isolated Arabidopsis defective in long-term acquired thermotolerance (dlt) mutants using a forward genetic screen. Two recessive missense alleles, dlt1-1 and dlt1-2, encode the molecular chaperone heat shock protein101 (HSP101). Results of immunoblot analyses suggest that HSP101 enhances the translation of HSA32 during recovery after heat treatment, and in turn, HSA32 retards the decay of HSP101. The dlt1-1 mutation has little effect on HSP101 chaperone activity and thermotolerance function but compromises the regulation of HSA32. In contrast, dlt1-2 impairs the chaperone activity and thermotolerance function of HSP101 but not the regulation of HSA32. These results suggest that HSP101 has a dual function, which could be decoupled by the mutations. Pulse-chase analysis showed that HSP101 degraded faster in the absence of HSA32. The autophagic proteolysis inhibitor E-64d, but not the proteasome inhibitor MG132, inhibited the degradation of HSP101. Ectopic expression of HSA32 confirmed its effect on the decay of HSP101 at the posttranscriptional level and showed that HSA32 was not sufficient to confer long-term acquired thermotolerance when the HSP101 level was low. Taken together, we propose that a positive feedback loop between HSP101 and HSA32 at the protein level is a novel mechanism for prolonging the memory of heat acclimation. PMID:23439916

The Dynamic Environment of Crypto Markets: The Lifespan of New Psychoactive Substances (NPS) and Vendors Selling NPS

PubMed Central

Wadsworth, Elle; Drummond, Colin; Deluca, Paolo

2018-01-01

The Internet has played a major role in the distribution of New Psychoactive Substances (NPS), and crypto markets are increasingly used for the anonymous sale of drugs, including NPS. This study explores the availability of individual NPS and vendors on the crypto markets and considers whether crypto markets are a reliable platform for the sale of NPS. Data was collected from 22 crypto markets that were accessed through the hidden web using the Onion Router (Tor). Data collection took place bimonthly from October 2015 to October 2016 as part of the CASSANDRA (Computer Assisted Solutions for Studying the Availability aNd DistRibution of novel psychoActive substances) project. In seven snapshots over 12 months, 808 unique vendors were found selling 256 unique NPS. The total number of individual NPS and vendors increased across the data collection period (increase of 93.6% and 71.6%, respectively). Only 24% (n = 61) of the total number of NPS and 4% (n = 31) of vendors appeared in every snapshot over the 12 months, whereas 21% (n = 54) of NPS and 45% (n = 365) of vendors only appeared once throughout the data collection. The individual NPS and vendors did not remain the same over the 12 months. However, the availability of NPS and vendors selling NPS grew. NPS consistently available on crypto markets could indicate popular substances. PMID:29547520

Biotin/Folate-decorated Human Serum Albumin Nanoparticles of Docetaxel: Comparison of Chemically Conjugated Nanostructures and Physically Loaded Nanoparticles for Targeting of Breast Cancer.

PubMed

Nateghian, Navid; Goodarzi, Navid; Amini, Mohsen; Atyabi, Fatemeh; Khorramizadeh, Mohammad Reza; Dinarvand, Rassoul

2016-01-01

Docetaxel (DTX) is a widely used chemotherapeutic agent with very low water solubility. Conjugation of DTX to human serum albumin (HSA) is an effective way to increase its water solubility. Attachment of folic acid (FA) or biotin as targeting moieties to DTX-HSA conjugates may lead to active targeting and specific uptake by cancer cells with overexpressed FA or biotin receptors. In this study, FA or biotin molecules were attached to DTX-HSA conjugates by two different methods. In one method, FA or biotin molecules were attached to remaining NH2 residues of HSA in DTX-HSA conjugate by covalent bonds. In the second method, HSA-FA or HSA-biotin conjugates were synthesized separately and then combined by DTX-HSA conjugate in proper ratio to prepare nanoparticles containing DTX-HSA plus HSA-FA or HSA-biotin. Cell viability of different nanoparticle was evaluated on MDA-MB-231 (folate receptor positive), A549 (folate receptor negative), and 4T1 (biotin receptor positive) and showed superior cytotoxicity compared with free docetaxel (Taxotere). In vivo studies of DTX-HSA-FA and DTX-HSA-biotin conjugates in BULB/c mice, tumorized by 4T1 cell line, showed the conjugates prepared in this study were more powerful in the reduction in tumor size and increasing the survival rate when compared to free docetaxel. © 2015 John Wiley & Sons A/S.

Delayed Wound Healing in Heat Stable Antigen (HSA/CD24)-Deficient Mice

PubMed Central

Shapira, Shiran; Ben-Amotz, Oded; Sher, Osnat; Kazanov, Dina; Mashiah, Jacob; Kraus, Sarah; Gur, Eyal; Arber, Nadir

2015-01-01

Background Healthy individuals rarely have problems with wound healing. Most skin lesions heal rapidly and efficiently within one to two weeks. However, many medical and surgical complications can be attributed to deficiencies in wound repair. Open wounds have lost the barrier that protects tissues from bacterial invasion and allows the escape of vital fluids. Without expeditious healing, infections become more frequent. The CD24 gene encodes a heavily-glycosylated cell surface protein anchored to the membrane by phosphatidylinositol. CD24 plays an important role in the adaptive immune response and controls an important genetic checkpoint for homeostasis and autoimmune diseases in both mice and humans. We have previously shown that overexpression of CD24 results in increased proliferation and migration rates. Aim To examine the role of CD24 in the wound healing process. Methods An excisional model of wound healing was used and delayed wound healing was studied in genetically modified heat stable antigen (HSA/CD24)-deficient mice (HSA -/-) compared to wild-type (WT) mice. Results Large full-thickness skin wounds, excised on the back of mice, exhibited a significant delay in the formation of granulation tissue, and in wound closure when compared to their WTHSA +/+ littermates. Wounds were histologically analyzed and scored, based on the degree of cellular invasion, granulation tissue formation, vascularity, and re-epithelialization. Additionally, in stitched wounds, the HSA -/- mice failed to maintain their stitches; they did not hold and fell already 24 hours, revealing erythematous wound fields. Re-expression of HSA, delivered by lentivirus, restored the normal healing phenotype, within 24 hours post-injury, and even improved the healing in WT, and in BalbC mice. Conclusions Delayed wound-healing in the absence of HSA/CD24 suggests that CD24 plays an important role in this process. Increased expression of CD24, even in the normal state, may be used to enhance wound

PEGylated human serum albumin (HSA) nanoparticles: preparation, characterization and quantification of the PEGylation extent

NASA Astrophysics Data System (ADS)

Fahrländer, E.; Schelhaas, S.; Jacobs, A. H.; Langer, K.

2015-04-01

Modification with poly(ethylene glycol) (PEG) is a widely used method for the prolongation of plasma half-life of colloidal carrier systems such as nanoparticles prepared from human serum albumin (HSA). However, the quantification of the PEGylation extent is still challenging. Moreover, the influence of different PEG derivatives, which are commonly used for nanoparticle conjugation, has not been investigated so far. The objective of the present study is to develop a method for the quantification of PEG and to monitor the influence of diverse PEG reagents on the amount of PEG linked to the surface of HSA nanoparticles. A size exclusion chromatography method with refractive index detection was established which enabled the quantification of unreacted PEG in the supernatant. The achieved results were confirmed using a fluorescent PEG derivative, which was detected by photometry and fluorimetry. Additionally, PEGylated HSA nanoparticles were enzymatically digested and the linked amount of fluorescently active PEG was directly determined. All the analytical methods confirmed that under optimized PEGylation conditions a PEGylation efficiency of up to 0.5 mg PEG per mg nanoparticle could be achieved. Model calculations made a ‘brush’ conformation of the PEG chains on the particle surface very likely. By incubating the nanoparticles with fetal bovine serum the reduced adsorption of serum proteins on PEGylated HSA nanoparticles compared to non-PEGylated HSA nanoparticles was demonstrated using sodium dodecylsulfate polyacrylamide gel electrophoresis. Finally, the positive effect of PEGylation on plasma half-life was demonstrated in an in vivo study in mice. Compared to unmodified nanoparticles the PEGylation led to a four times larger plasma half-life.

Green synthesis of biogenic silver nanoparticles using Solanum tuberosum extract and their interaction with human serum albumin: Evidence of "corona" formation through a multi-spectroscopic and molecular docking analysis.

PubMed

Ali, Mohd Sajid; Altaf, Mohammad; Al-Lohedan, Hamad A

2017-08-01

Biogenic silver nanoparticles (AgNPs) have been synthesized by using Solanum tuberosum (potato) extract (PE) as a reducing as well as stabilizing agent which is reasonably cheaper, non-toxic and easily available material. The green synthesis of silver nanoparticles has been carried out by very simple method and the nanoparticles were characterized by surface plasmon band as well as TEM measurements. The PE-AgNPs were highly dispersed in the solution and found to be spherical with around 10nm in size. Interaction of these nanoparticles was studied with plasma protein HSA by means of various spectroscopies, such as, UV-visible, fluorescence, DLS, CD and FTIR spectroscopies. The HSA was found to form the protein "corona" around the starch-capped PE-AgNPs. Absorption spectroscopy revealed that the interaction between HSA and PE-AgNPs resulted in the ground state complex formation. Due to the strong absorption of PE-AgNPs, the inner filter effect was corrected for the fluorescence data. PE-AgNPs were found to quench the fluorescence of HSA with a small blue shift attributed to the increase in the hydrophobicity near tryptophan residue due to the presence of amylopectin and amylose units in the starch. The value of n, Hill's constant, was found to be >1 which determines the existence of a cooperative binding between nanoparticle and albumin. Several parameters such as Stern-Volmer and binding constants in addition to the thermodynamic parameters have been analyzed and discussed which established that the complex formation has taken place via static quenching mechanism and the corona formation between albumin and PE-AgNPs was entropy driven process. Binding of biogenic PE-AgNPs to the HSA slightly affected the secondary structure of latter with a small decrease in α-helical contents resulting in the partial unfolding of the protein, though the structural motif remained the same. Molecular docking simulations revealed various possible binding modes between PE-AgNPs and

Real time imaging and infrared background scene analysis using the Naval Postgraduate School infrared search and target designation (NPS-IRSTD) system

NASA Astrophysics Data System (ADS)

Bernier, Jean D.

1991-09-01

The imaging in real time of infrared background scenes with the Naval Postgraduate School Infrared Search and Target Designation (NPS-IRSTD) System was achieved through extensive software developments in protected mode assembly language on an Intel 80386 33 MHz computer. The new software processes the 512 by 480 pixel images directly in the extended memory area of the computer where the DT-2861 frame grabber memory buffers are mapped. Direct interfacing, through a JDR-PR10 prototype card, between the frame grabber and the host computer AT bus enables each load of the frame grabber memory buffers to be effected under software control. The protected mode assembly language program can refresh the display of a six degree pseudo-color sector in the scanner rotation within the two second period of the scanner. A study of the imaging properties of the NPS-IRSTD is presented with preliminary work on image analysis and contrast enhancement of infrared background scenes.

The Dynamic Environment of Crypto Markets: The Lifespan of New Psychoactive Substances (NPS) and Vendors Selling NPS.

PubMed

Wadsworth, Elle; Drummond, Colin; Deluca, Paolo

2018-03-16

The Internet has played a major role in the distribution of New Psychoactive Substances (NPS), and crypto markets are increasingly used for the anonymous sale of drugs, including NPS. This study explores the availability of individual NPS and vendors on the crypto markets and considers whether crypto markets are a reliable platform for the sale of NPS. Data was collected from 22 crypto markets that were accessed through the hidden web using the Onion Router (Tor). Data collection took place bimonthly from October 2015 to October 2016 as part of the CASSANDRA ( C omputer A ssisted S olutions for S tudying the A vailability a N d D ist R ibution of novel psycho A ctive substances) project. In seven snapshots over 12 months, 808 unique vendors were found selling 256 unique NPS. The total number of individual NPS and vendors increased across the data collection period (increase of 93.6% and 71.6%, respectively). Only 24% ( n = 61) of the total number of NPS and 4% ( n = 31) of vendors appeared in every snapshot over the 12 months, whereas 21% ( n = 54) of NPS and 45% ( n = 365) of vendors only appeared once throughout the data collection. The individual NPS and vendors did not remain the same over the 12 months. However, the availability of NPS and vendors selling NPS grew. NPS consistently available on crypto markets could indicate popular substances.

A perspective of mitochondrial dysfunction in rats treated with silver and titanium nanoparticles (AgNPs and TiNPs).

PubMed

Pereira, Lilian Cristina; Pazin, Murilo; Franco-Bernardes, Mariana Furio; Martins, Airton da Cunha; Barcelos, Gustavo Rafael Mazzaron; Pereira, Márcio Cesar; Mesquita, João Paulo; Rodrigues, Jairo Lisboa; Barbosa, Fernando; Dorta, Daniel Junqueira

2018-05-01

Nanotechnology is a growing branch of science that deals with the development of structural features bearing at least one dimension in the nano range. More specifically, nanomaterials are defined as objects with dimensions that range from 1 to 100 nm, which give rise to interesting properties. In particular, silver and titanium nanoparticles (AgNPs and TiNPs, respectively) are known for their biological and biomedical properties and are often used in consumer products such as cosmetics, food additives, kitchen utensils, and toys. This situation has increased environmental and occupational exposure to AgNPs and TiNPs, which has placed demand for the risk assessment of NPs. Indeed, the same properties that make nanomaterials so attractive could also prove deleterious to biological systems. Of particular concern is the effect of NPs on mitochondria because these organelles play an essential role in cellular homeostasis. In this scenario, this work aimed to study how AgNPs and TiNPs interact with the mitochondrial respiration chain and to analyze how this interaction interferes in the bioenergetics and oxidative state of the organelles after sub-chronic exposure. Mitochondria were exposed to the NPs by gavage treatment for 21 days to check whether co-exposure of the organelles to the two types of NPs elicited any mitochondrion-NP interaction. More specifically, male Wistar rats were randomly assigned to four groups. Groups I, II, III, and IV received mineral oil, TiNPs (100 μg/kg/day), AgNPs (100 μg/kg/day), and TiNPs + AgNPs (100 μg/kg/day), respectively, by gavage. The liver was immediately removed, and the mitochondria were isolated and used within 3 h. Exposure of mitochondria to TiNPs + AgNPs lowered the respiratory control ratio, causing an uncoupling effect in the oxidative phosphorylation system. Moreover, both types of NPs induced mitochondrial swelling. Extended exposure of mitochondria to the NPs maintained increased ROS levels and

Role of Au(NPs) in the enhanced response of Au(NPs)-decorated MWCNT electrochemical biosensor

PubMed Central

Mehmood, Shahid; Ciancio, Regina; Carlino, Elvio; Bhatti, Arshad S

2018-01-01

Background The combination of Au-metallic-NPs and CNTs are a new class of hybrid nanomaterials for the development of electrochemical biosensor. Concentration of Au(nanoparticles [NPs]) in the electrochemical biosensor is crucial for the efficient charge transfer between the Au-NPs-MWCNTs modified electrode and electrolytic solution. Methods In this work, the charge transfer kinetics in the glassy carbon electrode (GCE) modified with Au(NPs)–multiwalled carbon nanotube (MWCNT) nanohybrid with varied concentrations of Au(NPs) in the range 40–100 nM was studied using electrochemical impedance spectroscopy (EIS). Field emission scanning electron microscopy and transmission electron microscopy confirmed the attachment of Au(NPs) on the surface of MWCNTs. Results The cyclic voltammetry and EIS results showed that the charge transfer mechanism was diffusion controlled and the rate of charge transfer was dependent on the concentration of Au(NPs) in the nanohybrid. The formation of spherical diffusion zone, which was dependent on the concentration of Au(NPs) in nanohybrids, was attributed to result in 3 times the increase in the charge transfer rate ks, 5 times increase in mass transfer, and 5% (9%) increase in Ipa (Ipc) observed in cyclic voltammetry in 80 nM Au(NP) nanohybrid-modified GCE from MWCNT-modified GCE. The work was extended to probe the effect of charge transfer rates at various concentrations of Au(NPs) in the nanohybrid-modified electrodes in the presence of Escherichia coli. The cyclic voltammetry results clearly showed the best results for 80 nM Au(NPs) in nanohybrid electrode. Conclusion The present study suggested that the formation of spherical diffusion zone in nanohybrid-modified electrodes is critical for the enhanced electrochemical biosensing applications. PMID:29713161

Bypassing Protein Corona Issue on Active Targeting: Zwitterionic Coatings Dictate Specific Interactions of Targeting Moieties and Cell Receptors.

PubMed

Safavi-Sohi, Reihaneh; Maghari, Shokoofeh; Raoufi, Mohammad; Jalali, Seyed Amir; Hajipour, Mohammad J; Ghassempour, Alireza; Mahmoudi, Morteza

2016-09-07

Surface functionalization strategies for targeting nanoparticles (NP) to specific organs, cells, or organelles, is the foundation for new applications of nanomedicine to drug delivery and biomedical imaging. Interaction of NPs with biological media leads to the formation of a biomolecular layer at the surface of NPs so-called as "protein corona". This corona layer can shield active molecules at the surface of NPs and cause mistargeting or unintended scavenging by the liver, kidney, or spleen. To overcome this corona issue, we have designed biotin-cysteine conjugated silica NPs (biotin was employed as a targeting molecule and cysteine was used as a zwitterionic ligand) to inhibit corona-induced mistargeting and thus significantly enhance the active targeting capability of NPs in complex biological media. To probe the targeting yield of our engineered NPs, we employed both modified silicon wafer substrates with streptavidin (i.e., biotin receptor) to simulate a target and a cell-based model platform using tumor cell lines that overexpress biotin receptors. In both cases, after incubation with human plasma (thus forming a protein corona), cellular uptake/substrate attachment of the targeted NPs with zwitterionic coatings were significantly higher than the same NPs without zwitterionic coating. Our results demonstrated that NPs with a zwitterionic surface can considerably facilitate targeting yield of NPs and provide a promising new type of nanocarriers in biological applications.

Senescence-associated microRNAs target cell cycle regulatory genes in normal human lung fibroblasts.

PubMed

Markopoulos, Georgios S; Roupakia, Eugenia; Tokamani, Maria; Vartholomatos, George; Tzavaras, Theodore; Hatziapostolou, Maria; Fackelmayer, Frank O; Sandaltzopoulos, Raphael; Polytarchou, Christos; Kolettas, Evangelos

2017-10-01

Senescence recapitulates the ageing process at the cell level. A senescent cell stops dividing and exits the cell cycle. MicroRNAs (miRNAs) acting as master regulators of transcription, have been implicated in senescence. In the current study we investigated and compared the expression of miRNAs in young versus senescent human fibroblasts (HDFs), and analysed the role of mRNAs expressed in replicative senescent HFL-1 HDFs. Cell cycle analysis confirmed that HDFs accumulated in G 1 /S cell cycle phase. Nanostring analysis of isolated miRNAs from young and senescent HFL-1 showed that a distinct set of 15 miRNAs were significantly up-regulated in senescent cells including hsa-let-7d-5p, hsa-let-7e-5p, hsa-miR-23a-3p, hsa-miR-34a-5p, hsa-miR-122-5p, hsa-miR-125a-3p, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-181a-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-503-5p, hsa-miR-574-3p, hsa-miR-574-5p and hsa-miR-4454. Importantly, pathway analysis of miRNA target genes down-regulated during replicative senescence in a public RNA-seq data set revealed a significant high number of genes regulating cell cycle progression, both G 1 /S and G 2 /M cell cycle phase transitions and telomere maintenance. The reduced expression of selected miRNA targets, upon replicative and oxidative-stress induced senescence, such as the cell cycle effectors E2F1, CcnE, Cdc6, CcnB1 and Cdc25C was verified at the protein and/or RNA levels. Induction of G1/S cell cycle phase arrest and down-regulation of cell cycle effectors correlated with the up-regulation of miR-221 upon both replicative and oxidative stress-induced senescence. Transient expression of miR-221/222 in HDFs promoted the accumulation of HDFs in G1/S cell cycle phase. We propose that miRNAs up-regulated during replicative senescence may act in concert to induce cell cycle phase arrest and telomere erosion, establishing a senescent phenotype. Copyright © 2017 Elsevier Inc. All rights reserved.

A theoretical elucidation of glucose interaction with HSA's domains.

PubMed

Nasiri, Rasoul; Bahrami, Homayoon; Zahedi, Mansour; Moosavi-Movahedi, Ali Akbar; Sattarahmady, Naghmeh

2010-10-01

The interaction of different domains belonging to Human Serum Albumin (HSA) with open form of glucose have been investigated using molecular dynamics simulation methods. Applying docking, primary structures involving interaction of some residues with glucose have been obtained. Subsequently, equilibrium geometries at 300 K and minimum geometries have been determined for each of aforementioned structures by employing MD simulation and simulated annealing. The stability of species has been evaluated using a SAWSA v2.0 model. Ultimately, NBO analysis has been carried out to specify possible hydrogen bonding regarding the HSA interaction with glucose. Results obtained show that glucose can interact with Lys195, Lys199, and Glu153. In these interactions, each lysine forms an H-bonding with glucose. The H-bonding is obtained by stretching of N-H bond belonging to NH(3)(+) group of lysine along an oxygen atom of glucose. In addition, the above mentioned lysines are protonated, and there is an electrostatic interaction between glucose with Lys195 or Lys199. In addition, an H-bonding is formed between O atom of -COO group belonging to Glu153 and H atom of OH group belonging to glucose. Because, the N-H group of Lys195 interacts with the O atom of latter OH group, reaction of Lys195 is more desirable than that of Lys199. In fact, glucose is placed in the vicinity of Lys195 along with electrostatic interaction and H-bonding to Lys195 and Lys199 as well as H-bonding with Glu153, which subsequently reacts with Lys195. Thus, Lys195 is the primary site in reaction of glucose with HSA.

The effect of initial pressure on growth of FeNPs in amorphous carbon films

NASA Astrophysics Data System (ADS)

Mashayekhi, Fatemeh; Shafiekhani, Azizollah; Sebt, S. Ali; Darabi, Elham

2018-04-01

Iron nanoparticles in amorphous hydrogenated carbon films (FeNPs@a-C:H) were prepared with RF-sputtering and RFPECVD methods by acetylene gas and Fe target. In this paper, deposition and sputtering process were carried out under influence of different initial pressure gas. The morphology and roughness of surface of samples were studied by AFM technique and also TEM images show the exact size of FeNPs and encapsulated FeNPs@a-C:H. The localized surface plasmon resonance peak (LSPR) of FeNPs was studied using UV-vis absorption spectrum. The results show that the intensity and position of LSPR peak are increased by increasing initial pressure. Also, direct energy gap of samples obtained by Tauc law is decreased with respect to increasing initial pressure.

Using circular RNA hsa_circ_0000190 as a new biomarker in the diagnosis of gastric cancer.

PubMed

Chen, Shijun; Li, Tianwen; Zhao, Qianfu; Xiao, Bingxiu; Guo, Junming

2017-03-01

Circular RNAs (circRNA) are an abundant class of non-coding RNAs in mammalian cells. However, their value in the diagnosis of cancers remains unknown. In this study, we focused on hsa_circ_0000190, which was found to be down-regulated in gastric cancer tissues in our previous microarray screening. The hsa_circ_0000190 levels in 104 paired gastric cancer tissues and adjacent non-tumor tissues, 104 plasma samples from patients with gastric cancer and 104 plasma samples from health controls were detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Then, the association between the expression level of hsa_circ_0000190 and the clinicopathological features of patients with gastric cancer was further analyzed. A receiver operating characteristic (ROC) curve was generated to evaluate the diagnostic value. Hsa_circ_0000190 was first found to be down-regulated in gastric cancer tissues (P<0.001) and plasma samples from patients with gastric cancer (P<0.001). Its expression levels were significantly correlated with tumor diameter (P=0.034), lymphatic metastasis (P=0.026), distal metastasis (P=0.001), TNM stage (P=0.001), and CA19-9 levels (P=0.019). The areas under the ROC curve (AUC) of hsa_circ_0000190 in tissues and plasma were up to 0.75 and 0.60, respectively. The sensitivity and specificity of the combination were 0.712 and 0.750; the AUC was increased to 0.775. These results indicated that hsa_circ_0000190 may be a novel non-invasive biomarker for the diagnosis of gastric cancer. Its AUC, sensitivity and specificity are better than commonly used biomarkers such as CEA and CA19-9. Copyright © 2017 Elsevier B.V. All rights reserved.

NPS and Online WOM

PubMed Central

Raassens, Néomie

2017-01-01

The Net Promoter Score (NPS) is, according to Reichheld, the single most reliable indicator of company growth, and many companies use this recommendation-based technique for measuring customer loyalty. Despite its widespread adoption by many companies across multiple industries, the debate about NPS goes on. A major concern is that managers treat NPS as being equivalent across customers, which is often very misleading. By using a unique data set that combines customers’ promoter scores and online word-of-mouth (eWOM) behavior, this research studies how individual customers’ promoter scores are related to eWOM, including its relationship with the three categories of customers that are identified by the NPS paradigm (i.e., promoters, passives, and detractors). Based on a sample of 189 customers, their promoter scores and corresponding eWOM, the results show that there is a positive relationship between customers’ promoter scores and the valence of online messages. Further, while detractors and promoters are homogeneous with respect to the valence of the eWOM messages they spread, passives show message valence heterogeneity. Thus, although passives, the largest group of customers, have no weight in calculating the NPS, our results reveal that companies should flag passives for further attention and action. PMID:29046609

New psychoactive substances (NPS) on cryptomarket fora: An exploratory study of characteristics of forum activity between NPS buyers and vendors.

PubMed

Van Hout, Marie Claire; Hearne, Evelyn

2017-02-01

The continual diversification of new psychoactive substances (NPS) circumventing legislation creates a public health and law enforcement challenge, and one particularly challenged by availability on Hidden Web cryptomarkets. This is the first study of its kind which aimed to explore and characterise cryptomarket forum members' views and perspectives on NPS vendors and products within the context of Hidden Web community dynamics. An internal site search was conducted on two cryptomarkets popular with NPS vendors and hosting fora; Alphabay and Valhalla, using the search terms of 40 popular NPS in the seven categories of stimulant/cathinone; GABA activating; hallucinogen, dissociative, cannabinoid, opioid and other/unspecified/uncategorised NPS. 852 identified threads relating to the discussion of these NPS were generated. Following exclusion of duplicates, 138 threads remained. The Empirical Phenomenological Psychological method of data analysis was applied. Four themes and 32 categories emerged. 120 vendors selling NPS were visible on Alphabay, and 21 on Valhalla. Themes were 'NPS Cryptomarkets and Crypto-community interest in NPS'; 'Motives for NPS use'; 'Indigenous Crypto Community Harm Reduction'; and 'Cryptomarket Characteristics underpinning NPS trafficking', with two higher levels of abstraction centring on 'NPS vendor reputation' and 'NPS transactioning for personal use'. NPS cryptomarket characteristics centred on generation of trust, honesty and excellent service. Users appeared well informed, with harm reduction and vendor information exchange central to NPS market dynamics. GABA activating substances appeared most popular in terms of buyer interest on cryptomarkets. Interest in sourcing 'old favorite' stimulant and dissociative NPS was evident, alongside the sequential and concurrent poly use of NPS, and use of NPS with illicit drugs such as MDMA. Continued monitoring of new trends in NPS within Surface Web and cryptomarkets are warranted. A particular

Evaluation of RGD-targeted albumin carriers for specific delivery of auristatin E to tumor blood vessels.

PubMed

Temming, Kai; Meyer, Damon L; Zabinski, Roger; Dijkers, Eli C F; Poelstra, Klaas; Molema, Grietje; Kok, Robbert J

2006-01-01

Induction of apoptosis in endothelial cells is considered an attractive strategy to therapeutically interfere with a solid tumor's blood supply. In the present paper, we constructed cytotoxic conjugates that specifically target angiogenic endothelial cells, thus preventing typical side effects of apoptosis-inducing drugs. For this purpose, we conjugated the potent antimitotic agent monomethyl-auristatin-E (MMAE) via a lysosomal cleavable linker to human serum albumin (HSA) and further equipped this drug-albumin conjugate with cyclic c(RGDfK) peptides for multivalent interaction with alphavbeta3-integrin. The RGD-peptides were conjugated via either an extended poly(ethylene glycol) linker or a short alkyl linker. The resulting drug-targeting conjugates RGDPEG-MMAE-HSA and RGD-MMAE-HSA demonstrated high binding affinity and specificity for alphavbeta3-integrin expressing human umbilical vein endothelial cells (HUVEC). Both types of conjugates were internalized by endothelial cells and killed the target cells at low nM concentrations. Furthermore, we observed RGD-dependent binding of the conjugates to C26 carcinoma. Upon i.v. administration to C26-tumor bearing mice, both drug-targeting conjugates displayed excellent tumor homing properties. Our results demonstrate that RGD-modified albumins are suitable carriers for cell selective intracellular delivery of cytotoxic compounds, and further studies will be conducted to assess the antivascular and tumor inhibitory potential of RGDPEG-MMAE-HSA and RGD-MMAE-HSA.

Screening differential circular RNA expression profiles reveal that hsa_circ_0128298 is a biomarker in the diagnosis and prognosis of hepatocellular carcinoma.

PubMed

Chen, Dawei; Zhang, Chenyue; Lin, Jiamao; Song, Xinyu; Wang, Haiyong

2018-01-01

The aim of this study was to analyze the diagnostic and prognostic values of the circular RNA (circRNA) hsa_circ_0128298 in hepatocellular carcinoma (HCC). The global circRNA expression was measured using circRNA microarray using three pairs of cancer and noncancerous tissues from HCC patients. The microarray analysis revealed that two circRNAs were differentially expressed in the three pairs of cancerous and noncancerous tissues. The higher levels of two representative circRNAs, such as hsa_circ_0128298 and hsa_circ_0091582, were further confirmed by real-time polymerase chain reaction. In addition, the association between the expression level of hsa_circ_0128298 and the clinicopathological features of patients with HCC was further analyzed. The clinical diagnosis value was confirmed by receiver operating characteristic (ROC) curve analysis. Independent prognostic factors of patient outcome were identified using the Cox regression model. The survival data were analyzed by the Kaplan-Meier method, and the differences were evaluated using log-rank tests. Two-sided P -values <0.05 were considered statistically significant. The expression levels of hsa_circ_0128298 in HCC were significantly higher than those of paratumorous tissues ( P <0.001). Additionally, hsa_circ_0128298 was a diagnostic factor, with the area under the ROC curve of 0.668 (95% CI =0.503-0.794, P <0.001). The sensitivity and specificity values were 0.716 and 0.815, respectively. The AFP and hsa_circ_0128298 expression levels were independent prognostic factors. The overall survival of patients with low hsa_circ_0128298 expression was significantly higher than that of patients with high hsa_circ_0128298 expression. hsa_circ_0128298 may promote proliferation and metastasis and potentially represents a novel diagnostic and prognostic biomarker for HCC patients. However, studies with larger sample size are needed to confirm our conclusion.

The albumin-exendin-4 recombinant protein E2HSA improves glycemic control and β-cell function in spontaneous diabetic KKAy mice.

PubMed

Li, Caina; Hou, Shaocong; Liu, Shuainan; Huan, Yi; Sun, Sujuan; Liu, Quan; Shen, Zhufang

2017-06-19

E2HSA is a genetic fusion protein that consists of two tandem exendin-4 molecules that are covalently bonded to recombinant human serum albumin via a peptide linker. Previous studies have demonstrated that E2HSA significantly decreased blood glucose levels, improved β-cell function and promoted β-cell proliferation in diabetic db/dB mice. This study aimed to evaluate the benefits of E2HSA on glucose and lipid metabolism in a spontaneous diabetes animal model, KKAy mice. E2HSA was acutely administered at doses of 1, 3 and 9 mg/kg by subcutaneous injection in diabetic KKAy mice with exendin-4 (2 μg/kg) as a positive reference, and then the non-fasting blood glucose and food intake levels were dynamically monitored. In addition, different doses of E2HSA were injected once daily, as well as with exendin-4 twice daily, for 7 weeks to evaluate the effect on glucose and lipid metabolism, as well as the body weight, food and water intake. Single injection of E2HSA decreased non-fasting blood glucose and food intake levels in a dose-dependent manner for 4 days and 2 days, respectively. Repeated injections with E2HSA significantly decreased variations in blood glucose levels with a reduction of HbA1c levels by 1.6% at a 9 mg/kg dose, simultaneously increased fasting blood insulin levels, inhibited fasting blood glucagon levels, improved the impaired oral glucose tolerance and enhanced glucose infusion rate, which is the gold standard for evaluating β-cell function. Moreover, repeated injections with E2HSA also ameliorated the dyslipidemia and reduced body weight, food and water intake in diabetic KKAy mice. E2HSA significantly reduced blood glucose levels over a prolonged duration, enhanced β-cell function, and ameliorated dyslipidemia and obesity in diabetic KKAy mice. Thus, E2HSA may be a new candidate for the treatment of type 2 diabetes.

Ligand-induced rapid skeletal muscle atrophy in HSA-Fv2E-PERK transgenic mice.

PubMed

Miyake, Masato; Kuroda, Masashi; Kiyonari, Hiroshi; Takehana, Kenji; Hisanaga, Satoshi; Morimoto, Masatoshi; Zhang, Jun; Oyadomari, Miho; Sakaue, Hiroshi; Oyadomari, Seiichi

2017-01-01

Formation of 43S and 48S preinitiation complexes plays an important role in muscle protein synthesis. There is no muscle-wasting mouse model caused by a repressed 43S preinitiation complex assembly. The aim of the present study was to develop a convenient mouse model of skeletal muscle wasting with repressed 43S preinitiation complex assembly. A ligand-activatable PERK derivative Fv2E-PERK causes the phosphorylation of eukaryotic initiation factor 2α (eIF2α), which inhibits 43S preinitiation complex assembly. Thus, muscle atrophic phenotypes, intracellular signaling pathways, and intracellular free amino acid profiles were investigated in human skeletal muscle α-actin (HSA) promoter-driven Fv2E-PERK transgenic (Tg) mice. HSA-Fv2E-PERK Tg mice treated with the artificial dimerizer AP20187 phosphorylates eIF2α in skeletal muscles and leads to severe muscle atrophy within a few days of ligand injection. Muscle atrophy was accompanied by a counter regulatory activation of mTORC1 signaling. Moreover, intracellular free amino acid levels were distinctively altered in the skeletal muscles of HSA-Fv2E-PERK Tg mice. As a novel model of muscle wasting, HSA-Fv2E-PERK Tg mice provide a convenient tool for studying the pathogenesis of muscle loss and for assessing putative therapeutics.

Using thermal energy produced by irradiation of Mn-Zn ferrite magnetic nanoparticles (MZF-NPs) for heat-inducible gene expression.

PubMed

Tang, Qiu-sha; Zhang, Dong-sheng; Cong, Xiao-ming; Wan, Mei-ling; Jin, Li-qiang

2008-06-01

One of the main advantages of gene therapy over traditional therapy is the potential to target the expression of therapeutic genes in desired cells or tissues. To achieve targeted gene expression, we developed a novel heat-inducible gene expression system in which thermal energy generated by Mn-Zn ferrite magnetic nanoparticles (MZF-NPs) under an alternating magnetic field (AMF) was used to activate gene expression. MZF-NPs, obtained by co-precipitation method, were firstly surface modified with cation poly(ethylenimine) (PEI). Then thermodynamic test of various doses of MZF-NPs was preformed in vivo and in vitro. PEI-MZF-NPs showed good DNA binding ability and high transfection efficiency. In AMF, they could rise to a steady temperature. To analyze the heat-induced gene expression under an AMF, we combined P1730OR vector transfection with hyperthermia produced by irradiation of MZF-NPs. By using LacZ gene as a reporter gene and Hsp70 as a promoter, it was demonstrated that expression of a heterogeneous gene could be elevated to 10 to 500-fold over background by moderate hyperthermia (added 12.24 or 25.81 mg MZF-NPs to growth medium) in tissue cultured cells. When injected with 2.6 or 4.6 mg MZF-NPs, the temperature of tumor-bearing nude mice could rise to 39.5 or 42.8 degrees C, respectively, and the beta-gal concentration could increase up to 3.8 or 8.1 mU/mg proteins accordingly 1 day after hyperthermia treatment. Our results therefore supported hyperthermia produced by irradiation of MZF-NPs under an AMF as a feasible approach for targeted heat-induced gene expression. This novel system made use of the relative low Curie point of MZF-NPs to control the in vivo hyperthermia temperature and therefore acquired safe and effective heat-inducible transgene expression.

Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1).

PubMed

Westhovens, R; Taylor, P C; Alten, R; Pavlova, D; Enríquez-Sosa, F; Mazur, M; Greenwald, M; Van der Aa, A; Vanhoutte, F; Tasset, C; Harrison, P

2017-06-01

To evaluate the efficacy and safety of different doses and regimens of filgotinib, an oral Janus kinase 1 inhibitor, as add-on treatment to methotrexate (MTX) in patients with active rheumatoid arthritis (RA) and inadequate response to MTX. In this 24-week phase IIb study, patients with moderate-to-severe active RA receiving a stable dose of MTX were randomised (1:1:1:1:1:1:1) to receive placebo or 50, 100 or 200 mg filgotinib, administered once daily or twice daily. Primary end point was the percentage of patients achieving a week 12 American College of Rheumatology (ACR)20 response. Overall, 594 patients were randomised and treated. At week 12, significantly more patients receiving filgotinib 100 mg once daily or 200 mg daily (both regimens) achieved an ACR20 response versus placebo. For other key end points at week 12 (ACR50, ACR-N, Disease Activity Score based on 28 joints and C reactive protein value, Clinical Disease Activity Index, Simplified Disease Activity Index and Health Assessment Questionnaire-Disability Index), differences in favour of 100  or 200 mg filgotinib daily were seen versus placebo; responses were maintained or improved through to week 24. Rapid onset of action and dose-dependent responses were observed for most efficacy end points and were associated with an increased haemoglobin concentration. No significant differences between once-daily and twice-daily regimens were seen. Treatment-emergent adverse event rates were similar in placebo and filgotinib groups. Serious infections occurred in one and five patients in the placebo and filgotinib groups, respectively. No tuberculosis or opportunistic infections were reported. Filgotinib as add-on to MTX improved the signs and symptoms of active RA over 24 weeks and was associated with a rapid onset of action. Filgotinib was generally well tolerated. NCT01888874. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go

Interaction of an antiepileptic drug, lamotrigine with human serum albumin (HSA): Application of spectroscopic techniques and molecular modeling methods.

PubMed

Poureshghi, Fatemeh; Ghandforoushan, Parisa; Safarnejad, Azam; Soltani, Somaieh

2017-01-01

Lamotrigine (an epileptic drug) interaction with human serum albumin (HSA) was investigated by fluorescence, UV-Vis, FTIR, CD spectroscopic techniques, and molecular modeling methods. Binding constant (K b ) of 5.74×10 3 and number of binding site of 0.97 showed that there is a slight interaction between lamotrigine and HSA. Thermodynamic studies was constructed using the flourimetric titrations in three different temperatures and the resulted data used to calculate the parameters using Vant Hoff equation. Decreased Stern Volmer quenching constant by enhanced temperature revealed the static quenching mechanism. Negative standard enthalpy (ΔH) and standard entropy (ΔS) changes indicated that van der Waals interactions and hydrogen bonds were dominant forces which facilitate the binding of Lamotrigine to HSA, the results were confirmed by molecular docking studies which showed no hydrogen binding. The FRET studies showed that there is a possibility of energy transfer between Trp214 and lamotrigine. Also the binding of lamotrigine to HSA in the studied concentrations was not as much as many other drugs, but the secondary structure of the HSA was significantly changed following the interaction in a way that α-helix percentage was reduced from 67% to 57% after the addition of lamotrigine in the molar ratio of 4:1 to HSA. According to the docking studies, lamotrigine binds to IB site preferably. Copyright © 2016. Published by Elsevier B.V.

Redox-responsive mesoporous selenium delivery of doxorubicin targets MCF-7 cells and synergistically enhances its anti-tumor activity.

PubMed

Zhao, Shuang; Yu, Qianqian; Pan, Jiali; Zhou, Yanhui; Cao, Chengwen; Ouyang, Jian-Ming; Liu, Jie

2017-05-01

To reduce the side effects and enhance the anti-tumor activities of anticancer drugs in the clinic, the use of nano mesoporous materials, with mesoporous silica (MSN) being the best-studied, has become an effective method of drug delivery. In this study, we successfully synthesized mesoporous selenium (MSe) nanoparticles and first introduced them to the field of drug delivery. Loading MSe with doxorubicin (DOX) is mainly driven by the physical adsorption mechanism of the mesopores, and our results demonstrated that MSe could synergistically enhance the antitumor activity of DOX. Coating the surface of MSe@DOX with Human serum albumin (HSA) generated a unique redox-responsive nanoparticle (HSA-MSe@DOX) that demonstrated glutathione-dependent drug release, increased tumor-targeting effects and enhanced cellular uptake throug nanoparticle interact with SPARC in MCF-7 cells. In vitro, HSA-MSe@DOX prominently induced cancer cell toxicity by synergistically enhancing the effects of MSe and DOX. Moreover, HSA-MSe@DOX possessed tumor-targeting abilities in tumor-bearing nude mice and not only decreased the side effects associated with DOX, but also enhanced its antitumor activity. Therefore, HSA-MSe@DOX is a promising new drug that warrants further evaluation in the treatments of tumors. To reduce the side effects and enhance the anti-tumor activities of anticancer drugs, we successfully synthesized mesoporous selenium (MSe) nanoparticles and first introduced them to the field of drug delivery. Loading MSe with doxorubicin (DOX) is mainly driven by the physical adsorption mechanism of the mesopores. Coating the surface of MSe@DOX with Human serum albumin (HSA) generated a unique redox-responsive nanoparticle (HSA-MSe@DOX) that demonstrated glutathione-dependent drug release, increased tumor-targeting effects and enhanced cellular uptake throug nanoparticle interact with SPARC in MCF-7 cells. In vitro and in vivo, HSA-MSe@DOX possessed tumor-targeting abilities and not only

A potential risk factor of essential hypertension in case-control study: Circular RNA hsa_circ_0037911.

PubMed

Bao, Xingjie; Zheng, Shuying; Mao, Shuqi; Gu, Tianlun; Liu, Shike; Sun, Jihan; Zhang, Lina

2018-04-15

Essential hypertension (EH) is a high prevalence with multifactorial diseases. Human studies on the impact of genes on this disease are just in the initial stage, the mechanism of gene regulation is still remains unclear. Circular RNAs (circRNAs) as a continuous cycle of covalent closure, RNA molecules added to the 3'-5' end covalently bound by the formation of incidental event. CircRNAs may be an important biomolecule in revealing the molecule regulate mechanisms of EH. The circRNAs were selected and validated with qRT-PCR followed. Our experiment was conducted with case-control studies among 200 EH participants. The t-test was used to evaluate the different expression of circRNAs and miRNAs, the significance of which was set as p < 0.05. The hsa_circ_0037911 expression level in EH cases were significantly higher than healthy controls (p = 0.005). There was still important significance when adjusted by logistic regression (adjusted p = 0.026). We also found that hsa_circ_0037911 was an effective marker of EH (area under curve = 0.627; p = 0.002). The levels of hsa_circ_0037911 were significantly differences in gender, BMI, smoking and drinking among EH cases. There was a positive correlation between Serum creatinine (Scr) and hsa_circ_0037911. Our findings suggested that higher expression hsa_circ_0037911 may be key circRNAs for EH development by changing the concentration of Scr and could be a stable biomarker for early diagnosis of EH. Copyright © 2018 Elsevier Inc. All rights reserved.

NPS National Transit Inventory, 2012

DOT National Transportation Integrated Search

2013-07-01

Working in coordination with the NPS regions and the U.S. Department of Transportations Volpe National Transportation Systems Center, the Alternative transportation program (ATP) developed a definition of National Park Service (NPS) transit system...

NPS national transit inventory, 2013

DOT National Transportation Integrated Search

2014-07-31

This document summarizes key highlights from the National Park Service (NPS) 2013 National Transit Inventory, and presents data for NPS transit systems system-wide. The document discusses statistics related to ridership, business models, fleet charac...

Cell-targeted platinum nanoparticles and nanoparticle clusters.

PubMed

Papst, Stefanie; Brimble, Margaret A; Evans, Clive W; Verdon, Daniel J; Feisst, Vaughan; Dunbar, P Rod; Tilley, Richard D; Williams, David E

2015-06-21

Herein, we report the facile preparation of cell-targeted platinum nanoparticles (PtNPs), through the design of peptides that, as a single molecule added in small concentration during the synthesis, control the size of PtNP clusters during their growth, stabilise the PtNPs in aqueous suspension and enable the functionalisation of the PtNPs with a versatile range of cell-targeting ligands. Water-soluble PtNPs targeted respectively at blood group antigens and at integrin receptors are demonstrated.

Inhibition of glioblastoma cell invasion by hsa-miR-145-5p and hsa-miR-31-5p co-overexpression in human mesenchymal stem cells.

PubMed

Kurogi, Ryota; Nakamizo, Akira; Suzuki, Satoshi O; Mizoguchi, Masahiro; Yoshimoto, Koji; Amano, Toshiyuki; Amemiya, Takeo; Takagishi, So; Iihara, Koji

2018-03-09

OBJECTIVE Human bone marrow-derived mesenchymal stem cells (hMSCs) show tropism for brain tumors and may be a useful vehicle for drug or gene delivery to malignant gliomas. Recently, some microRNAs (miRNAs) have been shown to suppress the invasiveness of malignant gliomas. METHODS To test their potential to become vehicles for the delivery of miRNA to malignant gliomas, hMSCs were engineered so that hMSC secretion of miRNAs that inhibit glioma cell invasion was enabled without altering the hMSC tropism for glioma cells. RESULTS In coculture, hMSCs cotransfected with hsa-miR-145-5p and -31-5p miRNAs showed markedly reduced invasion by U87 glioma cells in a contact-dependent manner both in vitro and ex vivo, with invasion of hMSCs cotransfected with these 2 miRNAs by the U87 cells reduced to 60.7% compared with control cells. According to a Matrigel invasion assay, the tropism of the hMSCs for U87 cells was not affected. In glioma cell lines U251 and LN229, hMSCs exhibited tropism in vivo, and invasion of hMSCs cotransfected with hsa-miR-145-5p and -31-5p was also significantly less than that of control cells. When U87 cells were coimplanted into the striatum of organotypic rat brain slices with hMSCs cotransfected with hsa-miR-145 and -31-5p, the relative invasive area decreased by 37.1%; interestingly, these U87 cells showed a change to a rounded morphology that was apparent at the invasion front. Whole-genome microarray analysis of the expression levels of 58,341 genes revealed that the co-overexpression of hsa-miR-145-5p and -31-5p downregulated FSCN1 expression in U87 cells. CONCLUSIONS This study demonstrates that miRNA overexpression in hMSCs can alter the function of glioma cells via contact-dependent transfer. Co-overexpression of multiple miRNAs may be a useful and novel therapeutic strategy. The study results suggest that hMSCs can be applied as a delivery vehicle for miRNAs.

Monitoring methotrexate in clinical samples from cancer patients during chemotherapy with a LSPR-based competitive sensor.

PubMed

Zhao, Sandy Shuo; Bichelberger, Mathilde A; Colin, Damien Y; Robitaille, Robert; Pelletier, Joelle N; Masson, Jean-François

2012-10-21

A competitive binding assay based on localized surface plasmon resonance (LSPR) of folic acid-functionalized gold nanoparticles (FA-AuNPs) and human dihydrofolate reductase enzyme (hDHFR) was developed to detect nanomolar to micromolar concentrations of the widely applied anti-cancer drug, methotrexate (MTX). By the nature of the competitive assay for MTX, the LSPR shift from specific binding between FA-AuNPs and the free enzyme was inversely proportional to the concentration of MTX. In addition, the dynamic range for MTX was tuned from 10(-11) to 10(-6) M by varying the concentration of hDHFR from 1 to 100 nM. Inter-day reproducibility and recovery of MTX spiked in phosphate buffer saline (PBS) were excellent. Potential interferents such as FA, trimethoprim (TMP) and 4-amino-4-deoxy-N-methylpteroic acid (DAMPA) did not occur in the concentration range of interest for MTX. Clinical samples of human serum from patients undergoing MTX chemotherapy were analyzed following a simple solid-phase extraction step to isolate MTX from the serum matrix, with a limit of detection of 155 nM. Validation of the LSPR method was carried out in comparison to Fluorescence Polarization Immunoassay (FPIA), a commonly used method in clinical settings, and LC-MS/MS, a reference technique. The results of the LSPR competitive assay compared well to FPIA and LC-MS/MS, with a slope of 2.4 and 1.1, respectively, for the correlation plots. The method established herein is intended for therapeutic drug monitoring (TDM) of MTX levels in patients undergoing chemotherapy to ensure safety and efficacy of the treatment.

NPS transportation innovative finance options

DOT National Transportation Integrated Search

2013-05-01

This paper provides a summary of innovative transportation finance techniques and discusses their applicability to the National Park Service (NPS). The primary finding of this analysis is that while NPS is engaging in innovative finance techniques su...

NPS Gas Gun for Planar Impact Studies

NASA Astrophysics Data System (ADS)

Cheong Ho, Chien; Hixson, Robert

2009-11-01

The Naval Postgraduate School (NPS) commissioned a Gas Gun for shock wave studies on 9^th October 2009, by performing the first experiment. The Gas Gun is the key element of NPS Shock Wave Research Program within the Physics Department, where well-characterized planar impacts are essential for obtaining high quality data, to characterize a solid material. This first experiment was very successful, and returned key data on the quality of the impact conditions created. The Gas Gun is designed by SANDIA NATIONAL LABORATORIES, and the NPS spent twelve months fabricating the components of the Gas Gun and six months assembling the Gas Gun. Three inch projectile are launched at velocities up to 0.5 km/s, creating high pressure and temperature states that can be used to characterize the fundamental response of relevant materials to dynamic loading. The projectile is launched from a `wrap around' gas breech where helium gas is pressurized to relatively low pressure. This gas is used to accelerate the projectile down a 3m barrel. Upon impact, the speed of the projectile and the flatness of the impact is measured, via a stepped circular pin array circuit. The next stage of development for the Gas Gun is to integrate a Velocity Interferometer System for Any Reflector (VISAR). The VISAR sees all the waves that flow through the target plate as a result of the impact. This is a key diagnostic for determining material properties under dynamic loading conditions.

Cinacalcet: AMG 073, Calcimimetics--Amgen/NPS Pharmaceuticals, KRN 1493, NPS 1493.

PubMed

2003-01-01

Cinacalcet [AMG 073, KRN 1493, NPS 1493] is an orally active, second-generation calcimimetic compound licensed by NPS Pharmaceuticals to Amgen in the US for potential treatment of hyperparathyroidism (HPT). Cinacalcet modulates (increases the sensitivity of) calcium receptors on the surface of parathyroid cells thereby inhibiting the oversecretion of parathyroid hormone, which characterises HPT. It also represents a potentially significant advance for chronic kidney disease patients diagnosed with secondary HPT, a common yet serious metabolic disorder where parathyroid hormone levels are elevated. Patients with this disease can suffer from bone disease, bone pain and fractures, soft tissue calcification, vascular calcification and cardiovascular complications. Amgen has rights to develop and sell cinacalcet throughout the world except in Japan, Taiwan and China, where the compound was licensed to Kirin Brewery. Kirin is developing it as KRN 1493 in phase II clinical studies in Japan. In December 2001, commencement of a phase III clinical trial with cinacalcet for the treatment of secondary HPT, triggered a 3 million US dollars milestone payment to NPS Pharmaceuticals. In September 2003, submission of an NDA to the US FDA for cinacalcet for secondary HPT will be followed by a milestone payment of 6 million US dollars to NPS. NPS, Kirin and Amgen were also developing another compound, tecalcet, for HPT, but that project has been discontinued in favour of cinacalcet. In September 2003, Amgen submitted an NDA to the US FDA for secondary HPT in patients with chronic kidney disease. In April 2003, Amgen announced positive results from a phase III clinical trial with cinacalcet in patients with secondary HPT. In a clinical study in patients on dialysis suffering from the effects of chronically elevated levels parathyroid hormone, cinacalcet appeared to be safe and well tolerated and was significantly more effective than placebo. Two more additional efficacy studies with

Comprehensive insight into the binding of sunitinib, a multi-targeted anticancer drug to human serum albumin

NASA Astrophysics Data System (ADS)

Kabir, Md. Zahirul; Tee, Wei-Ven; Mohamad, Saharuddin B.; Alias, Zazali; Tayyab, Saad

2017-06-01

Binding studies between a multi-targeted anticancer drug, sunitinib (SU) and human serum albumin (HSA) were made using fluorescence, UV-vis absorption, circular dichroism (CD) and molecular docking analysis. Both fluorescence quenching data and UV-vis absorption results suggested formation of SU-HSA complex. Moderate binding affinity between SU and HSA was evident from the value of the binding constant (3.04 × 104 M-1), obtained at 298 K. Involvement of hydrophobic interactions and hydrogen bonds as the leading intermolecular forces in the formation of SU-HSA complex was predicted from the thermodynamic data of the binding reaction. These results were in good agreement with the molecular docking analysis. Microenvironmental perturbations around Tyr and Trp residues as well as secondary and tertiary structural changes in HSA upon SU binding were evident from the three-dimensional fluorescence and circular dichroism results. SU binding to HSA also improved the thermal stability of the protein. Competitive displacement results and molecular docking analysis revealed the binding locus of SU to HSA in subdomain IIA (Sudlow's site I). The influence of a few common ions on the binding constant of SU-HSA complex was also noticed.

Interaction between holo transferrin and HSA-PPIX complex in the presence of lomefloxacin: An evaluation of PPIX aggregation in protein-protein interactions

NASA Astrophysics Data System (ADS)

Sattar, Zohreh; Iranfar, Hediye; Asoodeh, Ahmad; Saberi, Mohammad Reza; Mazhari, Mahboobeh; Chamani, Jamshidkhan

2012-11-01

Human serum albumin (HSA) and holo transferrin (TF) are two serum carrier proteins that are able to interact with each other, thereby altering their binding behavior toward their ligands. During the course of this study, the interaction between HSA-PPIX and TF, in the presence and absence of lomefloxacin (LMF), was for the first time investigated using different spectroscopic and molecular modeling techniques. Fluorescence spectroscopy experiments were performed in order to study conformational changes of proteins. The RLS technique was utilized to investigate the effect of LMF on J-aggregation of PPIX, which is the first report of its kind. Our findings present clear-cut evidence for the alteration of interactions between HSA and TF in the presence of PPIX and changes in drug-binding to HSA and HSA-PPIX complex upon interaction with TF. Moreover, molecular modeling studies suggested that the binding site for LMF became switched in the presence of PPIX, and that LMF bound to the site IIA of HSA. The obtained results should give new insight into research in this field and may cast some light on the dynamics of drugs in biological systems.

Individual and Co Transport Study of Titanium Dioxide NPs and Zinc Oxide NPs in Porous Media

PubMed Central

Kumari, Jyoti; Mathur, Ankita; Rajeshwari, A.; Venkatesan, Arthi; S, Satyavati; Pulimi, Mrudula; Chandrasekaran, Natarajan; Nagarajan, R.; Mukherjee, Amitava

2015-01-01

The impact of pH and ionic strength on the mobility (individual and co-transport) and deposition kinetics of TiO2 and ZnO NPs in porous media was systematically investigated in this study. Packed column experiments were performed over a series of environmentally relevant ionic strengths with both NaCl (0.1−10 mM) and CaCl2 (0.01–0.1mM) solutions and at pH 5, 7, and 9. The transport of TiO2 NPs at pH 5 was not significantly affected by ZnO NPs in solution. At pH 7, a decrease in TiO2 NP transport was noted with co-existence of ZnO NPs, while at pH 9 an increase in the transport was observed. At pH 5 and 7, the transport of ZnO NPs was decreased when TiO2 NPs was present in the solution, and at pH 9, an increase was noted. The breakthrough curves (BTC) were noted to be sensitive to the solution chemistries; the decrease in the breakthrough plateau with increasing ionic strength was observed under all examined pH (5, 7, and 9). The retention profiles were the inverse of the plateaus of BTCs, as expected from mass balance considerations. Overall, the results from this study suggest that solution chemistries (ionic strength and pH) are likely the key factors that govern the individual and co-transport behavior of TiO2 and ZnO NPs in sand. PMID:26252479

IGF-1/IGF-1R/hsa-let-7c axis regulates the committed differentiation of stem cells from apical papilla

PubMed Central

Ma, Shu; Liu, Genxia; Jin, Lin; Pang, Xiyao; Wang, Yanqiu; Wang, Zilu; Yu, Yan; Yu, Jinhua

2016-01-01

Insulin-like growth factor-1 (IGF-1) and its receptor IGF-1R play a paramount role in tooth/bone formation while hsa-let-7c actively participates in the osteogenic differentiation of mesenchymal stem cells. However, the interaction between IGF-1/IGF-1R and hsa-let-7c on the committed differentiation of stem cells from apical papilla (SCAPs) remains unclear. In this study, human SCAPs were isolated and treated with IGF-1 and hsa-let-7c over/low-expression viruses. The odonto/osteogenic differentiation of these stem cells and the involvement of mitogen-activated protein kinase (MAPK) pathway were subsequently investigated. Alizarin red staining showed that hsa-let-7c low-expression can significantly promote the mineralization of IGF-1 treated SCAPs, while hsa-let-7c over-expression can decrease the calcium deposition of IGF-1 treated SCAPs. Western blot assay and real-time reverse transcription polymerase chain reaction further demonstrated that the expression of odonto/osteogenic markers (ALP, RUNX2/RUNX2, OSX/OSX, OCN/OCN, COL-I/COL-I, DSPP/DSP, and DMP-1/DMP-1) in IGF-1 treated SCAPs were significantly upregulated in Let-7c-low group. On the contrary, hsa-let-7c over-expression could downregulate the expression of these odonto/osteogenic markers. Moreover, western blot assay showed that the JNK and p38 MAPK signaling pathways were activated in Let-7c-low SCAPs but inhibited in Let-7c-over SCAPs. Together, the IGF-1/IGF-1R/hsa-let-7c axis can control the odonto/osteogenic differentiation of IGF-1-treated SCAPs via the regulation of JNK and p38 MAPK signaling pathways. PMID:27833148

Spectroscopic interaction study of human serum albumin and human hemoglobin with Mersilea quadrifolia leaves extract mediated silver nanoparticles having antibacterial and anticancer activity

NASA Astrophysics Data System (ADS)

Maji, Anukul; Beg, Maidul; Mandal, Amit Kumar; Das, Somnath; Jha, Pradeep K.; Kumar, Anoop; Sarwar, Shamila; Hossain, Maidul; Chakrabarti, Pinak

2017-08-01

This study looks into a safe, proficient and low-cost way for the preparation of novel silver nanoparticles by using 5% aqueous leaves extract of a medicinal plant, Marsilea quadrifolia (family: Marsileaceae) without using any external reducing and stabilizing agents. The synthesized AgNPs showed maximum UV-Vis absorbance at 435 nm due to surface plasmon resonance (SPR). The average diameter (∼22.5 nm) of AgNPs was measured from TEM analysis and was also supported by FE-SEM. The existence of a silver signal in EDX spectra supported the AgNPs formation and negative zeta potential value (-18.7 mV) which suggested its stability. FT-IR spectroscopic analysis showed that the functional groups like sbnd Osbnd H, sbnd Nsbnd H and sbnd Cdbnd O were responsible for the synthesis of AgNPs. The antibacterial activity of the AgNPs was tested against E. coli ATCC 25922. The anticancer potential of AgNPs was also assessed using two different cell lines, such as MCF-7 and HeLa. The interaction study of AgNPs with human serum albumin (HSA) and human hemoglobin (Hb) was performed by means of UV-Vis, fluorescence spectroscopy, Circular dichroism (CD) and zeta potential measurement. More negative zeta potential values of AgNPs-HSA/Hb (-21.1/-19.5 mV) complexes than AgNPs (-18.7 mV) indicated corresponding stability of bio-conjugates. The basic structure of HSA/Hb remained unchanged and its secondary structure was slightly changed upon interaction with the AgNPs concluded from Circular dichroism. So, it can be predicted that this AgNPs may be applied in the medical field.

NPS-SCAT CONOPS and Radiation Environment

DTIC Science & Technology

2012-06-01

flexibility, as well as allows players in the space market who would otherwise not be able to enter due to budgetary limitations. Important to NPS is...commercial market . Although the time frame for completing NPS-SCAT has not been as short as possible due to the nature of the learning environment on its...Program ( STP ) seeks flight opportunities for approved experiments. The current NPS- SCAT launch date offers ample time to finish and test the

NPS: Medical Consequences Associated with Their Intake.

PubMed

Schifano, Fabrizio; Orsolini, Laura; Papanti, Duccio; Corkery, John

2017-01-01

Over the last decade, the 'traditional' drug scene has been supplemented - but not replaced - by the emergence of a range of novel psychoactive substances (NPS), which are either newly created or existing drugs, including medications, now being used in novel ways. By the end of 2014, in excess of 500 NPS had been reported by a large number of countries in the world. Most recent data show, however, that synthetic cathinones, synthetic cannabinoids, and psychedelics/phenethylamines account for the largest number of NPS.The present chapter aims at providing an overview of the clinical and pharmacological issues relating to these most popular NPS categories. Given the vast range of medical and psychopathological issues associated with the molecules here described, it is crucial for health professionals to be aware of the effects and toxicity of NPS. A general overview of the acute management of NPS adverse events is provided as well, although further studies are required to identify a range of evidence-based, index molecule-focused, treatment strategies. The rapid pace of change in the NPS online market constitutes a major challenge to the provision of current and reliable scientific knowledge on these substances.

Knowing Every Child: Validation of the Holistic Student Assessment (HSA) as a Measure of Social-Emotional Development.

PubMed

Malti, Tina; Zuffianò, Antonio; Noam, Gil G

2018-04-01

Knowing every child's social-emotional development is important as it can support prevention and intervention approaches to meet the developmental needs and strengths of children. Here, we discuss the role of social-emotional assessment tools in planning, implementing, and evaluating preventative strategies to promote mental health in all children and adolescents. We, first, selectively review existing tools and identify current gaps in the measurement literature. Next, we introduce the Holistic Student Assessment (HSA), a tool that is based in our social-emotional developmental theory, The Clover Model, and designed to measure social-emotional development in children and adolescents. Using a sample of 5946 students (51% boys, M age  = 13.16 years), we provide evidence for the psychometric validity of the self-report version of the HSA. First, we document the theoretically expected 7-dimension factor structure in a calibration sub-sample (n = 984) and cross-validate its structure in a validation sub-sample (n = 4962). Next, we show measurement invariance across development, i.e., late childhood (9- to 11-year-olds), early adolescence (12- to 14-year-olds), and middle adolescence (15- to 18-year-olds), and evidence for the HSA's construct validity in each age group. The findings support the robustness of the factor structure and confirm its developmental sensitivity. Structural equation modeling validity analysis in a multiple-group framework indicates that the HSA is associated with mental health in expected directions across ages. Overall, these findings show the psychometric properties of the tool, and we discuss how social-emotional tools such as the HSA can guide future research and inform large-scale dissemination of preventive strategies.

Photodynamic efficacy of hypericin targeted by two delivery techniques to hepatocellular carcinoma cells.

PubMed

Fadel, Maha; Kassab, Kawser; Youssef, Tareq

2010-09-01

The photocytotoxic effect of hypericin (Hyp) targeted by two different delivery techniques, namely, liposomes and anti-hepatocyte specific antigen (anti-HSA) was investigated. Optical absorption and steady-state fluorescence were used to analyze the conjugation of Hyp with anti-HSA model and to evaluate the encapsulation capacity and drug release in a liposome model. Particle size and thermal analysis of the prepared liposomes were performed using laser-light scattering and differential scanning calorimetry (DSC), respectively. Viability study of HepG2 cells exposed to Hyp in the two delivery systems, in the dark and following visible light irradiation, was performed in comparison to free Hyp. The intracellular uptake and localization of Hyp in HepG2 cells were analyzed by means of spectrofluorometry and fluorescence microscopy. Spectroscopic measurements demonstrated that Hyp binds to anti-HSA in its monomeric form. The photocytotoxic effect of Hyp depended clearly on the form of Hyp administered, either in free form, loaded into liposomes or conjugated with anti-HSA. While liposomes loaded with Hyp (Lip-Hyp) did not induce significant phototoxicity, both free Hyp or anti-HSA-Hyp inflicted substantial cell mortality, after photoirradiation. The intracellular uptake of Lip-Hyp by HepG2 cells was estimated to be 20% less compared to free Hyp or anti-HSA-Hyp. In spite of the equal uptake of both free Hyp and anti-HSA-Hyp, HepG2 cells demonstrated a relatively higher mortality with anti-HSA-Hyp compared to free Hyp.

Generation of TALE nickase-mediated gene-targeted cows expressing human serum albumin in mammary glands.

PubMed

Luo, Yan; Wang, Yongsheng; Liu, Jun; Cui, Chenchen; Wu, Yongyan; Lan, Hui; Chen, Qi; Liu, Xu; Quan, Fusheng; Guo, Zekun; Zhang, Yong

2016-02-08

Targeting exogenous genes at milk protein loci via gene-targeting technology is an ideal strategy for producing large quantities of pharmaceutical proteins. Transcription-activator-like effector (TALE) nucleases (TALENs) are an efficient genome-editing tool. However, the off-target effects may lead to unintended gene mutations. In this study, we constructed TALENs and TALE nickases directed against exon 2 of the bovine β-lactoglobulin (BLG) locus. The nickases can induce a site-specific DNA single-strand break, without inducing double-strand break and nonhomologous end joining mediated gene mutation, and lower cell apoptosis rate than TALENs. After co-transfecting the bovine fetal fibroblasts with human serum albumin (HSA) gene-targeting vector and TALE nickase expression vectors, approximately 4.8% (40/835) of the cell clones contained HSA at BLG locus. Unexpectedly, one homozygous gene-targeted cell clone (1/835, 0.1%) was obtained by targeting both alleles of BLG in a single round of transfection. The recombinant protein mimicking the endogenous BLG was highly expressed and correctly folded in the mammary glands of the targeted cows, and the expression level of HSA was significantly increased in the homozygous targeted cows. Results suggested that the combination of TALE nickase-mediated gene targeting and somatic cell nuclear transfer is a feasible and safe approach in producing gene-targeted livestock.

Improving cardiovascular disease management in Australia: NPS MedicineWise.

PubMed

Gadzhanova, Svetla V; Roughead, Elizabeth E; Bartlett, Mark J

2013-08-05

To determine the impact of four NPS MedicineWise programs targeting quality use of medicines in cardiovascular management in primary care. Interrupted time-series analysis using the Department of Veterans' Affairs (DVA) claims dataset from 1 January 2002 to 31 August 2010. We examined the use of antithrombotics in people with atrial fibrillation and in those who had had a stroke, and the use of echocardiography and spironolactone in the population with heart failure. All veterans and their dependants in Australia who had received cardiovascular medicines or health services related to the targeted intervention. NPS MedicineWise national programs to improve cardiovascular management in primary care, which included prescriber feedback, academic detailing, case studies and audits as well as printed educational materials. Changes in medication and health service use before and after the interventions. All national programs were positively associated with significant improvements in related prescribing or test request practice. The interventions to improve the use of antithrombotics resulted in a 1.27% (95% CI, 1.26%-1.28%) and 0.63% (95% CI, 0.62%-0.64%) relative increase in the use of aspirin or warfarin in the population with atrial fibrillation 6 and 12 months after the program, respectively, and in a 1.51% (95% CI, 1.49%-1.53%) relative increase in the use of aspirin as monotherapy for secondary stroke prevention 12 months after the intervention. The heart failure programs resulted in a 3.69% (95% CI, 3.67%-3.71%) relative increase in the use of low-dose spironolactone and a 4.31% (95% CI, 4.27%-4.35%) relative increase in the use of echocardiogram tests 12 months after the intervention. NPS MedicineWise programs were effective in achieving positive changes in medicine and health service use for patients with cardiovascular diseases.

Lipid-Polymer Nanoparticles for Folate-Receptor Targeting Delivery of Doxorubicin.

PubMed

Zheng, Mingbin; Gong, Ping; Zheng, Cuifang; Zhao, Pengfei; Luo, Zhenyu; Ma, Yifan; Cai, Lintao

2015-07-01

A biocompatible PLGA-lipid hybrid nanoparticles (NPs) was developed for targeted delivery of anticancer drugs with doxorubicin (DOX). The hydrodynamic diameter and zeta potential of DOX-loaded PLGA-lipid NPs (DNPs) were affected by the mass ratio of Lipid/PLGA or DSPE-PEG-COOH/Lecithin. At the 1:20 drug/polymer mass ratio, the mean hydrodynamic diameter of DNPs was the lowest (99.2 1.83 nm) and the NPs presented the encapsulation efficiency of DOX with 42.69 1.30%. Due to the folate-receptor mediated endocytosis, the PLGA-lipid NPs with folic acid (FA) targeting ligand showed significant higher uptake by folate-receptor-positive MCF-7 cells as compared to PLGA-lipid NPs without folate. Confocal microscopic observation and flow cytometry analysis also supported the enhanced cellular uptake of the FA-targeted NPs. The results indicated that the FA-targeted DNPs exhibited higher cytotoxicity in MCF-7 cells compared with non-targeted NPs. The lipid-polymer nanoparticles provide a solution of biocompatible nanocarrier for cancer targeting therapy.

Collaboration within the Context of the Healthy School Approach (HSA): The Case of a Disadvantaged Elementary School in Quebec

ERIC Educational Resources Information Center

Rivard, Marie-Claude; Deslandes, Rollande; Beaudoin, Charlotte

2011-01-01

This case study focuses on the groundwork aiming at developing school-family-community collaboration in the deployment of the HSA in a low socio-economic status elementary school. Two theoretical models--the HSA and Hoover-Dempsey et al. (1997, 2010) models--guided the analysis of five discussion groups (N = 31) regarding their perceptions of the…

Development of a new sensitive immunostrip assay based on mesoporous silica and colloidal Au nanoparticles.

PubMed

Omidfar, Kobra; Khorsand, Behnosh; Larijani, Bagher

2012-02-01

A new competitive immunostrip assay was developed to detect human serum albumin (HSA) in urine sample with use of conjugated monoclonal antibody gold nanoparticles (mAb-AuNPs) and mobile crystalline material (MCM)-41-HSA bioconjugate. To prepare the immunostrip, the colloidal AuNPs with an average particle diameter of 20 nm, was synthesized, labeled with antibody and applied on the conjugate pad as the detection reagent. Then, HSA was attached to the MCM-41 mesoporous nanoparticles and immobilized to a nitrocellulose membrane as the test line. In the optimized investigational conditions, the immunostrip could detect HSA in a high linear range (from 1 to 200 μg/ml) and low detection limit (ng/ml). The reliability of the testing procedure was examined by performing the immunostrip test with 30 urine samples and comparing the results with those obtained via immunoturbidimetry. The immunostrip was adequately sensitive and accurate for a rapid screening of HSA in the urine. This new strategy for competitive immunostrip design can be used and developed for other antigen based immunostrip assay.

Impact of Biologics With and Without Concomitant MTX and at Reduced Doses in Older Rheumatoid Arthritis Patients

PubMed Central

Zhang, Jie; Xie, Fenglong; Delzell, Elizabeth; Yun, Huifeng; Lewis, James D; Haynes, Kevin; Chen, Lang; Beukelman, Timothy; Saag, Kenneth G; Curtis, Jeffrey R

2014-01-01

Background This study examines whether concomitant methotrexate (MTX) use is associated with better biologic persistence and whether self-administered anti-TNF therapies are used at reduced doses in real-world clinical care settings, not just clinical trials. Methods We conducted a retrospective cohort study among RA patients using Medicare claims data from 2006 to 2012. Subjects were new initiators of etanercept, infliximab, adalimumab, abatacept and tocilizumab with at least 12 months of continuous medical and pharmacy coverage after treatment initiation. We examined the association between concomitant MTX use and persistence on biologics using Cox proportional hazard regression adjusting for demographics and baseline co-morbidities. We further identified a subgroup of patients who initiated and were adherent on etanercept or adalimumab for at least 12 months and examined the proportion of patients who subsequently used these therapies at reduced doses continuously for an additional 12, 18, and 24 months. Results Of 26,510 eligible RA patients, 10,511 initiated biologic monotherapy. Overall, patients initiated biologic monotherapy were 1.4 (95% CI, 1.3–1.5) times more likely to discontinue at 1-year and 1.8 (95% CI, 1.7–2.0) times more likely if starting infliximab monotherapy. Approximately 10–20% of patients who initiated and adhered to etanercept and adalimumab for ≥ 12 months subsequently used reduced-dose therapy for an 12 additional months and beyond. Conclusion In real-world practice, concomitant MTX was associated with improved persistence on biologic therapy, especially for infliximab users; reduced-dose injectable anti-TNF therapy was used by a substantial proportion of RA patients. PMID:25370912

Improving the safety of high-dose methotrexate for children with hematologic cancers in settings without access to MTX levels using extended hydration and additional leucovorin.

PubMed

Vaishnavi, Kalthi; Bansal, Deepak; Trehan, Amita; Jain, Richa; Attri, Savita Verma

2018-05-16

A lack of access to methotrexate levels is common in low- and middle-income countries (LMIC), relevant for 80% of children with cancer worldwide. We evaluated whether high-dose methotrexate (HD-MTX) can be administered safely with extended hydration and leucovorin rescue, with monitoring of serum creatinine and urine pH. The prospective study was conducted at a single centre in Chandigarh, India in 2015. Patients with B-cell acute lymphoblastic leukemia (ALL) or with T-cell ALL or non-Hodgkin lymphoma (T-NHL) were administered 3 and 5 gm/m 2 of MTX (24 hr infusion), respectively. Six doses of leucovorin (15 mg/m 2 /dose), instead of recommended three (for optimally reduced levels) at standard timing (42 hr from start of HD-MTX) were administered. Hydration (125 ml/m 2 /hr) was continued for 72 hr, instead of the recommended 30 hr. Hydration fluid consisted of 0.45% sodium chloride, 5% dextrose, 7.5% sodium bicarbonate (50 mmol/l) and potassium chloride (20 mmol/l). Serum creatinine and urine pH were measured at baseline, 24 and 48 hr. The volume of hydration was increased (200 ml/m 2 /hr) for a serum creatinine > 1.25 times the baseline. The study included 100 cycles of HD-MTX in 53 patients: B-ALL 25 patients (51 cycles), T-ALL 16 patients (28 cycles), T-NHL 10 patients (18 cycles), and relapsed ALL 2 patients (3 cycles). The mean age was 6.8 ± 3.2 years. Patients were underweight in 15 (15%) cycles. Patients in 23% of cycles had a rise in creatinine to >1.25 times the baseline. Toxicities (NCI CTCAE v4.0) included mucositis (32%), diarrhoea (10%), and febrile neutropenia (9%). One patient died from dengue shock syndrome. It is safe to administer 3 or 5 gm/m 2 of MTX (24 hr infusion) without measuring MTX levels, with extended hydration, additional doses of leucovorin, and monitoring of serum creatinine and urine pH. © 2018 Wiley Periodicals, Inc.

RES-loaded pegylated CS NPs: for efficient ocular delivery.

PubMed

Pandian, Saravanakumar; Jeevanesan, Vinoth; Ponnusamy, Chandrasekar; Natesan, Subramanian

2017-02-01

The objective of this study is to develop resveratrol (RES) loaded polyethylene glycols (PEGs) modified chitosan (CS) nanoparticles (NPs) by ionic gelation method for the treatment of glaucoma. While increasing the concentration of PEG, the particle size and polydispersity index of the formulations increased. Entrapment efficiency and RES loading (RL) of NPs decreased while increasing PEG concentration. The in vitro release of NPs showed an initial burst release of RES (45%) followed by controlled release. Osmolality of formulations revealed that the prepared NPs were iso-osmolar with the tear. Ocular tolerance of the NPs was evaluated using hen's egg test on the chorioallantoic membrane and it showed that the NPs were non-irritant. RES-loaded PEG-modified CS NPs shows an improved corneal permeation compared with RES dispersion. Fluorescein isothiocyanate loaded CS NPs accumulated on the surface of the cornea but the PEG-modified CS NPs crossed the cornea and reached retinal choroid. RES-loaded PEG-modified CS NPs reduced the intra-ocular pressure (IOP) by 4.3 ± 0.5 mmHg up to 8 h in normotensive rabbits. These results indicate that the developed NPs have efficient delivery of RES to the ocular tissues and reduce the IOP for the treatment of glaucoma.

Targeting NPY, CRF/UCNs and NPS Neuropeptide Systems to Treat Alcohol Use Disorder (AUD).

PubMed

Rodriguez, Francisco D; Coveñas, Rafael

2017-01-01

The term Alcohol Use Disorder (AUD) incorporates different states of disease related to the recurrent use of alcohol and linked to the relevant impairment, disability and failure to perform major responsibilities in different realms. Many neurotransmitter systems are involved in the phases or states of alcoholism from reward mechanisms, associated to binge intoxication, to stress and anxiety linked to relapse and withdrawal. Some neuropeptides play a key function in the control of anxiety and stress, and establish a close relationship with the pathological mechanisms underlying alcohol addiction. Among them, Neuropeptide Y (NPY), Corticotropin-releasing factor (CRF)/Urocortins and Neuropeptide S (NPS) cross-talk, and are responsible for some of the maladaptation processes that the brain exhibits during the progression of the disease. In this study, we review the literature mainly focused on the participation of these neuropeptides in the pathophysiology of AUD, as well as on the use of antagonists designed to investigate signaling mechanisms initiated after ligand binding and their connection to biochemical adaptation events coupled to alcohol addiction. The possibility that these systems may serve as therapeutic objectives to mitigate or eliminate the harm that drinking ethanol generates, is also discussed. The peptide systems reviewed here, together with other neurotransmitter systems and their mutual relationships, are firm candidates to be targeted to treat AUD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Spectroscopic and molecular modeling study on the separate and simultaneous bindings of alprazolam and fluoxetine hydrochloride to human serum albumin (HSA): With the aim of the drug interactions probing

NASA Astrophysics Data System (ADS)

Dangkoob, Faeze; Housaindokht, Mohmmad Reza; Asoodeh, Ahmad; Rajabi, Omid; Rouhbakhsh Zaeri, Zeinab; Verdian Doghaei, Asma

2015-02-01

The objective of the present research is to study the interaction of separate and simultaneous of alprazolam (ALP) and fluoxetine hydrochloride (FLX) with human serum albumin (HSA) in phosphate buffer (pH 7.4) using different kinds of spectroscopic, cyclic voltammetry and molecular modeling techniques. The absorbance spectra of protein, drugs and protein-drug showed complex formation between the drugs and HSA. Fluorescence analysis demonstrated that ALP and FLX could quench the fluorescence spectrum of HSA and demonstrated the conformational change of HSA in the presence of both drugs. Also, fluorescence quenching mechanism of HSA-drug complexes both separately and simultaneously was suggested as static quenching. The analysis of UV absorption data and the fluorescence quenching of HSA in the binary and ternary systems showed that FLX decreased the binding affinity between ALP and HSA. On the contrary, ALP increased the binding affinity of FLX and HSA. The results of synchronous fluorescence and three-dimensional fluorescence spectra indicated that the binding of drugs to HSA would modify the microenvironment around the Trp and Tyr residues and the conformation of HSA. The distances between Trp residue and the binding sites of the drugs were estimated according to the Förster theory, and it was demonstrated that non-radiative energy transfer from HSA to the drugs occurred with a high probability. Moreover, according to CV measurements, the decrease of peak current in the cyclic voltammogram of the both drugs in the presence of HSA revealed that they interacted with albumin and binding constants were calculated for binary systems which were in agreement with the binding constants obtained from UV absorption and fluorescence spectroscopy. The prediction of the best binding sites of ALP and FLX in binary and ternary systems in molecular modeling approach was done using of Gibbs free energy.

Spectroscopic and molecular modeling study on the separate and simultaneous bindings of alprazolam and fluoxetine hydrochloride to human serum albumin (HSA): with the aim of the drug interactions probing.

PubMed

Dangkoob, Faeze; Housaindokht, Mohmmad Reza; Asoodeh, Ahmad; Rajabi, Omid; Rouhbakhsh Zaeri, Zeinab; Verdian Doghaei, Asma

2015-02-25

The objective of the present research is to study the interaction of separate and simultaneous of alprazolam (ALP) and fluoxetine hydrochloride (FLX) with human serum albumin (HSA) in phosphate buffer (pH 7.4) using different kinds of spectroscopic, cyclic voltammetry and molecular modeling techniques. The absorbance spectra of protein, drugs and protein-drug showed complex formation between the drugs and HSA. Fluorescence analysis demonstrated that ALP and FLX could quench the fluorescence spectrum of HSA and demonstrated the conformational change of HSA in the presence of both drugs. Also, fluorescence quenching mechanism of HSA-drug complexes both separately and simultaneously was suggested as static quenching. The analysis of UV absorption data and the fluorescence quenching of HSA in the binary and ternary systems showed that FLX decreased the binding affinity between ALP and HSA. On the contrary, ALP increased the binding affinity of FLX and HSA. The results of synchronous fluorescence and three-dimensional fluorescence spectra indicated that the binding of drugs to HSA would modify the microenvironment around the Trp and Tyr residues and the conformation of HSA. The distances between Trp residue and the binding sites of the drugs were estimated according to the Förster theory, and it was demonstrated that non-radiative energy transfer from HSA to the drugs occurred with a high probability. Moreover, according to CV measurements, the decrease of peak current in the cyclic voltammogram of the both drugs in the presence of HSA revealed that they interacted with albumin and binding constants were calculated for binary systems which were in agreement with the binding constants obtained from UV absorption and fluorescence spectroscopy. The prediction of the best binding sites of ALP and FLX in binary and ternary systems in molecular modeling approach was done using of Gibbs free energy. Copyright © 2014 Elsevier B.V. All rights reserved.

A targeted drug delivery system based on dopamine functionalized nano graphene oxide

NASA Astrophysics Data System (ADS)

Masoudipour, Elham; Kashanian, Soheila; Maleki, Nasim

2017-01-01

The cellular targeting property of a biocompatible drug delivery system can widely increase the therapeutic effect against various diseases. Here, we report a dopamine conjugated nano graphene oxide (DA-nGO) carrier for cellular delivery of the anticancer drug, Methotrexate (MTX) into DA receptor positive human breast adenocarcinoma cell line. The material was characterized using scanning electron microscopy, atomic force microscopy, Fourier transform infrared spectroscopy and UV-vis spectroscopy. Furthermore, the antineoplastic action of MTX loaded DA-nGO against DA receptor positive and negative cell lines were explored. The results presented in this article demonstrated that the application of DA functionalized GO as a targeting drug carrier can improve the drug delivery efficacy for DA receptor positive cancer cell lines and promise future designing of carrier conjugates based on it.

Agreement With Conjoined NPs Reflects Language Experience.

PubMed

Lorimor, Heidi; Adams, Nora C; Middleton, Erica L

2018-01-01

An important question within psycholinguistic research is whether grammatical features, such as number values on nouns, are probabilistic or discrete. Similarly, researchers have debated whether grammatical specifications are only set for individual lexical items, or whether certain types of noun phrases (NPs) also obtain number valuations at the phrasal level. Through a corpus analysis and an oral production task, we show that conjoined NPs can take both singular and plural verb agreement and that notional number (i.e., the numerosity of the referent of the subject noun phrase) plays an important role in agreement with conjoined NPs. In two written production tasks, we show that participants who are exposed to plural (versus singular or unmarked) agreement with conjoined NPs in a biasing story are more likely to produce plural agreement with conjoined NPs on a subsequent production task. This suggests that, in addition to their sensitivity to notional information, conjoined NPs have probabilistic grammatical specifications that reflect their distributional properties in language. These results provide important evidence that grammatical number reflects language experience, and that this language experience impacts agreement at the phrasal level, and not just the lexical level.

Agreement With Conjoined NPs Reflects Language Experience

PubMed Central

Lorimor, Heidi; Adams, Nora C.; Middleton, Erica L.

2018-01-01

An important question within psycholinguistic research is whether grammatical features, such as number values on nouns, are probabilistic or discrete. Similarly, researchers have debated whether grammatical specifications are only set for individual lexical items, or whether certain types of noun phrases (NPs) also obtain number valuations at the phrasal level. Through a corpus analysis and an oral production task, we show that conjoined NPs can take both singular and plural verb agreement and that notional number (i.e., the numerosity of the referent of the subject noun phrase) plays an important role in agreement with conjoined NPs. In two written production tasks, we show that participants who are exposed to plural (versus singular or unmarked) agreement with conjoined NPs in a biasing story are more likely to produce plural agreement with conjoined NPs on a subsequent production task. This suggests that, in addition to their sensitivity to notional information, conjoined NPs have probabilistic grammatical specifications that reflect their distributional properties in language. These results provide important evidence that grammatical number reflects language experience, and that this language experience impacts agreement at the phrasal level, and not just the lexical level. PMID:29725311

Dual channel sensitive detection of hsa-miR-21 based on rolling circle amplification and quantum dots tagging.

PubMed

Wangt, Dan-Chen; Hu, Li-Hui; Zhou, Yu-Hui; Huang, Yu-Ting; Li, Xinhua; Zhu, Jun-Jie

2014-04-01

An isothermal, highly sensitive and specific assay for the detection of hsa-miR-21 with the integration of QDs tagging and rolling circle amplification was offered. In addition, a dual channel strategy for miRNA detection was proposed: anodic stripping voltammetry (ASV) and fluorescent method were both performed for the final Cd2+ signal readout. The designed strategy exhibited good specificity to hsa-miR-21 and presented comparable detection results by detection methods.

Olive-oil nanocapsules stabilized by HSA: influence of processing variables on particle properties

NASA Astrophysics Data System (ADS)

Molina-Bolívar, J. A.; Galisteo-González, F.

2015-10-01

Liquid lipid nanocapsules (LLN) are considered to be promising drug carriers in the medical field. The size and the surface charge of these nanocarriers are of major importance, affecting their bioavailability and the in vivo behaviour after intravenous injection. This research provides a comprehensive study on the preparation of olive-oil nanocapsules stabilized with a human serum albumin shell (HSA). LLN were prepared by modified solvent-displacement method. Numerous experimental variables were examined in order to characterize their impact on LLN size, distribution, and electrophoretic mobility. Physicochemical parameters of LLN were controlled by adjusting the nanodroplet stabilizing shell of adsorbed protein molecules, which was affected by the oil:HSA ratio, pH, and ionic strength of aqueous medium. The stronger the repulsion between adsorbed HSA molecules, the smaller and more monodisperse the particles proved. Other process parameters, including the ethanol:acetone ratio, organic:aqueous phase ratio, speed of organic-phase injection, and stirring rate were examined to achieve optimum preparation conditions. LLN produced by our standardized formulation were in the range of 170-175 nm with low polydispersity index (<0.1). Long-term colloidal stability of samples was evaluated after 6 months of storage. Efficient incorporation of curcumin, a model for a water-insoluble drug, into olive-oil nanocapsules was achieved (90 %). Encapsulation of curcumin into LLN had a stabilizing effect with respect to drug photodecomposition compared to that of the free molecule in solution.

Drug-loaded gold/iron/gold plasmonic nanoparticles for magnetic targeted chemo-photothermal treatment of rheumatoid arthritis.

PubMed

Kim, Hyung Joon; Lee, Sun-Mi; Park, Kyu-Hyung; Mun, Chin Hee; Park, Yong-Beom; Yoo, Kyung-Hwa

2015-08-01

We have developed methotrexate (MTX)-loaded poly(lactic-co-glycolic acid, PLGA) gold (Au)/iron (Fe)/gold (Au) half-shell nanoparticles conjugated with arginine-glycine-aspartic acid (RGD), which can be applied for magnetic targeted chemo-photothermal treatment, and in vivo multimodal imaging of rheumatoid arthritis (RA). Upon near-infrared (NIR) irradiation, local heat is generated at the inflammation region due to the NIR resonance of Au half-shells and MTX release from PLGA nanoparticles is accelerated. The Fe half-shell layer embedded between the Au half-shell layers enables in vivo T2-magnetic resonance (MR) imaging in addition to NIR absorbance imaging. Furthermore, the delivery of the nanoparticles to the inflammation region in collagen-induced arthritic (CIA) mice, and their retention can be enhanced under external magnetic field. When combined with consecutive NIR irradiation and external magnetic field application, these nanoparticles provide enhanced therapeutic effects with an MTX dosages of only 0.05% dosage compared to free MTX therapy for the treatment of RA. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effects of E2HSA, a Long-Acting Glucagon Like Peptide-1 Receptor Agonist, on Glycemic Control and Beta Cell Function in Spontaneous Diabetic db/db Mice.

PubMed

Hou, Shaocong; Li, Caina; Huan, Yi; Liu, Shuainan; Liu, Quan; Sun, Sujuan; Jiang, Qian; Jia, Chunming; Shen, Zhufang

2015-01-01

Glucagon like peptide-1 (GLP-1) receptor agonists such as exendin-4 have been widely used but their short half-life limits their therapeutic value. The recombinant protein, E2HSA, is a novel, long-acting GLP-1 receptor agonist generated by the fusion of exendin-4 with human serum albumin. In mouse pancreatic NIT-1 cells, E2HSA activated GLP-1 receptor with similar efficacy as exendin-4. After single-dose administration in ICR mice, E2HSA showed prolonged glucose lowering effects which lasted up to four days and extended inhibition on gastric emptying for at least 72 hours. Chronic E2HSA treatment in db/db mice significantly improved glucose tolerance, reduced elevated nonfasting and fasting plasma glucose levels, and also decreased HbA1c levels. E2HSA also increased insulin secretion and decreased body weight and appetite. Furthermore, immunofluorescence analysis showed that E2HSA increased β-cell area, improved islet morphology, and reduced β-cell apoptosis. In accordance with the promotion of β-cell function and survival, E2HSA upregulated genes such as Irs2, Pdx-1, Nkx6.1, and MafA and downregulated the expression levels of FoxO1 and proapoptotic Bcl-2 family proteins. In conclusion, with prolonged glucose lowering effects and promoting β-cell function and survival, the fusion protein, E2HSA, is a promising new therapeutic for once weekly treatment of type 2 diabetes.

Effects of E2HSA, a Long-Acting Glucagon Like Peptide-1 Receptor Agonist, on Glycemic Control and Beta Cell Function in Spontaneous Diabetic db/db Mice

PubMed Central

Hou, Shaocong; Li, Caina; Liu, Shuainan; Liu, Quan; Sun, Sujuan; Jia, Chunming; Shen, Zhufang

2015-01-01

Glucagon like peptide-1 (GLP-1) receptor agonists such as exendin-4 have been widely used but their short half-life limits their therapeutic value. The recombinant protein, E2HSA, is a novel, long-acting GLP-1 receptor agonist generated by the fusion of exendin-4 with human serum albumin. In mouse pancreatic NIT-1 cells, E2HSA activated GLP-1 receptor with similar efficacy as exendin-4. After single-dose administration in ICR mice, E2HSA showed prolonged glucose lowering effects which lasted up to four days and extended inhibition on gastric emptying for at least 72 hours. Chronic E2HSA treatment in db/db mice significantly improved glucose tolerance, reduced elevated nonfasting and fasting plasma glucose levels, and also decreased HbA1c levels. E2HSA also increased insulin secretion and decreased body weight and appetite. Furthermore, immunofluorescence analysis showed that E2HSA increased β-cell area, improved islet morphology, and reduced β-cell apoptosis. In accordance with the promotion of β-cell function and survival, E2HSA upregulated genes such as Irs2, Pdx-1, Nkx6.1, and MafA and downregulated the expression levels of FoxO1 and proapoptotic Bcl-2 family proteins. In conclusion, with prolonged glucose lowering effects and promoting β-cell function and survival, the fusion protein, E2HSA, is a promising new therapeutic for once weekly treatment of type 2 diabetes. PMID:26351642

Detection of micro RNA hsa-let-7e in peripheral blood mononuclear cells infected with dengue virus serotype-2: preliminary study

NASA Astrophysics Data System (ADS)

Masyeni, S.; Hadi, U.; Kuntaman; Yohan, B.; Margyaningsih, N. I.; Sasmono, R. T.

2018-03-01

Pathogenesis of dengue infection is still obscure. Recently, the role of microRNA has been associated with the cytokine storm which leads to plasma leakage in endothelial cells. The objective of our study was to determine whether particular microRNA is overexpressed in PBMCs infected with DENV and to assess its correlation to the expression of suppressor of cytokine signaling 3 (SOCS3) proteins to increase the production of pro-inflammatory cytokines. We report the result of a preliminary study on the expression of microRNA hsa-let-7e. The peripheral blood mononuclear cells (PBMCs) from the healthy volunteer were infected with the clinical isolate of DENV-2. RNA was extracted with miRCURYLNATMExiqon. Quantitative Real-Time PCR was used to measure the relative expression of hsa-let-7e micro RNA and the mRNA of SOCS3 proteins. MicroRNA hsa-let-7e expression was increased in PBMCs upon DENV-2 infection. The relative expression of hsa-let-7e is detected at 1.46 folds relative to uninfected PBMCs in 4 hours post-infection and decreased in 19 hours post infection. In contrast, the expression of mRNA of SOCS3 was inversely expressed with hsa-let-7 expression. MicroRNA was overexpressed in PBMCs upon infection with DENV-2. This microRNA may bind the SOCS3 and contribute to the pathogenesis of dengue infection.

Spectroscopic analysis of the impact of oxidative stress on the structure of human serum albumin (HSA) in terms of its binding properties

NASA Astrophysics Data System (ADS)

Maciążek-Jurczyk, M.; Sułkowska, A.

2015-02-01

Oxygen metabolism has an important role in the pathogenesis of rheumatoid arthritis (RA). Reactive oxygen species (ROS) are produced in the course of cellular oxidative phosphorylation and by activated phagocytic cells during oxidative bursts, exceed the physiological buffering capacity and result in oxidative stress. ROS result in oxidation of serum albumin, which causes a number of structural changes in the spatial structure, may influence the binding and cause significant drug interactions, particularly in polytherapy. During the oxidation modification of amino acid residues, particularly cysteine and methionine may occur. The aim of the study was to investigate the influence of oxidative stress on human serum albumin (HSA) structure and evaluate of possible alterations in the binding of the drug to oxidized human serum albumin (oHSA). HSA was oxidized by a chloramine-T (CT). CT reacts rapidly with sulfhydryl groups and at pH 7.4 the reaction was monitored by spectroscopic techniques. Modification of free thiol group in the Cys residue in HSA was quantitatively determined by the use of Ellman's reagent. Changes of albumin conformation were examined by comparison of modified (oHSA) and nonmodified human serum albumin (HSA) absorption spectra, emission spectra, red-edge shift (REES) and synchronous spectroscopy. Studies of absorption spectra indicated that changes in the value of absorbance associated with spectral changes in the region of 200-250 nm involve structural alterations in peptide backbone conformation. Synchronous fluorescence spectroscopy technique confirmed changes of position of tryptophanyl and tyrosyl residues fluorescent band caused by CT. Moreover analysis of REES effect allowed to observe structural changes caused by CT in the region of the hydrophobic pocket containing the tryptophanyl residue. Effect of oxidative stress on binding of anti-rheumatic drugs, sulfasalazine (SSZ) and sulindac (SLD) in the high and low affinity binding sites was

A novel double-targeted nondrug delivery system for targeting cancer stem cells

PubMed Central

Qiao, Shupei; Zhao, Yufang; Geng, Shuai; Li, Yong; Hou, Xiaolu; Liu, Yi; Lin, Feng-Huei; Yao, Lifen; Tian, Weiming

2016-01-01

Instead of killing cancer stem cells (CSCs), the conventional chemotherapy used for cancer treatment promotes the enrichment of CSCs, which are responsible for tumor growth, metastasis, and recurrence. However, most therapeutic agents are only able to kill a small proportion of CSCs by targeting one or two cell surface markers or dysregulated CSC pathways, which are usually shared with normal stem cells (NSCs). In this study, we developed a novel nondrug delivery system for the dual targeting of CSCs by conjugating hyaluronic acid (HA) and grafting the doublecortin-like kinase 1 (DCLK1) monoclonal antibody to the surface of poly(ethylene glycol) (PEG)–poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs), which can specifically target CD44 receptors and the DCLK1 surface marker – the latter was shown to possess the capacity to distinguish between CSCSs and NSCs. The size and morphology of these NPs were characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), and scanning electron microscopy (SEM). This was followed by studies of NP encapsulation efficiency and in vitro drug release properties. Then, the cytotoxicity of the NPs was tested via Cell Counting Kit-8 assay. Finally, the 4T1 CSCs were obtained from the alginate-based platform, which we developed as an in vitro tumor model. Tumor-bearing nude mice were used as in vivo models to systematically detect the ability of NPs to target CSCs. Our results showed that the DCLK1–HA–PEG–PLGA NPs exhibited a targeting effect toward CSCs both in vitro and in vivo. These findings have important implications for the rational design of drug delivery systems that target CSCs with high efficacy. PMID:27994463

NPS-SCAT: Electrical Power System

DTIC Science & Technology

2009-09-01

ground station . An initial low power receive mode will allow the ground station to contact SCAT 16 M.P. Schroer, NPS-SCAT; A... station . As shown in Table 6, the power loads of the subsystems using the Watt hour method discussed in section B above, it can be seen that 0.966...telemetry data back to the NPS ground station , the only subsystem open to manipulation with respect to power saving is the beacon secondary transmissions

The multilayer nanoparticles formed by layer by layer approach for cancer-targeting therapy.

PubMed

Oh, Keun Sang; Lee, Hwanbum; Kim, Jae Yeon; Koo, Eun Jin; Lee, Eun Hee; Park, Jae Hyung; Kim, Sang Yoon; Kim, Kwangmeyung; Kwon, Ick Chan; Yuk, Soon Hong

2013-01-10

The multilayer nanoparticles (NPs) were prepared for cancer-targeting therapy using the layer by layer approach. When drug-loaded Pluronic NPs were mixed with vesicles (liposomes) in the aqueous medium, Pluronic NPs were incorporated into the vesicles to form the vesicle NPs. Then, the multilayer NPs were formed by freeze-drying the vesicle NPs in a Pluronic aqueous solution. The morphology and size distribution of the multilayer NPs were observed using a TEM and a particle size analyzer. In order to apply the multilayer NPs as a delivery system for docetaxel (DTX), which is a model anticancer drug, the release pattern of the DTX was observed and the tumor growth was monitored by injecting the multilayer NPs into the tail veins of tumor (squamous cell carcinoma)-bearing mice. The cytotoxicity of free DTX (commercial DTX formulation (Taxotere®)) and the multilayer NPs was evaluated using MTT assay. We also evaluated the tumor targeting ability of the multilayer NPs using magnetic resonance imaging. The multilayer NPs showed excellent tumor targetability and antitumor efficacy in tumor-bearing mice, caused by the enhanced permeation and retention (EPR) effect. These results suggest that the multilayer NPs could be a potential drug delivery system for cancer-targeting therapy. Copyright © 2012 Elsevier B.V. All rights reserved.

MiRNA Analysis by Quantitative PCR in Preterm Human Breast Milk Reveals Daily Fluctuations of hsa-miR-16-5p

PubMed Central

Floris, Ilaria; Billard, Hélène; Boquien, Clair-Yves; Joram-Gauvard, Evelyne; Simon, Laure; Legrand, Arnaud; Boscher, Cécile; Rozé, Jean-Christophe; Bolaños-Jiménez, Francisco; Kaeffer, Bertrand

2015-01-01

Background and Aims Human breast milk is an extremely dynamic fluid containing many biologically-active components which change throughout the feeding period and throughout the day. We designed a miRNA assay on minimized amounts of raw milk obtained from mothers of preterm infants. We investigated changes in miRNA expression within month 2 of lactation and then over the course of 24 hours. Materials and Methods Analyses were performed on pooled breast milk, made by combining samples collected at different clock times from the same mother donor, along with time series collected over 24 hours from four unsynchronized mothers. Whole milk, lipids or skim milk fractions were processed and analyzed by qPCR. We measured hsa-miR-16-5p, hsa-miR-21-5p, hsa-miR-146-5p, and hsa-let-7a, d and g (all -5p). Stability of miRNA endogenous controls was evaluated using RefFinder, a web tool integrating geNorm, Normfinder, BestKeeper and the comparative ΔΔCt method. Results MiR-21 and miR-16 were stably expressed in whole milk collected within month 2 of lactation from four mothers. Analysis of lipids and skim milk revealed that miR-146b and let-7d were better references in both fractions. Time series (5H-23H) allowed the identification of a set of three endogenous reference genes (hsa-let-7d, hsa-let-7g and miR-146b) to normalize raw quantification cycle (Cq) data. We identified a daily oscillation of miR-16-5p. Perspectives Our assay allows exploring miRNA levels of breast milk from mother with preterm baby collected in time series over 48–72 hours. PMID:26474056

MiRNA Analysis by Quantitative PCR in Preterm Human Breast Milk Reveals Daily Fluctuations of hsa-miR-16-5p.

PubMed

Floris, Ilaria; Billard, Hélène; Boquien, Clair-Yves; Joram-Gauvard, Evelyne; Simon, Laure; Legrand, Arnaud; Boscher, Cécile; Rozé, Jean-Christophe; Bolaños-Jiménez, Francisco; Kaeffer, Bertrand

2015-01-01

Human breast milk is an extremely dynamic fluid containing many biologically-active components which change throughout the feeding period and throughout the day. We designed a miRNA assay on minimized amounts of raw milk obtained from mothers of preterm infants. We investigated changes in miRNA expression within month 2 of lactation and then over the course of 24 hours. Analyses were performed on pooled breast milk, made by combining samples collected at different clock times from the same mother donor, along with time series collected over 24 hours from four unsynchronized mothers. Whole milk, lipids or skim milk fractions were processed and analyzed by qPCR. We measured hsa-miR-16-5p, hsa-miR-21-5p, hsa-miR-146-5p, and hsa-let-7a, d and g (all -5p). Stability of miRNA endogenous controls was evaluated using RefFinder, a web tool integrating geNorm, Normfinder, BestKeeper and the comparative ΔΔCt method. MiR-21 and miR-16 were stably expressed in whole milk collected within month 2 of lactation from four mothers. Analysis of lipids and skim milk revealed that miR-146b and let-7d were better references in both fractions. Time series (5H-23H) allowed the identification of a set of three endogenous reference genes (hsa-let-7d, hsa-let-7g and miR-146b) to normalize raw quantification cycle (Cq) data. We identified a daily oscillation of miR-16-5p. Our assay allows exploring miRNA levels of breast milk from mother with preterm baby collected in time series over 48-72 hours.

Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naive with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab's Efficacy in MTX iNadequate rEsponders (SERENE)).

PubMed

Emery, P; Deodhar, A; Rigby, W F; Isaacs, J D; Combe, B; Racewicz, A J; Latinis, K; Abud-Mendoza, C; Szczepanski, L J; Roschmann, R A; Chen, A; Armstrong, G K; Douglass, W; Tyrrell, H

2010-09-01

This phase III study evaluated the efficacy and safety of rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to MTX and who were naïve to prior biological treatment. Patients with active disease on stable MTX (10-25 mg/week) were randomised to rituximab 2 x 500 mg (n=168), rituximab 2 x 1000 mg (n=172), or placebo (n=172). From week 24, patients not in remission (Disease Activity Score (28 joints) > or =2.6) received a second course of rituximab; patients initially assigned to placebo switched to rituximab 2 x 500 mg. The primary end point was American College of Rheumatology 20 (ACR20) response at week 24. All patients were followed until week 48. At week 24, both doses of rituximab showed statistically superior efficacy (p<0.0001) to placebo (ACR20: 54%, 51% and 23%; rituximab (2 x 500 mg) + MTX, rituximab (2 x 1000 mg) + MTX and placebo + MTX, respectively). Secondary end points were also significantly improved for both rituximab groups compared with placebo. Further improvements in both rituximab arms were observed from week 24 to week 48. Rituximab + MTX was well tolerated, demonstrating comparable safety to placebo + MTX through to week 24, and between rituximab doses through to week 48. Rituximab (at 2 x 500 mg and 2 x 1000 mg) plus MTX significantly improved clinical outcomes at week 24, which were further improved by week 48. No significant differences in either clinical or safety outcomes were apparent between the rituximab doses.

Nuclear blebbing of biologically active organoselenium compound towards human cervical cancer cell (HeLa): in vitro DNA/HSA binding, cleavage and cell imaging studies.

PubMed

Rizvi, Masood Ahmad; Zaki, Mehvash; Afzal, Mohd; Mane, Manoj; Kumar, Manjeet; Shah, Bhahwal Ali; Srivastav, Saurabh; Srikrishna, Saripella; Peerzada, Ghulam Mustafa; Tabassum, Sartaj

2015-01-27

New pharmacophore organoselenium compound (1) was designed, synthesized and characterized by various spectroscopic methods (IR, ESI-MS, (1)H, (13)C and (77)Se NMR) and further confirmed by X-ray crystallography. Compound 1 consists of two 3,5-bis(trifluoromethyl)phenyl units which are connected to the selenium atom via the organometallic C-Se bond. In vitro DNA binding studies of 1 was investigated by absorption and emission titration methods which revealed that 1 recognizes the minor groove of DNA in accordance with molecular docking studies with the DNA duplex. Gel electrophoretic assay demonstrates the ability of 1 to cleave pBR322 DNA through hydrolytic process which was further validated by T4 religation assay. To understand the drug-protein interaction of which ultimate molecular target was DNA, the affinity of 1 towards HSA was also investigated by the spectroscopic and molecular modeling techniques which showed hydrophobic interaction in the subdomain IIA of HSA. Furthermore, the intracellular localization of 1 was evidenced by cell imaging studies using HeLa cells. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Synthesis, characterization, crystal structure and HSA binding of two new N,O,O-donor Schiff-base ligands derived from dihydroxybenzaldehyde and tert-butylamine

NASA Astrophysics Data System (ADS)

Khosravi, Iman; Hosseini, Farnaz; Khorshidifard, Mahsa; Sahihi, Mehdi; Rudbari, Hadi Amiri

2016-09-01

Two new o-hydroxy Schiff-bases compounds, L1 and L2, were derived from the 1:1 M condensation of 2,3-dihydroxybenzaldehyde and 2,4-dihydroxybenzaldehyde with tert-butylamine and were characterized by elemental analysis, FT-IR, 1H and 13C NMR spectroscopies. The crystal structure of L2 was also determined by single crystal X-ray analysis. The crystal structure of L2 showed that the compound exists as a zwitterionic form in the solid state, with the H atom of the phenol group being transferred to the imine N atom. It adopts an E configuration about the central Cdbnd N double bond. Furthermore, binding of these Schiff base ligands to Human Serum Albumin (HSA) was investigated by fluorescence quenching, absorption spectroscopy, molecular docking and molecular dynamics (MD) simulation methods. The fluorescence emission of HSA was quenched by ligands. Also, suitable models were used to analyze the UV-vis absorption spectroscopy data for titration of HSA solution by various amounts of Schiff bases. The spectroscopic studies revealed that these Schiff bases formed 1:1 complex with HSA. Energy transfer mechanism of quenching was discussed and the values of 3.35 and 1.57 nm as the mean distances between the bound ligands and the HSA were calculated for L1 and L2, respectively. Molecular docking results indicated that the main active binding site for these Schiff bases ligands is in subdomain IB. Moreover, MD simulation results suggested that this Schiff base complex can interact with HSA, with a slight modification of its tertiary structure.

Exciton-Plasmon Interaction between AuNPs/Graphene Nanohybrids and CdS Quantum Dots/TiO2 for Photoelectrochemical Aptasensing of Prostate-Specific Antigen.

PubMed

Cai, Guoneng; Yu, Zhengzhong; Ren, Rongrong; Tang, Dianping

2018-03-23

A competitive-displacement reaction strategy based on target-induced dissociation of gold nanoparticle coated graphene nanosheet (AuNPs/GN) from CdS quantum dot functionalized mesoporous titanium dioxide (CdS QDs/TiO 2 ) was designed for the sensitive photoelectrochemical (PEC) aptasensing of prostate-specific antigen (PSA) through the exciton-plasmon interaction (EPI) between CdS QDs and AuNPs. To construct such an aptasensing system, capture DNA was initially conjugated covalently onto CdS QDs/TiO 2 -modified electrode, and then AuNPs/GN-labeled PSA aptamer was bound onto biofunctionalized CdS QDs/TiO 2 via hybridization chain reaction of partial bases with capture DNA. Introduction of AuNPs/GN efficiently quenched the photocurrent of CdS QDs/TiO 2 thanks to energy transfer. Upon addition of target PSA, the sandwiched aptamer between CdS QDs/TiO 2 and AuNPs/GN reacted with the analyte analyte, thus resulting in the dissociation of AuNPs/GN from the CdS QDs/TiO 2 to increase the photocurrent. Under optimum conditions, the aptasensing platform exhibited a high sensitivity for PSA detection within a dynamic linear range of 1.0 pg/mL to 8.0 ng/mL at a low limitat of detection of 0.52 pg/mL. The interparticle distance of exciton-plasmon interaction and contents of AuNPs corresponding to EPI effect in this system were also studied. Good selectivity and high reproducibility were obtained for the analysis of target PSA. Importantly, the accuracy and matrix effect of PEC aptasensor was evaluated for the determination of human serum specimens and newborn calf serum-diluted PSA standards, giving a well-matched result with the referenced PSA ELISA kit.

The inhibitory effect of disulfiram encapsulated PLGA NPs on tumor growth: Different administration routes.

PubMed

Fasehee, Hamidreza; Zarrinrad, Ghazaleh; Tavangar, Seyed Mohammad; Ghaffari, Seyed Hamidollah; Faghihi, Shahab

2016-06-01

The strong anticancer activity of disulfiram is hindered by its rapid degradation in blood system. A novel folate-receptor-targeted poly (lactide-co-glycolide) (PLGA)-polyethylene glycol (PEG) nanoparticle (NP) is developed for encapsulation and delivery of disulfiram into breast cancer tumor using passive (EPR effect) and active (folate receptor) targeting. The anticancer activity of disulfiram and its effect on caspase-3 activity and cell cycle are studied. The administration of encapsulated PLGA NPs using intra-peritoneal, intravenous and intra-tumor routes is investigated using animal model. Disulfiram shows strong cytotoxicity against MCF7 cell line. The activity of caspase-3 inhibited with disulfiram via dose dependent manner while the drug causes cell cycle arrest in G0/G1 and S phase time-dependently. The encapsulated disulfiram shows higher activity in apoptosis induction as compared to free drug. In nontoxic dose of encapsulated disulfiram, the highest and lowest efficacy of NPs in tumor growth inhibition is observed for intravenous injection and intraperitoneal injection. It is suggested that administration of disulfiram by targeted PLGA nanoparticles using intravenous injection would present an alternative therapeutic approach for solid tumor treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

NPS CubeSat Launcher Program Management

DTIC Science & Technology

2009-09-01

NAVAL POSTGRADUATE SCHOOL MONTEREY, CALIFORNIA THESIS Approved for public release; distribution is unlimited NPS CUBESAT LAUNCHER ...CubeSat Launcher Program Management 6. AUTHOR(S) Christina M. Hicks 5. FUNDING NUMBERS 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES...article in support of the NPS CubeSat Launcher (NPSCuL) project. This thesis will describe the process, experience, and results of managing the NPSCuL

Formulation and evaluation of targeted nanoparticles for breast cancer theranostic system.

PubMed

Dadras, Pegah; Atyabi, Fatemeh; Irani, Shiva; Ma'mani, Leila; Foroumadi, Alireza; Mirzaie, Zahra Hadavand; Ebrahimi, Marzieh; Dinarvand, R

2017-01-15

Theranostic polymeric NPs developed for both cancer diagnosis and cancer therapy. This multifunctional polymeric vehicle was prepared by a single emulsion evaporation method, using carboxyl-terminated PLGA. LHRH as a targeting moiety, was conjugated to the surface of polymeric carrier by applying polyethylene glycol. The results indicated that the diameter of NPs was ~185.4±4.6nm as defined by DLS. The entrapment efficacy of docetaxel, silibinin, and SPIONs was 84.6±4.1%, 80.6±2.7%, and 77.9±4.3%, respectively. The NPs showed a triphasic in-vitro drug release pattern. MTT assay was done on two cell lines, MCF-7 and SKOV-3. Enhanced cellular uptake ability of the targeted NPs to MCF-7 was evaluated in-vitro by confocal laser scanning microscopy. The results indicated that compared to non-targeted NPs, the LHRH targeted NPs had significant efficacy at IC50 concentration. The effect of the NPs on VEGF expression in MCF-7 and SKOV-3 cells was investigated by Real-Time PCR method. VEGF mRNA level expression in MCF-7 cell line reduced by 83% in comparison to control cell line. The designed NPs can be used as promising multifunctional platform for detection and targeted drug delivery in breast cancer. Copyright © 2016 Elsevier B.V. All rights reserved.

Enhanced Cellular Cytotoxicity and Antibacterial Activity of 18-β-Glycyrrhetinic Acid by Albumin-conjugated PLGA Nanoparticles.

PubMed

Darvishi, B; Manoochehri, S; Esfandyari-Manesh, M; Samadi, N; Amini, M; Atyabi, F; Dinarvand, R

2015-12-01

The aim of the present work was to encapsulate 18-β-Glycyrrhetinic acid (GLA) in albumin conjugated poly(lactide-co-glycolide) (PLGA) nanoparticles by a modified nanoprecipitation method. Nanoparticles (NPs) were prepared by different drug to polymer ratios, human serum albumin (HSA) content, dithiothreitol (as producer of free thiol groups) content, and acetone (as non-solvent in nanoprecipitation). NPs with a size ranging from 126 to 174 nm were achieved. The highest entrapment efficiency (89.4±4.2%) was achieved when the ratio of drug to polymer was 1:4. The zeta potential of NPs was fairly negative (-8 to -12). Fourier transform infrared spectroscopy and differential scanning calorimetry proved the conjugation of HSA to PLGA NPs. In vitro release profile of NPs showed 2 phases: an initial burst for 4 h (34-49%) followed by a slow release pattern up to the end. The antibacterial effects of NPs against Staphylococcus aureus, Staphylococcus epidermidis and Pseudomonas aeruginosa were studied by microdilution method. The GLA-loaded NPs showed more antibacterial effect than pure GLA (2-4 times). The anticancer MTT test revealed that GLA-loaded NPs were approximately 9 times more effective than pure GLA in Hep G2 cells. © Georg Thieme Verlag KG Stuttgart · New York.

Andrographolide-loaded nanoparticles for brain delivery: Formulation, characterisation and in vitro permeability using hCMEC/D3 cell line.

PubMed

Guccione, Clizia; Oufir, Mouhssin; Piazzini, Vieri; Eigenmann, Daniela Elisabeth; Jähne, Evelyn Andrea; Zabela, Volha; Faleschini, Maria Teresa; Bergonzi, Maria Camilla; Smiesko, Martin; Hamburger, Matthias; Bilia, Anna Rita

2017-10-01

Andrographolide (AG) is a major diterpenoid of the Asian medicinal plant Andrographis paniculata which has shown exciting pharmacological potential for the treatment of inflammation-related pathologies including neurodegenerative disorders. Conversely, the low bioavailability of AG still represents a limiting factor for its use. To overcome these limitations, AG was loaded into human serum albumin based nanoparticles (HSA NPs) and poly ethylcyanoacrylate nanoparticles (PECA NPs). HSA NPs were prepared by thermal (HSAT AG NPs) and chemical cross-linking (HSAC AG NPs), while PECA AG NPs were produced by emulsion-polymerization. NPs were characterized in terms of size, zeta (ζ)-potential, polydispersity, and release studies of AG. In addition, the ability of free AG and AG-loaded in PECA and HSAT NPs to cross the blood-brain barrier (BBB) was assessed using an in vitro BBB model based on human cerebral microvascular endothelial cell line (hCMEC/D3). For BBB drug permeability assays, a quantitative UPLC-MS/MS method for AG in Ringer HEPES buffer was developed and validated according to international regulatory guidelines for industry. Free AG did not permeate the BBB model, as also predicted by in silico studies. HSAT NPs improved by two-fold the permeation of AG while maintaining the integrity of the cell layer, while PECA NPs temporarily disrupted BBB integrity. Copyright © 2017 Elsevier B.V. All rights reserved.

Hypothesis: Do miRNAs Targeting the Leucine-Rich Repeat Kinase 2 Gene (LRRK2) Influence Parkinson's Disease Susceptibility?

PubMed

Yılmaz, Şenay Görücü; Geyik, Sırma; Neyal, Ayşe Münife; Soko, Nyarai D; Bozkurt, Hakan; Dandara, Collet

2016-04-01

Parkinson's disease (PD) is a frequently occurring neurodegenerative motor disorder adversely impacting global health. There is a paucity of biomarkers and diagnostics that can forecast susceptibility to PD. A new research frontier for PD pathophysiology is the study of variations in microRNA (miRNA) expression whereby miRNAs serve as "upstream regulators" of gene expression in relation to functioning of the dopamine neuronal pathways. Leucine-Rich Repeat Kinase 2 (LRRK2) is a frequently studied gene in PD. Little is known about the ways in which expression of miRNAs targeting LRKK2 impact PD susceptibility. In a sample of 204 unrelated subjects (102 persons with PD and 102 healthy controls), we report here candidate miRNA expression in whole blood samples as measured by real-time PCR (hsa-miR-4671-3p, hsa-miR-335-3p, hsa-miR-561-3p, hsa-miR-579-3p, and hsa-miR-3143) that target LRRK2. Using step-wise logistic regression, and controlling for covariates such as age, gender, PD disease severity, concomitant medications, and co-morbidity, we found that the combination of has-miR-335-3p, has-miR-561-3p, and has-miR-579-3p account for 50% of the variation in regards to PD susceptibility (p<0.0001). Notably, the hsa-miR-561-3p expression was the most robust predictor of PD in both univariate and multivariate analyses (p<0.001). Moreover, the biological direction (polarity) of the association was plausible in that the candidate miRNAs displayed a diminished expression in patients. This is consistent with the hypothesis that decreased levels of miRNAs targeting LRRK2 might result in a gain of function for LRRK2, and by extension, loss of neuronal viability. To the best of our knowledge, this is the first clinical association study of the above candidate miRNAs' expression in PD using peripheral samples. These observations may guide future clinical diagnostics research on PD.

In vitro and in vivo evaluation of anti-nucleolin-targeted magnetic PLGA nanoparticles loaded with doxorubicin as a theranostic agent for enhanced targeted cancer imaging and therapy.

PubMed

Mosafer, Jafar; Abnous, Khalil; Tafaghodi, Mohsen; Mokhtarzadeh, Ahad; Ramezani, Mohammad

2017-04-01

A superparamagnetic iron oxide nanoparticles (SPIONs)/doxorubicin (Dox) co-loaded poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles targeted with AS1411 aptamer (Apt) against murine C26 colon carcinoma cells is successfully developed via a modified multiple emulsion solvent evaporation method for theranostic purposes. The mean size of SPIO/Dox-NPs (NPs) was 130nm with a narrow particle size distribution and Dox loading of 3.0%. The SPIO loading of 16.0% and acceptable magnetic properties are obtained and analyzed using thermogravimetric and vibration simple magnetometer analysis, respectively. The best release profile from NPs was observed in PBS at pH 7.4, in which very low burst release was observed. Nucleolin is a targeting ligand to facilitate anti-tumor delivery of AS1411-targeted NPs. The Apt conjugation to NPs (Apt-NPs) enhanced cellular uptake of Dox in C26 cancer cells. Apt-NPs enhance the cytotoxicity effect of Dox followed by a significantly higher tumor inhibition and prolonged animal survival in mice bearing C26 colon carcinoma xenografts. Furthermore, Apt-NPs enhance the contrast of magnetic resonance images in tumor site. Altogether, these Apt-NPs could be considered as a powerful tumor-targeted delivery system for their potential as dual therapeutic and diagnostic applications in cancers. Copyright © 2016 Elsevier B.V. All rights reserved.

Mitochondria-targeting nanomedicine: An effective and potent strategy against aminoglycosides-induced ototoxicity.

PubMed

Zhou, Shuang; Sun, Yanhui; Kuang, Xiao; Hou, Shanshan; Yang, YinXian; Wang, Zhenjie; Liu, Hongzhuo

2018-04-21

We report a proof-of-concept for the development of mitochondria-targeting nanoparticles (NPs) loaded with geranylgeranylacetone (GGA) to protect against a wide range of gentamicin-induced ototoxicity symptoms in a zebrafish model. The polymeric NPs were functionalized with a mitochondrial-homing peptide (d‑Arg‑Dmt‑Orn‑Phe‑NH 2 ) and exhibited greater mitochondrial uptake and lower gentamicin uptake in hair cells via mechanotransduction (MET) channels and tuned machinery in the hair bundle than the ordinary NPs did. Blockade of MET channels rapidly reversed this effect, indicating the reversible responses of hair cells to the targeting NPs were mediated by MET channels. Pretreatment of hair cells with mitochondria-targeting GGA-loaded NPs exhibited a superior acute or chronic protective efficacy against subsequent exposure to gentamicin compared with unmodified formulations. Mitochondrial delivery regulating the death pathway of hair cells appeared to cause the therapeutic failure of untargeted NPs. Thus, peptide-directed mitochondria-targeting NPs may represent a novel therapeutic strategy for mitochondrial dysfunction-linked diseases. Copyright © 2018 Elsevier B.V. All rights reserved.

Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naïve with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab's Efficacy in MTX iNadequate rEsponders (SERENE))

PubMed Central

Emery, P; Deodhar, A; Rigby, W F; Isaacs, J D; Combe, B; Racewicz, A J; Latinis, K; Abud-Mendoza, C; Szczepański, L J; Roschmann, R A; Chen, A; Armstrong, G K; Douglass, W; Tyrrell, H

2010-01-01

Objectives This phase III study evaluated the efficacy and safety of rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to MTX and who were naïve to prior biological treatment. Methods Patients with active disease on stable MTX (10–25 mg/week) were randomised to rituximab 2×500 mg (n=168), rituximab 2×1000 mg (n=172), or placebo (n=172). From week 24, patients not in remission (Disease Activity Score (28 joints) ≥2.6) received a second course of rituximab; patients initially assigned to placebo switched to rituximab 2×500 mg. The primary end point was American College of Rheumatology 20 (ACR20) response at week 24. All patients were followed until week 48. Results At week 24, both doses of rituximab showed statistically superior efficacy (p<0.0001) to placebo (ACR20: 54%, 51% and 23%; rituximab (2×500 mg) + MTX, rituximab (2×1000 mg) + MTX and placebo + MTX, respectively). Secondary end points were also significantly improved for both rituximab groups compared with placebo. Further improvements in both rituximab arms were observed from week 24 to week 48. Rituximab + MTX was well tolerated, demonstrating comparable safety to placebo + MTX through to week 24, and between rituximab doses through to week 48. Conclusions Rituximab (at 2×500 mg and 2×1000 mg) plus MTX significantly improved clinical outcomes at week 24, which were further improved by week 48. No significant differences in either clinical or safety outcomes were apparent between the rituximab doses. PMID:20488885

Fe₃O₄ Nanoparticles in Targeted Drug/Gene Delivery Systems.

PubMed

Shen, Lazhen; Li, Bei; Qiao, Yongsheng

2018-02-23

Fe₃O₄ nanoparticles (NPs), the most traditional magnetic nanoparticles, have received a great deal of attention in the biomedical field, especially for targeted drug/gene delivery systems, due to their outstanding magnetism, biocompatibility, lower toxicity, biodegradability, and other features. Naked Fe₃O₄ NPs are easy to aggregate and oxidize, and thus are often made with various coatings to realize superior properties for targeted drug/gene delivery. In this review, we first list the three commonly utilized synthesis methods of Fe₃O₄ NPs, and their advantages and disadvantages. In the second part, we describe coating materials that exhibit noticeable features that allow functionalization of Fe₃O₄ NPs and summarize their methods of drug targeting/gene delivery. Then our efforts will be devoted to the research status and progress of several different functionalized Fe₃O₄ NP delivery systems loaded with chemotherapeutic agents, and we present targeted gene transitive carriers in detail. In the following section, we illuminate the most effective treatment systems of the combined drug and gene therapy. Finally, we propose opportunities and challenges of the clinical transformation of Fe₃O₄ NPs targeting drug/gene delivery systems.

Design and assembly of ternary Pt/Re/SnO2 NPs by controlling the zeta potential of individual Pt, Re, and SnO2 NPs

NASA Astrophysics Data System (ADS)

Drzymała, Elżbieta; Gruzeł, Grzegorz; Pajor-Świerzy, Anna; Depciuch, Joanna; Socha, Robert; Kowal, Andrzej; Warszyński, Piotr; Parlinska-Wojtan, Magdalena

2018-05-01

In this study Pt, Re, and SnO2 nanoparticles (NPs) were combined in a controlled manner into binary and ternary combinations for a possible application for ethanol oxidation. For this purpose, zeta potentials as a function of the pH of the individual NPs solutions were measured. In order to successfully combine the NPs into Pt/SnO2 and Re/SnO2 NPs, the solutions were mixed together at a pH guaranteeing opposite zeta potentials of the metal and oxide NPs. The individually synthesized NPs and their binary/ternary combinations were characterized by Fourier transform infrared spectroscopy (FTIR) and scanning transmission electron microscopy (STEM) combined with energy dispersive X-ray spectroscopy (EDS) analysis. FTIR and XPS spectroscopy showed that the individually synthesized Pt and Re NPs are metallic and the Sn component was oxidized to SnO2. STEM showed that all NPs are well crystallized and the sizes of the Pt, Re, and SnO2 NPs were 2.2, 1.0, and 3.4 nm, respectively. Moreover, EDS analysis confirmed the successful formation of binary Pt/SnO2 and Re/SnO2 NP, as well as ternary Pt/Re/SnO2 NP combinations. This study shows that by controlling the zeta potential of individual metal and oxide NPs, it is possible to assemble them into binary and ternary combinations. [Figure not available: see fulltext.

DNA sensors and aptasensors based on the hemin/G-quadruplex-controlled aggregation of Au NPs in the presence of L-cysteine.

PubMed

Niazov-Elkan, Angelica; Golub, Eyal; Sharon, Etery; Balogh, Dora; Willner, Itamar

2014-07-23

L-cysteine induces the aggregation of Au nanoparticles (NPs), resulting in a color transition from red to blue due to interparticle plasmonic coupling in the aggregated structure. The hemin/G-quadruplex horseradish peroxidase-mimicking DNAzyme catalyzes the aerobic oxidation of L-cysteine to cystine, a process that inhibits the aggregation of the NPs. The degree of inhibition of the aggregation process is controlled by the concentration of the DNAzyme in the system. These functions are implemented to develop sensing platforms for the detection of a target DNA, for the analysis of aptamer-substrate complexes, and for the analysis of L-cysteine in human urine samples. A hairpin DNA structure that includes a recognition site for the DNA analyte and a caged G-quadruplex sequence, is opened in the presence of the target DNA. The resulting self-assembled hemin/G-quadruplex acts as catalyst that controls the aggregation of the Au NPs. Also, the thrombin-binding aptamer folds into a G-quadruplex nanostructure upon binding to thrombin. The association of hemin to the resulting G-quadruplex aptamer-thrombin complex leads to a catalytic label that controls the L-cysteine-mediated aggregation of the Au NPs. The hemin/G-qaudruplex-controlled aggregation of Au NPs process is further implemented for visual and spectroscopic detection of L-cysteine concentration in urine samples. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Inadequate response to treat-to-target methotrexate therapy in patients with new-onset rheumatoid arthritis: development and validation of clinical predictors.

PubMed

Teitsma, Xavier M; Jacobs, Johannes W G; Welsing, Paco M J; de Jong, Pascal H P; Hazes, Johanna M W; Weel, Angelique E A M; Pethö-Schramm, Attila; Borm, Michelle E A; van Laar, Jacob M; Lafeber, Floris P J G; Bijlsma, Johannes W J

2018-05-14

To identify and validate clinical baseline predictors associated with inadequate response (IR) to methotrexate (MTX) therapy in newly diagnosed patients with rheumatoid arthritis (RA). In U-Act-Early, 108 disease-modifying antirheumatic drug (DMARD)-naive patients with RA were randomised to initiate MTX therapy and treated to target until sustained remission (disease activity score assessing 28 joints (DAS28) <2.6 with four or less swollen joints for ≥24 weeks) was achieved. If no remission, hydroxychloroquine was added to the treatment regimen (ie, 'MTX+') and replaced by tocilizumab if the target still was not reached thereafter. Regression analyses were performed to identify clinical predictors for IR, defined as needing addition of a biological DMARD, to 'MTX+'. Data from the treatment in the Rotterdam Early Arthritis Cohort were used for external validation of the prediction model. Within 1 year, 56/108 (52%) patients in U-Act-Early showed IR to 'MTX+'. DAS28 (adjusted OR (OR adj ) 2.1, 95% CI 1.4 to 3.2), current smoking (OR adj 3.02, 95% CI 1.1 to 8.0) and alcohol consumption (OR adj 0.4, 95% CI 0.1 to 0.9) were identified as baseline predictors. The area under the receiver operator characteristic curve (AUROC) of the prediction model was 0.75 (95% CI 0.66 to 0.84); the positive (PPV) and negative predictive value (NPV) were 65% and 80%, respectively. When applying the model to the validation cohort, the AUROC slightly decreased to 0.67 (95% CI 0.55 to 0.79) and the PPV and NPV to 54% and 80%, respectively. Higher DAS28, current smoking and no alcohol consumption are predictive factors for IR to step-up 'MTX+' in DMARD-naive patients with new-onset RA. NCT01034137; Post-results, ISRCTN26791028; Post-results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

NPS national transit inventory and performance report, 2015

DOT National Transportation Integrated Search

2017-02-01

This document summarizes key highlights and performance measures relating to the National Park Service (NPS) 2015 National Transit Inventory, by presenting data for NPS transit systems and vehicles nationwide. These highlights and performance measure...

NPS National Transit Inventory and Performance Report, 2016

DOT National Transportation Integrated Search

2017-12-01

This document summarizes key highlights and performance measures relating to the National Park Service (NPS) 2016 National Transit Inventory, by presenting data for NPS transit systems and vehicles nationwide. These highlights and performance measure...

Enhanced antitumor efficacy of folate targeted nanoparticles co-loaded with docetaxel and curcumin.

PubMed

Hu, Liandong; Pang, Saixi; Hu, Qiaofeng; Gu, Deliang; Kong, Dongqian; Xiong, Xiaoyun; Su, Jianying

2015-10-01

The current study aimed to investigate whether the novel folate (FT) modified nanoparticles (NPs) co-loaded with docetaxel (DT) and curcumin (CU) (named as FT-NPs) could enhance the delivery efficiency to tumor compared with the NPs without FT (non-targeted NPs). FT-NPs were successfully formulated in this article. In vitro cytotoxic activity against A549 cells and in vivo antitumor activity of FT-NPs in S180 cell bearing mice were conducted. Cellular uptake test was used to evaluate uptake efficiency of FT-NPs. Histological observation was used to determine the lung security. Besides, the physical chemical properties such as stability, particle size, zeta potential, drug encapsulation efficiency, transmission electron microscopy (TEM) were also conducted. FT-NPs exhibited stronger growth inhibition effects on A549 cells compared with non-targeted NPs, moreover, the novel FT-NPs indicated more effective antitumor efficacy in inhibiting tumor growth. Confocal laser scanning microscopy indicated that the uptake of FT-NPs was facilitated and effective. Histological observation meant that FT-NPs were biocompatible and appropriate for pulmonary administration. These results confirmed that FT-NPs with relatively high drug loading capacity could effectively inhibit tumor growth and reduce toxicity. The novel FT-NPs could produce as an outstanding nanocarrier for the targeted treatment of cancers. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Solvent induced modifications to fiber nanostructure and morphology for 12HSA molecular gels

NASA Astrophysics Data System (ADS)

Gao, Jie

Molecular organogels are thermo reversible quasi-solid materials, which are formed by low molecular weight organogelators (LMOGs) undergoing supramolecular aggregation via non-covalent interactions, forming a three-dimensional fibrillar network. Numerous applications of molecular organogels are been investigated as edible oils, drug release matrices and personal care products. The chemistry of the organic phase (i.e., solvent) influences every level of structure in organogels. Different solvents induce LMOG to assemble into "crystal like" fibers, which have more than one crystal form, lamellar arrangement and domain size. Differences in these solid states are known to affect the macroscopic properties of the gel, including critical gelator concentration (CGC), melting point, melting enthalpy and opacity.12-hydroxystearic acid (12HSA) was examined in several classes of organic solvents with different function groups. These gels, sols or precipitates were analyzed using a series of techniques including: powder x-ray diffraction (XRD), differential scanning calorimetry (DSC), fourier-transform infrared spectroscopy (FT-IR), pulsed nuclear magnetic resonance spectroscopy (pNMR) and microscopy. Specifically, certain solvents caused 12HSA to self-assemble into a triclinic parallel polymorphic form with subcell spacing of ~4.6, 3.9, and 3.8 A and an interdigitated unit cell with a lamellar arrangement (38~44 A). This polymorphic form corresponded to a less effective sphereultic supramolecular crystalline network, which immobilizes solvents at CGC greater than 1.5 wt %. The other group of solvents induce a hexagonal subcell spacing (i.e., unit sub cell spacing ~4.1 A) and are arranged in a multi lamellar fashion with a unit cell greater than the bimolecular length of 12HSA (~54 A).This polymorphic form corresponds to fibrillar aggregates with a CGC less than 1 wt %.

Pharmacokinetics of 99mTc-MAA- and 99mTc-HSA-Microspheres Used in Preradioembolization Dosimetry: Influence on the Liver-Lung Shunt.

PubMed

Grosser, Oliver S; Ruf, Juri; Kupitz, Dennis; Pethe, Annette; Ulrich, Gerhard; Genseke, Philipp; Mohnike, Konrad; Pech, Maciej; Richter, Wolf S; Ricke, Jens; Amthauer, Holger

2016-06-01

Perfusion scintigraphy using (99m)Tc-labeled albumin aggregates is mandatory before hepatic radioembolization with (90)Y-microspheres. As part of a prospective trial, the intrahepatic and intrapulmonary stability of 2 albumin compounds, (99m)Tc-MAA (macroaggregated serum albumin [MAA]) and (99m)Tc-HSA (human serum albumin [HSA]), was assessed. In 24 patients with metastatic colorectal cancer, biodistribution (liver, lung) and liver-lung shunt (LLS) of both tracers (12 patients each) were assessed by sequential planar scintigraphy (1, 5, and 24 h after injection). Liver uptake of both albumin compounds decreased differently. Although initial LLSs at 1 h after injection were similar in both groups, MAA-LLS increased significantly from 1 (3.9%) to 5 h (7.7%) and 24 h (9.9%) after injection, respectively. HSA-LLS did not change significantly (1 to 5 h), indicating a steady state of pulmonary and intrahepatic degradation. Compared with (99m)Tc-MAA-microspheres, (99m)Tc-HSA-microspheres are likely more resistant to degradation over time, allowing a reliable LLS determination even at later time points. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

NPS National Transit Inventory and Performance Report, 2014

DOT National Transportation Integrated Search

2015-09-09

This document summarizes key highlights and performance measures from the National Park Service (NPS) 2014 National Transit Inventory, and presents data for NPS transit systems system-wide. The document discusses statistics related to ridership, busi...

Hsa-mir-182 suppresses lung tumorigenesis through down regulation of RGS17 expression in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, Yihua; Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai 200031; Fang, Rong

2010-05-28

Lung cancer is one of the most devastating diseases worldwide. RGS17 is previously shown to be over-expressed in human lung adenocarcinomas and plays an important role in lung tumor growth. Here we have identified a miRNA, has-mir-182, involved in the regulation of RGS17 expression through two conserved sites located in its 3' UTR region. Consistently, endogenous RGS17 expression level is regulated by hsa-mir-182 in human lung cancer cell lines. Similar to the knockdown of RGS17, ectopic expression of hsa-mir-182 significantly inhibits lung cancer cell proliferation and anchorage-independent cell growth, which can be rescued by re-expression of RGS17. Taken together, thesemore » data have provided the first evidence of miRNA regulation of RGS17 expression in lung cancer.« less

Glycoprotein CD98 as a receptor for colitis-targeted delivery of nanoparticle.

PubMed

Xiao, Bo; Yang, Yang; Viennois, Emilie; Zhang, Yuchen; Ayyadurai, Saravanan; Baker, Mark; Laroui, Hamed; Merlin, Didier

2014-03-21

Treatment strategies for inflammatory bowel disease have been constrained by limited therapeutic efficacy and serious adverse effects owing to a lack of receptor for targeted drug delivery to the inflamed colon. Upon inflammation, CD98 expression is highly elevated in colonic epithelial cells and infiltrating immune cells. To investigate whether CD98 can be used as a colitis-targeted delivery receptor, we constructed CD98 Fab'-bearing quantum dots (QDs)-loaded nanoparticles (Fab'-NPs). The resultant Fab'-NPs had desired particle size (~458 nm) with a narrow size distribution and zeta-potential (approximately +19 mV), low cytotoxicity, and excellent fluorescence properties. Electron microscopy images provided direct evidence for the well-dispersed distribution of QDs within spherical Fab'-NPs. Cellular uptake experiments demonstrated that Fab'-NPs were efficiently internalized into Colon-26 and RAW 264.7 cells through the CD98-mediated endocytosis pathway, and showed that the targeting effect of CD98 Fab' markedly increased their cellular uptake efficiency compared with control pegylated QDs-loaded NPs (PEG-NPs). Furthermore, ex vivo studies showed much more effective accumulation of Fab'-NPs in colitis tissue than that of PEG-NPs. These findings suggest that because of inflammation-dependent over-expression of CD98, active colitis-targeted delivery can be accomplished using NPs decorated with CD98 antibody.

Hyaluronic acid-functionalized polymeric nanoparticles for colon cancer-targeted combination chemotherapy

NASA Astrophysics Data System (ADS)

Xiao, Bo; Han, Moon Kwon; Viennois, Emilie; Wang, Lixin; Zhang, Mingzhen; Si, Xiaoying; Merlin, Didier

2015-10-01

Nanoparticle (NP)-based combination chemotherapy has been proposed as an effective strategy for achieving synergistic effects and targeted drug delivery for colon cancer therapy. Here, we fabricated a series of hyaluronic acid (HA)-functionalized camptothecin (CPT)/curcumin (CUR)-loaded polymeric NPs (HA-CPT/CUR-NPs) with various weight ratios of CPT to CUR (1 : 1, 2 : 1 and 4 : 1). The resultant spherical HA-CPT/CUR-NPs had a desirable particle size (around 289 nm), relative narrow size distribution, and slightly negative zeta potential. These NPs exhibited a simultaneous sustained release profile for both drugs throughout the time frame examined. Subsequent cellular uptake experiments demonstrated that the introduction of HA to the NP surface endowed NPs with colon cancer-targeting capability and markedly increased cellular uptake efficiency compared with chitosan-coated NPs. Importantly, the combined delivery of CPT and CUR in one HA-functionalized NP exerted strong synergistic effects. HA-CPT/CUR-NP (1 : 1) showed the highest antitumor activity among the three HA-CPT/CUR-NPs, resulting in an extremely low combination index. Collectively, our findings indicate that this HA-CPT/CUR-NP can be exploited as an efficient formulation for colon cancer-targeted combination chemotherapy.Nanoparticle (NP)-based combination chemotherapy has been proposed as an effective strategy for achieving synergistic effects and targeted drug delivery for colon cancer therapy. Here, we fabricated a series of hyaluronic acid (HA)-functionalized camptothecin (CPT)/curcumin (CUR)-loaded polymeric NPs (HA-CPT/CUR-NPs) with various weight ratios of CPT to CUR (1 : 1, 2 : 1 and 4 : 1). The resultant spherical HA-CPT/CUR-NPs had a desirable particle size (around 289 nm), relative narrow size distribution, and slightly negative zeta potential. These NPs exhibited a simultaneous sustained release profile for both drugs throughout the time frame examined. Subsequent cellular uptake experiments

The utilization of SiNWs/AuNPs-modified indium tin oxide (ITO) in fabrication of electrochemical DNA sensor.

PubMed

Rashid, Jahwarhar Izuan Abdul; Yusof, Nor Azah; Abdullah, Jaafar; Hashim, Uda; Hajian, Reza

2014-12-01

This work describes the incorporation of SiNWs/AuNPs composite as a sensing material for DNA detection on indium tin-oxide (ITO) coated glass slide. The morphology of SiNWs/AuNPs composite as the modifier layer on ITO was studied by scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDX). The morphological studies clearly showed that SiNWs were successfully decorated with 20 nm-AuNPs using self-assembly monolayer (SAM) technique. The effective surface area for SiNWs/AuNPs-modified ITO enhanced about 10 times compared with bare ITO electrode. SiNWs/AuNPs nanocomposite was further explored as a matrix for DNA probe immobilization in detection of dengue virus as a bio-sensing model to evaluate its performance in electrochemical sensors. The hybridization of complementary DNA was monitored by differential pulse voltammetry (DPV) using methylene blue (MB) as the redox indicator. The fabricated biosensor was able to discriminate significantly complementary, non-complementary and single-base mismatch oligonucleotides. The electrochemical biosensor was sensitive to target DNA related to dengue virus in the range of 9.0-178.0 ng/ml with detection limit of 3.5 ng/ml. In addition, SiNWs/AuNPs-modified ITO, regenerated up to 8 times and its stability was up to 10 weeks at 4°C in silica gel. Copyright © 2014 Elsevier B.V. All rights reserved.

Development and in vitro evaluation of mucoadhesive patches of methotrexate for targeted delivery in oral cancer

PubMed Central

Jin, Bao-Zhong; Dong, Xiao-Qi; Xu, Xin; Zhang, Feng-He

2018-01-01

The present study focused on the development of a mucoadhesive patch of methotrexate (MTX) for targeted delivery in oral cancer. Initially, MTX-loaded liposomes were prepared using the thin film hydration method, and had a mean diameter of 105.7–137.4 nm and percentage entrapment efficiency of 54.6±3.5. These liposomes were cast in optimized mucoadhesive film. The film was characterized by its release pattern, thickness, weight and percentage swelling index and the sustained release profile of the optimized film was evaluated. The developed liposomes and liposomes cast in the film formulation were evaluated for cytotoxicity in HSC-3 cells using an MTT assay, and a significant decrease in the half maximal inhibitory concentration of MTX was identified with the MTX-entrapped liposomal film, M-LP-F7. The results of the mitochondria-dependent intrinsic pathway demonstrated that there was significant mitochondrial membrane potential disruption with M-LP-F7 compared with the plain drug. M-LP-F7 increased the rate of apoptosis in HSC-3 cells by almost 3-fold. Elevated levels of reactive oxygen species provided evidence that M-LP-F7 exerts a pro-oxidant effect in HSC-3 cells. PMID:29434971

Targeted polymeric therapeutic nanoparticles: design, development and clinical translation†

PubMed Central

Kamaly, Nazila; Xiao, Zeyu; Valencia, Pedro M.; Radovic-Moreno, Aleksandar F.; Farokhzad, Omid C.

2013-01-01

Polymeric materials have been used in a range of pharmaceutical and biotechnology products for more than 40 years. These materials have evolved from their earlier use as biodegradable products such as resorbable sutures, orthopaedic implants, macroscale and microscale drug delivery systems such as microparticles and wafers used as controlled drug release depots, to multifunctional nanoparticles (NPs) capable of targeting, and controlled release of therapeutic and diagnostic agents. These newer generations of targeted and controlled release polymeric NPs are now engineered to navigate the complex in vivo environment, and incorporate functionalities for achieving target specificity, control of drug concentration and exposure kinetics at the tissue, cell, and subcellular levels. Indeed this optimization of drug pharmacology as aided by careful design of multifunctional NPs can lead to improved drug safety and efficacy, and may be complimentary to drug enhancements that are traditionally achieved by medicinal chemistry. In this regard, polymeric NPs have the potential to result in a highly differentiated new class of therapeutics, distinct from the original active drugs used in their composition, and distinct from first generation NPs that largely facilitated drug formulation. A greater flexibility in the design of drug molecules themselves may also be facilitated following their incorporation into NPs, as drug properties (solubility, metabolism, plasma binding, biodistribution, target tissue accumulation) will no longer be constrained to the same extent by drug chemical composition, but also become in-part the function of the physicochemical properties of the NP. The combination of optimally designed drugs with optimally engineered polymeric NPs opens up the possibility of improved clinical outcomes that may not be achievable with the administration of drugs in their conventional form. In this critical review, we aim to provide insights into the design and development

Hierarchically Structured Recommender System for Improving NPS

ERIC Educational Resources Information Center

Kuang, Jieyan

2016-01-01

Net Promoter System (NPS) is well known as an evaluation measure of the growth engine of big companies in the business area. The ultimate goal of my research is to build an action rules and meta-actions based recommender system for improving NPS scores of 34 companies (clients) dealing with similar businesses in the US and Canada. With the given…

Relative binding affinity of carboxylate-, phosphonate-, and bisphosphonate-functionalized gold nanoparticles targeted to damaged bone tissue

NASA Astrophysics Data System (ADS)

Ross, Ryan D.; Cole, Lisa E.; Roeder, Ryan K.

2012-10-01

Functionalized Au NPs have received considerable recent interest for targeting and labeling cells and tissues. Damaged bone tissue can be targeted by functionalizing Au NPs with molecules exhibiting affinity for calcium. Therefore, the relative binding affinity of Au NPs surface functionalized with either carboxylate ( l-glutamic acid), phosphonate (2-aminoethylphosphonic acid), or bisphosphonate (alendronate) was investigated for targeted labeling of damaged bone tissue in vitro. Targeted labeling of damaged bone tissue was qualitatively verified by visual observation and backscattered electron microscopy, and quantitatively measured by the surface density of Au NPs using field-emission scanning electron microscopy. The surface density of functionalized Au NPs was significantly greater within damaged tissue compared to undamaged tissue for each functional group. Bisphosphonate-functionalized Au NPs exhibited a greater surface density labeling damaged tissue compared to glutamic acid- and phosphonic acid-functionalized Au NPs, which was consistent with the results of previous work comparing the binding affinity of the same functionalized Au NPs to synthetic hydroxyapatite crystals. Targeted labeling was enabled not only by the functional groups but also by the colloidal stability in solution. Functionalized Au NPs were stabilized by the presence of the functional groups, and were shown to remain well dispersed in ionic (phosphate buffered saline) and serum (fetal bovine serum) solutions for up to 1 week. Therefore, the results of this study suggest that bisphosphonate-functionalized Au NPs have potential for targeted delivery to damaged bone tissue in vitro and provide motivation for in vivo investigation.

Molecular-Targeted Immunotherapeutic Strategy for Melanoma via Dual-Targeting Nanoparticles Delivering Small Interfering RNA to Tumor-Associated Macrophages.

PubMed

Qian, Yuan; Qiao, Sha; Dai, Yanfeng; Xu, Guoqiang; Dai, Bolei; Lu, Lisen; Yu, Xiang; Luo, Qingming; Zhang, Zhihong

2017-09-26

Tumor-associated macrophages (TAMs) are a promising therapeutic target for cancer immunotherapy. Targeted delivery of therapeutic drugs to the tumor-promoting M2-like TAMs is challenging. Here, we developed M2-like TAM dual-targeting nanoparticles (M2NPs), whose structure and function were controlled by α-peptide (a scavenger receptor B type 1 (SR-B1) targeting peptide) linked with M2pep (an M2 macrophage binding peptide). By loading anti-colony stimulating factor-1 receptor (anti-CSF-1R) small interfering RNA (siRNA) on the M2NPs, we developed a molecular-targeted immunotherapeutic approach to specifically block the survival signal of M2-like TAMs and deplete them from melanoma tumors. We confirmed the validity of SR-B1 for M2-like TAM targeting and demonstrated the synergistic effect of the two targeting units (α-peptide and M2pep) in the fusion peptide (α-M2pep). After being administered to tumor-bearing mice, M2NPs had higher affinity to M2-like TAMs than to tissue-resident macrophages in liver, spleen, and lung. Compared with control treatment groups, M2NP-based siRNA delivery resulted in a dramatic elimination of M2-like TAMs (52%), decreased tumor size (87%), and prolonged survival. Additionally, this molecular-targeted strategy inhibited immunosuppressive IL-10 and TGF-β production and increased immunostimulatory cytokines (IL-12 and IFN-γ) expression and CD8 + T cell infiltration (2.9-fold) in the tumor microenvironment. Moreover, the siRNA-carrying M2NPs down-regulated expression of the exhaustion markers (PD-1 and Tim-3) on the infiltrating CD8 + T cells and stimulated their IFN-γ secretion (6.2-fold), indicating the restoration of T cell immune function. Thus, the dual-targeting property of M2NPs combined with RNA interference provides a potential strategy of molecular-targeted cancer immunotherapy for clinical application.

Hsa_circ_0054633 in peripheral blood can be used as a diagnostic biomarker of pre-diabetes and type 2 diabetes mellitus.

PubMed

Zhao, Zhenzhou; Li, Xuejie; Jian, Dongdong; Hao, Peiyuan; Rao, Lixin; Li, Muwei

2017-03-01

The purpose of the current study was to investigate the characteristic expression of circular RNAs (circRNAs) in the peripheral blood of type 2 diabetes mellitus (T2DM) patients and their potential as diagnostic biomarkers for pre-diabetes and T2DM. CircRNAs in the peripheral blood from six healthy individuals and six T2DM patients were collected for microarray analysis, and an independent cohort study consisting of 20 normal cases, 20 pre-diabetes patients and 20 T2DM patients was conducted to verify the five chosen circRNAs. We then tested hsa_circ_0054633 in a third cohort (control group, n = 60; pre-diabetes group, n = 63; and T2DM group, n = 64) by quantitative real-time polymerase chain reaction (Q-PCR). In total, 489 circRNAs were discovered to be differentially expressed between the two groups, and of these, 78 were upregulated and 411 were downregulated in the T2DM group. Five circRNAs were then selected as candidate biomarkers and further verified in a second cohort. Hsa_circ_0054633 was found to have the largest area under the curve (AUC). The diagnostic capacity of hsa_circ_0054633 was tested in a third cohort. After introducing the risk factors of T2DM, the hsa_circ_0054633 AUCs for the diagnosis of pre-diabetes and T2DM slightly increased from 0.751 (95% confidence interval [0.666-0.835], P < 0.001) to 0.841 ([0.773-0.910], P < 0.001) and from 0.793 ([0.716-0.871], P < 0.001) to 0.834 ([0.762-0.905], P < 0.001), respectively. Hsa_circ_0054633 presented a certain diagnostic capability for pre-diabetes and T2DM.

An effective established biosensor of bifunctional probes-labeled AuNPs combined with LAMP for detection of fish pathogen Streptococcus iniae.

PubMed

Zhou, Ya; Xiao, Jingfan; Ma, Xin; Wang, Qiyao; Zhang, Yuanxing

2018-06-01

In purpose of valid Streptococcus iniae detection, we established a colorimetric biosensor using gold nanoparticles (AuNPs) labeled with dual functional probes and along with loop-mediated isothermal amplification (LAMP) assay (LAMP-AuNPs). Based on the characteristics of self-aggregation and bio-conjugation with ligands, AuNPs were chosen for observable color change in tandem with LAMP amplification method to reach high sensitivity and easy operation. Meanwhile, the improvement of dual probes that could fully utilize the LAMP product gave the biosensor a stable result exhibition. LAMP-AuNPs targeting gene ftsB, one of the ATP transporter-related genes, turned out favorable specificity in cross reaction among other fish pathogens. The detect limit of 10 2 CFU revealed a better sensitivity compared with polymerase chain reaction (PCR) method and AuNPs lateral flow test strip (LFTS). It was also proved to be effective by zebrafish infection model trials with less than 2-h time consumption and nearly no devices which make it a convenient biosensor for point-to-care S. iniae detection.

Comparative Study of Antimicrobial Activity of AgBr and Ag Nanoparticles (NPs)

PubMed Central

Suchomel, Petr; Kvitek, Libor; Panacek, Ales; Prucek, Robert; Hrbac, Jan; Vecerova, Renata; Zboril, Radek

2015-01-01

The diverse mechanism of antimicrobial activity of Ag and AgBr nanoparticles against gram-positive and gram-negative bacteria and also against several strains of candida was explored in this study. The AgBr nanoparticles (NPs) were prepared by simple precipitation of silver nitrate by potassium bromide in the presence of stabilizing polymers. The used polymers (PEG, PVP, PVA, and HEC) influence significantly the size of the prepared AgBr NPs dependently on the mode of interaction of polymer with Ag+ ions. Small NPs (diameter of about 60–70 nm) were formed in the presence of the polymer with low interaction as are PEG and HEC, the polymers which interact with Ag+ strongly produce nearly two times bigger NPs (120–130 nm). The prepared AgBr NPs were transformed to Ag NPs by the reduction using NaBH4. The sizes of the produced Ag NPs followed the same trends – the smallest NPs were produced in the presence of PEG and HEC polymers. Prepared AgBr and Ag NPs dispersions were tested for their biological activity. The obtained results of antimicrobial activity of AgBr and Ag NPs are discussed in terms of possible mechanism of the action of these NPs against tested microbial strains. The AgBr NPs are more effective against gram-negative bacteria and tested yeast strains while Ag NPs show the best antibacterial action against gram-positive bacteria strains. PMID:25781988

Size control of Au NPs supported by pH operation

NASA Astrophysics Data System (ADS)

Ichiji, Masumi; Akiba, Hiroko; Hirasawa, Izumi

2017-07-01

Au NPs are expected to become useful functional particles, as particle gun used for plant gene transfer and also catalysts. We have studied PSD (particle size distribution) control of Au NPs by reduction crystallization. Previous study found out importance of seeds policy and also feeding profile. In this paper, effect of pH in the reduction crystallization was investigated to clarify the possibility of Au NPs PSD control by pH operation and also their growth process. Au NPs of size range 10-600 nm were obtained in single-jet system using ascorbic acid (AsA) as a reducing agent with adjusting pH of AsA. Au NPs are found to grow in the process of nucleation, agglomeration, agglomeration growth and surface growth. Au NPs tend to grow by agglomeration and become larger size in lower pH regions, and to grow only by surface growth and become smaller size in higher pH regions.

Novel Psychoactive Substances (NPS): a Study on Persian Language Websites

PubMed Central

BIGDELI, Imanollah; CORAZZA, Ornella; ASLANPOUR, Zoe; SCHIFANO, Fabrizio

2013-01-01

Background During the past few years, there has been an increasing recognition that Internet is playing a significant role in the synthesis, the distribution and the consumption of Novel Psychoactive Substances (NPS).The aim of this study was to assess the online availability of NPS in Persian language websites. Methods: The Google search engine was used to carry out an accurate qualitative assessment of information available on NPS in a sample of 104 websites. Results: The monitoring has led to the identification of 14 NPS including herbal, synthetic, pharmaceutical and combination drugs that have been sold online. Conclusion: The availability of online marketing of NPS in Persian language websites may constitute a public health challenge at least across three Farsi-speaking countries in the Middle East. Hence, descriptions of this phenomenon are valuable to clinicians and health professional in this region. Further international collaborative efforts may be able to tackle the growth and expansion of regular offer of NPS. PMID:23802109

Novel Psychoactive Substances (NPS): a Study on Persian Language Websites.

PubMed

Bigdeli, Imanollah; Corazza, Ornella; Aslanpour, Zoe; Schifano, Fabrizio

2013-01-01

During the past few years, there has been an increasing recognition that Internet is playing a significant role in the synthesis, the distribution and the consumption of Novel Psychoactive Substances (NPS).The aim of this study was to assess the online availability of NPS in Persian language websites. The Google search engine was used to carry out an accurate qualitative assessment of information available on NPS in a sample of 104 websites. The monitoring has led to the identification of 14 NPS including herbal, synthetic, pharmaceutical and combination drugs that have been sold online. The availability of online marketing of NPS in Persian language websites may constitute a public health challenge at least across three Farsi-speaking countries in the Middle East. Hence, descriptions of this phenomenon are valuable to clinicians and health professional in this region. Further international collaborative efforts may be able to tackle the growth and expansion of regular offer of NPS.

Exploring the Attractiveness of New Psychoactive Substances (NPS) among Experienced Drug Users.

PubMed

van Amsterdam, Jan G C; Nabben, Ton; Keiman, Daan; Haanschoten, Gijs; Korf, Dirk

2015-01-01

A growing number of New Psychoactive Substances (NPS) appear yearly on the European market (81 for the first time in 2013, adding to a total of over 350 NPS). Using semi-structured interviews with 25 Dutch experienced recreational drug users, the role of the Internet and friends in gathering and exchanging information about NPS was elaborated. Furthermore, we investigated how NPS were acquired and which aspects make NPS more or less attractive, including their legal status. It appeared that the Internet was an important source of information about NPS in general. Personal experiences with NPS were preferably shared face-to-face with friends, as for privacy reasons users were cautious to post their experiences on web sites and forums. NPS were usually obtained or bought from friends or-to a lesser extent-purchased via the Internet. The preference for a specific NPS depended on the desired effects (mostly stimulant or psychedelic), price (similar to MDMA or amphetamine), duration of effect (preferably around four hours), and setting (at home, at festivals, or in nightlife). Legal status was not relevant for the decision to use NPS. Most NPS are not superior to the already marketed drugs, and do not displace conventional illicit drugs.

Cholesterol-modified poly(lactide-co-glycolide) nanoparticles for tumor-targeted drug delivery.

PubMed

Lee, Jeong-Jun; Lee, Song Yi; Park, Ju-Hwan; Kim, Dae-Duk; Cho, Hyun-Jong

2016-07-25

Poly(lactide-co-glycolide)-cholesterol (PLGA-C)-based nanoparticles (NPs) were developed for the tumor-targeted delivery of curcumin (CUR). PLGA-C/CUR NPs with ∼200nm mean diameter, narrow size distribution, and neutral zeta potential were fabricated by a modified emulsification-solvent evaporation method. The existence of cholesterol moiety in PLGA-C copolymer was confirmed by proton nuclear magnetic resonance ((1)H NMR) analysis. In vitro stability of developed NPs after 24h incubation was confirmed in phosphate buffered saline (PBS) and serum media. Sustained (∼6days) and pH-responsive drug release profiles from PLGA-C NPs were presented. Blank PLGA and PLGA-C NPs exhibited a negligible cytotoxicity in Hep-2 (human laryngeal carcinoma) cells in the tested concentration range. According to the results of flow cytometry and confocal laser scanning microscopy (CLSM) studies, PLGA-C NPs presented an improved cellular accumulation efficiency, compared to PLGA NPs, in Hep-2 cells. Enhanced in vivo tumor targetability of PLGA-C NPs, compared to PLGA NPs, in Hep-2 tumor-xenografted mouse model was also verified by a real-time near-infrared fluorescence (NIRF) imaging study. Developed PLGA-C NPs may be a candidate of efficient and biocompatible nanosystems for tumor-targeted drug delivery and cancer imaging. Copyright © 2016 Elsevier B.V. All rights reserved.

A new target ligand Ser-Glu for PEPT1-overexpressing cancer imaging.

PubMed

Dai, Tongcheng; Li, Na; Zhang, Lingzhi; Zhang, Yuanxing; Liu, Qin

2016-01-01

Nanoparticles functionalized with active target ligands have been widely used for tumor-specific diagnosis and therapy. The target ligands include antibodies, peptides, proteins, small molecules, and nucleic acid aptamers. Here, we utilize dipeptide Ser-Glu (DIP) as a new ligand to functionalize polymer-based fluorescent nanoparticles (NPs) for pancreatic cancer target imaging. We demonstrate that in the first step, Ser-Glu-conjugated NPs (NPs-DIP) efficiently bind to AsPC-1 and in the following NPs-DIP are internalized into AsPC-1 in vitro. The peptide transporter 1 inhibition experiment reveals that the targeting effects mainly depend on the specific binding of DIP to peptide transporter 1, which is remarkably upregulated in pancreatic cancer cells compared with varied normal cells. Furthermore, NPs-DIP specifically accumulate in the site of pancreatic tumor xenograft and are further internalized into the tumor cells in vivo after intravenous administration, indicating that DIP successfully enhanced nanoparticles internalization efficacy into tumor cells in vivo. This work establishes Ser-Glu to be a new tumor-targeting ligand and provides a promising tool for future tumor diagnostic or therapeutic applications.

Health and Social Problems Associated with Recent Novel Psychoactive Substance (NPS) Use Amongst Marginalised, Nightlife and Online Users in Six European Countries.

PubMed

Van Hout, Marie Claire; Benschop, Annemieke; Bujalski, Michal; Dąbrowska, Katarzyna; Demetrovics, Zsolt; Felvinczi, Katalin; Hearne, Evelyn; Henriques, Susana; Kaló, Zsuzsa; Kamphausen, Gerrit; Korf, Dirk; Silva, Joana Paula; Wieczorek, Łukasz; Werse, Bernd

2018-01-01

Continued diversification and use of new psychoactive substances (NPS) across Europe remains a public health challenge. The study describes health and social consequences of recent NPS use as reported in a survey of marginalised, nightlife and online NPS users in the Netherlands, Hungary, Portugal, Ireland, Germany and Poland ( n  = 3023). Some respondents were unable to categorise NPS they had used. Use of ' herbal blends ' and ' synthetic cannabinoids obtained pure ' was most reported in Germany, Poland and Hungary, and use of ' branded stimulants ' and ' stimulants/empathogens/nootropics obtained pure ' was most reported in the Netherlands. Increased heart rate and palpitation, dizziness, anxiety, horror trips and headaches were most commonly reported acute side effects. Marginalised users reported substantially more acute side effects, more mid- and long-term mental and physical problems, and more social problems. Development of country-specific NPS awareness raising initiatives, health and social service needs assessments, and targeted responses are warranted.

Anionic clay as the drug delivery vehicle: tumor targeting function of layered double hydroxide-methotrexate nanohybrid in C33A orthotopic cervical cancer model.

PubMed

Choi, Goeun; Piao, Huiyan; Alothman, Zeid A; Vinu, Ajayan; Yun, Chae-Ok; Choy, Jin-Ho

2016-01-01

Methotrexate (MTX), an anticancer agent, was successfully intercalated into the anionic clay, layered double hydroxides to form a new nanohybrid drug. The coprecipitation and subsequent hydrothermal method were used to prepare chemically, structurally, and morphologically well-defined two-dimensional drug-clay nanohybrid. The resulting two-dimensional drug-clay nanohybrid showed excellent colloidal stability not only in deionized water but also in an electrolyte solution of Dulbecco's Modified Eagle's Medium with 10% fetal bovine serum, in which the average particle size in colloid and the polydispersity index were determined to be around 100 and 0.250 nm, respectively. The targeting property of the nanohybrid drug was confirmed by evaluating the tumor-to-blood and tumor-to-liver ratios of the MTX with anionic clay carrier, and these ratios were compared to those of free MTX in the C33A orthotopic cervical cancer model. The biodistribution studies indicated that the mice treated with the former showed 3.5-fold higher tumor-to-liver ratio and fivefold higher tumor-to-blood ratio of MTX than those treated with the latter at 30 minutes postinjection.

Influence of particle coating and matrix constituents on the cloud point extraction efficiency of silver nanoparticles (Ag-NPs) and application for monitoring the formation of Ag-NPs from Ag(+).

PubMed

Hartmann, Georg; Baumgartner, Tanja; Schuster, Michael

2014-01-07

For the quantification of silver nanoparticles (Ag-NPs) in environmental samples using cloud point extraction (CPE) for selective enrichment, surface modification of the Ag-NPs and matrix effects can play a key role. In this work we validate CPE with respect to the influence of different coatings and naturally occurring matrix components. The Ag-NPs tested were functionalized with inorganic and organic compounds as well as with biomolecules. Commercially available NPs and NPs synthesized according to methods published in the literature were used. We found that CPE can extract almost all Ag-NPs tested with very good efficiencies (82-105%). Only Ag-NPs functionalized with BSA (bovine serum albumin), which is a protein with the function to keep colloids in solution, cannot be extracted. No or little effect of environmentally relevant salts, organic matter, and inorganic colloids on the CPE of AgNPs was found. Additionally we used CPE to observe the in situ formation of Ag-NPs produced by the reduction of Ag(+) with natural organic matter (NOM).

Boronic acid-tethered amphiphilic hyaluronic acid derivative-based nanoassemblies for tumor targeting and penetration.

PubMed

Jeong, Jae Young; Hong, Eun-Hye; Lee, Song Yi; Lee, Jae-Young; Song, Jae-Hyoung; Ko, Seung-Hak; Shim, Jae-Seong; Choe, Sunghwa; Kim, Dae-Duk; Ko, Hyun-Jeong; Cho, Hyun-Jong

2017-04-15

(3-Aminomethylphenyl)boronic acid (AMPB)-installed hyaluronic acid-ceramide (HACE)-based nanoparticles (NPs), including manassantin B (MB), were fabricated for tumor-targeted delivery. The amine group of AMPB was conjugated to the carboxylic acid group of hyaluronic acid (HA) via amide bond formation, and synthesis was confirmed by spectroscopic methods. HACE-AMPB/MB NPs with a 239-nm mean diameter, narrow size distribution, negative zeta potential, and >90% drug encapsulation efficiency were fabricated. Exposed AMPB in the outer surface of HACE-AMPB NPs (in the aqueous environment) may react with sialic acid of cancer cells. The improved cellular accumulation efficiency, in vitro antitumor efficacy, and tumor penetration efficiency of HACE-AMPB/MB NPs, compared with HACE/MB NPs, in MDA-MB-231 cells (CD44 receptor-positive human breast adenocarcinoma cells) may be based on the CD44 receptor-mediated endocytosis and phenylboronic acid-sialic acid interaction. Enhanced in vivo tumor targetability, infiltration efficiency, and antitumor efficacies of HACE-AMPB NPs, compared with HACE NPs, were observed in a MDA-MB-231 tumor-xenografted mouse model. In addition to passive tumor targeting (based on an enhanced permeability and retention effect) and active tumor targeting (interaction between HA and CD44 receptor), the phenylboronic acid-sialic acid interaction can play important roles in augmented tumor targeting and penetration of HACE-AMPB NPs. STATEMENT OF SIGNIFICANCE: (3-Aminomethylphenyl)boronic acid (AMPB)-tethered hyaluronic acid-ceramide (HACE)-based nanoparticles (NPs), including manassantin B (MB), were fabricated and their tumor targeting and penetration efficiencies were assessed in MDA-MB-231 (CD44 receptor-positive human adenocarcinoma) tumor models. MB, which exhibited antitumor efficacies via the inhibition of angiogenesis and hypoxia inducible factor (HIF)-1, was entrapped in HACE-AMPB NPs in this study. Phenylboronic acid located in the outer surface

Development, Characterization and Validation of Trastuzumab-Modified Gold Nanoparticles for Molecularly Targeted Radiosensitization of Breast Cancer

NASA Astrophysics Data System (ADS)

Chattopadhyay, Niladri

The overexpression of the human epidermal growth factor receptor-2 (HER-2) in 20--25% of human breast cancers was investigated as a target for development of a gold nanoparticle (AuNP) based radiosensitizer for improving the efficacy of neoadjuvant X-radiation therapy of the disease. HER-2 targeted AuNPs were developed by covalently conjugating trastuzumab, a Health Canada approved monoclonal antibody for the treatment of HER-2-overexpressing breast cancer, to 30 nm AuNPs. Trastuzumab conjugated AuNPs were efficiently internalized by HER-2-overexpressing breast cancer cells (as assessed by darkfield microscopy and transmission electron microscopy) and increased DNA damage from X-radiation in these cells by more than 5-fold. To optimize delivery of AuNPs to HER-2-overexpressing tumors, high resolution microSPECT/CT imaging was used to track the in vivo fate of 111In-labelled non-targeted and HER-2 targeted AuNPs following intravenous (i.v.) or intratumoral (i.t.) injection. For i.v. injection, the effects of GdCl3 (for deactivation of macrophages) and non-specific (anti-CD20) antibody rituximab (for blocking of Fc mediated liver and spleen uptake) were studied. It was found that HER-2 targeting via attachment of trastuzumab paradoxically decreased tumor uptake as a result of faster elimination of the targeted AuNPs from the blood while improving internalization in HER-2-positive tumor cells as compared to non-targeted AuNPs. This phenomenon could be attributed to Fc-mediated recognition and subsequent sequestration of trastuzumab conjugated AuNP by the reticuloendothelial system (RES). Blocking of the RES did not increase tumor uptake of either HER-2 targeted or non-targeted AuNPs. Following i.t. injection, our results suggest that Au-NTs redistribute over time and traffick to the liver via the ipsilateral axillary lymph node leading to comparable exposure as seen with i.v. administration. In contrast, targeted AuNPs are bound and internalized by HER-2

Investigation of human serum albumin (HSA) binding specificity of certain photosensitizers related to pyropheophorbide-a and bacteriopurpurinimide by circular dichroism spectroscopy and its correlation with in vivo photosensitizing efficacy.

PubMed

Chen, Yihui; Miclea, Razvan; Srikrishnan, Thamarapu; Balasubramanian, Sathyamangalam; Dougherty, Thomas J; Pandey, Ravindra K

2005-07-01

A series of pyropheophorbide-a and bacteriopurpurinimides were investigated to understand the correlation between HSA (site II) binding affinity and in vivo photosensitizing activity. In our study, photosensitizers that bound to site II of HSA produced a significant difference in the circular dichroism spectra of the corresponding complexes, especially at Soret band region of the photosensitizers. Our results suggest that CD spectroscopy of the photosensitizer-HSA complexes could be a valuable tool in screening new photosensitizers before evaluating them for in vivo efficacy.

Targeted silver nanoparticles for ratiometric cell phenotyping

NASA Astrophysics Data System (ADS)

Willmore, Anne-Mari A.; Simón-Gracia, Lorena; Toome, Kadri; Paiste, Päärn; Kotamraju, Venkata Ramana; Mölder, Tarmo; Sugahara, Kazuki N.; Ruoslahti, Erkki; Braun, Gary B.; Teesalu, Tambet

2016-04-01

Affinity targeting is used to deliver nanoparticles to cells and tissues. For efficient targeting, it is critical to consider the expression and accessibility of the relevant receptors in the target cells. Here, we describe isotopically barcoded silver nanoparticles (AgNPs) as a tool for auditing affinity ligand receptors in cells. Tumor penetrating peptide RPARPAR (receptor: NRP-1) and tumor homing peptide GKRK (receptor: p32) were used as affinity ligands on the AgNPs. The binding and uptake of the peptide-functionalized AgNPs by cultured PPC-1 prostate cancer and M21 melanoma cells was dependent on the cell surface expression of the cognate peptide receptors. Barcoded peptide-functionalized AgNPs were synthesized from silver and palladium isotopes. The cells were incubated with a cocktail of the barcoded nanoparticles [RPARPAR (R), GKRK (K), and control], and cellular binding and internalization of each type of nanoparticle was assessed by inductively coupled plasma mass spectrometry. The results of isotopic analysis were in agreement with data obtained using optical methods. Using ratiometric measurements, we were able to classify the PPC-1 cell line as mainly NRP-1-positive, with 75 +/- 5% R-AgNP uptake, and the M21 cell line as only p32-positive, with 89 +/- 9% K-AgNP uptake. The isotopically barcoded multiplexed AgNPs are useful as an in vitro ratiometric phenotyping tool and have potential uses in functional evaluation of the expression of accessible homing peptide receptors in vivo.Affinity targeting is used to deliver nanoparticles to cells and tissues. For efficient targeting, it is critical to consider the expression and accessibility of the relevant receptors in the target cells. Here, we describe isotopically barcoded silver nanoparticles (AgNPs) as a tool for auditing affinity ligand receptors in cells. Tumor penetrating peptide RPARPAR (receptor: NRP-1) and tumor homing peptide GKRK (receptor: p32) were used as affinity ligands on the AgNPs. The

ITO nanoparticles reused from ITO scraps and their applications to sputtering target for transparent conductive electrode layer.

PubMed

Hong, Sung-Jei; Song, Sang-Hyun; Kim, Byeong Jun; Lee, Jae-Yong; Kim, Young-Sung

2017-01-01

In this study, ITO nanoparticles (ITO-NPs) were reused from ITO target scraps to synthesize low cost ITO-NPs and to apply to make sputtering target for transparent conductive electrodes (TCEs). By controlling heat-treatment temperature as 980 °C, we achieved reused ITO-NPs having Brunauer, Emmett and Teller specific surface area (BET SSA) and average particle size 8.05 m 2 /g and 103.8 nm, respectively. The BET SSA decreases along with increasing heat-treatment temperature. The ITO-NPs were grown as round mound shape, and highly crystallized to (222) preferred orientations. Also, applying the reused ITO-NPs, we achieved an ITO target of which density was 99.6%. Using the ITO target, we achieved high quality TCE layer of which sheet resistance and optical transmittance at 550 nm were 29.5 Ω/sq. and 82.3%. Thus, it was confirmed that the reused ITO-NPs was feasible to sputtering target for TCEs layer.

ITO nanoparticles reused from ITO scraps and their applications to sputtering target for transparent conductive electrode layer

NASA Astrophysics Data System (ADS)

Hong, Sung-Jei; Song, Sang-Hyun; Kim, Byeong Jun; Lee, Jae-Yong; Kim, Young-Sung

2017-09-01

In this study, ITO nanoparticles (ITO-NPs) were reused from ITO target scraps to synthesize low cost ITO-NPs and to apply to make sputtering target for transparent conductive electrodes (TCEs). By controlling heat-treatment temperature as 980 °C, we achieved reused ITO-NPs having Brunauer, Emmett and Teller specific surface area (BET SSA) and average particle size 8.05 m2/g and 103.8 nm, respectively. The BET SSA decreases along with increasing heat-treatment temperature. The ITO-NPs were grown as round mound shape, and highly crystallized to (222) preferred orientations. Also, applying the reused ITO-NPs, we achieved an ITO target of which density was 99.6%. Using the ITO target, we achieved high quality TCE layer of which sheet resistance and optical transmittance at 550 nm were 29.5 Ω/sq. and 82.3%. Thus, it was confirmed that the reused ITO-NPs was feasible to sputtering target for TCEs layer.

Study of protein-probe interaction and protective action of surfactant sodium dodecyl sulphate in urea-denatured HSA using charge transfer fluorescence probe methyl ester of N,N-dimethylamino naphthyl acrylic acid.

PubMed

Mahanta, Subrata; Singh, Rupashree Balia; Guchhait, Nikhil

2009-03-01

We have demonstrated that the intramolecular charge transfer (ICT) probe Methyl ester of N,N-dimethylamino naphthyl acrylic acid (MDMANA) serves as an efficient reporter of the proteinous microenvironment of Human Serum Albumin (HSA). This work reports the binding phenomenon of MDMANA with HSA and spectral modulation thereupon. The extent of binding and free energy change for complexation reaction along with efficient fluorescence resonance energy transfer from Trp-214 of HSA to MDMANA indicates strong binding between probe and protein. Fluorescence anisotropy, red edge excitation shift, acrylamide quenching and time resolved measurements corroborate the binding nature of the probe with protein and predicts that the probe molecule is located at the hydrophobic site of the protein HSA. Due to the strong binding ability of MDMANA with HSA, it is successfully utilized for the study of stabilizing action of anionic surfactant Sodium Dodecyl Sulphate to the unfolding and folding of protein with denaturant urea in concentration range 1M to 9M.

Multifunctional Au NPs-polydopamine-polyvinylidene fluoride membrane chips as probe for enrichment and rapid detection of organic contaminants.

PubMed

Wang, Saihua; Niu, Hongyun; Cai, Yaqi; Cao, Dong

2018-05-01

High-throughput and rapid detection of hazardous compounds in complicated samples is essential for the solution of environmental problems. We have prepared a "pH-paper-like" chip which can rapidly "indicate" the occurrence of organic contaminants just through dipping the chip in water samples for short time followed by fast analysis with surface-assisted laser desorption/ionization time-of-flight mass spectrometry (SALDI-TOF MS). The chips are composed of polyvinylidene fluoride membrane (PVDFM), polydopamine (PDA) film and Au nanoparticles (Au NPs), which are layer-by-layer assembled according to the adhesion, self-polymerization and reduction property of dopamine. In the Au NPs loaded polydopamine-polyvinylidene fluoride membrane (Au NPs-PDA-PVDFM) chips, PVDFM combined with PDA film are responsible for the enrichment of organic analyte through hydrophobic interactions and π-π stacking; Au NPs serve as effective SALDI matrix for the rapid detection of target analyte. After dipping into water solution for minutes, the Au-PDA-PVDFM chips with enriched organic analytes can be detected directly with SALDI-TOF MS. The good solid-phase extraction performance of the PDA-PVDFM components, remarkable matrix effect of the loaded AuNPs, and sensitivity of the SALDI-TOF MS technique ensure excellent sensitivity and reproducibility for the quantification of trace levels of organic contaminants in environmental water samples. Copyright © 2018 Elsevier B.V. All rights reserved.

Novel Nano-Therapeutic Approach Actively Targets Human Ovarian Cancer Stem Cells after Xenograft into Nude Mice.

PubMed

Abou-ElNaga, Amoura; Mutawa, Ghada; El-Sherbiny, Ibrahim M; Abd-ElGhaffar, Hassan; Allam, Ahmed A; Ajarem, Jamaan; Mousa, Shaker A

2017-04-12

The power of tumorigenesis, chemo-resistance and metastasis in malignant ovarian tumors resides in a tiny population of cancer cells known as ovarian cancer stem cells (OCSCs). Developing nano-therapeutic targeting of OCSCs is considered a great challenge. The potential use of poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) was investigated as a drug delivery system for paclitaxel (PTX) against OCSCs in vitro and in vivo. PTX-loaded PLGA NPs were prepared by an emulsion solvent evaporation method, supported by incorporation of folic acid (FA) as the ligand. NPs were characterized for size, surface morphology, drug loading, and encapsulation efficiency. In vitro cytotoxicity of PTX-loaded FA/PLGA NPs was tested against OCSCs with MTT assay. In vivo anti-tumoral efficiency and active targeting potential of prepared NPs against tumors in nude mice were investigated. In vitro results revealed that IC 50 of PTX was significantly reduced after loading on PLGA NPs. On the other hand, in vivo results showed that PLGA NPs enhanced the tumor suppression efficiency of PTX. Investigation with real time quantitative PCR analysis revealed the limiting expression of chemo-resistant genes ( ABCG2 and MDR1 ) after applying PLGA NPs as a drug delivery system for PTX. Histopathological examination of tumors showed the effective biological influence of PTX-loaded FA/PLGA NPs through the appearance of reactive lymphoid follicles. Targeting potential of PTX was activated by FA/PLGA NPs through significant preservation of body weight ( p < 0.0001) and minimizing the systemic toxicity in healthy tissues. Immunohistochemical investigation revealed a high expression of apoptotic markers in tumor tissue, supporting the targeting effect of FA/PLGA NPs. A drug delivery system based on FA/PLGA NPs can enhance PTX's in vitro cytotoxicity and in vivo targeting potential against OCSCs.

Fe3O4 Nanoparticles in Targeted Drug/Gene Delivery Systems

PubMed Central

Shen, Lazhen; Li, Bei; Qiao, Yongsheng

2018-01-01

Fe3O4 nanoparticles (NPs), the most traditional magnetic nanoparticles, have received a great deal of attention in the biomedical field, especially for targeted drug/gene delivery systems, due to their outstanding magnetism, biocompatibility, lower toxicity, biodegradability, and other features. Naked Fe3O4 NPs are easy to aggregate and oxidize, and thus are often made with various coatings to realize superior properties for targeted drug/gene delivery. In this review, we first list the three commonly utilized synthesis methods of Fe3O4 NPs, and their advantages and disadvantages. In the second part, we describe coating materials that exhibit noticeable features that allow functionalization of Fe3O4 NPs and summarize their methods of drug targeting/gene delivery. Then our efforts will be devoted to the research status and progress of several different functionalized Fe3O4 NP delivery systems loaded with chemotherapeutic agents, and we present targeted gene transitive carriers in detail. In the following section, we illuminate the most effective treatment systems of the combined drug and gene therapy. Finally, we propose opportunities and challenges of the clinical transformation of Fe3O4 NPs targeting drug/gene delivery systems. PMID:29473914

Decreased Expression of hsa-miR-4274 in Cerebrospinal Fluid of Normal Pressure Hydrocephalus Mimics with Parkinsonian Syndromes.

PubMed

Jurjević, Ivana; Miyajima, Masakazu; Ogino, Ikuko; Akiba, Chihiro; Nakajima, Madoka; Kondo, Akihide; Kikkawa, Mika; Kanai, Mitsuyasu; Hattori, Nobutaka; Arai, Hajime

2017-01-01

Patients presenting with the classical idiopathic normal pressure hydrocephalus (iNPH) triad often show additional parkinsonian spectrum signs. Accurate differential diagnosis strongly influences the long-term outcome of cerebrospinal fluid (CSF) shunting. The aim of this study was to find potential CSF microRNA (miRNA) biomarkers for NPH mimics with parkinsonian syndromes that can reliably distinguish them from iNPH patients. Two cohorts of 81 patients (cohort 1, n = 55; cohort 2, n = 26) with possible iNPH who were treated in two centers between January 2011 and May 2014 were studied. In both cohorts, CSF samples were obtained from patients clinically diagnosed with iNPH (n = 21 and n = 10, respectively), possible iNPH with parkinsonian spectrum (PS) (n = 18, n = 10, respectively), possible iNPH with Alzheimer's disease (AD) (n = 16), and non-affected elderly individuals (NC) (n = 6). A three-step qRT-PCR analysis of the CSF samples was performed to detect miRNAs that were differentially expressed in the groups. The expression of hsa-miR-4274 in CSF was decreased in both cohorts of PS group patients (cohort 1: p < 0.0001, cohort 2: p < 0.0001), and was able to distinguish PS from iNPH with high accuracy (area under the curve = 0.908). The CSF concentration of hsa-miR-4274 also correlated with the specific binding ratio of ioflupane (123I) dopamine transporter scan (r = -0.494, p = 0.044). By contrast, the level of hsa-miR-4274 was significantly increased in the PS group after CSF diversion. Levels of CSF hsa-miR-4274 can differentiate PS from patients with iNPH, AD, and NC. This may be clinically useful for diagnostic purposes and predicting shunt treatment responses.

Transferrin receptor-targeted theranostic gold nanoparticles for photosensitizer delivery in brain tumors

PubMed Central

Dixit, Suraj; Novak, Thomas; Miller, Kayla; Zhu, Yun; Kenney, Malcolm E.

2015-01-01

Therapeutic drug delivery across the blood-brain barrier (BBB) is not only inefficient, but also nonspecific to brain stroma. These are major limitations in the effective treatment of brain cancer. Transferrin peptide (Tfpep) targeted gold nanoparticles (Tfpep-Au NPs) loaded with the photodynamic pro-drug, Pc 4, have been designed and compared with untargeted Au NPs for delivery of the photosensitizer to brain cancer cell lines. In vitro studies of human glioma cancer lines (LN229 and U87) overexpressing the transferrin receptor (TfR) show a significant increase in cellular uptake for targeted conjugates as compared to un-targeted particles. Pc 4 delivered from Tfpep-Au NPs clusters within vesicles after targeting with the Tfpep. Pc 4 continues to accumulate over a 4 hour period. Our work suggests that TfR-targeted Au NPs may have important therapeutic implications for delivering brain tumor therapies and/or providing a platform for noninvasive imaging. PMID:25519743

Hyaluronic acid-modified hydrothermally synthesized iron oxide nanoparticles for targeted tumor MR imaging.

PubMed

Li, Jingchao; He, Yao; Sun, Wenjie; Luo, Yu; Cai, Hongdong; Pan, Yunqi; Shen, Mingwu; Xia, Jindong; Shi, Xiangyang

2014-04-01

We report a polyethyleneimine (PEI)-mediated approach to synthesizing hyaluronic acid (HA)-targeted magnetic iron oxide nanoparticles (Fe3O4 NPs) for in vivo targeted tumor magnetic resonance (MR) imaging applications. In this work, Fe3O4 NPs stabilized by PEI were first synthesized via a one-pot hydrothermal method. The formed PEI-stabilized Fe3O4 NPs were then modified with fluorescein isothiocyanate (FI) and HA with two different molecular weights to obtain two different Fe3O4 NPs (Fe3O4-PEI-FI-HA6K and Fe3O4-PEI-FI-HA31K NPs) with a size of 15-16 nm. The formed HA-modified multifunctional Fe3O4 NPs were characterized via different techniques. We show that the multifunctional Fe3O4 NPs are water-dispersible and colloidal stable in different aqueous media. In vitro cell viability and hemolysis studies reveal that the particles are quite cytocompatible and hemocompatible in the given concentration range. Furthermore, confocal microscopy and flow cytometry data demonstrate that HA-targeted Fe3O4 NPs are able to be uptaken specifically by cancer cells overexpressing CD44 receptors, and be used as efficient probes for targeted MR imaging of cancer cells in vitro and xenografted tumor models in vivo. With the tunable amine-based conjugation chemistry, the PEI-stabilized Fe3O4 NPs may be functionalized with other biological ligands or drugs for diagnosis and therapy of different biological systems. Copyright © 2014 Elsevier Ltd. All rights reserved.

USGS-NPS Servicewide Benthic Mapping Program (SBMP) workshop report

USGS Publications Warehouse

Moses, Christopher S.; Nayagandhi, Amar; Brock, John; Beavers, Rebecca

2010-01-01

The National Park Service (NPS) Inventory and Monitoring (I&M) Program recently allocated funds to initiate a benthic mapping program in ocean and Great Lakes parks in alignment with the NPS Ocean Park Stewardship 2007-2008 Action Plan. Seventy-four (ocean and Great Lakes) parks, spanning more than 5,000 miles of coastline, many affected by increasing coastal storms and other natural and anthropogenic processes, make the development of a Servicewide Benthic Mapping Program (SBMP) timely. The resulting maps and associated reports will be provided to NPS managers in a consistent servicewide format to help park managers protect and manage the 3 million acres of submerged National Park System natural and cultural resources. Of the 74 ocean and Great Lakes park units, the 40 parks with submerged acreage will be the focus in the early years of the SBMP. The NPS and U.S. Geological Survey (USGS) convened a workshop (June 3-5, 2008) in Lakewood, CO. The assembly of experts from the NPS and other Federal and non-Federal agencies clarified the needs and goals of the NPS SBMP and was one of the key first steps in designing the benthic mapping program. The central needs for individual parks, park networks, and regions identified by workshop participants were maps including bathymetry, bottom type, geology, and biology. This workshop, although not an exhaustive survey of data-acquisition technologies, highlighted the more promising technologies being used, existing sources of data, and the need for partnerships to leverage resources. Workshop products include recommended classification schemes and management approaches for consistent application and products similar to other long-term NPS benthic mapping efforts. As part of the SBMP, recommendations from this workshop, including application of an improved version of the Coastal and Marine Ecological Classification Standard (CMECS), will be tested in several pilot parks. In 2008, in conjunction with the findings of this workshop

Concerted functions of Streptococcus gordonii surface proteins PadA and Hsa mediate activation of human platelets and interactions with extracellular matrix.

PubMed

Haworth, Jennifer A; Jenkinson, Howard F; Petersen, Helen J; Back, Catherine R; Brittan, Jane L; Kerrigan, Steve W; Nobbs, Angela H

2017-01-01

A range of Streptococcus bacteria are able to interact with blood platelets to form a thrombus (clot). Streptococcus gordonii is ubiquitous within the human oral cavity and amongst the common pathogens isolated from subjects with infective endocarditis. Two cell surface proteins, Hsa and Platelet adherence protein A (PadA), in S. gordonii mediate adherence and activation of platelets. In this study, we demonstrate that PadA binds activated platelets and that an NGR (Asparagine-Glycine-Arginine) motif within a 657 amino acid residue N-terminal fragment of PadA is responsible for this, together with two other integrin-like recognition motifs RGT and AGD. PadA also acts in concert with Hsa to mediate binding of S. gordonii to cellular fibronectin and vitronectin, and to promote formation of biofilms. Evidence is presented that PadA and Hsa are each reliant on the other's active presentation on the bacterial cell surface, suggesting cooperativity in functions impacting both colonization and pathogenesis. © 2016 The Authors Cellular Microbiology Published by John Wiley & Sons Ltd.

Structural studies of bovine, equine, and leporine serum albumin complexes with naproxen.

PubMed

Bujacz, Anna; Zielinski, Kamil; Sekula, Bartosz

2014-09-01

Serum albumin, a protein naturally abundant in blood plasma, shows remarkable ligand binding properties of numerous endogenous and exogenous compounds. Most of serum albumin binding sites are able to interact with more than one class of ligands. Determining the protein-ligand interactions among mammalian serum albumins is essential for understanding the complexity of this transporter. We present three crystal structures of serum albumins in complexes with naproxen (NPS): bovine (BSA-NPS), equine (ESA-NPS), and leporine (LSA-NPS) determined to 2.58 Å (C2), 2.42 Å (P61), and 2.73 Å (P2₁2₁2₁) resolutions, respectively. A comparison of the structurally investigated complexes with the analogous complex of human serum albumin (HSA-NPS) revealed surprising differences in the number and distribution of naproxen binding sites. Bovine and leporine serum albumins possess three NPS binding sites, but ESA has only two. All three complexes of albumins studied here have two common naproxen locations, but BSA and LSA differ in the third NPS binding site. None of these binding sites coincides with the naproxen location in the HSA-NPS complex, which was obtained in the presence of other ligands besides naproxen. Even small differences in sequences of serum albumins from various species, especially in the area of the binding pockets, influence the affinity and the binding mode of naproxen to this transport protein. © 2014 Wiley Periodicals, Inc.

Nonlinear absorption enhancement of AuNPs based polymer nanocomposites

NASA Astrophysics Data System (ADS)

Zulina, Natalia A.; Baranov, Mikhail A.; Kniazev, Kirill I.; Kaliabin, Viacheslav O.; Denisyuk, Igor Yu.; Achor, Susan U.; Sitnikova, Vera E.

2018-07-01

Au nanoparticles (AuNPs) based polymer nanocomposites with high nonlinear absorption coefficient were synthesized by UV-photocuring. AuNPs were synthesized by laser ablation method in liquid monomer isodecyl acrylate (IDA). In this research, two colloids with 70 nm and 20 nm nanoparticles average sizes were studied. Size control was performed with SEM and STEM. Prepared nanomaterials exhibit strong third-order nonlinear optical responses under CW laser irradiation at 532 nm, which was estimated by using z-scan technique performed with open aperture. It was found experimentally that nonlinear absorption β is almost twice higher for nanocomposites with smaller AuNPs.

Targeted delivery of 10-hydroxycamptothecin to human breast cancers by cyclic RGD-modified lipid-polymer hybrid nanoparticles.

PubMed

Yang, Zhe; Luo, Xingen; Zhang, Xiaofang; Liu, Jie; Jiang, Qing

2013-04-01

Lipid-polymer hybrid nanoparticles (NPs) combining the positive attributes of both liposomes and polymeric NPs are increasingly being considered as promising candidates to carry therapeutic agents safely and efficiently into targeted sites. Herein, a modified emulsification technique was developed and optimized for the targeting lipid-polymer hybrid NPs fabrication; the surface properties and stability of the hybrid NPs were systematically investigated, which confirmed that the hybrid NPs consisted of a poly (lactide-co-glycolide) core with ∼90% surface coverage of the lipid monolayer and a ∼4.4 nm hydrated polyethylene glycol (PEG) shell. Optimization results showed that the lipid:polymer mass ratio and the lipid-PEG:lipid molar ratio could affect the size, lipid association efficiency and stability of hybrid NPs. Furthermore, a model chemotherapy drug, 10-hydroxycamptothecin, was encapsulated into hybrid NPs with a higher drug loading compared to PLGA NPs. Surface modification of the lipid layer and the PEG conjugated targeting ligand did not affect their drug release kinetics. Finally, the cytotoxicity and cellular uptake studies indicated that the lipid coverage and the c(RGDyk) conjugation of the hybrid NPs gained a significantly enhanced ability of cell killing and endocytosis. Our results suggested that lipid-polymer hybrid NPs prepared by the modified emulsion technique have great potential to be utilized as an engineered drug delivery system with precise control ability of surface targeting modification.

Effects of TiO2 NPs on Silkworm Growth and Feed Efficiency.

PubMed

Li, YangYang; Ni, Min; Li, FanChi; Zhang, Hua; Xu, KaiZun; Zhao, XiaoMing; Tian, JiangHai; Hu, JingSheng; Wang, BinBin; Shen, WeiDe; Li, Bing

2016-02-01

Silkworm (Bombyx mori) (B. mori) is an economically important insect and a model species for Lepidoptera. It has been reported that feeding of low concentrations of titanium dioxide nanoparticles (TiO2 NPs) can improve feed efficiency and increase cocoon mass, cocoon shell mass, and the ratio of cocoon shell. However, high concentrations of TiO2 NPs are toxic. In this study, we fed B. mori with different concentrations of TiO2 NPs (5, 10, 20, 40, 80, and 160 mg/L) and investigated B. mori growth, feed efficiency, and cocoon quality. We found that low concentrations of TiO2 NPs (5 and 10 mg/L) were more effective for weight gains, with significant weight gain being obtained at 72 h (P < 0.05). TiO2 NPs at 20 mg/L or higher had certain inhibitory effects, with significant inhibition to B. mori growth being observed at 48 h. The feed efficiency was significantly improved at low concentrations of 5 and 10 mg/L for 14.6 and 13.1 %, respectively (P < 0.05). All B. mori fed with TiO2 NPs showed increased cocoon mass and cocoon shell mass; at 5 and 10 mg/L TiO2 NPs, cocoon mass was significantly increased by 8.29 and 9.39 %, respectively (P < 0.05). We also found that low concentrations (5 and 10 mg/L) of TiO2 NPs promoted B. mori growth and development, improved feed efficiency, and increased cocoon production, while high concentrations (20 mg/L or higher) of TiO2 NPs showed inhibitory effect to the B. mori. Consecutive feeding of high concentrations of TiO2 NPs led to some degrees of adaptability. This study provides a reference for the research on TiO2 NPs toxicity and the basis for the development of TiO2 NPs as a feed additive for B. mori.

Tracking targeted bimodal nanovaccines: immune responses and routing in cells, tissue, and whole organism.

PubMed

Cruz, Luis J; Tacken, Paul J; Zeelenberg, Ingrid S; Srinivas, Mangala; Bonetto, Fernando; Weigelin, Bettina; Eich, Christina; de Vries, I Jolanda; Figdor, Carl G

2014-12-01

Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs), involved in the induction of immunity and currently exploited for antitumor immunotherapies. An optimized noninvasive imaging modality capable of determining and quantifying DC-targeted nanoparticle (NP) trajectories could provide valuable information regarding therapeutic vaccine outcome. Here, targeted poly(d,l-lactide-co-glycolide) nanoparticles (PLGA NPs) recognizing DC receptors were equipped with superparamagnetic iron oxide particles (SPIO) or gold nanoparticles with fluorescently labeled antigen. The fluorescent label allowed for rapid analysis and quantification of DC-specific uptake of targeted PLGA NPs in comparison to uptake by other cells. Transmission electron microscopy (TEM) showed that a fraction of the encapsulated antigen reached the lysosomal compartment of DCs, where SPIO and gold were already partially released. However, part of the PLGA NPs localized within the cytoplasm, as confirmed by confocal microscopy. DCs targeted with NPs carrying SPIO or fluorescent antigen were detected within lymph nodes as early as 1 h after injection by magnetic resonance imaging (MRI). Despite the fact that targeting did not markedly affect PLGA NP biodistribution on organism and tissue level, it increased delivery of NPs to DCs residing in peripheral lymph nodes and resulted in enhanced T cell proliferation. In conclusion, two imaging agents within a single carrier allows tracking of targeted PLGA NPs at the subcellular, cellular, and organismal levels, thereby facilitating the rational design of in vivo targeted vaccination strategies.

Impact of surfactants on the target recognition of Fab-conjugated PLGA nanoparticles.

PubMed

Kennedy, Patrick J; Perreira, Ines; Ferreira, Daniel; Nestor, Marika; Oliveira, Carla; Granja, Pedro L; Sarmento, Bruno

2018-06-01

Targeted drug delivery with nanoparticles (NPs) requires proper surface ligand presentation and availability. Surfactants are often used as stabilizers in the production of targeted NPs. Here, we evaluated the impact of surfactants on ligand functionalization and downstream molecular recognition. Our model system consisted of fluorescent poly(lactic-co-glycolic acid) (PLGA) NPs that were nanoprecipitated in one of a small panel of commonly-used surfactants followed by equivalent washes and conjugation of an engineered Fab antibody fragment. Size, polydispersity index and zeta potential were determined by dynamic light scattering and laser Doppler anemometry, and Fab presence on the NPs was assessed by enzyme-linked immunosorbent assay. Most importantly, Fab-decorated NP binding to the cell surface receptor was monitored by fluorescence-activated cell sorting. 2% polyvinyl alcohol, 1% sodium cholate, 0.5% Pluronic F127 (F127) and 2% Tween-80 were initially tested. Of the four surfactants tested, PLGA NPs in 0.5% F127 and 2% Tween-80 had the highest cell binding. These two surfactants were then retested in two different concentrations, 0.5% and 2%. The Fab-decorated PLGA NPs in 2% F127 had the highest cell binding. This study highlights the impact of common surfactants and their concentrations on the downstream targeting of ligand-decorated NPs. Similar principles should be applied in the development of future targeted nanosystems where surfactants are employed. Copyright © 2018 Elsevier B.V. All rights reserved.

Study of energy transfer between riboflavin (vitamin B2) and AgNPs

NASA Astrophysics Data System (ADS)

Mokashi, Vidya V.; Walekar, Laxman S.; Anbhule, Prashant V.; Lee, Sang Hak; Patil, Shivajirao R.; Kolekar, Govind B.

2014-03-01

Here, we report the studies on the interaction and formation of nanobiocomplex between silver nanoparticle (AgNPs) and vitamin B2, i.e., riboflavin (RF). The binding study of AgNP to RF was studied by fluorescence, UV-Vis, and TEM techniques. AgNPs were prepared by reducing AgNO3 with trisodium citrate. Prepared nanoparticles size obtained at 20 nm having surface Plasmon resonance band at 426 nm. The absorbance band of RF at 264, 374, and 444 nm changes significantly in the presence of AgNPs suggests that there is change in the chemical environment surrounding AgNPs. A fluorescence spectral change for a solution of RF upon the addition of AgNPs and rapid quenching is suggestive of a rapid adsorption of RF on AgNPs.

NPS Solar Cell Array Tester Cubesat Flight Testing and Integration

DTIC Science & Technology

2014-09-01

with current (I). P V I      (2.1) This is significant because the battery discharge test will not lineup perfectly with Figure 12...accordance with the charging procedures [13]. 3. NPS-SCAT Power Budget A power budget analysis was performed to determine if the NPS-SCAT is self...using procedures developed by Marissa Brummitt, and with the assistance of Adam Hill, NPS-SCAT Program Manager. 1. ELaNa IV Random Vibration Levels

Anionic clay as the drug delivery vehicle: tumor targeting function of layered double hydroxide-methotrexate nanohybrid in C33A orthotopic cervical cancer model

PubMed Central

Choi, Goeun; Piao, Huiyan; Alothman, Zeid A; Vinu, Ajayan; Yun, Chae-Ok; Choy, Jin-Ho

2016-01-01

Methotrexate (MTX), an anticancer agent, was successfully intercalated into the anionic clay, layered double hydroxides to form a new nanohybrid drug. The coprecipitation and subsequent hydrothermal method were used to prepare chemically, structurally, and morphologically well-defined two-dimensional drug-clay nanohybrid. The resulting two-dimensional drug-clay nanohybrid showed excellent colloidal stability not only in deionized water but also in an electrolyte solution of Dulbecco’s Modified Eagle’s Medium with 10% fetal bovine serum, in which the average particle size in colloid and the polydispersity index were determined to be around 100 and 0.250 nm, respectively. The targeting property of the nanohybrid drug was confirmed by evaluating the tumor-to-blood and tumor-to-liver ratios of the MTX with anionic clay carrier, and these ratios were compared to those of free MTX in the C33A orthotopic cervical cancer model. The biodistribution studies indicated that the mice treated with the former showed 3.5-fold higher tumor-to-liver ratio and fivefold higher tumor-to-blood ratio of MTX than those treated with the latter at 30 minutes postinjection. PMID:26855572

Effects of inhibitors of vascular endothelial growth factor receptor 2 and downstream pathways of receptor tyrosine kinases involving phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin or mitogen-activated protein kinase in canine hemangiosarcoma cell lines.

PubMed

Adachi, Mami; Hoshino, Yuki; Izumi, Yusuke; Sakai, Hiroki; Takagi, Satoshi

2016-07-01

Canine hemangiosarcoma (HSA) is a progressive malignant neoplasm with no current effective treatment. Previous studies showed that receptor tyrosine kinases and molecules within their downstream pathways involving phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (m-TOR) or mitogen-activated protein kinase (MAPK) were overexpressed in canine, human, and murine tumors, including HSA. The present study investigated the effects of inhibitors of these pathways in canine splenic and hepatic HSA cell lines using assays of cell viability and apoptosis. Inhibitors of the MAPK pathway did not affect canine HSA cell viability. However, cell viability was significantly reduced by exposure to inhibitors of vascular endothelial growth factor receptor 2 and the PI3K/Akt/m-TOR pathway; these inhibitors also induced apoptosis in these cell lines. These results suggest that these inhibitors reduce the proliferation of canine HSA cells by inducing apoptosis. Further study of these inhibitors, using xenograft mouse models of canine HSA, are warranted to explore their potential for clinical application.

Targeted nanoparticles encapsulating (-)-epigallocatechin-3-gallate for prostate cancer prevention and therapy

NASA Astrophysics Data System (ADS)

Sanna, Vanna; Singh, Chandra K.; Jashari, Rahime; Adhami, Vaqar M.; Chamcheu, Jean Christopher; Rady, Islam; Sechi, Mario; Mukhtar, Hasan; Siddiqui, Imtiaz A.

2017-02-01

Earlier we introduced the concept of ‘nanochemoprevention’ i.e. the use of nanotechnology to improve the outcome of cancer chemoprevention. Here, we extended our work and developed polymeric EGCG-encapsulated nanoparticles (NPs) targeted with small molecular entities, able to bind to prostate specific membrane antigen (PSMA), a transmembrane protein that is overexpressed in prostate cancer (PCa), and evaluated their efficacy in preclinical studies. First, we performed a molecular recognition of DCL- and AG-PEGylation on ligand binding on PSMA active site. Next, the biocompatible polymers PLGA-PEG-A were synthesized and used as base to conjugate DCL or AG to obtain the respective copolymers, needed for the preparation of targeted NPs. The resulting EGCG encapsulating NPs led to an enhanced anti-proliferative activity in PCa cell lines compared to the free EGCG. The behavior of EGCG encapsulated in NPs in modulating apoptosis and cell-cycle, was also determined. Then, in vivo experiments, in mouse xenograft model of prostatic tumor, using EGCG-loaded NPs, with a model of targeted nanosystems, were conducted. The obtained data supported our hypothesis of target-specific enhanced bioavailability and limited unwanted toxicity, thus leading to a significant potential for probable clinical outcome.

Real time imaging of infrared scene data generated by the Naval Postgraduate School Infrared Search and Target Designation (NPS-IRSTD) system

NASA Astrophysics Data System (ADS)

Baca, Michael J.

1990-09-01

A system to display images generated by the Naval Postgraduate School Infrared Search and Target Designation (a modified AN/SAR-8 Advanced Development Model) in near real time was developed using a 33 MHz NIC computer as the central controller. This computer was enhanced with a Data Translation DT2861 Frame Grabber for image processing and an interface board designed and constructed at NPS to provide synchronization between the IRSTD and Frame Grabber. Images are displayed in false color in a video raster format on a 512 by 480 pixel resolution monitor. Using FORTRAN, programs have been written to acquire, unscramble, expand and display a 3 deg sector of data. The time line for acquisition, processing and display has been analyzed and repetition periods of less than four seconds for successive screen displays have been achieved. This represents a marked improvement over previous methods necessitating slower Direct Memory Access transfers of data into the Frame Grabber. Recommendations are made for further improvements to enhance the speed and utility of images produced.

Transferrin receptor-targeted theranostic gold nanoparticles for photosensitizer delivery in brain tumors

NASA Astrophysics Data System (ADS)

Dixit, Suraj; Novak, Thomas; Miller, Kayla; Zhu, Yun; Kenney, Malcolm E.; Broome, Ann-Marie

2015-01-01

Therapeutic drug delivery across the blood-brain barrier (BBB) is not only inefficient, but also nonspecific to brain stroma. These are major limitations in the effective treatment of brain cancer. Transferrin peptide (Tfpep) targeted gold nanoparticles (Tfpep-Au NPs) loaded with the photodynamic pro-drug, Pc 4, have been designed and compared with untargeted Au NPs for delivery of the photosensitizer to brain cancer cell lines. In vitro studies of human glioma cancer lines (LN229 and U87) overexpressing the transferrin receptor (TfR) show a significant increase in cellular uptake for targeted conjugates as compared to untargeted particles. Pc 4 delivered from Tfpep-Au NPs clusters within vesicles after targeting with the Tfpep. Pc 4 continues to accumulate over a 4 hour period. Our work suggests that TfR-targeted Au NPs may have important therapeutic implications for delivering brain tumor therapies and/or providing a platform for noninvasive imaging.

Bioconjugated PLGA-4-arm-PEG branched polymeric nanoparticles as novel tumor targeting carriers

NASA Astrophysics Data System (ADS)

Ding, Hong; Yong, Ken-Tye; Roy, Indrajit; Hu, Rui; Wu, Fang; Zhao, Lingling; Law, Wing-Cheung; Zhao, Weiwei; Ji, Wei; Liu, Liwei; Bergey, Earl J.; Prasad, Paras N.

2011-04-01

In this study, we have developed a novel carrier, micelle-type bioconjugated PLGA-4-arm-PEG branched polymeric nanoparticles (NPs), for the detection and treatment of pancreatic cancer. These NPs contained 4-arm-PEG as corona, and PLGA as core, the particle surface was conjugated with cyclo(arginine-glycine-aspartate) (cRGD) as ligand for in vivo tumor targeting. The hydrodynamic size of the NPs was determined to be 150-180 nm and the critical micellar concentration (CMC) was estimated to be 10.5 mg l - 1. Our in vitro study shows that these NPs by themselves had negligible cytotoxicity to human pancreatic cancer (Panc-1) and human glioblastoma (U87) cell lines. Near infrared (NIR) microscopy and flow cytometry demonstrated that the cRGD conjugated PLGA-4-arm-PEG polymeric NPs were taken up more efficiently by U87MG glioma cells, over-expressing the αvβ3 integrin, when compared with the non-targeted NPs. Whole body imaging showed that the cRGD conjugated PLGA-4-arm-PEG branched polymeric NPs had the highest accumulation in the pancreatic tumor site of mice at 48 h post-injection. Physical, hematological, and pathological assays indicated low in vivo toxicity of this NP formulation. These studies on the ability of these bioconjugated PLGA-4-arm-PEG polymeric NPs suggest that the prepared polymeric NPs may serve as a promising platform for detection and targeted drug delivery for pancreatic cancer.

Biodegradable double-targeted PTX-mPEG-PLGA nanoparticles for ultrasound contrast enhanced imaging and antitumor therapy in vitro.

PubMed

Ma, Jing; Shen, Ming; Xu, Chang Song; Sun, Ying; Duan, You Rong; Du, Lian Fang

2016-11-29

A porous-structure nano-scale ultrasound contrast agent (UCA) was made of monomethoxypoly (ethylene glycol)-poly (lactic-co-glycolic acid) (mPEG-PLGA), and modified by double-targeted antibody: anti-carcinoembryonic antigen (CEA) and anti-carbohydrate antigen 19-9 (CA19-9), as a double-targeted nanoparticles (NPs). Anti-tumor drug paclitaxel (PTX) was encapsulated in the double-targeted nanoparticles (NPs). The morphor and release curve were characterized. We verified a certain anticancer effect of PTX-NPs through cytotoxicity experiments. The cell uptake result showed much more NPs may be facilitated to ingress the cells or tissues with ultrasound (US) or ultrasound targeted microbubble destruction (UTMD) transient sonoporation in vitro. Ultrasound contrast-enhanced images in vitro and in vivo were investigated. Compared with SonoVue, the NPs prolonged imaging time in rabbit kidneys and tumor of nude mice, which make it possible to further enhance anti-tumor effects by extending retention time in the tumor region. The novel double-targeted NPs with the function of ultrasound contrast enhanced imaging and anti-tumor therapy can be a promising way in clinic.

A novel strategy for water disinfection with a AgNPs/gelatin sponge filter.

PubMed

Wei, Feng; Zhao, Xiaole; Li, Chao; Han, Xiaojun

2018-05-05

Disinfection of bacteria in water with sustainable and energy-efficient methods is still a great challenge. Herein, a novel gelatin sponge with embedded AgNPs is fabricated via freeze-drying using gelatin as the reducing agent to synthesize AgNPs in situ. UV-vis spectroscopy, HRTEM, XRD, and XPS characterization prove the formation of AgNPs with an average size of 8.55 ± 0.35 nm. TEM and SEM images confirm the even distribution of AgNPs throughout the AgNPs/gelatin sponges. The composite sponge has a low bulk density of 20 ± 3.5 mg/cm 3 and a pore size of 6.2 ± 1.5 μm. The AgNPs/gelatin sponges exhibit excellent antibacterial performance to E. coli in water, probably by destroying their cell membranes. The porous AgNPs/gelatin composite sponges are promising filter materials for water disinfection. The removal rate of AgNPs/gelatin composite sponges on E. coli reached almost 100%. Graphical abstract ᅟ.

The adsorption of human serum albumin (HSA) on CO2 laser modified magnesia partially stabilised zirconia (MgO-PSZ).

PubMed

Hao, L; Lawrence, J

2004-03-15

Magnesia partially stabilised zirconia (MgO-PSZ), a bioinert ceramic, exhibits high mechanical strength, excellent corrosion resistance and good biocompatibility, but it does not naturally form a direct bond with bone resulting in a lack of osteointegration. The surface properties and structure of a biomaterial play an essential role in protein adsorption. As such, changes in the surface properties and structure of biomaterials may in turn alter their bioactivity. So, the fundamental reactions at the interface of biomaterials and tissue should influence their integration and bone-bonding properties. To this end, CO2 laser radiation was used to modify the surface roughness, crystal size, phase and surface energy of the MgO-PSZ. The basic mechanisms active in improving the surface energy were analysed and found to be the phase change and augmented surface area. The adsorption of human serum albumin (HSA), which is a non-cell adhesive protein, was compared on the untreated and CO2 laser modified MgO-PSZ. It was observed that the thickness of the adsorbed HSA decreased as the polar surface energy of the MgO-PSZ increased, indicating that HSA adsorbed more effectively on the hydrophobic MgO-PSZ surface than the hydrophilic surface. The current study provided important information regarding protein-biomaterial interactions and possible mechanisms behind the cell interaction and in vivo behaviour.

Dual-Functional Nanoparticles Targeting CXCR4 and Delivering Antiangiogenic siRNA Ameliorate Liver Fibrosis.

PubMed

Liu, Chun-Hung; Chan, Kun-Ming; Chiang, Tsaiyu; Liu, Jia-Yu; Chern, Guann-Gen; Hsu, Fu-Fei; Wu, Yu-Hsuan; Liu, Ya-Chi; Chen, Yunching

2016-07-05

The progression of liver fibrosis, an intrinsic response to chronic liver injury, is associated with hepatic hypoxia, angiogenesis, abnormal inflammation, and significant matrix deposition, leading to the development of cirrhosis and hepatocellular carcinoma (HCC). Due to the complex pathogenesis of liver fibrosis, antifibrotic drug development has faced the challenge of efficiently and specifically targeting multiple pathogenic mechanisms. Therefore, CXCR4-targeted nanoparticles (NPs) were formulated to deliver siRNAs against vascular endothelial growth factor (VEGF) into fibrotic livers to block angiogenesis during the progression of liver fibrosis. AMD3100, a CXCR4 antagonist that was incorporated into the NPs, served dual functions: it acted as a targeting moiety and suppressed the progression of fibrosis by inhibiting the proliferation and activation of hepatic stellate cells (HSCs). We demonstrated that CXCR4-targeted NPs could deliver VEGF siRNAs to fibrotic livers, decrease VEGF expression, suppress angiogenesis and normalize the distorted vessels in the fibrotic livers in the carbon tetrachloride (CCl4) induced mouse model. Moreover, blocking SDF-1α/CXCR4 by CXCR4-targeted NPs in combination with VEGF siRNA significantly prevented the progression of liver fibrosis in CCl4-treated mice. In conclusion, the multifunctional CXCR4-targeted NPs delivering VEGF siRNAs provide an effective antifibrotic therapeutic strategy.

AS1411 aptamer tagged PLGA-lecithin-PEG nanoparticles for tumor cell targeting and drug delivery.

PubMed

Aravind, Athulya; Jeyamohan, Prashanti; Nair, Remya; Veeranarayanan, Srivani; Nagaoka, Yutaka; Yoshida, Yasuhiko; Maekawa, Toru; Kumar, D Sakthi

2012-11-01

Liposomes and polymers are widely used drug carriers for controlled release since they offer many advantages like increased treatment effectiveness, reduced toxicity and are of biodegradable nature. In this work, anticancer drug-loaded PLGA-lecithin-PEG nanoparticles (NPs) were synthesized and were functionalized with AS1411 anti-nucleolin aptamers for site-specific targeting against tumor cells which over expresses nucleolin receptors. The particles were characterized by transmission electron microscope (TEM) and X-ray photoelectron spectroscopy (XPS). The drug-loading efficiency, encapsulation efficiency and in vitro drug release studies were conducted using UV spectroscopy. Cytotoxicity studies were carried out in two different cancer cell lines, MCF-7 and GI-1 cells and two different normal cells, L929 cells and HMEC cells. Confocal microscopy and flowcytometry confirmed the cellular uptake of particles and targeted drug delivery. The morphology analysis of the NPs proved that the particles were smooth and spherical in shape with a size ranging from 60 to 110 nm. Drug-loading studies indicated that under the same drug loading, the aptamer-targeted NPs show enhanced cancer killing effect compared to the corresponding non-targeted NPs. In addition, the PLGA-lecithin-PEG NPs exhibited high encapsulation efficiency and superior sustained drug release than the drug loaded in plain PLGA NPs. The results confirmed that AS1411 aptamer-PLGA-lecithin-PEG NPs are potential carrier candidates for differential targeted drug delivery. Copyright © 2012 Wiley Periodicals, Inc.

P-gp, MRP2 and OAT1/OAT3 mediate the drug-drug interaction between resveratrol and methotrexate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jia, Yongming

The purpose of present study was to investigate the effect of resveratrol (Res) on altering methotrexate (MTX) pharmacokinetics and clarify the related molecular mechanism. Res significantly increased rat intestinal absorption of MTX in vivo and in vitro. Simultaneously, Res inhibited MTX efflux transport in MDR1-MDCK and MRP2-MDCK cell monolayers, suggesting that the target of drug interaction was MDR1 and MRP2 in the intestine during the absorption process. Furthermore, there was a significant decrease in renal clearance of MTX after simultaneous intravenous administration. Similarly, MTX uptake was markedly inhibited by Res in rat kidney slices and hOAT1/3-HEK293 cell, indicating that OAT1more » and OAT3 were involved in the drug interaction in the kidney. Additionally, concomitant administration of Res decreased cytotoxic effects of MTX in hOAT1/3-HEK293 cells, and ameliorated nephrotoxicity caused by MTX in rats. Conversely, intestinal damage caused by MTX was not exacerbated after Res treatment. In conclusion, Res enhanced MTX absorption in intestine and decreased MTX renal elimination by inhibiting P-gp, MRP2, OAT1 and OAT3 in vivo and in vitro. Res improved MTX-induced renal damage without increasing intestinal toxicity. - Highlights: • DDI between MTX and Res will occur when they are co-administered. • The first targets of the DDI are P-gp and MRP2 located in intestine. • The second targets of the DDI are OAT1 and OAT3 in kidney. • Res improved MTX-induced renal damage without increasing intestinal toxicity.« less

A green approach to dual-drug nanoformulations with targeting and synergistic effects for cancer therapy.

PubMed

Wu, Shichao; Yang, Xiangrui; Lu, Yue; Fan, Zhongxiong; Li, Yang; Jiang, Yuan; Hou, Zhenqing

2017-11-01

Exploration of efficient dual-drug nanohybrids, particularly those with high drug loading, specific targeting property, and long-termed stability, is of highly importance in cancer therapy. A pH-driven coprecipitation was performed in the aqueous phase to obtain a dual-drug nanoformulation, composed of 10-hydroxycamptothecine (HCPT) nanoneedles integrated with an exterior thin layer of the methotrexate (MTX)-chitosan conjugate. The high stability of nanohybrids in water and the targeting property provided by the MTX ingredient function synergistically to the prolonged and sustained drug release property in tumor tissues and the increased cellular uptake. The cytotoxicity test illustrates that dual-drug nanoneedles possess the remarkable killing ability to HeLa cells with the combination index at 0.33 ± 0.07. After cellular internalization, the release of both drug ingredients results in an excellent anticancer activity in vivo with the minimized adverse side effects. Design of a green approach to the carrier-free, dual-drug nanoformulations enables to develop emerging drug delivery systems for cancer diagnosis and treatment.

Decreased Expression of hsa-miR-4274 in Cerebrospinal Fluid of Normal Pressure Hydrocephalus Mimics with Parkinsonian Syndromes

PubMed Central

Jurjević, Ivana; Miyajima, Masakazu; Ogino, Ikuko; Akiba, Chihiro; Nakajima, Madoka; Kondo, Akihide; Kikkawa, Mika; Kanai, Mitsuyasu; Hattori, Nobutaka; Arai, Hajime

2016-01-01

Background: Patients presenting with the classical idiopathic normal pressure hydrocephalus (iNPH) triad often show additional parkinsonian spectrum signs. Accurate differential diagnosis strongly influences the long-term outcome of cerebrospinal fluid (CSF) shunting. Objective: The aim of this study was to find potential CSF microRNA (miRNA) biomarkers for NPH mimics with parkinsonian syndromes that can reliably distinguish them from iNPH patients. Methods: Two cohorts of 81 patients (cohort 1, n = 55; cohort 2, n = 26) with possible iNPH who were treated in two centers between January 2011 and May 2014 were studied. In both cohorts, CSF samples were obtained from patients clinically diagnosed with iNPH (n = 21 and n = 10, respectively), possible iNPH with parkinsonian spectrum (PS) (n = 18, n = 10, respectively), possible iNPH with Alzheimer’s disease (AD) (n = 16), and non-affected elderly individuals (NC) (n = 6). A three-step qRT-PCR analysis of the CSF samples was performed to detect miRNAs that were differentially expressed in the groups. Results: The expression of hsa-miR-4274 in CSF was decreased in both cohorts of PS group patients (cohort 1: p < 0.0001, cohort 2: p < 0.0001), and was able to distinguish PS from iNPH with high accuracy (area under the curve = 0.908). The CSF concentration of hsa-miR-4274 also correlated with the specific binding ratio of ioflupane (123I) dopamine transporter scan (r = –0.494, p = 0.044). By contrast, the level of hsa-miR-4274 was significantly increased in the PS group after CSF diversion. Conclusion: Levels of CSF hsa-miR-4274 can differentiate PS from patients with iNPH, AD, and NC. This may be clinically useful for diagnostic purposes and predicting shunt treatment responses. PMID:27911315

Targeting Glioblastoma with the Use of Phytocompounds and Nanoparticles.

PubMed

Pistollato, Francesca; Bremer-Hoffmann, Susanne; Basso, Giuseppe; Cano, Sandra Sumalla; Elio, Iñaki; Vergara, Manuel Masias; Giampieri, Francesca; Battino, Maurizio

2016-02-01

Glioblastoma multiforme (GBM) are extremely lethal and still poorly treated primary brain tumors, characterized by the presence of highly tumorigenic cancer stem cell (CSC) subpopulations, considered responsible for tumor relapse. In order to successfully eradicate GBM growth and recurrence, new anti-cancer strategies selectively targeting CSCs should be designed. CSCs might be eradicated by targeting some of their cell surface markers and transporters, inducing their differentiation, impacting their hyper-glycolytic metabolism, inhibiting CSC-related signaling pathways and/or by targeting their microenvironmental niche. In this regard, phytocompounds such as curcumin, isothiocyanates, resveratrol and epigallocatechin-3-gallate have been shown to prevent or reverse cancer-related epigenetic dysfunctions, reducing tumorigenesis, preventing metastasis and/or increasing chemotherapy and radiotherapy efficacy. However, the actual bioavailability and metabolic processing of phytocompounds is generally unknown, and the presence of the blood brain barrier often represents a limitation to glioma treatments. Nowadays, nanoparticles (NPs) can be loaded with therapeutic compounds such as phytochemicals, improving their bioavailability and their targeted delivery within the GBM tumor bulk. Moreover, NPs can be designed to increase their tropism and specificity toward CSCs by conjugating their surface with antibodies specific for CSC antigens, with ligands or with glucose analogues. Here we discuss the use of phytochemicals as anti-glioma agents and the applicability of phytochemical-loaded NPs as drug delivery systems to target GBM. Additionally, we provide some examples on how NPs can be specifically formulated to improve CSC targeting.

Targeted nanoparticles encapsulating (−)-epigallocatechin-3-gallate for prostate cancer prevention and therapy

PubMed Central

Sanna, Vanna; Singh, Chandra K.; Jashari, Rahime; Adhami, Vaqar M.; Chamcheu, Jean Christopher; Rady, Islam; Sechi, Mario; Mukhtar, Hasan; Siddiqui, Imtiaz A.

2017-01-01

Earlier we introduced the concept of ‘nanochemoprevention’ i.e. the use of nanotechnology to improve the outcome of cancer chemoprevention. Here, we extended our work and developed polymeric EGCG-encapsulated nanoparticles (NPs) targeted with small molecular entities, able to bind to prostate specific membrane antigen (PSMA), a transmembrane protein that is overexpressed in prostate cancer (PCa), and evaluated their efficacy in preclinical studies. First, we performed a molecular recognition of DCL- and AG-PEGylation on ligand binding on PSMA active site. Next, the biocompatible polymers PLGA-PEG-A were synthesized and used as base to conjugate DCL or AG to obtain the respective copolymers, needed for the preparation of targeted NPs. The resulting EGCG encapsulating NPs led to an enhanced anti-proliferative activity in PCa cell lines compared to the free EGCG. The behavior of EGCG encapsulated in NPs in modulating apoptosis and cell-cycle, was also determined. Then, in vivo experiments, in mouse xenograft model of prostatic tumor, using EGCG-loaded NPs, with a model of targeted nanosystems, were conducted. The obtained data supported our hypothesis of target-specific enhanced bioavailability and limited unwanted toxicity, thus leading to a significant potential for probable clinical outcome. PMID:28145499

Total synthesis of isotopically enriched Si-29 silica NPs as potential spikes for isotope dilution quantification of natural silica NPs.

PubMed

Pálmai, Marcell; Szalay, Roland; Bartczak, Dorota; Varga, Zoltán; Nagy, Lívia Naszályi; Gollwitzer, Christian; Krumrey, Michael; Goenaga-Infante, Heidi

2015-05-01

A new method was developed for the preparation of highly monodisperse isotopically enriched Si-29 silica nanoparticles ((29)Si-silica NPs) with the purpose of using them as spikes for isotope dilution mass spectrometry (IDMS) quantification of silica NPs with natural isotopic distribution. Si-29 tetraethyl orthosilicate ((29)Si-TEOS), the silica precursor was prepared in two steps starting from elementary silicon-29 pellets. In the first step Si-29 silicon tetrachloride ((29)SiCl4) was prepared by heating elementary silicon-29 in chlorine gas stream. By using a multistep cooling system and the dilution of the volatile and moisture-sensitive (29)SiCl4 in carbon tetrachloride as inert medium we managed to reduce product loss caused by evaporation. (29)Si-TEOS was obtained by treating (29)SiCl4 with absolute ethanol. Structural characterisation of (29)Si-TEOS was performed by using (1)H and (13)C nuclear magnetic resonance (NMR) spectroscopy and Fourier-transform infrared (FTIR) spectroscopy. For the NP preparation, a basic amino acid catalysis route was used and the resulting NPs were analysed using transmission electron microscopy (TEM), small angle X-ray scattering (SAXS), dynamic light scattering (DLS) and zeta potential measurements. Finally, the feasibility of using enriched NPs for on-line field-flow fractionation coupled with multi-angle light scattering and inductively coupled plasma mass spectrometry (FFF/MALS/ICP-MS) has been demonstrated. Copyright © 2015 Elsevier Inc. All rights reserved.

Effect of AgCl NPs: Physical, thermal, absorption and luminescence properties

NASA Astrophysics Data System (ADS)

Nurhafizah, H.; Rohani, M. S.

2017-06-01

Silver nanoparticles (AgCl NPs) are embedded in Er3+/Nd3+ co-doped lithium niobate tellurite glasses of the form (68-x)TeO2-15Li2CO3-15Nb2O5-1Er2O3-1Nd2O3-(x)AgCl with x = 1,2 and 3 mol% via conventional melt-quenching technique. The physical properties such as density, ionic packing density, refractive index and electronic polarizability are computed utilizing the usual method. The existence of AgCl NPs with an average size of 3.7 nm is confirmed using TEM analysis. Moreover, the thermal stability and Hruby criterion of the glass decreases as the AgCl NPs content increases. The direct optical band gap are found decrease as the AgCl NPs content increase, but both indirect optical band gap and Urbach energy are found increases as AgCl NPs content increases. The luminescence spectra shows two strong emission which is the purple emission at 436 nm and red emission at 724 nm which also been observed has strong quenching due to the AgCl NPs, Er3+/Nd3+ dopant and modifier, lithium niobate which possessed magnetic penetration. These glass compositions may be potential for various applications such as solid state devices including laser.

26 CFR 54.4980G-5 - HSA comparability rules and cafeteria plans and waiver of excise tax.

Code of Federal Regulations, 2012 CFR

2012-04-01

... nondiscrimination rules (eligibility rules, contributions and benefits tests and key employee concentration tests... portion of the HSA contributions are available as pre-tax salary reduction amounts), regardless of whether... benefits tests and key employee concentration tests). See Q & A-1 of this section. Q-3: If under the...

Effects of inhibitors of vascular endothelial growth factor receptor 2 and downstream pathways of receptor tyrosine kinases involving phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin or mitogen-activated protein kinase in canine hemangiosarcoma cell lines

PubMed Central

Adachi, Mami; Hoshino, Yuki; Izumi, Yusuke; Sakai, Hiroki; Takagi, Satoshi

2016-01-01

Canine hemangiosarcoma (HSA) is a progressive malignant neoplasm with no current effective treatment. Previous studies showed that receptor tyrosine kinases and molecules within their downstream pathways involving phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (m-TOR) or mitogen-activated protein kinase (MAPK) were overexpressed in canine, human, and murine tumors, including HSA. The present study investigated the effects of inhibitors of these pathways in canine splenic and hepatic HSA cell lines using assays of cell viability and apoptosis. Inhibitors of the MAPK pathway did not affect canine HSA cell viability. However, cell viability was significantly reduced by exposure to inhibitors of vascular endothelial growth factor receptor 2 and the PI3K/Akt/m-TOR pathway; these inhibitors also induced apoptosis in these cell lines. These results suggest that these inhibitors reduce the proliferation of canine HSA cells by inducing apoptosis. Further study of these inhibitors, using xenograft mouse models of canine HSA, are warranted to explore their potential for clinical application. PMID:27408334

Docetaxel (DTX)-loaded polydopamine-modified TPGS-PLA nanoparticles as a targeted drug delivery system for the treatment of liver cancer.

PubMed

Zhu, Dunwan; Tao, Wei; Zhang, Hongling; Liu, Gan; Wang, Teng; Zhang, Linhua; Zeng, Xiaowei; Mei, Lin

2016-01-01

Polydopamine-based surface modification is a simple way to functionalize polymeric nanoparticle (NP) surfaces with ligands and/or additional polymeric layers. In this work, we developed DTX-loaded formulations using polydopamine-modified NPs synthesized using D-α-tocopherol polyethylene glycol 1000 succinate-poly(lactide) (pD-TPGS-PLA/NPs). To target liver cancer cells, galactosamine was conjugated on the prepared NPs (Gal-pD-TPGS-PLA/NPs) to enhance the delivery of DTX via ligand-mediated endocytosis. The size and morphology of pD-TPGS-PLA/NPs and Gal-pD-TPGS-PLA/NPs changed obviously compared with TPGS-PLA/NPs. In vitro studies showed that TPGS-PLA/NPs, pD-TPGS-PLA/NPs and Gal-pD-TPGS-PLA/NPs had similar release profiles of DTX. Both confocal laser scanning microscopy and flow cytometric results showed that coumarin 6-loaded Gal-pD-TPGS-PLA/NPs had the highest cellular uptake efficiency in liver cancer cell line HepG2. Moreover, DTX-loaded Gal-pD-TPGS-PLA/NPs inhibited the growth of HepG2 cells more potently than TPGS-PLA/NPs, pD-TPGS-PLA/NPs, and a clinically available DTX formulation (Taxotere®). The in vivo biodistribution experiments show that the Gal-pD-TPGS-PLA/NPs are specifically targeted to the tumor. Furthermore, the in vivo anti-tumor effects study showed that injecting DTX-loaded Gal-pD-TPGS-PLA/NPs reduced the tumor size most significantly on hepatoma-bearing nude mice. These results suggest that Gal-pD-TPGS-PLA/NPs prepared in the study specifically interacted with the hepatocellular carcinoma cells through ligand-receptor recognition and they may be used as a potentially eligible drug delivery system targeting liver cancers. Polydopamine-based surface modification is a simple way to functionalize polymeric nanoparticle surfaces with ligands and/or additional polymeric layers. In this work, we developed docetaxel (DTX)-loaded formulations using polydopamine-modified NPs synthesized from D-α-tocopherol polyethylene glycol 1000 succinate

Folate Receptor Targeted Polymeric Micellar Nanocarriers for Delivery of Orlistat as a Repurposed Drug against Triple Negative Breast Cancer

PubMed Central

Paulmurugan, Ramasamy; Bhethanabotla, Rohith; Mishra, Kaushik; Devulapally, Rammohan; Foygel, Kira; Sekar, Thillai V; Ananta, Jeyarama S; Massoud, Tarik F; Joy, Abraham

2015-01-01

Triple negative breast cancer (TNBC) is a recalcitrant malignancy with no available targeted therapy. Off target effects and poor bioavailability of the FDA approved anti-obesity drug orlistat hinder its clinical translation as a repurposed new drug against TNBC. Here we demonstrate a newly engineered drug formulation for packaging orlistat tailored to TNBC treatment. We synthesized TNBC-specific folate receptor targeted micellar nanoparticles (NPs) carrying orlistat, which improved the solubility (70-80 μg/ml) of this water insoluble drug. The targeted NPs also improved the delivery and bioavailability of orlistat to MDA-MB-231 cells in culture and to tumor xenografts in nude mouse model. We prepared HEA-EHA copolymer micellar NPs by copolymerization of 2-hydroxyethylacrylate (HEA) and 2-ethylhexylacrylate (EHA), and functionalized them with folic acid and an imaging dye. Fluorescence activated cell sorting (FACS) analysis of TNBC cells indicated a dose dependent increase in apoptotic populations in cells treated with free orlistat, orlistat NPs, and folate-receptor targeted Fol-HEA-EHA-orlistat NPs in which Fol-HEA-EHA-orlistat NPs showed significantly higher cytotoxicity than free orlistat. In vitro analysis data demonstrated significant apoptosis at nanomolar concentrations in cells activated through caspase 3 and PARP inhibition. In vivo analysis demonstrated significant antitumor effects in living mice after targeted treatment of tumors, and confirmed by fluorescence imaging. Moreover, Folate receptor targeted Fol-DyLight747-orlistat NPs treated mice exhibited significantly higher reduction in tumor volume compared to control group. Taken together, these results indicate that orlistat packaged in HEA-b-EHA micellar NPs is a highly promising new drug formulation for TNBC therapy. PMID:26553061

Self-Propelled Soft Protein Microtubes with a Pt Nanoparticle Interior Surface.

PubMed

Kobayakawa, Satoshi; Nakai, Yoko; Akiyama, Motofusa; Komatsu, Teruyuki

2017-04-11

Human serum albumin (HSA) microtubes with an interior surface composed of Pt nanoparticles (PtNPs) are self-propelled in aqueous H 2 O 2 medium. They can capture cyanine dye and Escherichia coli (E. coli) efficiently. Microtubes were prepared by wet templating synthesis by using a track-etched polycarbonate (PC) membrane with alternate filtrations of aqueous HSA, poly-l-arginine (PLA), and citrate-PtNPs. Subsequent dissolution of the PC template yielded uniform hollow cylinders made of (PLA/HSA) 8 PLA/PtNP stacking layers (1.16±0.02 μm outer diameter, ca. 23 μm length). In aqueous H 2 O 2 media, the soft protein microtubes are self-propelled by jetting O 2 bubbles from the open-end terminus. The effects of H 2 O 2 and surfactant concentrations on the velocity were investigated. The swimming microtube captured cyanine dye in the HSA component of the wall. Addition of an intermediate γ-Fe 3 O 4 layer allowed manipulation of the direction of movement of the tubule by using a magnetic field. Because the exterior surface is positively charged, the bubble-propelled microtubes adsorbed E. coli with high efficiency. The removal ratio of E. coli by a single treatment reached 99 %. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Hsa-circRNA11783-2 in peripheral blood is correlated with coronary artery disease and type 2 diabetes mellitus.

PubMed

Li, Xuejie; Zhao, Zhenzhou; Jian, Dongdong; Li, Wentao; Tang, Haiyu; Li, Muwei

2017-11-01

The purpose of this study was to identify the expression characteristics of circular RNAs in the peripheral blood of coronary artery disease patients and type 2 diabetes mellitus patients. Circular RNA in the peripheral blood from 6 control individuals, 6 coronary artery disease patients, 6 type 2 diabetes mellitus patients and 6 coronary artery disease combined with type 2 diabetes mellitus patients was collected for microarray analysis, and a further independent cohort consisting of 20 normal individuals, 20 type 2 diabetes mellitus subjects and 20 coronary artery disease subjects was used to verify the expression of five circular RNAs chosen for further analysis. The findings were then tested in a third cohort using quantitative real-time polymerase chain reaction. In total, 40 circular RNAs differentially expressed between the three experimental groups and the control group were identified by microarray analysis: 13 were upregulated in the experimental groups, while 27 were downregulated. Of the five circular RNAs chosen for further analysis, three were significantly downregulated in the experimental groups. The crude odds ratios and adjusted odds ratios of hsa-circRNA11783-2 showed significant differences in both the coronary artery disease group and type 2 diabetes mellitus group. We then verified hsa-circRNA11783-2 in the third cohort, and it remained closely related to both coronary artery disease and type 2 diabetes mellitus. Hsa-circRNA11783-2 is closely related to both coronary artery disease and type 2 diabetes mellitus.

Bisphosphonate-coated BSA nanoparticles lack bone targeting after systemic administration.

PubMed

Wang, Guilin; Kucharski, Cezary; Lin, Xiaoyue; Uludağ, Hasan

2010-09-01

A polymeric conjugate of polyethyleneimine-graft-poly(ethylene glycol) and 2-(3-mercaptopropylsulfanyl)-ethyl-1,1-bisphosphonic acid (PEI-PEG-thiolBP) was prepared and used for surface coating of bovine serum albumin (BSA) nanoparticles (NPs) designed for bone-specific delivery of bone morphogenetic protein-2 (BMP-2). The NP coating was achieved with a dialysis and an evaporation method, and the obtained NPs were characterized by particle size, zeta-potential, morphology, and cytotoxicity in vitro. The particle size and surface charge of the NPs could be effectively tuned by the PEG and thiolBP substitution ratios of the conjugate, the coating method, and the polymer concentration used for coating. The PEG modification on PEI reduced the toxicity of PEI and the coated NPs, based on in vitro assessment with human C2C12 cells and rat bone marrow stromal cells. On the basis of an alkaline phosphatase (ALP) induction assay, the NP-encapsulated BMP-2 displayed full retention of its bioactivity, except for BMP-2 in PEI-coated NPs. By encapsulating (125)I-labeled BMP-2, the polymer-coated NPs were assessed for hydroxyapatite (HA) affinity; all NP-encapsulated BMP-2 showed significant affinity to HA as compared with free BMP-2 in vitro, and the PEI-PEG-thiolBP coated NPs improved the in vivo retention of BMP-2 compared with uncoated NPs. However, the biodistribution of NPs after intravenous injection in a rat model indicated no beneficial effects of thiolBP-coated NPs for bone targeting. Our results suggested that the BP-conjugated NPs are useful for localized delivery of BMP-2 in bone repair and regeneration, but they are not effective for bone targeting after intravenous administration.

Biotin-Conjugated Multilayer Poly [D,L-lactide-co-glycolide]-Lecithin-Polyethylene Glycol Nanoparticles for Targeted Delivery of Doxorubicin.

PubMed

Dai, Yu; Xing, Han; Song, Fuling; Yang, Yue; Qiu, Zhixia; Lu, Xiaoyu; Liu, Qi; Ren, Shuangxia; Chen, Xijing; Li, Ning

2016-09-01

Multilayer nanoparticle combining the merits of liposome and polymer nanoparticle has been designed for the targeted delivery of doxorubicin (DOX) in cancer treatment. In this study, DOX-PLGA-lecithin-PEG-biotin nanoparticles (DOX-PLPB-NPs) were fabricated and functionalized with biotin for specific tumor targeting. Under the transmission electron microscopy observation, the lipid layer was found to be coated on the polymer core. The physical characteristics of PLPB-NPs were also evaluated. The confocal laser scanning microscopy confirmed the cellular uptake of nanoparticles and targeted delivery PLPB-NPs. The in vitro release experiment demonstrated a pH-depending release of DOX from drug-loaded PLPB-NPs. Cytotoxicity studies in HepG2 cells and in vivo antitumor experiment in tumor-bearing mice both proved DOX-PLPB-NPs showed the best inhibition effect of tumor proliferation. In biodistribution studies, DOX-PLPB-NPs showed a higher DOX concentration than free DOX and DOX-PLGA-lecithin-PEG nanoparticles (DOX-PLP-NPs) in tumor site, especially in 24 h, and the lowest DOX level in normal organs. The results were coincident with the strongest antitumor ability showed among in vivo antitumor experiment. Histopathology analysis demonstrated that DOX-PLPB-NPs exhibited the strongest antitumor ability and lowest cardiotoxicity. In brief, the PLPB-NPs were proved to be an efficient delivery system for tumor-targeting treatment. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Spheroid-forming subpopulation of breast cancer cells demonstrates vasculogenic mimicry via hsa-miR-299–5p regulated de novo expression of osteopontin

PubMed Central

Shevde, Lalita A; Metge, Brandon J; Mitra, Aparna; Xi, Yaguang; Ju, Jingfang; King, Judy A; Samant, Rajeev S

2010-01-01

Abstract The growth of cancer cells as multicellular spheroids has frequently been reported to mimic the in vivo tumour architecture and physiology and has been utilized to study antitumour drugs. In order to determine the distinctive characteristics of the spheroid-derived cells compared to the corresponding monolayer-derived cells, we enriched multicellular spheroid-forming subpopulations of cells from three human breast cancer cell lines (MCF7, MCF10AT and MCF10DCIS.com). These spheroid-derived cells were injected into female athymic nude mice to assess their tumorigenic potential and were profiled for their characteristic miRNA signature. We discovered that the spheroid-derived cells expressed increased levels of osteopontin (OPN), an oncogenic protein that has been clinically correlated with increased tumour burden and adverse prognosis in patients with breast cancer metastasis. Our studies further show that increased OPN levels are brought about in part, by decreased levels of hsa-mir-299–5p in the spheroid-forming population from all three cell lines. Moreover, the spheroid-forming cells can organize into vascular structures in response to nutritional limitation; these structures recapitulate a vascular phenotype by the expression of endothelial markers CD31, Angiopoeitin-1 and Endoglin. In this study, we have validated that hsa-mir-299–5p targets OPN; de novo expression of OPN in turn plays a critical role in enhancing proliferation, tumorigenicity and the ability to display vasculogenic mimicry of the spheroid-forming cells. PMID:19538464

Preparation of folate-modified pullulan acetate nanoparticles for tumor-targeted drug delivery.

PubMed

Zhang, Hui-zhu; Li, Xue-min; Gao, Fu-ping; Liu, Ling-rong; Zhou, Zhi-min; Zhang, Qi-qing

2010-01-01

The purpose of this work was to develop a novel nano-carrier with targeting property to tumor. In this study, pullulan acetate (PA) was synthesized by the acetylation of pullulan to simplify the preparation technique of nanoparticles. Folic acid (FA) was conjugated to PA in order to improve the cancer-targeting activity. The products were characterized by proton nuclear magnetic resonance (¹H NMR) spectroscopy. Epirubicin-loaded nanoparticles were prepared by a solvent diffusion method. The loading efficiencies and EPI content increased with the amount of triethylamine (TEA) increasing in some degree. FPA nanoparticles could incorporate more epirubicin than PA nanoparticles. The folate-modified PA nanoparticles (FPA/EPI NPs) exhibited faster drug release than PA nanoparticles (PA/EPI NPs) in vitro. Confocal image analysis and flow cytometry test revealed that FPA/EPI NPs exhibited a greater extent of cellular uptake than PA/EPI NPs against KB cells over-expressing folate receptors on the surface. FPA/EPI NPs also showed higher cytotoxicity than PA/EPI NPs. The cytotoxic effect of FPA/EPI NPs to KB cells was inhibited by an excess amount of folic acid, suggesting that the binding and/or uptake were mediated by the folate receptor.

Enhanced wound healing activity of Ag-ZnO composite NPs in Wistar Albino rats.

PubMed

Kantipudi, Sravani; Sunkara, Jhansi Rani; Rallabhandi, Muralikrishna; Thonangi, Chandi Vishala; Cholla, Raga Deepthi; Kollu, Pratap; Parvathaneni, Madhu Kiran; Pammi, Sri Venkata Narayana

2018-06-01

In the present study, silver (Ag) and Ag-zinc oxide (ZnO) composite nanoparticles (NPs) were synthesised and studied their wound-healing efficacy on rat model. Ultraviolet-visible spectroscopy of AgNPs displayed an intense surface plasmon (SP) resonance absorption at 450 nm. After the addition of aqueous Zn acetate solution, SP resonance band has shown at 413.2 nm indicating a distinct blue shift of about 37 nm. X-ray diffraction analysis Ag-ZnO composite NPs displayed existence of two mixed sets of diffraction peaks, i.e. both Ag and ZnO, whereas AgNPs exhibited face-centred cubic structures of metallic Ag. Scanning electron microscope (EM) and transmission EM analyses of Ag-ZnO composite NPs revealed the morphology to be monodispersed hexagonal and quasi-hexagonal NPs with distribution of particle size of 20-40 nm. Furthermore, the authors investigated the wound-healing properties of Ag-ZnO composite NPs in an animal model and found that rapid healing within 10 days when compared with pure AgNPs and standard drug dermazin.

MicroRNA-490 regulates lung cancer metastasis by targeting poly r(C)-binding protein 1.

PubMed

Li, Jindong; Feng, Qingchuan; Wei, Xudong; Yu, Yongkui

2016-11-01

Lung cancer remains a leading cause of cancer-related mortality, with metastatic progression remaining the single largest cause of lung cancer mortality. Hence, it is imperative to determine reliable biomarkers of lung cancer prognosis. MicroRNA-490-3p has been previously reported to be a positive prognostic biomarker for hepatocellular cancer. However, its role in human lung cancer has not yet been elucidated. Here, we report that hsa-miR-490-3p expression is significantly higher in human lung cancer tissue specimens and cell line. Gain- and loss-of-function studies of hsa-miR-490-3p showed that it regulates cell proliferation and is required for induction of in vitro migration and invasion-the latter being a hallmark of epithelial to mesenchymal transition. In situ analysis revealed that hsa-miR-490-3p targets poly r(C)-binding protein 1 (PCBP1), which has been previously shown to be a negative regulator of lung cancer metastasis. Reporter assays confirmed PCBP1 as a bona fide target of miR-490-3p, and metagenomic analysis revealed an inverse relation between expression of miR-490-3p and PCBP1 in metastatic lung cancer patients. In fact, PCBP1 expression, as detected by immunohistochemistry, was undetectable in advanced stages of lung cancer patients' brain and lymph node tissues. Xenograft tail vein colonization assays proved that high expression of miR-490-3p is a prerequisite for metastatic progression of lung cancer. Our results suggest that hsa-miR-490-3p might be a potential biomarker for lung cancer prognosis. In addition, we can also conclude that the lung cancer cells have evolved refractory mechanisms to downregulate the expression of the metastatic inhibitor, PCBP1.

Navy-wide Personnel Survey (NPS) 2007-2008: Tabulated Results

DTIC Science & Technology

2011-02-01

wide Personnel Survey (NPS) is a major product of the Navy Personnel Survey System ( NPSS ). Administered regularly by the Navy Personnel Research...2008 NPS was conducted under the sponsorship of the Chief of Naval Personnel (N1) within the Navy Personnel Survey System ( NPSS ) funding line...the Chief of Naval Personnel instituted the Navy Personnel Survey System ( NPSS ) as a means of collecting and organizing information regarding the

Colorimetric Detection of Small Molecules in Complex Matrixes via Target-Mediated Growth of Aptamer-Functionalized Gold Nanoparticles.

PubMed

Soh, Jun Hui; Lin, Yiyang; Rana, Subinoy; Ying, Jackie Y; Stevens, Molly M

2015-08-04

A versatile and sensitive colorimetric assay that allows the rapid detection of small-molecule targets using the naked eye is demonstrated. The working principle of the assay integrates aptamer-target recognition and the aptamer-controlled growth of gold nanoparticles (Au NPs). Aptamer-target interactions modulate the amount of aptamer strands adsorbed on the surface of aptamer-functionalized Au NPs via desorption of the aptamer strands when target molecules bind with the aptamer. Depending on the resulting aptamer coverage, Au NPs grow into morphologically varied nanostructures, which give rise to different colored solutions. Au NPs with low aptamer coverage grow into spherical NPs, which produce red-colored solutions, whereas Au NPs with high aptamer coverage grow into branched NPs, which produce blue-colored solutions. We achieved visible colorimetric response and nanomolar detection limits for the detection of ochratoxin A (1 nM) in red wine samples, as well as cocaine (1 nM) and 17β-estradiol (0.2 nM) in spiked synthetic urine and saliva, respectively. The detection limits were well within clinically and physiologically relevant ranges, and below the maximum food safety limits. The assay is highly sensitive, specific, and able to detect an array of analytes rapidly without requiring sophisticated equipment, making it relevant for many applications, such as high-throughput drug and clinical screening, food sampling, and diagnostics. Furthermore, the assay is easily adapted as a chip-based platform for rapid and portable target detection.

Antimicrobial and anticancer activity of AgNPs coated with Alphonsea sclerocarpa extract.

PubMed

Doddapaneni, Suman Joshi D S; Amgoth, Chander; Kalle, Arunasree M; Suryadevara, Surya Narayana; Alapati, Krishna Satya

2018-03-01

The synthesis and characterization of an aggregate of AgNPs coated with plant extract (PE) from Alphonsea sclerocarpa and its significant antimicrobial activity and inhibition on K562 (blood cancer) cells have been appended in the article. Synthesis of aggregate [(AgNPs)-(PE)] has been followed by a facile eco-friendly approach without using any harmful chemicals. The morphology of an aggregate [(AgNPs)-(PE)] was confirmed by TEM and SEM microscopic characterizations. Properties like solid state, the presence of functional groups, and elemental composition have been characterized through the XRD, FTIR, and EDAX. The biocompatibility of synthesized aggregate of [(AgNPs)-(PE)] was confirmed by the MTT assay. An in vitro cell (HEK293)-based studies were performed for the biocompatibility tests and it is found that the aggregate [(AgNPs)-(PE)] is not harmful to normal/healthy cells. Even though A. sclerocarpa show the antimicrobial (antibacterial and antifungal) activity, it has been further enhanced with the developed aggregate of [(AgNPs)-(PE)]. Furthermore, it has been extended to examine the cellular inhibition on K562 cells and obtained > 75% cell inhibition for 24 h treated cells.

Antifungal Effects of Silver Nanoparticles (AgNPs) against Various Plant Pathogenic Fungi.

PubMed

Kim, Sang Woo; Jung, Jin Hee; Lamsal, Kabir; Kim, Yun Seok; Min, Ji Seon; Lee, Youn Su

2012-03-01

This research is concerned with the fungicidal properties of nano-size silver colloidal solution used as an agent for antifungal treatment of various plant pathogens. We used WA-CV-WA13B, WA-AT-WB13R, and WA-PR-WB13R silver nanoparticles (AgNPs) at concentrations of 10, 25, 50, and 100 ppm. Eighteen different plant pathogenic fungi were treated with these AgNPs on potato dextrose agar (PDA), malt extract agar, and corn meal agar plates. We calculated fungal inhibition in order to evaluate the antifungal efficacy of silver nanoparticles against pathogens. The results indicated that AgNPs possess antifungal properties against these plant pathogens at various levels. Treatment with WA-CV-WB13R AgNPs resulted in maximum inhibition of most fungi. Results also showed that the most significant inhibition of plant pathogenic fungi was observed on PDA and 100 ppm of AgNPs.

Biosynthesis and Characterization of AgNPs-Silk/PVA Film for Potential Packaging Application.

PubMed

Tao, Gang; Cai, Rui; Wang, Yejing; Song, Kai; Guo, Pengchao; Zhao, Ping; Zuo, Hua; He, Huawei

2017-06-17

Bionanocomposite packaging materials have a bright future for a broad range of applications in the food and biomedical industries. Antimicrobial packaging is one of the bionanocomposite packaging materials. Silver nanoparticle (AgNP) is one of the most attractive antimicrobial agents for its broad spectrum of antimicrobial activity against microorganisms. However, the traditional method of preparing AgNPs-functionalized packaging material is cumbersome and not environmentally friendly. To develop an efficient and convenient biosynthesis method to prepare AgNPs-modified bionanocomposite material for packaging applications, we synthesized AgNPs in situ in a silk fibroin solution via the reduction of Ag⁺ by the tyrosine residue of fibroin, and then prepared AgNPs-silk/poly(vinyl alcohol) (PVA) composite film by blending with PVA. AgNPs were synthesized evenly on the surface or embedded in the interior of silk/PVA film. The prepared AgNPs-silk/PVA film exhibited excellent mechanical performance and stability, as well as good antibacterial activity against both Gram-negative and Gram-positive bacteria. AgNPs-silk/PVA film offers more choices to be potentially applied in the active packaging field.

Bioengineering targeted nanodrugs for hematologic malignancies: An innovation in pediatric oncology

NASA Astrophysics Data System (ADS)

Krishnan, Vinu

Chemotherapy for pediatric cancers employs combinations of highly toxic drugs. This has achieved 5-year survival rates exceeding 90% in children treated for leukemia -- the most prominent form of pediatric cancer. However, delayed onset of harmful side effects in more than 60% of survivors result in death or low quality of life post therapy. This is primarily due to the non-specific effect of drugs on healthy dividing cells in a growing child. Nanomedicine has advanced tremendously to improve adult cancer therapy, but as yet has had minimal impact in pediatric oncology. There is a pressing need for innovative therapeutic strategies that can reduce life-threatening side effects caused by conventional chemotherapy in the clinic. Targeting chemotherapeutic agents specifically to leukemia cells may alleviate treatment-related toxicity in children. The research objective of this dissertation is to bioengineer and advance preclinically a novel nanotherapeutic approach that can specifically target and deliver drugs into leukemic cells. Dexamethasone (Dex) is one of the most commonly used chemotherapeutic drugs in treating pediatric leukemia. For the first part in this study, we encapsulated Dex in polymeric NPs and validated its anti-leukemic potential in vitro and in vivo. NPs with an average diameter of 110 nm were assembled from an amphiphilic block copolymer of poly(ethylene glycol) (PEG) and poly-caprolactone (PCL) bearing pendant cyclic ketals (ECT2). The blank NPs were nontoxic to cultured cells in vitro and to mice in vivo. Encapsulation of Dex into the NPs (Dex-NP) did not compromise the bioactivity of the drug. Dex-NPs induced glucocorticoid phosphorylation and showed cytotoxicity similar to free drug when treated with leukemic cells. Studies using NPs labeled with fluorescent dyes revealed leukemic cell surface binding and internalization. In vivo biodistribution studies showed NP accumulation in the liver and spleen with subsequent clearance of particles with

Modeling techniques and fluorescence imaging investigation of the interactions of an anthraquinone derivative with HSA and ctDNA

NASA Astrophysics Data System (ADS)

Fu, Zheng; Cui, Yanrui; Cui, Fengling; Zhang, Guisheng

2016-01-01

A new anthraquinone derivative (AORha) was synthesized. Its interactions with human serum albumin (HSA) and calf thymus DNA (ctDNA) were investigated by fluorescence spectroscopy, UV-visible absorption spectroscopy and molecular modeling. Cell viability assay and cell imaging experiment were performed using cervical cancer cells (HepG2 cells). The fluorescence results revealed that the quenching mechanism was static quenching. At different temperatures (290, 300, 310 K), the binding constants (K) and the number of binding sites (n) were determined, respectively. The positive ΔH and ΔS values showed that the binding of AORha with HSA was hydrophobic force, which was identical with the molecular docking result. Studying the fluorescence spectra, UV spectra and molecular modeling also verified that the binding mode of AORha and ctDNA might be intercalative. When HepG2 cells were treated with AORha, the fluorescence became brighter and turned green, which could be used for bioimaging.

Modeling techniques and fluorescence imaging investigation of the interactions of an anthraquinone derivative with HSA and ctDNA.

PubMed

Fu, Zheng; Cui, Yanrui; Cui, Fengling; Zhang, Guisheng

2016-01-15

A new anthraquinone derivative (AORha) was synthesized. Its interactions with human serum albumin (HSA) and calf thymus DNA (ctDNA) were investigated by fluorescence spectroscopy, UV-visible absorption spectroscopy and molecular modeling. Cell viability assay and cell imaging experiment were performed using cervical cancer cells (HepG2 cells). The fluorescence results revealed that the quenching mechanism was static quenching. At different temperatures (290, 300, 310 K), the binding constants (K) and the number of binding sites (n) were determined, respectively. The positive ΔH and ΔS values showed that the binding of AORha with HSA was hydrophobic force, which was identical with the molecular docking result. Studying the fluorescence spectra, UV spectra and molecular modeling also verified that the binding mode of AORha and ctDNA might be intercalative. When HepG2 cells were treated with AORha, the fluorescence became brighter and turned green, which could be used for bioimaging. Copyright © 2015 Elsevier B.V. All rights reserved.

Multifunctional AgNPs@Wool: colored, UV-protective and antioxidant functional textiles

NASA Astrophysics Data System (ADS)

Shabbir, Mohd; Mohammad, Faqeer

2018-02-01

Nanomaterials have great impact on textile industry for multifunctional and smart clothing as per the need of present, and further, green nanotechnology is the current hotspot of research and industrial developments. Silver nanoparticles (AgNPs) are synthesized (in situ) by using natural compounds of plant extracts (naphthoquinones, phenolics/flavonoids, polyphenols) as reducing or stabilizing agents, and simultaneously deposited on wool fabric for coloration, UV protection and antioxidant properties. UV-visible spectroscopy is used to monitor the route of biosynthesis of nanoparticles and transmission electron microscopy for morphological characteristics of synthesized AgNPs. Spherical and almost oval-shaped AgNPs were synthesized by naphthoquinones, polyphenols and flavonoids, respectively. Scanning electron microscopy (SEM) coupled with energy dispersive X-ray (EDX) spectroscopy, X-ray diffraction pattern (XRD) and Fourier transform infrared spectroscopy were used for the AgNPs@Wool fabrics characterization. SEM-EDX analysis and XRD patterns confirmed the successful deposition of silver nanoparticles on wool. Coloration characteristics in terms of color strength (K/S) and CIEL*a*b*c*h° values, UV protection abilities in terms of UV transmittance and UV protection factor, and % antioxidant activity of AgNPs@Wool are suggestive of good-to-excellent results.

NPS R-568 halts or reverses osteitis fibrosa in uremic rats.

PubMed

Wada, M; Ishii, H; Furuya, Y; Fox, J; Nemeth, E F; Nagano, N

1998-02-01

Osteitis fibrosa is a common bone injury associated with secondary hyperparathyroidism (2(o)HPT). NPS R-568 is a phenylalkylamine derivative that acts as an agonist at the cell-surface Ca2+ receptor ("calcimimetic") and inhibits parathyroid hormone (PTH) secretion. In the present study, we tested whether NPS R-568 could ameliorate osteitis fibrosa in partially nephrectomized (Nx) rats with 2(o)HPT. Six months after surgery, Nx rats had developed mild but progressive 2(o)HPT and osteitis fibrosa. Two groups of Nx rats received NPS R-568 (3 and 30 mg/kg body wt x day) by daily gavage for 30 days, which led to a dose-related decrease in serum PTH levels and to a marked reduction in peritrabecular fibrosis (0.96 +/- 0.49% to < 0.1%). Furthermore, 2(o)HPT was associated with decreases in volumetric cortical bone mineral density (vCtBMD) and in cortical bone stiffness at the femoral midshaft. NPS R-568 significantly restored the deficits in vCtBMD and stiffness. These results indicate that NPS R-568 has beneficial effects on bones with osteitis fibrosa by normalizing serum PTH levels.

NPS Cubesat Launcher-Lite Sequencer

DTIC Science & Technology

2009-06-01

AND SUBTITLE NPS Cubesat Launcher-Lite Sequencer 6. AUTHOR(S) Harris, Anthony D. 5. FUNDING NUMBERS RSPXL 7. PERFORMING ORGANIZATION NAME(S) AND...ADDRESS(ES) Naval Postgraduate School Monterey, CA 93943-5000 8. PERFORMING ORGANIZATION REPORT NUMBER 9. SPONSORING /MONITORING AGENCY...international nanosatellite manufacturers. On April 28, 2009, Indian Space Research Organization launched 8 nanosatellites on the Polar Satellite Launch

Bacteria-Targeting Nanoparticles for Managing Infections

NASA Astrophysics Data System (ADS)

Radovic-Moreno, Aleksandar Filip

Bacterial infections continue to be a significant concern particularly in healthcare settings and in the developing world. Current challenges include the increasing spread of drug resistant (DR) organisms, the side effects of antibiotic therapy, the negative consequences of clearing the commensal bacterial flora, and difficulties in developing prophylactic vaccines. This thesis was an investigation of the potential of a class of polymeric nanoparticles (NP) to contribute to the management of bacterial infections. More specifically, steps were taken towards using these NPs (1) to achieve greater spatiotemporal control over drug therapy by more targeted antibiotic delivery to bacteria, and (2) to develop a prophylactic vaccine formulation against the common bacterial sexually transmitted disease (STD) caused by Chlamydia trachomatis. In the first part, we synthesized polymeric NPs containing poly(lactic-co-glycolic acid)-block-poly(L-histidine)-block-poly(ethylene glycol) (PLGA-PLH-PEG). We show that these NPs are able to bind to bacteria under model acidic infection conditions and are able to encapsulate and deliver vancomycin to inhibit the growth of Staphylococcus aureus bacteria in vitro. Further work showed that the PLGA-PLH-PEG-based NPs demonstrated the potential for competition for binding bacteria at a site of infection from soluble protein and model phagocytic and tissue-resident cells in a NP composition dependent manner. The NPs demonstrated low toxicity in vitro, were well tolerated by mice in vivo, and circulated in the blood on timescales comparable to control PLGA-PEG NPs. In the second part, we used PLGA-PLH-PEG-based NPs to design a prophylactic vaccine against the obligate intracellular bacterium Chlamydia trachomatis, the most common cause of bacterial STD in the world. Currently, no vaccines against this pathogen are approved for use in humans. We first formulated NPs encapsulating the TLR7 agonist R848 conjugated to poly(lactic acid) (R848-PLA

Enhanced Delivery of Gold Nanoparticles with Therapeutic Potential for Targeting Human Brain Tumors

NASA Astrophysics Data System (ADS)

Etame, Arnold B.

The blood brain barrier (BBB) remains a major challenge to the advancement and application of systemic anti-cancer therapeutics into the central nervous system. The structural and physiological delivery constraints of the BBB significantly limit the effectiveness of conventional chemotherapy, thereby making systemic administration a non-viable option for the vast majority of chemotherapy agents. Furthermore, the lack of specificity of conventional systemic chemotherapy when applied towards malignant brain tumors remains a major shortcoming. Hence novel therapeutic strategies that focus both on targeted and enhanced delivery across the BBB are warranted. In recent years nanoparticles (NPs) have emerged as attractive vehicles for efficient delivery of targeted anti-cancer therapeutics. In particular, gold nanoparticles (AuNPs) have gained prominence in several targeting applications involving systemic cancers. Their enhanced permeation and retention within permissive tumor microvasculature provide a selective advantage for targeting. Malignant brain tumors also exhibit transport-permissive microvasculature secondary to blood brain barrier disruption. Hence AuNPs may have potential relevance for brain tumor targeting. However, the permeation of AuNPs across the BBB has not been well characterized, and hence is a potential limitation for successful application of AuNP-based therapeutics within the central nervous system (CNS). In this dissertation, we designed and characterized AuNPs and assessed the role of polyethylene glycol (PEG) on the physical and biological properties of AuNPs. We established a size-dependent permeation profile with respect to core size as well as PEG length when AuNPs were assessed through a transport-permissive in-vitro BBB. This study was the first of its kind to systematically examine the influence of design on permeation of AuNPs through transport-permissive BBB. Given the significant delivery limitations through the non

Development of poly(lactic-co-glycolic) acid nanoparticles-embedded hyaluronic acid-ceramide-based nanostructure for tumor-targeted drug delivery.

PubMed

Park, Ju-Hwan; Lee, Jae-Young; Termsarasab, Ubonvan; Yoon, In-Soo; Ko, Seung-Hak; Shim, Jae-Seong; Cho, Hyun-Jong; Kim, Dae-Duk

2014-10-01

A hyaluronic acid-ceramide (HACE) nanostructure embedded with docetaxel (DCT)-loaded poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) was fabricated for tumor-targeted drug delivery. NPs with a narrow size distribution and negative zeta potential were prepared by embedding DCT-loaded PLGA NPs into a HACE nanostructure (DCT/PLGA/HACE). DCT-loaded PLGA and DCT/PLGA/HACE NPs were characterized by solid-state techniques, including Fourier-transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD). A sustained drug release pattern from the NPs developed was observed and negligible cytotoxicity was seen in NIH3T3 cells (normal fibroblast, CD44 receptor negative) and MDA-MB-231 cells (breast cancer cells, CD44 receptor positive). PLGA/HACE NPs containing coumarin 6, used as a fluorescent dye, exhibited improved cellular uptake efficiency, based on the HA-CD44 receptor interaction, compared to plain PLGA NPs. Cyanine 5.5 (Cy5.5)-labeled PLGA/HACE NPs were injected intravenously into a MDA-MB-231 tumor xenograft mouse model and demonstrated enhanced tumor targetability, compared with Cy5.5-PLGA NPs, according to a near-infrared fluorescence (NIRF) imaging study. Considering these experimental results, the DCT/PLGA/HACE NPs developed may be useful as a tumor-targeted drug delivery system. Copyright © 2014 Elsevier B.V. All rights reserved.

Orally Targeted Delivery of Tripeptide KPV via Hyaluronic Acid-Functionalized Nanoparticles Efficiently Alleviates Ulcerative Colitis.

PubMed

Xiao, Bo; Xu, Zhigang; Viennois, Emilie; Zhang, Yuchen; Zhang, Zhan; Zhang, Mingzhen; Han, Moon Kwon; Kang, Yuejun; Merlin, Didier

2017-07-05

Overcoming adverse effects and selectively delivering drug to target cells are two major challenges in the treatment of ulcerative colitis (UC). Lysine-proline-valine (KPV), a naturally occurring tripeptide, has been shown to attenuate the inflammatory responses of colonic cells. Here, we loaded KPV into hyaluronic acid (HA)-functionalized polymeric nanoparticles (NPs). The resultant HA-KPV-NPs had a desirable particle size (∼272.3 nm) and a slightly negative zeta potential (∼-5.3 mV). These NPs successfully mediated the targeted delivery of KPV to key UC therapy-related cells (colonic epithelial cells and macrophages). In addition, these KPV-loaded NPs appear to be nontoxic and biocompatible with intestinal cells. Intriguingly, we found that HA-KPV-NPs exert combined effects against UC by both accelerating mucosal healing and alleviating inflammation. Oral administration of HA-KPV-NPs encapsulated in a hydrogel (chitosan/alginate) exhibited a much stronger capacity to prevent mucosa damage and downregulate TNF-α, thus they showed a much better therapeutic efficacy against UC in a mouse model, compared with a KPV-NP/hydrogel system. These results collectively demonstrate that our HA-KPV-NP/hydrogel system has the capacity to release HA-KPV-NPs in the colonic lumen and that these NPs subsequently penetrate into colitis tissues and enable KPV to be internalized into target cells, thereby alleviating UC. Copyright © 2016 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Multiplexed Thiol Reactivity Profiling for Target Discovery of Electrophilic Natural Products.

PubMed

Tian, Caiping; Sun, Rui; Liu, Keke; Fu, Ling; Liu, Xiaoyu; Zhou, Wanqi; Yang, Yong; Yang, Jing

2017-11-16

Electrophilic groups, such as Michael acceptors, expoxides, are common motifs in natural products (NPs). Electrophilic NPs can act through covalent modification of cysteinyl thiols on functional proteins, and exhibit potent cytotoxicity and anti-inflammatory/cancer activities. Here we describe a new chemoproteomic strategy, termed multiplexed thiol reactivity profiling (MTRP), and its use in target discovery of electrophilic NPs. We demonstrate the utility of MTRP by identifying cellular targets of gambogic acid, an electrophilic NP that is currently under evaluation in clinical trials as anticancer agent. Moreover, MTRP enables simultaneous comparison of seven structurally diversified α,β-unsaturated γ-lactones, which provides insights into the relative proteomic reactivity and target preference of diverse structural scaffolds coupled to a common electrophilic motif and reveals various potential druggable targets with liganded cysteines. We anticipate that this new method for thiol reactivity profiling in a multiplexed manner will find broad application in redox biology and drug discovery. Copyright © 2017 Elsevier Ltd. All rights reserved.

SOX11 identified by target gene evaluation of miRNAs differentially expressed in focal and non-focal brain tissue of therapy-resistant epilepsy patients.

PubMed

Haenisch, Sierk; Zhao, Yi; Chhibber, Aparna; Kaiboriboon, Kitti; Do, Lynn V; Vogelgesang, Silke; Barbaro, Nicholas M; Alldredge, Brian K; Lowenstein, Daniel H; Cascorbi, Ingolf; Kroetz, Deanna L

2015-05-01

MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally control the expression of their target genes via RNA interference. There is increasing evidence that expression of miRNAs is dysregulated in neuronal disorders, including epilepsy, a chronic neurological disorder characterized by spontaneous recurrent seizures. Mesial temporal lobe epilepsy (MTLE) is a common type of focal epilepsy in which disease-induced abnormalities of hippocampal neurogenesis in the subgranular zone as well as gliosis and neuronal cell loss in the cornu ammonis area are reported. We hypothesized that in MTLE altered miRNA-mediated regulation of target genes could be involved in hippocampal cell remodeling. A miRNA screen was performed in hippocampal focal and non-focal brain tissue samples obtained from the temporal neocortex (both n=8) of MTLE patients. Out of 215 detected miRNAs, two were differentially expressed (hsa-miR-34c-5p: mean increase of 5.7 fold (p=0.014), hsa-miR-212-3p: mean decrease of 76.9% (p=0.0014)). After in-silico target gene analysis and filtering, reporter gene assays confirmed RNA interference for hsa-miR-34c-5p with 3'-UTR sequences of GABRA3, GRM7 and GABBR2 and for hsa-miR-212-3p with 3'-UTR sequences of SOX11, MECP2, ADCY1 and ABCG2. Reporter gene assays with mutated 3'-UTR sequences of the transcription factor SOX11 identified two different binding sites for hsa-miR-212-3p and its primary transcript partner hsa-miR-132-3p. Additionally, there was an inverse time-dependent expression of Sox11 and miR-212-3p as well as miR-132-3p in rat neonatal cortical neurons. Transfection of neurons with anti-miRs for miR-212-3p and miR-132-3p suggest that both miRNAs work synergistically to control Sox11 expression. Taken together, these results suggest that differential miRNA expression in neurons could contribute to an altered function of the transcription factor SOX11 and other genes in the setting of epilepsy, resulting not only in impaired neural

Navy-wide Personnel Survey (NPS) 2005: Summary of Survey Results

DTIC Science & Technology

2008-11-01

Personnel Survey Strategy. The NPS focuses on quality of work life topics including satisfaction with Navy life, work climate, morale, organizational...commitment, leadership, communication, job security, Navy image, fairness, detailing, duty assignments, job satisfaction , career development...Ph.D. Director v Summary The Navy Personnel Survey (NPS) is a multi-faceted survey that focuses on topics such as satisfaction with Navy

Anthelmintic Effect of Biocompatible Zinc Oxide Nanoparticles (ZnO NPs) on Gigantocotyle explanatum, a Neglected Parasite of Indian Water Buffalo

PubMed Central

Khan, Yasir Akhtar; Singh, Braj Raj; Ullah, Rizwan; Shoeb, Mohd; Naqvi, Alim H.; Abidi, Syed M. A.

2015-01-01

Helminth parasites of veterinary importance cause huge revenue losses to agrarian economy worldwide. With the emergence of drug resistance against the current formulations, there is a need to focus on the alternative approaches in order to control this menace. In the present study, biocompatible zinc oxide nanoparticles (ZnO NPs) were used to see their in vitro effect on the biliary amphistomes, Gigantocotyle explanatum, infecting Bubalus bubalis because these nanoparticles are involved in generation of free radicals that induce oxidative stress, resulting in disruption of cellular machinery. The ZnO NPs were synthesized by using egg albumin as a biotemplate and subsequently characterized by Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), X-ray Diffraction and Spectrophotometrical, which showed that ZnO NPs were highly purified wurtzite type polycrystals, with a mean size of 16.7 nm. When the parasites were treated with lower concentrations (0.004% and 0.008%) of the ZnO NPs, the worms mounted a protective response by stimulating the antioxidant system but the treatment of G. explanatum with 0.012% ZnO NPs produced significant inhibition of the antioxidant enzymes like superoxide dismutase (SOD) (p< 0.05) and glutathione S- transferase (GST) (p<0.01), while the level of malondialdehyde (MDA), a lipid peroxidation marker, was significantly (p< 0.01) elevated. SEM and histopathology revealed pronounced tegumental damage showing the disruption of surface papillae and the annulations, particularly in the posterior region near acetabulum. The under expression of a number of polypeptides, loss of worm motility in a time dependent manner, further reflect strong anthelmintic potential of ZnO NPs. It can be concluded that the anthelmintic effect might be due to the production of reactive oxygen species that target a variety of macromolecules such as nucleic acid, protein and lipids which are involved in different cellular processes. PMID:26177503

Anthelmintic Effect of Biocompatible Zinc Oxide Nanoparticles (ZnO NPs) on Gigantocotyle explanatum, a Neglected Parasite of Indian Water Buffalo.

PubMed

Khan, Yasir Akhtar; Singh, Braj Raj; Ullah, Rizwan; Shoeb, Mohd; Naqvi, Alim H; Abidi, Syed M A

2015-01-01

Helminth parasites of veterinary importance cause huge revenue losses to agrarian economy worldwide. With the emergence of drug resistance against the current formulations, there is a need to focus on the alternative approaches in order to control this menace. In the present study, biocompatible zinc oxide nanoparticles (ZnO NPs) were used to see their in vitro effect on the biliary amphistomes, Gigantocotyle explanatum, infecting Bubalus bubalis because these nanoparticles are involved in generation of free radicals that induce oxidative stress, resulting in disruption of cellular machinery. The ZnO NPs were synthesized by using egg albumin as a biotemplate and subsequently characterized by Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), X-ray Diffraction and Spectrophotometrical, which showed that ZnO NPs were highly purified wurtzite type polycrystals, with a mean size of 16.7 nm. When the parasites were treated with lower concentrations (0.004% and 0.008%) of the ZnO NPs, the worms mounted a protective response by stimulating the antioxidant system but the treatment of G. explanatum with 0.012% ZnO NPs produced significant inhibition of the antioxidant enzymes like superoxide dismutase (SOD) (p< 0.05) and glutathione S- transferase (GST) (p<0.01), while the level of malondialdehyde (MDA), a lipid peroxidation marker, was significantly (p< 0.01) elevated. SEM and histopathology revealed pronounced tegumental damage showing the disruption of surface papillae and the annulations, particularly in the posterior region near acetabulum. The under expression of a number of polypeptides, loss of worm motility in a time dependent manner, further reflect strong anthelmintic potential of ZnO NPs. It can be concluded that the anthelmintic effect might be due to the production of reactive oxygen species that target a variety of macromolecules such as nucleic acid, protein and lipids which are involved in different cellular processes.

Targeted delivery of peptide-conjugated biocompatible gold nanoparticles into cancer cell nucleus

NASA Astrophysics Data System (ADS)

Qian, Wei; Curry, Taeyjuana; Che, Yong; Kopelman, Raoul

2013-02-01

Nucleus remains a significant target for nanoparticles with diagnostic and therapeutic applications because both genetic information of the cell and transcription machinery reside there. Novel therapeutic strategies (for example, gene therapy), enabled by safe and efficient delivery of nanoparticles and drug molecules into the nucleus, are heralded by many as the ultimate treatment for severe and intractable diseases. However, most nanomaterials and macromolecules are incapable of reaching the cell nucleus on their own, because of biological barriers carefully honed by evolution including cellular membrane and nuclear envelope. In this paper, we have demonstrated an approach of fabrication of biocompatible gold nanoparticle (Au NP)-based vehicles which can entering into cancer cell nucleus by modifying Au NPs with both PEG 5000 and two different peptides (RGD and nuclear localization signal (NLS) peptide). The Au NPs used were fabricated via femtosecond laser ablation of Au bulk target in deionized water. The Au NPs produced by this method provide chemical free, virgin surface, which allows us to carry out "Sequential Conjugation" to modify their surface with PEG 5000, RGD, and NLS. "Sequential Conjugation" described in this presentation is very critical for the fabrication of Au NP-based vehicles capable of entering into cancer cell nucleus as it enables the engineering and tuning surface chemistries of Au NPs by independently adjusting amounts of PEG and peptides bound onto surface of Au NPs so as to maximize their nuclear targeting performance and biocompatibility regarding the cell line of interest. Both optical microscopy and transmission electron microscopy (TEM) are used to confirm the in vitro targeted nuclear delivery of peptide-conjugated biocompatible Au NPs by showing their presence in the cancer cell nucleus.

NaNO3/NaCl Oxidant and Polyethylene Glycol (PEG) Capped Gold Nanoparticles (AuNPs) as a Novel Green Route for AuNPs Detection in Electrochemical Biosensors.

PubMed

López-Marzo, Adaris M; Hoyos-de-la-Torre, Raquel; Baldrich, Eva

2018-03-20

Gold nanoparticles (AuNPs) have been exploited as signal-producing tags in electrochemical biosensors. However, the electrochemical detection of AuNPs is currently performed using corrosive acid solutions, which may raise health and environmental concerns. Here, oxidant salts, and specifically the environmentally friendly and occupational safe NaNO 3 /NaCl mixture, have been evaluated for the first time as potential alternatives to the acid solutions traditionally used for AuNPs electrooxidation. In addition, a new strategy to improve the sensitivity of the biosensor through PEG-based ligand exchange to produce less compact and easier to oxidize AuNPs immunoconjugates is presented too. As we show, the electrochemical immunosensor using NaNO 3 /NaCl measurement solution for AuNPs electrooxidation and detection, coupled to the employment of PEG-capped nanoimmunoconjugates, produced results comparable to classical HCl detection. The procedure developed was next tested for human matrix metallopeptidase-9 (hMMP9) analysis, exhibiting a 0.18-23 ng/mL linear range, a detection limit of 0.06 ng/mL, and recoveries between 95 and 105% in spiked human plasma. These results show that the procedure developed is applicable to the analysis of protein biomarkers in blood plasma and could contribute to the development of more environmentally friendly AuNP-based electrochemical biosensors.

CMAQ and NPS : exploring the applicability of the Congestion Mitigation and Air Quality Improvement program to NPS transit

DOT National Transportation Integrated Search

2014-03-06

The Congestion Mitigation and Air Quality Improvement (CMAQ) Program is a funding program that was most recently : re-authorized in Moving Ahead for Progress in the 21st Century. CMAQ offers a potential funding opportunity for NPS park units : with e...

Structural mechanical and antibacterial properties of HPMC/SF-AgNPs nanocomposite films

NASA Astrophysics Data System (ADS)

Harish, K. V.; Rao, B. Lakshmeesha; Asha, S.; Vipin, C.; Sangappa, Y.

2018-04-01

In the present study, Hydroxypropyl Methylcellulose (HPMC) pure and HPMC/SF-AgNPs biopolymer nanocomposite films were prepared by simple solution casting method. The prepared nanocomposite films were characterized using UV-Visible spectroscopy(UV-Vis), X-ray diffraction (XRD) measurements. The mechanical properties of HPMC/SF-AgNPs nanocomposites were found to be decrease with increase in the AgNP's concentrations. The HPMC/SF-AgNPs nanocomposites showed very good antibacterial activity against human pathogens P. aeruginosa, E.coli, and S.aureus.

Bio-nano complexes of ZVFeNPs/Fe-s-M13 and Cd (II)/Cd-s-M13 accelerate Cd (II) reduction by FeNPs through dual dispersing and separate deposition

NASA Astrophysics Data System (ADS)

Zhang, Shuai; Nakano, Kazuhiko; Yu, Huimin; Shen, Zhongyao

2014-03-01

Reduction of Cd (II) in liquor by solid zero valent Fe nanoparticles (ZVFeNPs) is a liquid-solid biphasic reaction in which the reduction efficiency was often lowered by either aggregation of ZVFeNPs or coating of the generated ZVCd. In light of the filamentous nanostructure of bacteriophage M13 with ˜2700 copies of pVIII protein in delicate distribution at the coat, a novel dual dispersing reduction route was designed by introducing two different kinds of M13 with Fe-binding specificity (Fe-s-M13) and Cd-binding specificity (Cd-s-M13) to disperse ZVFeNPs and Cd (II) ions, respectively. The Fe-s-M13 was used for synthesis of the ZVFeNPs/Fe-s-M13 complex, where ZVFeNPs were uniformly dispersed into small nanoparticles (5-10 nm) on Fe-s-M13. The engineered Cd-s-M13, constructed by genetic recombination of pVIII through inserting the gene of a biopanned 7-mer Cd-specific peptide (SCPICPG) into the N-terminus of pVIII gene, was used for Cd (II) dispersion before reduction. The dispersed complex of Cd(II)/Cd-s-M13 was rapidly reduced by complex of ZVFeNPs/Fe-s-M13. Kinetics results showed that the initial reduction rate and final reduction ratio of Cd (II) increased by 35.7% and 16.4%, respectively, through dispersion of ZVFeNPs by Fe-s-M13; they improved again by 53.6% and 37.0%, respectively, through further dispersion of Cd (II) by Cd-s-M13. TEM and EDS results revealed that the acceleration effect of the dual dispersing reduction was arising from uniform dispersion of the small ZVFeNPs and separate deposition of the reduced ZVCd on the two different M13 phages.

Electrical response from nanocomposite PDMS-Ag NPs generated by in situ laser ablation in solution

NASA Astrophysics Data System (ADS)

Kalyva, Maria; Kumar, Susmit; Brescia, Rosaria; Petroni, Simona; La Tegola, Carola; Bertoni, Giovanni; De Vittorio, Massimo; Cingolani, Roberto; Athanassiou, Athanassia

2013-01-01

Laser ablation technique is employed in order to generate polydimethylsiloxane (PDMS)/Ag NPs in situ, starting from a silver target in a solution of PDMS prepolymer and toluene. The produced surfactant-free nanoparticles are characterized by high resolution transmission electron microscopy (HRTEM) and scanning TEM-high angle annular dark field (STEM-HAADF) imaging modes, showing the majority of them to be of the order of 4 nm in diameter with a small percentage of larger Ag-AgCl multidomain NPs, embedded into a PDMS matrix. Low concentrations of carbon onion-like nanoparticles or larger fibers are also formed in the toluene-PDMS prepolymer solution. In accordance with this, UV-vis spectra shows no peak from silver NPs; their small size and their coverage by the PDMS matrix suppresses the signal of surface plasmon absorption. Inductively coupled plasma measurements reveal that the concentration of silver in the polymer is characteristically low, ˜0.001% by weight. The electrical properties of the PDMS nanocomposite films are modified, with current versus voltage (I-V) measurements showing a low current of up to a few tenths of a pA at 5 V. The surface resistivity of the films is found to be up to ˜1010 Ω/sq. Under pressure (e.g. stress) applied by a dynamic mechanical analyzer (DMA), the I-V measurements demonstrate the current decreasing during the elastic deformation, and increasing during the plastic deformation.

HOXB7 and Hsa-miR-222 as the Potential Therapeutic Candidates for Metastatic Colorectal Cancer.

PubMed

Iman, Maryam; Mostafavi, Seyede Samaneh; Arab, Seyed Shahriar; Azimzadeh, Sadegh; Poorebrahim, Mansour

2016-01-01

Recent studies have shown that the high mortality of patients with colorectal cancer (CRC) is related to its ability to spread the surrounding tissues, thus there is a need for designing and developing new drugs. Here, we proposed a combinational therapy strategy, an inhibitory peptide in combination with miRNA targeting, for modulating CRC metastasis. In this study, some of the recent patents were also reviewed. After data analysis with GEO2R and gene annotation using DAVID server, regulatory interactions of differentially expressed genes (DEGs) were obtained from STRING, GeneMANIA, KEGG and TRED databases. In parallel, the corresponding validated microRNAs (miRNAs) were obtained from mirDIP web server and a miRNA-DEG regulatory network was also reconstructed. Clustering and topological analyses of the regulatory networks were performed using Cytoscape plug-ins. We found the HOXB family as the most important functional complex in DEG-derived regulatory network. Accordingly, an anti-HOXB7 peptide was designed based on the binding interface of its coactivator, PBX1. Topological analysis of miRNA-DEG network indicated that hsa-miR-222 is one of the most important oncomirs involved in regulation of DEGs activities. Thus, this miRNA, along with HOXB7, was also considered as the potential target for inhibiting CRC metastasis. Molecular docking studies exhibited that the designed peptide can bind to desired binding pocket of HOXB7 in a highaffinity manner. Further confirmations were also observed in Molecular dynamics (MD) simulations carried out by GROMACS v5.0.2 simulation package. In conclusion, our findings suggest that simultaneous targeting of key regulatory genes and miRNAs may be a useful strategy for prevention of CRC metastasis.

Nanoparticle targeted therapy against childhood acute lymphoblastic leukemia

NASA Astrophysics Data System (ADS)

Satake, Noriko; Lee, Joyce; Xiao, Kai; Luo, Juntao; Sarangi, Susmita; Chang, Astra; McLaughlin, Bridget; Zhou, Ping; Kenney, Elaina; Kraynov, Liliya; Arnott, Sarah; McGee, Jeannine; Nolta, Jan; Lam, Kit

2011-06-01

The goal of our project is to develop a unique ligand-conjugated nanoparticle (NP) therapy against childhood acute lymphoblastic leukemia (ALL). LLP2A, discovered by Dr. Kit Lam, is a high-affinity and high-specificity peptidomimetic ligand against an activated α4β1 integrin. Our study using 11 fresh primary ALL samples (10 precursor B ALL and 1 T ALL) showed that childhood ALL cells expressed activated α4β1 integrin and bound to LLP2A. Normal hematopoietic cells such as activated lymphocytes and monocytes expressed activated α4β1 integrin; however, normal hematopoietic stem cells showed low expression of α4β1 integrin. Therefore, we believe that LLP2A can be used as a targeted therapy for childhood ALL. The Lam lab has developed novel telodendrimer-based nanoparticles (NPs) which can carry drugs efficiently. We have also developed a human leukemia mouse model using immunodeficient NOD/SCID/IL2Rγ null mice engrafted with primary childhood ALL cells from our patients. LLP2A-conjugated NPs will be evaluated both in vitro and in vivo using primary leukemia cells and this mouse model. NPs will be loaded first with DiD near infra-red dye, and then with the chemotherapeutic agents daunorubicin or vincristine. Both drugs are mainstays of current chemotherapy for childhood ALL. Targeting properties of LLP2A-conjugated NPs will be evaluated by fluorescent microscopy, flow cytometry, MTS assay, and mouse survival after treatment. We expect that LLP2A-conjugated NPs will be preferentially delivered and endocytosed to leukemia cells as an effective targeted therapy.

Hyaluronic acid grafted PLGA copolymer nanoparticles enhance the targeted delivery of Bromelain in Ehrlich's Ascites Carcinoma.

PubMed

Bhatnagar, Priyanka; Pant, Aditya Bhushan; Shukla, Yogeshwer; Panda, Amulya; Gupta, Kailash Chand

2016-08-01

Rapidly increasing malignant neoplastic disease demands immediate attention. Several dietary compounds have recently emerged as strong anti-cancerous agents. Among, Bromelain (BL), a protease from pineapple plant, was used to enhance its anti-cancerous efficacy using nanotechnology. In lieu of this, hyaluronic acid (HA) grafted PLGA copolymer, having tumor targeting ability, was developed. BL was encapsulated in copolymer to obtain BL-copolymer nanoparticles (NPs) that ranged between 140 to 281nm in size. NPs exhibited higher cellular uptake and cytotoxicity in cells with high CD44 expression as compared with non-targeted NPs. In vivo results on tumor bearing mice showed that NPs were efficient in suppressing the tumor growth. Hence, the formulation could be used as a self-targeting drug delivery cargo for the remission of cancer. Copyright © 2016 Elsevier B.V. All rights reserved.

Confocal Raman microspectroscopic study of folate receptor-targeted delivery of 6-mercaptopurine-embedded gold nanoparticles in a single cell.

PubMed

Park, Jin; Jeon, Won Il; Lee, So Yeong; Ock, Kwang-Su; Seo, Ji Hye; Park, Jinho; Ganbold, Erdene-Ochir; Cho, Keunchang; Song, Nam Woong; Joo, Sang-Woo

2012-05-01

We investigate the cellular uptake behaviors and efficacy of folate-coated gold nanoparticles (AuNPs) for the targeted drug delivery system in human cancer cells. Folate-conjugated AuNPs embedded with a purine analogue cancer drug of 6-mercaptopurine (6MP) were assembled via a 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride (EDC) coupling reaction between the amino group of 4-aminobenzenethiol (ABT) and the carboxyl group of folic acid. The assembly of folate and 6MP on AuNPs has been examined by absorption spectroscopy, transmission electron microscopy (TEM), and confocal Raman spectroscopy. The internalization of the conjugated AuNPs inside the folate receptor-positive HeLa and KB cells was checked by TEM and dark-field microscopy (DFM) combined with label-free confocal spectroscopy over the depth variable z at a micrometer resolution. DFM live cell imaging of folate-conjugated AuNPs in HeLa cells indicated that the targeted AuNPs appeared to attach on the cell surfaces and enter into the cell with an hour. The cell viability was also compared to estimate the efficacy of folate-conjugated AuNP delivery systems. Folate receptor-targeted AuNP systems appeared to decrease cancer cell viability both in vitro and in vivo more than did the use of the 6MP-coated AuNPs drug without any targeting systems. Copyright © 2012 Wiley Periodicals, Inc.

Application of coupled affinity-sizing chromatography for the detection of proteolyzed HSA-tagged proteins.

PubMed

London, Anne Serdakowski; Patel, Kunal; Quinn, Lisa; Lemmerer, Martin

2015-04-01

Coupled affinity liquid chromatography and size exclusion chromatography (ALC-SEC) is a technique that has been shown to successfully report product quality of proteins during cell expression and prior to the commencement of downstream processing chromatography steps. This method was applied to monitoring the degradation and subsequent partial remediation of a HSA-tagged protein which showed proteolysis, allowing for rapid cell line development to address this product quality dilemma. This paper outlines the novel application of this method for measuring and addressing protease-induced proteolysis. Copyright © 2014 Elsevier Inc. All rights reserved.

Targeted drug delivery of Sunitinib Malate to tumor blood vessels by cRGD-chiotosan-gold nanoparticles.

PubMed

Saber, Mohaddeseh Mahmoudi; Bahrainian, Sara; Dinarvand, Rassoul; Atyabi, Fatemeh

2017-01-30

The unique characteristics of tumor vasculature represent an attractive strategy for targeted delivery of antitumor and antiangiogenic agents to the tumor. The purpose of this study was to prepare c(RGDfK) labeled chitosan capped gold nanoparticles [cRGD(CS-Au) NPs] as a carrier for selective intracellular delivery of Sunitinib Malate (STB) to the tumor vasculature. cRGD(CS-Au) NPs was formed by electrostatic interaction between cationic CS and anionic AuNPs. cRGD modified CS-Au NPs had a spherical shape with a narrow size distribution. The entrapment efficiency of sunitinib molecule was found to be 45.2%±2.05. Confocal microscopy showed enhanced and selective uptake of cRGD(CS-Au) NPs into MCF-7 and HUVEC cells compared with non-targeted CS-Au NPs. Our results suggest that it may be possible to use cRGD(CS-Au) NPs as a carrier for delivery of anticancer drugs, genes and biomolecules for inhibiting tumor vasculature. Copyright © 2016. Published by Elsevier B.V.

MEN1 mutations and potentially MEN1-targeting miRNAs are responsible for menin deficiency in sporadic and MEN1 syndrome-associated primary hyperparathyroidism.

PubMed

Grolmusz, Vince Kornél; Borka, Katalin; Kövesdi, Annamária; Németh, Kinga; Balogh, Katalin; Dékány, Csaba; Kiss, András; Szentpéteri, Anna; Sármán, Beatrix; Somogyi, Anikó; Csajbók, Éva; Valkusz, Zsuzsanna; Tóth, Miklós; Igaz, Péter; Rácz, Károly; Patócs, Attila

2017-09-01

Inherited, germline mutations of menin-coding MEN1 gene cause multiple endocrine neoplasia type 1 (MEN1), while somatic MEN1 mutations are the sole main driver mutations in sporadic primary hyperparathyroidism (PHPT), suggesting that menin deficiency has a central role in the pathogenesis of PHPT. MiRNAs are small, noncoding RNAs posttranscriptionally regulating gene expression. Our aim was to investigate both the role of MEN1 mutations and potentially MEN1-targeting miRNAs as the underlying cause of menin deficiency in MEN1-associated and sporadic PHPT tissues. Fifty six PHPT tissues, including 16 MEN1-associated tissues, were evaluated. Diagnosis of MEN1 syndrome was based on identification of germline MEN1 mutations. In silico target prediction was used to identify miRNAs potentially targeting MEN1. Menin expression was determined by immunohistochemistry while expression of miRNAs was analyzed by quantitative real-time PCR. Sporadic PHPT tissues were subjected to somatic MEN1 mutation analysis as well. Lack of nuclear menin was identified in all MEN1-associated and in 28% of sporadic PHPT tissues. Somatic MEN1 mutations were found in 25% of sporadic PHPTs. The sensitivity and specificity of menin immunohistochemistry to detect a MEN1 mutation were 86 and 87%, respectively. Expression levels of hsa-miR-24 and hsa-miR-28 were higher in sporadic compared to MEN1-associated PHPT tissues; however, no difference in miRNA levels occurred between menin-positive and menin-negative PHPT tissues. Menin deficiency is the consequence of a MEN1 mutation in most menin-negative PHPT tissues. Elevated expression of hsa-miR-24 and hsa-miR-28 mark the first epigenetic changes observed between sporadic and MEN1-associated PHPT.

Fab’-bearing siRNA TNFα-loaded nanoparticles targeted to colonic macrophages offer an effective therapy for experimental colitis

PubMed Central

Hamed, Laroui; Emilie, Viennois; Xiao, Bo; Canup, Brandon S.; Duke, Geem; Denning, Timothy L.; Didier, Merlin

2014-01-01

Patients suffering from Inflammatory Bowel Disease (IBD) are currently treated by systemic drugs that can have significant side effects. Thus, it would be highly desirable to target TNFα siRNA (a therapeutic molecule) to the inflamed tissue. Here, we demonstrate that TNFα siRNA can be efficiently loaded into nanoparticles (NPs) made of poly (lactic acid) poly (ethylene glycol) block copolymer (PLA-PEG), and that grafting of the Fab’ portion of the F4/80 Ab (Fab’-bearing) onto the NP surface via maleimide/thiol group-mediated covalent bonding improves the macrophage (MP)-targeting kinetics of the NPs to RAW264.7 cells in vitro. Direct binding was shown between MPs and the Fab’-bearing NPs. Next, we orally administered hydrogel (chitosan/alginate)-encapsulated Fab’-bearing TNFα-siRNA-loaded NPs to 3% dextran sodium sulfate (DSS)-treated mice and investigated the therapeutic effect on colitis. In vivo, the release of TNFα-siRNA-loaded NPs into the mouse colon attenuated colitis more efficiently when the NPs were covered with Fab’-bearing, compared to uncovered NPs. All DSS-induced parameters of colonic inflammation (e.g., weight loss, myeloperoxidase activity, and Iκbα accumulation) were more attenuated Fab’-bearing NPs loaded with TNFα siRNA than without the Fab’-bearing. Grafting the Fab’-bearing onto the NPs improved the kinetics of endocytosis as well as the MP-targeting ability, as indicated by flow cytometry. Collectively, our results show that Fab’-bearing PLA-PEG NPs are powerful and efficient nanosized tools for delivering siRNAs into colonic macrophages. PMID:24810114

Targeted nanomedicine for cancer therapeutics: Towards precision medicine overcoming drug resistance.

PubMed

Bar-Zeev, Maya; Livney, Yoav D; Assaraf, Yehuda G

2017-03-01

Intrinsic anticancer drug resistance appearing prior to chemotherapy as well as acquired resistance due to drug treatment, remain the dominant impediments towards curative cancer therapy. Hence, novel targeted strategies to overcome cancer drug resistance constitute a key aim of cancer research. In this respect, targeted nanomedicine offers innovative therapeutic strategies to overcome the various limitations of conventional chemotherapy, enabling enhanced selectivity, early and more precise cancer diagnosis, individualized treatment as well as overcoming of drug resistance, including multidrug resistance (MDR). Delivery systems based on nanoparticles (NPs) include diverse platforms enabling a plethora of rationally designed therapeutic nanomedicines. Here we review NPs designed to enhance antitumor drug uptake and selective intracellular accumulation using strategies including passive and active targeting, stimuli-responsive drug activation or target-activated release, triggered solely in the cancer cell or in specific organelles, cutting edge theranostic multifunctional NPs delivering drug combinations for synergistic therapy, while facilitating diagnostics, and personalization of therapeutic regimens. In the current paper we review the recent findings of the past four years and discuss the advantages and limitations of the various novel NPs-based drug delivery systems. Special emphasis is put on in vivo study-based evidences supporting significant therapeutic impact in chemoresistant cancers. A future perspective is proposed for further research and development of complex targeted, multi-stage responsive nanomedical drug delivery systems for personalized cancer diagnosis and efficacious therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Erlotinib-Conjugated Iron Oxide Nanoparticles as a Smart Cancer-Targeted Theranostic Probe for MRI.

PubMed

Ali, Ahmed Atef Ahmed; Hsu, Fei-Ting; Hsieh, Chia-Ling; Shiau, Chia-Yang; Chiang, Chiao-Hsi; Wei, Zung-Hang; Chen, Cheng-Yu; Huang, Hsu-Shan

2016-11-11

We designed and synthesized novel theranostic nanoparticles that showed the considerable potential for clinical use in targeted therapy, and non-invasive real-time monitoring of tumors by MRI. Our nanoparticles were ultra-small with superparamagnetic iron oxide cores, conjugated to erlotinib (FeDC-E NPs). Such smart targeted nanoparticles have the preference to release the drug intracellularly rather than into the bloodstream, and specifically recognize and kill cancer cells that overexpress EGFR while being non-toxic to EGFR-negative cells. MRI, transmission electron microscopy and Prussian blue staining results indicated that cellular uptake and intracellular accumulation of FeDC-E NPs in the EGFR overexpressing cells was significantly higher than those of the non-erlotinib-conjugated nanoparticles. FeDC-E NPs inhibited the EGFR-ERK-NF-κB signaling pathways, and subsequently suppressed the migration and invasion capabilities of the highly invasive and migrative CL1-5-F4 cancer cells. In vivo tumor xenograft experiments using BALB/c nude mice showed that FeDC-E NPs could effectively inhibit the growth of tumors. T 2 -weighted MRI images of the mice showed significant decrease in the normalized signal within the tumor post-treatment with FeDC-E NPs compared to the non-targeted control iron oxide nanoparticles. This is the first study to use erlotinib as a small-molecule targeting agent for nanoparticles.

Erlotinib-Conjugated Iron Oxide Nanoparticles as a Smart Cancer-Targeted Theranostic Probe for MRI

NASA Astrophysics Data System (ADS)

Ali, Ahmed Atef Ahmed; Hsu, Fei-Ting; Hsieh, Chia-Ling; Shiau, Chia-Yang; Chiang, Chiao-Hsi; Wei, Zung-Hang; Chen, Cheng-Yu; Huang, Hsu-Shan

2016-11-01

We designed and synthesized novel theranostic nanoparticles that showed the considerable potential for clinical use in targeted therapy, and non-invasive real-time monitoring of tumors by MRI. Our nanoparticles were ultra-small with superparamagnetic iron oxide cores, conjugated to erlotinib (FeDC-E NPs). Such smart targeted nanoparticles have the preference to release the drug intracellularly rather than into the bloodstream, and specifically recognize and kill cancer cells that overexpress EGFR while being non-toxic to EGFR-negative cells. MRI, transmission electron microscopy and Prussian blue staining results indicated that cellular uptake and intracellular accumulation of FeDC-E NPs in the EGFR overexpressing cells was significantly higher than those of the non-erlotinib-conjugated nanoparticles. FeDC-E NPs inhibited the EGFR-ERK-NF-κB signaling pathways, and subsequently suppressed the migration and invasion capabilities of the highly invasive and migrative CL1-5-F4 cancer cells. In vivo tumor xenograft experiments using BALB/c nude mice showed that FeDC-E NPs could effectively inhibit the growth of tumors. T2-weighted MRI images of the mice showed significant decrease in the normalized signal within the tumor post-treatment with FeDC-E NPs compared to the non-targeted control iron oxide nanoparticles. This is the first study to use erlotinib as a small-molecule targeting agent for nanoparticles.

Nanoparticle-neural stem cells for targeted ovarian cancer treatment: optimization of silica nanoparticles for efficient drug loading

NASA Astrophysics Data System (ADS)

Patel, Z.; Berlin, J.; Abidi, W.

2018-02-01

One of the drugs used to treat ovarian cancer is cisplatin. However, cisplatin kills normal surrounding tissue in addition to cancer cells. To improve tumor targeting efficiency, our lab uses neural stem cells (NSCs), which migrate directly to ovarian tumors. If free cisplatin is loaded into NSCs for targeted drug delivery, it will kill the NSCs. To prevent the drug cisplatin from killing both the NSCs and normal surrounding tissue, our lab synthesizes silica nanoparticles (SiNPs) that act as a protective carrier. The big picture here is to maximize efficiency of tumor targeting using NSCs and minimize toxicity to these NSCs using SiNPs. The goal of this project is to optimize the stability of SiNPs, which is important for efficient drug loading. To do this, the concentration of tetraethyl orthosilicate (TEOS), one of the main components of SiNPs, was varied. We hypothesized that more TEOS equates to more stable SiNPs because TEOS contributes carbon to SiNPs, and thus a tightly-packed chemical structure results in a stable particle. Then, the stability of the SiNPs were checked in cell media and phosphate buffered saline (PBS). Lastly, the SiNPs were analyzed for their porosity using the transmission electron microscope (TEM). TEM imaging showed white spots in the 200-800 μL TEOS batches and no white spots in the 1000-1800 μL TEOS batches. The white spots were pores, which indicate instability. We concluded that the ultimate factor that determines the stability of SiNPs (100 nm) is the concentration of organic substance.

New cobalt(II) and nickel(II) complexes of benzyl carbazate Schiff bases: Syntheses, crystal structures, in vitro DNA and HSA binding studies.

PubMed

Nithya, Palanivelu; Helena, Sannasi; Simpson, Jim; Ilanchelian, Malaichamy; Muthusankar, Aathi; Govindarajan, Subbiah

2016-12-01

In the present study, new Schiff base complexes with the composition [M(NCS) 2 (L1) 2 ]·nH 2 O, where M=Co (n=0) (1) and Ni (n=2) (2); [M(NCS) 2 (L2) 2 ], M=Co (3) and Ni (4) as well as [M(NCS) 2 (L3) 2 ], M=Co (5) and Ni (6); (L1=benzyl 2-(propan-2-ylidene)hydrazinecarboxylate, L2=benzyl 2-(butan-2-ylidene)hydrazinecarboxylate and L3=benzyl 2-(pentan-3-ylidene)hydrazinecarboxylate) have been synthesized by a template method. The complexes were characterised by analytical methods, spectroscopic studies, thermal and X-ray diffraction techniques. The structures of all the complexes explore that the metal(II) cation has a trans-planar coordination environment, the monomeric units containing a six-coordinated metal center in octahedral geometry with N-bound isothiocyanate anions coordinated as terminal ligands. Furthermore, the binding of the two Schiff base ligands to the metal centers involves the azomethine nitrogen and the carbonyl oxygen in mutually trans configuration. The binding interactions of all the complexes with Calf thymus-deoxyribonucleic acid (CT-DNA) and human serum albumin (HSA) have been investigated using absorption and emission spectral techniques. The CT-DNA binding properties of these complexes reveal that they bind to CT-DNA through a partial intercalation mode and the binding constant values were calculated using the absorption and emission spectral data. The binding constant values (~10×10 6 moldm -3 ) indicate strong binding of metal complexes with CT-DNA. HSA binding interaction studies showed that the cobalt and nickel complexes can quench the intrinsic fluorescence of HSA through static quenching process. Also, molecular docking studies were supported out to apprehend the binding interactions of these complexes with DNA and HSA which offer new understandings into the experimental model observations. Copyright © 2016 Elsevier B.V. All rights reserved.

Molecular Mechanisms of Zinc Oxide Nanoparticle-Induced Genotoxicity Short Running Title: Genotoxicity of ZnO NPs

PubMed Central

Scherzad, Agmal; Meyer, Till; Kleinsasser, Norbert

2017-01-01

Background: Zinc oxide nanoparticles (ZnO NPs) are among the most frequently applied nanomaterials in consumer products. Evidence exists regarding the cytotoxic effects of ZnO NPs in mammalian cells; however, knowledge about the potential genotoxicity of ZnO NPs is rare, and results presented in the current literature are inconsistent. Objectives: The aim of this review is to summarize the existing data regarding the DNA damage that ZnO NPs induce, and focus on the possible molecular mechanisms underlying genotoxic events. Methods: Electronic literature databases were systematically searched for studies that report on the genotoxicity of ZnO NPs. Results: Several methods and different endpoints demonstrate the genotoxic potential of ZnO NPs. Most publications describe in vitro assessments of the oxidative DNA damage triggered by dissoluted Zn2+ ions. Most genotoxicological investigations of ZnO NPs address acute exposure situations. Conclusion: Existing evidence indicates that ZnO NPs possibly have the potential to damage DNA. However, there is a lack of long-term exposure experiments that clarify the intracellular bioaccumulation of ZnO NPs and the possible mechanisms of DNA repair and cell survival. PMID:29240707

Enzymatic degradation of poly(L-lactide) nanoparticles followed by the release of octenidine and their bactericidal effects.

PubMed

Baier, Grit; Cavallaro, Alex; Friedemann, Kathrin; Müller, Beate; Glasser, Gunnar; Vasilev, Krasimir; Landfester, Katharina

2014-01-01

The enzyme-triggered release of the antimicrobial agent octenidine out of poly(l-lactide)-based nanoparticles (PLLA-NPs) and their in vitro antibacterial activities in the presence of gram-positive and gram-negative bacteria are presented. The formation of the nanoparticles was achieved using a combination of the solvent evaporation and the miniemulsion approach. For the stabilization of the polymeric nanoparticles, non-ionic polymers (polyvinylalcohol [PVA], hydroxyethyl starch [HES], human serum albumin [HSA]) were successfully used for enzymatic degradation; ionic surfactants such as sodium dodecyl sulfate and cetyltrimethylammonium chloride inhibited the enzymatic degradation. The change in pH, size, size distribution and morphology during the degradation process of PLLA-NPs and the release of the antimicrobial agent was studied. The influence of the different amounts of octenidine and of the different stabilizers on the NPs' stability, size, size distribution, morphology, zeta potential and on the surface group's density is discussed. Fluorescently labeled HES-stabilized PLLA-NPs are immobilized by colloidal electrospinning. The observed data from HPLC measurements show that octenidine is released out of PLLA-NPs which are stabilized with PVA, HES or HSA. In bacteria tests the PLLA nanoparticles showed a greater ability to inhibit the growth of Staphylococcus aureus compared to Escherichia coli. This article discusses the enzyme-triggered release and antibacterial effects of octenidine from poly(l-lactide)-based nanoparticles demonstrating the viability of this approach for potential future antibacterial therapy. © 2013.

A Comparative Evaluation of Hydroxycamptothecin Drug Nanorods With and Without Methotrexate Prodrug Functionalization for Drug Delivery

NASA Astrophysics Data System (ADS)

Guo, Fuqiang; Fan, Zhongxiong; Yang, Jinbin; Li, Yang; Wang, Yange; Zhao, Hai; Xie, Liya; Hou, Zhenqing

2016-08-01

We developed a novel self-targeted multi-drug co-delivery system based on rod-shaped 10-hydroxycamptothecin (CPT) nanoanticancer drug (CPT NRs) followed by a surface functionalization with self-targeting PEGylated lipid-conjugated methotrexate (MTX) pro-anticancer drug. The self-targeting effect and in vitro cell viability of the MTX-PEG-CPT NRs on HeLa cells were demonstrated by comparative cellular uptake and MTT assay of the PEG-CPT NRs. In vitro studies showed the feasibility of using this high drug-loading MTX-PEG-CPT NRs in self-targeted drug delivery, controlled-/sustained-release, and synergistic cancer therapy. More importantly, this work would stimulate interest in the use of PEGylated lipid-conjugated MTX by introducing an early-phase tumor-targeting role and then driving a late-phase anticancer role for the highly convergent design of nanomulti-drug, which may advantageously offer a new and simple strategy for simultaneously targeting and treating FA receptor-overexpressing cancer cells.

Prevention of abdominal aortic aneurysm progression by targeted inhibition of matrix metalloproteinase activity with batimastat-loaded nanoparticles.

PubMed

Nosoudi, Nasim; Nahar-Gohad, Pranjal; Sinha, Aditi; Chowdhury, Aniqa; Gerard, Patrick; Carsten, Christopher G; Gray, Bruce H; Vyavahare, Naren R

2015-11-06

Matrix metalloproteinases (MMPs)-mediated extracellular matrix destruction is the major cause of development and progression of abdominal aortic aneurysms. Systemic treatments of MMP inhibitors have shown effectiveness in animal models, but it did not translate to clinical success either because of low doses used or systemic side effects of MMP inhibitors. We propose a targeted nanoparticle (NP)-based delivery of MMP inhibitor at low doses to the abdominal aortic aneurysms site. Such therapy will be an attractive option for preventing expansion of aneurysms in patients without systemic side effects. Our previous study showed that poly(d,l-lactide) NPs conjugated with an antielastin antibody could be targeted to the site of an aneurysm in a rat model of abdominal aortic aneurysms. In the study reported here, we tested whether such targeted NPs could deliver the MMP inhibitor batimastat (BB-94) to the site of an aneurysm and prevent aneurysmal growth. Poly(d,l-lactide) NPs were loaded with BB-94 and conjugated with an elastin antibody. Intravenous injections of elastin antibody-conjugated BB-94-loaded NPs targeted the site of aneurysms and delivered BB-94 in a calcium chloride injury-induced abdominal aortic aneurysms in rats. Such targeted delivery inhibited MMP activity, elastin degradation, calcification, and aneurysmal development in the aorta (269% expansion in control versus 40% elastin antibody-conjugated BB-94-loaded NPs) at a low dose of BB-94. The systemic administration of BB-94 alone at the same dose was ineffective in producing MMP inhibition. Targeted delivery of MMP inhibitors using NPs may be an attractive strategy to inhibit aneurysmal progression. © 2015 American Heart Association, Inc.

Nanoparticle-macrophage interactions: A balance between clearance and cell-specific targeting

PubMed Central

Rattan, Rahul; Bhattacharjee, Somnath; Zong, Hong; Swain, Corban; Siddiqui, Muneeb A.; Visovatti, Scott H.; Kanthi, Yogendra; Desai, Sajani; Pinsky, David J.; Goonewardena, Sascha N.

2017-01-01

The surface properties of nanoparticles (NPs) are a major factor that influences how these nanomaterials interact with biological systems. Interactions between NPs and macrophages of the reticuloendothelial system (RES) can reduce the efficacy of NP diagnostics and therapeutics. Traditionally, to limit NP clearance by the RES system, the NP surface is neutralized with molecules like poly(ethylene glycol) (PEG) which are known to resist protein adsorption and RES clearance. Unfortunately, PEG modification is not without drawbacks including difficulties with the synthesis and associations with immune reactions. To overcome some of these obstacles, we neutralized the NP surface by acetylation and compared this modification to PEGylation for RES clearance and tumor-specific targeting. We found that acetylation was comparable to PEGylation in reducing RES clearance. Additionally, we found that dendrimer acetylation did not impact folic acid (FA)-mediated targeting of tumor cells whereas PEG surface modification reduced the targeting ability of the NP. These results clarify the impact of different NP surface modifications on RES clearance and cell-specific targeting and provide insights into the design of more effective NPs. PMID:28705434

Recent Advances in Nanoparticle-Based Targeted Drug-Delivery Systems Against Cancer and Role of Tumor Microenvironment.

PubMed

Ashfaq, Usman Ali; Riaz, Muhammad; Yasmeen, Erum; Yousaf, Muhammad Zubair

2017-01-01

Cancer is one of the major causes of death worldwide. The silent activation of cellular factors responsible for deviation from normal regulatory pathways leads to the development of cancer. Nano-biotechnology is a novel drug-delivery system with high potential of efficacy and accuracy to target lethal cancers. Various biocompatible nanoparticle (NP)-based drug-delivery systems such as liposomes, dendrimers, micelles, silica, quantum dots, and magnetic, gold, and carbon nanotubes have already been reported for successful targeted cancer treatment. NPs are functionalized with different biological molecules, peptides, antibody, and protein ligands for targeted drug delivery. These systems include a hydrophilic central core, a target-oriented biocompatible outer layer, and a middle hydrophobic core where the drug destined to reach target site resides. Most of the NPs have the ability to maintain their structural shape and are constructed according to the cancer microenvironment. The self-assembling and colloidal properties of NPs have caused them to become the best vehicles for targeted drug delivery. The tumor microenvironment (TME) plays a major role in cancer progression, detection, and treatment. Due to its continuous complex behavior, the TME can hinder delivery systems, thus halting cancer treatment. Nonetheless, a successful biophysiological interaction between the NPs and the TME results in targeted release of drugs. Currently, a number of drugs and NP-based delivery systems against cancer are in clinical and preclinical trials and a few have been approved by Food and Drug Administration (FDA); for example: taxol, doxil, cerubidine, and adrucil. This review summarizes topical advances about the drugs being used for cancer treatment, their targeted delivery systems based on NPs, and the role of TME in this connection.

Anti-tumor Study of Chondroitin Sulfate-Methotrexate Nanogels

NASA Astrophysics Data System (ADS)

Wang, Jinyu; Zhao, Weibo; Chen, Haixiao; Qin, An; Zhu, Peizhi

2017-10-01

Self-assembly nanogels (NGs) were formed by bioconjugating methotrexate (MTX) with chondroitin sulfate (CS). MTX-CS NGs can greatly enhance the solubility and improve the delivery efficacy of MTX due to the CD44 binding property of CS. Vivo experiments revealed that MTX-CS NGs showed less toxicity than MTX. MTX-CS NGs can improve the anti-tumor effect while reducing the side effects of MTX. Due to their CD44 binding property, chondroitin sulfate-drug conjugates could be a promising and efficient platform for improving the solubility of sparingly soluble drug molecules as well as targeted delivery to cancer cells and tumor tissues.

Transferrin-conjugated magnetic dextran-spermine nanoparticles for targeted drug transport across blood-brain barrier.

PubMed

Ghadiri, Maryam; Vasheghani-Farahani, Ebrahim; Atyabi, Fatemeh; Kobarfard, Farzad; Mohamadyar-Toupkanlou, Farzaneh; Hosseinkhani, Hossein

2017-10-01

Application of many vital hydrophilic medicines have been restricted by blood-brain barrier (BBB) for treatment of brain diseases. In this study, a targeted drug delivery system based on dextran-spermine biopolymer was developed for drug transport across BBB. Drug loaded magnetic dextran-spermine nanoparticles (DS-NPs) were prepared via ionic gelation followed by transferrin (Tf) conjugation as targeting moiety. The characteristics of Tf conjugated nanoparticles (TDS-NPs) were analyzed by different methods and their cytotoxicity effects on U87MG cells were tested. The superparamagnetic characteristic of TDS-NPs was verified by vibration simple magnetometer. Capecitabine loaded TDS-NPs exhibited pH-sensitive release behavior with enhanced cytotoxicity against U87MG cells, compared to DS-NPs and free capecitabine. Prussian-blue staining and TEM-imaging showed the significant cellular uptake of TDS-NPs. Furthermore, a remarkable increase of Fe concentrations in brain was observed following their biodistribution and histological studies in vivo, after 1 and 7 days of post-injection. Enhanced drug transport across BBB and pH-triggered cellular uptake of TDS-NPs indicated that these theranostic nanocarriers are promising candidate for the brain malignance treatment. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2851-2864, 2017. © 2017 Wiley Periodicals, Inc.

Targeted Drug Delivery Based on Gold Nanoparticle Derivatives.

PubMed

Gholipourmalekabadi, Mazaher; Mobaraki, Mohammadmahdi; Ghaffari, Maryam; Zarebkohan, Amir; Omrani, Vahid Fallah; Urbanska, Aleksandra M; Seifalian, Alexander

2017-01-01

Drug delivery systems are effective and attractive methods which allow therapeutic substances to be introduced into the body more effectively and safe by having tunable delivery rate and release target site. Gold nanoparticles (AuNPs) have a myriad of favorable physical, chemical, optical, thermal and biological properties that make them highly suitable candidates as non-toxic carriers for drug and gene delivery. The surface modifications of AuNPs profoundly improve their circulation, minimize aggregation rates, enhance attachment to therapeutic molecules and target agents due to their nano range size which further increases their ability to cross cell membranes and reduce overall cytotoxicity. This comprehensive article reviews the applications of the AuNPs in drug delivery systems along with their corresponding surface modifications. The highlighting results obtained from the preclinical trial are promising and next five years have huge possibility move to the clinical setting. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Hyaluronan-decorated polymer nanoparticles targeting the CD44 receptor for the combined photo/chemo-therapy of cancer

NASA Astrophysics Data System (ADS)

Maiolino, Sara; Moret, Francesca; Conte, Claudia; Fraix, Aurore; Tirino, Pasquale; Ungaro, Francesca; Sortino, Salvatore; Reddi, Elena; Quaglia, Fabiana

2015-03-01

In the attempt to develop novel concepts in designing targeted nanoparticles for combination therapy of cancer, we propose here CD44-targeted hyaluronan-decorated double-coated nanoparticles (dcNPs) delivering the lipophilic chemotherapeutic docetaxel (DTX) and an anionic porphyrin (TPPS4). dcNPs are based on electrostatic interactions between a negative DTX-loaded nanoscaffold of poly(lactide-co-glycolide), a polycationic shell of polyethyleneimine entangling negatively-charged TPPS4 and finally decorated with hyaluronan (HA) to promote internalization through CD44 receptor-mediated endocytosis. DTX/TPPS4-dcNPs, prepared through layer-by-layer deposition, showed a hydrodynamic diameter of around 180 nm, negative zeta potential and efficient loading of both DTX and TPPS4. DTX/TPPS4-dcNPs were freeze-dried with trehalose giving a powder that could be easily dispersed in different media. Excellent stability of dcNPs in specific salt- and protein-containing media was found. Spectroscopic behavior of DTX/TPPS4-dcNPs demonstrated a face-to-face arrangement of the TPPS4 units in non-photoresponsive H-type aggregates accounting for an extensive aggregation of the porphyrin embedded in the shell. Experiments in MDA-MB-231 cells overexpressing the CD44 receptor demonstrated a 9.4-fold increase in the intracellular level of TPPS4 delivered from dcNPs as compared to free TPPS4. Light-induced death increased tremendously in cells that had been treated with a combination of TPPS4 and DTX delivered through dcNPs as compared with free drugs, presumably due to efficient uptake and co-localization inside the cells. In perspective, the strategy proposed here to target synergistic drug combinations through HA-decorated nanoparticles seems very attractive to improve the specificity and efficacy of cancer treatment.In the attempt to develop novel concepts in designing targeted nanoparticles for combination therapy of cancer, we propose here CD44-targeted hyaluronan-decorated double

Off to the Organelles - Killing Cancer Cells with Targeted Gold Nanoparticles

PubMed Central

Kodiha, Mohamed; Wang, Yi Meng; Hutter, Eliza; Maysinger, Dusica; Stochaj, Ursula

2015-01-01

Gold nanoparticles (AuNPs) are excellent tools for cancer cell imaging and basic research. However, they have yet to reach their full potential in the clinic. At present, we are only beginning to understand the molecular mechanisms that underlie the biological effects of AuNPs, including the structural and functional changes of cancer cells. This knowledge is critical for two aspects of nanomedicine. First, it will define the AuNP-induced events at the subcellular and molecular level, thereby possibly identifying new targets for cancer treatment. Second, it could provide new strategies to improve AuNP-dependent cancer diagnosis and treatment. Our review summarizes the impact of AuNPs on selected subcellular organelles that are relevant to cancer therapy. We focus on the nucleus, its subcompartments, and mitochondria, because they are intimately linked to cancer cell survival, growth, proliferation and death. While non-targeted AuNPs can damage tumor cells, concentrating AuNPs in particular subcellular locations will likely improve tumor cell killing. Thus, it will increase cancer cell damage by photothermal ablation, mechanical injury or localized drug delivery. This concept is promising, but AuNPs have to overcome multiple hurdles to perform these tasks. AuNP size, morphology and surface modification are critical parameters for their delivery to organelles. Recent strategies explored all of these variables, and surface functionalization has become crucial to concentrate AuNPs in subcellular compartments. Here, we highlight the use of AuNPs to damage cancer cells and their organelles. We discuss current limitations of AuNP-based cancer research and conclude with future directions for AuNP-dependent cancer treatment. PMID:25699096

NPS assessment of color medical displays using a monochromatic CCD camera

NASA Astrophysics Data System (ADS)

Roehrig, Hans; Gu, Xiliang; Fan, Jiahua

2012-02-01

This paper presents an approach to Noise Power Spectrum (NPS) assessment of color medical displays without using an expensive imaging colorimeter. The R, G and B color uniform patterns were shown on the display under study and the images were taken using a high resolution monochromatic camera. A colorimeter was used to calibrate the camera images. Synthetic intensity images were formed by the weighted sum of the R, G, B and the dark screen images. Finally the NPS analysis was conducted on the synthetic images. The proposed method replaces an expensive imaging colorimeter for NPS evaluation, which also suggests a potential solution for routine color medical display QA/QC in the clinical area, especially when imaging of display devices is desired.

LnPO 4 Nanoparticles Doped with Ac-225 and Sequestered Daughters for Targeted Alpha Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

McLaughlin, Mark F.; Robertson, David; Pevsner, Paul H.

2014-02-01

For targeted alpha therapy (TAT) with 225Ac, daughter radioisotopes from the parent emissions should be controlled. We report on a second-generation layered nanoparticle (NP) with improved daughter retention that can mediate TAT of lung tumor colonies. NPs of La 3+, Gd 3+, and 225Ac 3+ ions were coated with additional layers of GdPO 4 and then coated with gold via citrate reduction of NaAuCl 4. MAb 201b, targeting thrombomodulin in lung endothelium, was added to a polyethylene glycol (dPEG)-COOH linker. Furthermore, we quantified the NPs:mAb ratio by labeling the mAb with 125I. NPs showed 30% injected dose/organ antibody-mediated uptake inmore » the lung, which increased to 47% in mice pretreated with clodronate liposomes to reduce phagocytosis. Retention of daughter 213Bi in lung tissue was more than 70% at one hour and about 90% at 24 hours postinjection. Treatment of mice with lung-targeted 225Ac NP reduced EMT-6 lung colonies relative to cold antibody competition for targeting or phosphate-buffered saline injected controls. Finally, we show that LnPO 4 NPs represent a viable solution to deliver the 225Ac as an in vivo α generator. The NPs successfully retain a large percentage of the daughter products without compromising the tumoricidal properties of the α-radiation.« less

pH-Sensitive Reversible Programmed Targeting Strategy by the Self-Assembly/Disassembly of Gold Nanoparticles.

PubMed

Ma, Jinlong; Hu, Zhenpeng; Wang, Wei; Wang, Xinyu; Wu, Qiang; Yuan, Zhi

2017-05-24

A reversible programmed targeting strategy could achieve high tumor accumulation due to its long blood circulation time and high cellular internalization. Here, targeting ligand-modified poly(ethylene glycol) (PEG-ligand), dibutylamines (Bu), and pyrrolidinamines (Py) were introduced on the surface of gold nanoparticles (Au NPs) for reversible shielding/deshielding of the targeting ligands by pH-responsive self-assembly. Hydrophobic interaction and steric repulsion are the main driving forces for the self-assembly/disassembly of Au NPs. The precise self-assembly (pH ≥ 7.2) and disassembly (pH ≤ 6.8) of Au NPs with different ligands could be achieved by fine-tuning the modifying molar ratio of Bu and Py (R m ), which followed the formula R m = 1/(-0.0013X 2 + 0.0323X + 1), in which X is the logarithm of the partition coefficient of the targeting ligand. The assembled/disassembled behavior of Au NPs at pH 7.2 and 6.8 was confirmed by transmission electron microscopy and dynamic light scattering. Enzyme-linked immunosorbent assays and cellular uptake studies showed that the ligands could be buried inside the assembly and exposed when disassembled. More importantly, this process was reversible, which provides the possibility of prolonging blood circulation by shielding ligands associated with the NPs that were effused from tumor tissue.

Editor’s Highlight: A Genome-wide Screening of Target Genes Against Silver Nanoparticles in Fission Yeast

PubMed Central

Lee, Sook-Jeong; Lee, Minho; Nam, Miyoung; Lee, Sol; Choi, Jian; Lee, Hye-Jin; Kim, Dong-Uk; Hoe, Kwang-Lae

2018-01-01

Abstract To identify target genes against silver nanoparticles (AgNPs), we screened a genome-wide gene deletion library of 4843 fission yeast heterozygous mutants covering 96% of all protein encoding genes. A total of 33 targets were identified by a microarray and subsequent individual confirmation. The target pattern of AgNPs was more similar to those of AgNO3 and H2O2, followed by Cd and As. The toxic effect of AgNPs on fission yeast was attributed to the intracellular uptake of AgNPs, followed by the subsequent release of Ag+, leading to the generation of reactive oxygen species (ROS). Next, we focused on the top 10 sensitive targets for further studies. As described previously, 7 nonessential targets were associated with detoxification of ROS, because their heterozygous mutants showed elevated ROS levels. Three novel essential targets were related to folate metabolism or cellular component organization, resulting in cell cycle arrest and no induction in the transcriptional level of antioxidant enzymes such as Sod1 and Gpx1 when 1 of the 2 copies was deleted. Intriguingly, met9 played a key role in combating AgNP-induced ROS generation via NADPH production and was also conserved in a human cell line. PMID:29294138

Targeted Therapies for Myeloma and Metastatic Bone Cancers

DTIC Science & Technology

2010-09-01

to produce NPs for in-vivo studies compatible with the short half life of Tc99m. (Fig 6,7) Developed methods to radiolabel polymer nanoparticles...fully characterize PLA-b-PEG-Maleimide block Polymer (PLA-b-PEG-MAL) Propose: To synthesize Maleimide modified PLGA-b-PEG 2000 for NPs bone-targeted... polymer was synthesized and characterized by H-NMR. (Appendix 2) Improved lyostability of polymer nanoparticles, with and without PEG modification

Killing mechanism of stable N-halamine cross-linked polymethacrylamide nanoparticles that selectively target bacteria.

PubMed

Natan, Michal; Gutman, Ori; Lavi, Ronit; Margel, Shlomo; Banin, Ehud

2015-02-24

Increased resistance of bacteria to disinfection and antimicrobial treatment poses a serious public health threat worldwide. This has prompted the search for agents that can inhibit both bacterial growth and withstand harsh conditions (e.g., high organic loads). In the current study, N-halamine-derivatized cross-linked polymethacrylamide nanoparticles (NPs) were synthesized by copolymerization of the monomer methacrylamide (MAA) and the cross-linker monomer N,N-methylenebis(acrylamide) (MBAA) and were subsequently loaded with oxidative chlorine using sodium hypochlorite (NaOCl). The chlorinated NPs demonstrated remarkable stability and durability to organic reagents and to repetitive bacterial loading cycles as compared with the common disinfectant NaOCl (bleach), which was extremely labile under these conditions. The antibacterial mechanism of the cross-linked P(MAA-MBAA)-Cl NPs was found to involve generation of reactive oxygen species (ROS) only upon exposure to organic media. Importantly, ROS were not generated upon suspension in water, revealing that the mode of action is target-specific. Further, a unique and specific interaction of the chlorinated NPs with Staphylococcus aureus was discovered, whereby these microorganisms were all specifically targeted and marked for destruction. This bacterial encircling was achieved without using a targeting module (e.g., an antibody or a ligand) and represents a highly beneficial, natural property of the P(MAA-MBAA)-Cl nanostructures. Our findings provide insights into the mechanism of action of P(MAA-MBAA)-Cl NPs and demonstrate the superior efficacy of the NPs over bleach (i.e., stability, specificity, and targeting). This work underscores the potential of developing sustainable P(MAA-MBAA)-Cl NP-based devices for inhibiting bacterial colonization and growth.

Green synthesis of AuNPs for eco-friendly functionalization of cellulosic substrates

NASA Astrophysics Data System (ADS)

Ibrahim, Nabil A.; Eid, Basma M.; Abdel-Aziz, Mohamed S.

2016-12-01

In this research work, extracellular biosynthesis of gold nanoparticles (AuNPs) using marine bacterial isolates (Streptomyces sp.) as a reducing/capping/stabilizing bio-agent and chlolauric acid (HAuCl4) as a precursor has been investigated. Surface modification of cotton and viscose knitted fabrics using O2-plasma followed by subsequent treatment with bio-synthesized AuNPs alone and in combination with TiO2NPs or ZnONPs to impart new functional properties namely antibacterial and UV-blocking were studied. The results show that loading of nominated nanomaterials onto the activated fabric samples results in a significant improvement in antibacterial activity against both G+ve (S. aureus) and G-ve (E. coli) along with a remarkable enhancement in the UV-protection functionality of the treated fabrics. The highest antibacterial and anti-UV values were obtained when O2-plasma treated fabrics were loaded with AuNPs/ZnONPs combination, irrespective of the used substrate. The imparted functional properties demonstrated remarkable retention even after 15 washings.

Anti-enrofloxacin antibody production by using enrofloxacin-screened HSA as an immunogen

NASA Astrophysics Data System (ADS)

Liu, Chune; Lin, Hong; Cao, Limin; Jiang, Jie

2005-07-01

A two-step zero-length cross-linking procedure using active esters was successfully adopted for conjugating enrofloxacin (EF) to human serum albumin (HSA). The derived conjugate was characterized by UV spectrum and then used for immunization of BALB/C mice. In enzyme-linked immunosorbent assay (ELISA) and competitive inhibition ELISA experiments, the derived antiserum exhibited high antibody titer (greater than 1:250 000) as well as varied cross-reactivity (from 97.8% to 161.7%) to three analogs of EF belonging to fluoroquinolones family. But over the concentration range studied, no significant cross-reactivity was observed to other group of antibiotics (chloramphenicol, oxytetracycline, sulphamethoxazole and nysfungin). It was confirmed that the synthesized immunogen was highly antigenic and elicited specific antibody responses in BALB/C mice against EF.

Dual-targeting hybrid nanoparticles for the delivery of SN38 to Her2 and CD44 overexpressed human gastric cancer

NASA Astrophysics Data System (ADS)

Yang, Zhe; Luo, Huiyan; Cao, Zhong; Chen, Ya; Gao, Jinbiao; Li, Yingqin; Jiang, Qing; Xu, Ruihua; Liu, Jie

2016-06-01

Gastric cancer (GC), particularly of the type with high expression of both human epidermal growth factor receptor 2 (Her2) and cluster determinant 44 (CD44), is one of the most malignant human tumors which causes a high mortality rate due to rapid tumor growth and metastasis. To develop effective therapeutic treatments, a dual-targeting hybrid nanoparticle (NP) system was designed and constructed to deliver the SN38 agent specifically to human solid gastric tumors bearing excessive Her2 and CD44. The hybrid NPs consist of a particle core made of the biodegradable polymer PLGA and a lipoid shell prepared by conjugating the AHNP peptides and n-hexadecylamine (HDA) to the carboxyl groups of hyaluronic acid (HA). Upon encapsulation of the SN38 agent in the NPs, the AHNP peptides and HA on the NP surface allow preferential delivery of the drug to gastric cancer cells (e.g., HGC27 cells) by targeting Her2 and CD44. Cellular uptake and in vivo biodistribution experiments verified the active targeting and prolonged in vivo circulation properties of the dual-targeting hybrid NPs, leading to enhanced accumulation of the drug in tumors. Furthermore, the anti-proliferation mechanism studies revealed that the inhibition of the growth and invasive activity of HGC27 cells was not only attributed to the enhanced cellular uptake of dual-targeting NPs, but also benefited from the suppression of CD44 and Her2 expression by HA and AHNP moieties. Finally, intravenous administration of the SN38-loaded dual-targeting hybrid NPs induced significant growth inhibition of HGC27 tumor xenografted in nude mice compared with a clinical antitumor agent, Irinotecan (CPT-11), and the other NP formulations. These results demonstrate that the designed dual-targeting hybrid NPs are promising for targeted anti-cancer drug delivery to treat human gastric tumors over-expressing Her2 and CD44.Gastric cancer (GC), particularly of the type with high expression of both human epidermal growth factor receptor

Comprehensive gene and microRNA expression profiling on cardiovascular system in zebrafish co-exposured of SiNPs and MeHg.

PubMed

Hu, Hejing; Shi, Yanfeng; Zhang, Yannan; Wu, Jing; Asweto, Collins Otieno; Feng, Lin; Yang, Xiaozhe; Duan, Junchao; Sun, Zhiwei

2017-12-31

Air pollution has been shown to increase cardiovascular diseases. However, little attention has been paid to the combined effects of PM and air pollutants on the cardiovascular system. To explore this, a high-throughput sequencing technology was used to determine combined effects of silica nanoparticles (SiNPs) and MeHg in zebrafish. Our study demonstrated that SiNPs and MeHg co-exposure could cause significant changes in mRNA and miRNA expression patterns in zebrafish. The differentially expressed (DE) genes in profiles 17 and 26 of STC analysis suggest that SiNPs and MeHg co-exposure had more proinflammatory and cardiovascular toxicity in zebrafish than single exposure. Major gene functions associated with cardiovascular system in the co-exposed zebrafish were discerned from the dynamic-gene-network, including stxbp1a, celf4, ahr1b and bai2. In addition, the prominently expressed pathway of cardiac muscle contraction was targeted by 3 DE miRNAs identified by the miRNA-pathway-network (dre-miR-7147, dre-miR-26a and dre-miR-375), which included 23 DE genes. This study presents a global view of the combined SiNPs and MeHg toxicity on the dynamic expression of both mRNAs and miRNAs in zebrafish, and could serve as fundamental research clues for future studies, especially on cardiovascular system toxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

Hsa-miR-134 suppresses non-small cell lung cancer (NSCLC) development through down-regulation of CCND1

PubMed Central

Sun, Cheng-Cao; Li, Shu-Jun; Li, De-Jia

2016-01-01

Hsa-miRNA-134 (miR-134) has recently been discovered to have anticancer efficacy in different organs. However, the role of miR-134 on non-small cell lung cancer (NSCLC) is still ambiguous. In this study, we investigated the role of miR-134 on the development of NSCLC. The results indicated that miR-134 was significantly down-regulated in primary tumor tissues and very low levels were found in NSCLC cell lines. Ectopic expression of miR-134 in NSCLC cell lines significantly suppressed cell growth as evidenced by cell viability assay, colony formation assay and BrdU staining, through inhibition of cyclin D1, cyclin D2, CDK4 and up-regulation of p57(Kip2) and p21(Waf1/Cip1). In addition, miR-134 induced apoptosis, as indicated by concomitantly with up-regulation of key apoptosis protein cleaved caspase-3, and down-regulation of anti-apoptosis protein Bcl2. Moreover, miR-134 inhibited cellular migration and invasiveness through inhibition of matrix metalloproteinases (MMP)-7 and MMP-9. Further, oncogene CCND1 was revealed to be a putative target of miR-134, which was inversely correlated with miR-134 expression in NSCLC. Taken together, our results demonstrated that miR-134 played a pivotal role on NSCLC through inhibiting cell proliferation, migration, invasion, and promoting apoptosis by targeting oncogenic CCND1. PMID:27166267

Green Synthesis of AgNPs Stabilized with biowaste and their antimicrobial activities

PubMed Central

Jasuja, Nakuleshwar Dut; Gupta, Deepak Kumar; Reza, Mohtashim; Joshi, Suresh C.

2014-01-01

In the present study, rapid reduction and stabilization of Ag+ ions with different NaOH molar concentration (0.5 mM, 1.0 mM and 1.5 mM) has been carried out in the aqueous solution of silver nitrate by the bio waste peel extract of P.granatum. Generally, chemical methods used for the synthesis of AgNPs are quite toxic, flammable and have adverse effect in medical application but green synthesis is a better option due to eco-friendliness, non-toxicity and safe for human. Stable AgNPs were synthesized by treating 90 mL aqueous solution of 2 mM AgNO3 with the 5 mL plant peels extract (0.4% w/v) at different NaOH concentration (5 mL). The synthesized AgNPs were characterized by UV-Vis spectroscopy, TEM and SEM. Further, antimicrobial activities of AgNPs were performed on Gram positive i.e. Staphylococcus aureus, Bacillus subtilius and Gram negative i.e. E. coli, Pseudomonas aeruginosa bacteria. The AgNPs synthesized at 1.5 mM NaOH concentration had shown maximum zone of inhibition (ZOI) i.e. 49 ± 0.64 in E. coli, whereas Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilius had shown 40 ± 0.29 mm, 28 ± 0.13 and 42 ± 0.49 mm ZOI respectively. The MIC value of 30 μg/mL observed for E. coli Whereas, Staphylococcus aureus, Bacillus subtilius and Pseudomonas aeruginosa had shown 45 μg/mL, 38 μg/mL, 35 μg/mL respectively. The study revealed that AgNPs had shown significant antimicrobial activity as compared to Streptomycin. PMID:25763037

Green Synthesis of AgNPs Stabilized with biowaste and their antimicrobial activities.

PubMed

Jasuja, Nakuleshwar Dut; Gupta, Deepak Kumar; Reza, Mohtashim; Joshi, Suresh C

2014-01-01

In the present study, rapid reduction and stabilization of Ag+ ions with different NaOH molar concentration (0.5 mM, 1.0 mM and 1.5 mM) has been carried out in the aqueous solution of silver nitrate by the bio waste peel extract of P.granatum. Generally, chemical methods used for the synthesis of AgNPs are quite toxic, flammable and have adverse effect in medical application but green synthesis is a better option due to eco-friendliness, non-toxicity and safe for human. Stable AgNPs were synthesized by treating 90 mL aqueous solution of 2 mM AgNO₃ with the 5 mL plant peels extract (0.4% w/v) at different NaOH concentration (5 mL). The synthesized AgNPs were characterized by UV-Vis spectroscopy, TEM and SEM. Further, antimicrobial activities of AgNPs were performed on Gram positive i.e. Staphylococcus aureus, Bacillus subtilius and Gram negative i.e. E. coli, Pseudomonas aeruginosa bacteria. The AgNPs synthesized at 1.5 mM NaOH concentration had shown maximum zone of inhibition (ZOI) i.e. 49 ± 0.64 in E. coli, whereas Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilius had shown 40 ± 0.29 mm, 28 ± 0.13 and 42 ± 0.49 mm ZOI respectively. The MIC value of 30 μg/mL observed for E. coli Whereas, Staphylococcus aureus, Bacillus subtilius and Pseudomonas aeruginosa had shown 45 μg/mL, 38 μg/mL, 35 μg/mL respectively. The study revealed that AgNPs had shown significant antimicrobial activity as compared to Streptomycin.

Hsa-let-7c controls the committed differentiation of IGF-1-treated mesenchymal stem cells derived from dental pulps by targeting IGF-1R via the MAPK pathways.

PubMed

Liu, Gen-Xia; Ma, Shu; Li, Yao; Yu, Yan; Zhou, Yi-Xiang; Lu, Ya-Die; Jin, Lin; Wang, Zi-Lu; Yu, Jin-Hua

2018-04-13

The putative tumor suppressor microRNA let-7c is extensively associated with the biological properties of cancer cells. However, the potential involvement of let-7c in the differentiation of mesenchymal stem cells has not been fully explored. In this study, we investigated the influence of hsa-let-7c (let-7c) on the proliferation and differentiation of human dental pulp-derived mesenchymal stem cells (DPMSCs) treated with insulin-like growth factor 1 (IGF-1) via flow cytometry, CCK-8 assays, alizarin red staining, real-time RT-PCR, and western blotting. In general, the proliferative capabilities and cell viability of DPMSCs were not significantly affected by the overexpression or deletion of let-7c. However, overexpression of let-7c significantly inhibited the expression of IGF-1 receptor (IGF-1R) and downregulated the osteo/odontogenic differentiation of DPMSCs, as indicated by decreased levels of several osteo/odontogenic markers (osteocalcin, osterix, runt-related transcription factor 2, dentin sialophosphoprotein, dentin sialoprotein, alkaline phosphatase, type 1 collagen, and dentin matrix protein 1) in IGF-1-treated DPMSCs. Inversely, deletion of let-7c resulted in increased IGF-1R levels and enhanced osteo/odontogenic differentiation. Furthermore, the ERK, JNK, and P38 MAPK pathways were significantly inhibited following the overexpression of let-7c in DPMSCs. Deletion of let-7c promoted the activation of the JNK and P38 MAPK pathways. Our cumulative findings indicate that Let-7c can inhibit the osteo/odontogenic differentiation of IGF-1-treated DPMSCs by targeting IGF-1R via the JNK/P38 MAPK signaling pathways.

High-throughput screening for new psychoactive substances (NPS) in whole blood by DLLME extraction and UHPLC-MS/MS analysis.

PubMed

Odoardi, Sara; Fisichella, Marco; Romolo, Francesco Saverio; Strano-Rossi, Sabina

2015-09-01

The increasing number of new psychoactive substances (NPS) present in the illicit market render their identification in biological fluids/tissues of great concern for clinical and forensic toxicology. Analytical methods able to detect the huge number of substances that can be used are sought, considering also that many NPS are not detected by the standard immunoassays generally used for routine drug screening. The aim of this work was to develop a method for the screening of different classes of NPS (a total of 78 analytes including cathinones, synthetic cannabinoids, phenethylamines, piperazines, ketamine and analogues, benzofurans, tryptamines) from blood samples. The simultaneous extraction of analytes was performed by Dispersive Liquid/Liquid Microextraction DLLME, a very rapid, cheap and efficient extraction technique that employs microliters amounts of organic solvents. Analyses were performed by a target Ultrahigh Performance Liquid Chromatography tandem Mass Spectrometry (UHPLC-MS/MS) method in multiple reaction monitoring (MRM). The method allowed the detection of the studied analytes with limits of detection (LODs) ranging from 0.2 to 2ng/mL. The proposed DLLME method can be used as an alternative to classical liquid/liquid or solid-phase extraction techniques due to its rapidity, necessity to use only microliters amounts of organic solvents, cheapness, and to its ability to extract simultaneously a huge number of analytes also from different chemical classes. The method was then applied to 60 authentic real samples from forensic cases, demonstrating its suitability for the screening of a wide number of NPS. Copyright © 2015 Elsevier B.V. All rights reserved.

N-Succinyl-chitosan nanoparticles coupled with low-density lipoprotein for targeted osthole-loaded delivery to low-density lipoprotein receptor-rich tumors

PubMed Central

Zhang, Chun-ge; Zhu, Qiao-ling; Zhou, Yi; Liu, Yang; Chen, Wei-liang; Yuan, Zhi-Qiang; Yang, Shu-di; Zhou, Xiao-feng; Zhu, Ai-jun; Zhang, Xue-nong; Jin, Yong

2014-01-01

N-Succinyl-chitosan (NSC) was synthesized and NSC nanoparticles (NPs) with loaded osthole (Ost) (Ost/NSC-NPs) were prepared by emulsion solvent diffusion. Subsequently, low-density lipoprotein (LDL)-mediated NSC-NPs with loaded Ost (Ost/LDL-NSC-NPs) were obtained by coupling LDL with Ost/NSC-NPs through amide linkage. The average particle size of Ost/NSC-NPs was approximately 145 nm, the entrapment efficiency was 78.28%±2.06%, and the drug-loading amount was 18.09%±0.17%. The release of Ost from Ost/NSC-NPs in vitro showed a more evident sustained effect than the native material. The half maximal inhibitory concentration of Ost/LDL-NSC-NPs was only 16.23% that of the free Ost at 24 hours in HepG2 cells. Ost inhibited HepG2 cell proliferation by arresting cells in the synthesis phase of the cell cycle and by triggering apoptosis. Cellular uptake and subcellular localization in vitro and near-infrared fluorescence real-time imaging in vivo showed that Ost/LDL-NSC-NPs had high targeting efficacy. Therefore, LDL-NSC-NPs are a promising system for targeted Ost delivery to liver tumor. PMID:24966673

Tumor-targeted pH/redox dual-sensitive unimolecular nanoparticles for efficient siRNA delivery.

PubMed

Chen, Guojun; Wang, Yuyuan; Xie, Ruosen; Gong, Shaoqin

2017-08-10

A unique pH/redox dual-sensitive cationic unimolecular nanoparticle (NP) enabling excellent endosomal/lysosomal escape and efficient siRNA decomplexation inside the target cells was developed for tumor-targeted delivery of siRNA. siRNA was complexed into the cationic core of the unimolecular NP through electrostatic interactions. The cationic core used for complexing siRNA contained reducible disulfide bonds that underwent intracellular reduction owing to the presence of high concentrations of reduced glutathione (GSH) inside the cells, thereby facilitating the decomplexation of siRNA from the unimolecular NPs. The cationic polymers were conjugated onto the hyperbranched core (H40) via a pH-sensitive bond, which further facilitated the decomplexation of siRNA from the NPs. In vitro studies on the siRNA release behaviors showed that dual stimuli (pH=5.3, 10mM GSH) induced the quickest release of siRNA from the NPs. In addition, the imidazole groups attached to the cationic polymer segments enhanced the endosomal/lysosomal escape of NPs via the proton sponge effect. Intracellular tracking studies revealed that siRNA delivered by unimolecular NPs was efficiently released to the cytosol. Moreover, the GE11 peptide, an anti-EGFR peptide, enhanced the cellular uptake of NPs in MDA-MB-468, an EFGR-overexpressing triple negative breast cancer (TNBC) cell line. The GE11-conjugated, GFP-siRNA-complexed NPs exhibited excellent GFP gene silencing efficiency in GFP-MDA-MB-468 TNBC cells without any significant cytotoxicity. Therefore, these studies suggest that this smart unimolecular NP could be a promising nanoplatform for targeted siRNA delivery to EFGR-overexpressing cancer cells. Copyright © 2017 Elsevier B.V. All rights reserved.

Peptide-biphenyl hybrid-capped AuNPs: stability and biocompatibility under cell culture conditions

NASA Astrophysics Data System (ADS)

Connolly, Mona; Pérez, Yolanda; Mann, Enrique; Herradón, Bernardo; Fernández-Cruz, María L.; Navas, José M.

2013-07-01

In this study, we explored the biocompatibility of Au nanoparticles (NPs) capped with peptide-biphenyl hybrid (PBH) ligands containing glycine (Gly), cysteine (Cys), tyrosine (Tyr), tryptophan (Trp) and methionine (Met) amino acids in the human hepatocellular carcinoma cell line Hep G2. Five AuNPs, Au[(Gly-Tyr-Met)2B], Au[(Gly-Trp-Met)2B], Au[(Met)2B], Au[(Gly-Tyr-TrCys)2B] and Au[(TrCys)2B], were synthesised. Physico-chemical and cytotoxic properties were thoroughly studied. Transmission electron micrographs showed isolated near-spherical nanoparticles with diameters of 1.5, 1.6, 2.3, 1.8 and 2.3 nm, respectively. Dynamic light scattering evidenced the high stability of suspensions in Milli-Q water and culture medium, particularly when supplemented with serum, showing in all cases a tendency to form agglomerates with diameters approximately 200 nm. In the cytotoxicity studies, interference caused by AuNPs with some typical cytotoxicity assays was demonstrated; thus, only data obtained from the resazurin based assay were used. After 48-h incubation, only concentrations ≥50 μg/ml exhibited cytotoxicity. Such doses were also responsible for an increase in reactive oxygen species (ROS). Some differences were observed among the studied NPs. Of particular importance is the AuNPs capped with the PBH ligand (Gly-Tyr-TrCys)2B showing remarkable stability in culture medium, even in the absence of serum. Moreover, these AuNPs have unique biological effects on Hep G2 cells while showing low toxicity. The production of ROS along with supporting optical microscopy images suggests cellular interaction/uptake of these particular AuNPs. Future research efforts should further test this hypothesis, as such interaction/uptake is highly relevant in drug delivery systems.

Breakable mesoporous silica nanoparticles for targeted drug delivery

NASA Astrophysics Data System (ADS)

Maggini, Laura; Cabrera, Ingrid; Ruiz-Carretero, Amparo; Prasetyanto, Eko A.; Robinet, Eric; de Cola, Luisa

2016-03-01

``Pop goes the particle''. Here we report on the preparation of redox responsive mesoporous organo-silica nanoparticles containing disulfide (S-S) bridges (ss-NPs) that, even upon the exohedral grafting of targeting ligands, retained their ability to undergo structural degradation, and increase their local release activity when exposed to a reducing agent. This degradation could be observed also inside glioma C6 cancer cells. Moreover, when anticancer drug-loaded pristine and derivatized ss-NPs were fed to glioma C6 cells, the responsive hybrids were more effective in their cytotoxic action compared to non-breakable particles. The possibility of tailoring the surface functionalization of this hybrid, yet preserving its self-destructive behavior and enhanced drug delivery properties, paves the way for the development of effective biodegradable materials for in vivo targeted drug delivery.``Pop goes the particle''. Here we report on the preparation of redox responsive mesoporous organo-silica nanoparticles containing disulfide (S-S) bridges (ss-NPs) that, even upon the exohedral grafting of targeting ligands, retained their ability to undergo structural degradation, and increase their local release activity when exposed to a reducing agent. This degradation could be observed also inside glioma C6 cancer cells. Moreover, when anticancer drug-loaded pristine and derivatized ss-NPs were fed to glioma C6 cells, the responsive hybrids were more effective in their cytotoxic action compared to non-breakable particles. The possibility of tailoring the surface functionalization of this hybrid, yet preserving its self-destructive behavior and enhanced drug delivery properties, paves the way for the development of effective biodegradable materials for in vivo targeted drug delivery. Electronic supplementary information (ESI) available: Full experimental procedures, additional SEM and TEM images of particles, complete UV-Vis and PL-monitored characterization of the breakdown of

Green synthesized conditions impacting on the reactivity of Fe NPs for the degradation of malachite green.

PubMed

Huang, Lanlan; Luo, Fang; Chen, Zuliang; Megharaj, Mallavarapu; Naidu, Ravendra

2015-02-25

This study investigates green tea extract synthesized conditions impacting on the reactivity of iron nanoparticles (Fe NPs) used for the degradation of malachite green (MG), including the volume ratio of Fe(2+) and tea extract, the solution pH and temperature. Results indicated that the reactivity of Fe NPs increased with higher temperature, but fell with increasing pH and the volume ratio of Fe(2+) and tea extract. Scanning electron microscope (SEM), energy-dispersive spectrometer (EDS), Fourier transform infrared spectroscope (FTIR) and X-ray diffraction (XRD) indicated that Fe NPs were spherical in shape, their diameter was 70-80 nm and they were mainly composed of iron oxide nanoparticles. UV-visible (UV-vis) indicated that reactivity of Fe NPs used in degradation of MG significantly depended on the synthesized conditions of Fe NPs. This was due to their impact on the reactivity and morphology of Fe NPs. Finally, degradation of MG showed that 90.56% of MG was removed using Fe NPs. Copyright © 2014 Elsevier B.V. All rights reserved.

Ratiometric fluorescence detection of superoxide anion based on AuNPs-BSA@Tb/GMP nanoscale coordination polymers.

PubMed

Liu, Nan; Hao, Juan; Cai, Keying; Zeng, Mulan; Huang, Zhenzhong; Chen, Lili; Peng, Bingxian; Li, Ping; Wang, Li; Song, Yonghai

2018-02-01

A novel ratiometric fluorescence nanosensor for superoxide anion (O 2 •- ) detection was designed with gold nanoparticles-bovine serum albumin (AuNPs-BSA)@terbium/guanosine monophosphate disodium (Tb/GMP) nanoscale coordination polymers (NCPs) (AuNPs-BSA@Tb/GMP NCPs). The abundant hydroxyl and amino groups of AuNPs-BSA acted as binding points for the self-assembly of Tb 3+ and GMP to form core-shell AuNPs-BSA@Tb/GMP NCP nanosensors. The obtained probe exhibited the characteristic fluorescence emission of both AuNPs-BSA and Tb/GMP NCPs. The AuNPs-BSA not only acted as a template to accelerate the growth of Tb/GMP NCPs, but also could be used as the reference fluorescence for the detection of O 2 •- . The resulting AuNPs-BSA@Tb/GMP NCP ratiometric fluorescence nanosensor for the detection of O 2 •- demonstrated high sensitivity and selectivity with a wide linear response range (14 nM-10 μM) and a low detection limit (4.7 nM). Copyright © 2017 John Wiley & Sons, Ltd.

Discovery and in vivo evaluation of novel RGD-modified lipid-polymer hybrid nanoparticles for targeted drug delivery.

PubMed

Zhao, Yinbo; Lin, Dayong; Wu, Fengbo; Guo, Li; He, Gu; Ouyang, Liang; Song, Xiangrong; Huang, Wei; Li, Xiang

2014-09-29

In the current study, the lipid-shell and polymer-core hybrid nanoparticles (lpNPs) modified by Arg-Gly-Asp(RGD) peptide, loaded with curcumin (Cur), were developed by emulsification-solvent volatilization method. The RGD-modified hybrid nanoparticles (RGD-lpNPs) could overcome the poor water solubility of Cur to meet the requirement of intravenous administration and tumor active targeting. The obtained optimal RGD-lpNPs, composed of PLGA (poly(lactic-co-glycolic acid))-mPEG (methoxyl poly(ethylene- glycol)), RGD-polyethylene glycol (PEG)-cholesterol (Chol) copolymers and lipids, had good entrapment efficiency, submicron size and negatively neutral surface charge. The core-shell structure of RGD-lpNPs was verified by TEM. Cytotoxicity analysis demonstrated that the RGD-lpNPs encapsulated Cur retained potent anti-tumor effects. Flow cytometry analysis revealed the cellular uptake of Cur encapsulated in the RGD-lpNPs was increased for human umbilical vein endothelial cells (HUVEC). Furthermore, Cur loaded RGD-lpNPs were more effective in inhibiting tumor growth in a subcutaneous B16 melanoma tumor model. The results of immunofluorescent and immunohistochemical studies by Cur loaded RGD-lpNPs therapies indicated that more apoptotic cells, fewer microvessels, and fewer proliferation-positive cells were observed. In conclusion, RGD-lpNPs encapsulating Cur were developed with enhanced anti-tumor activity in melanoma, and Cur loaded RGD-lpNPs represent an excellent tumor targeted formulation of Cur which might be an attractive candidate for cancer therapy.

In situ crosslinked smart polypeptide nanoparticles for multistage responsive tumor-targeted drug delivery

NASA Astrophysics Data System (ADS)

Yi, Huqiang; Liu, Peng; Sheng, Nan; Gong, Ping; Ma, Yifan; Cai, Lintao

2016-03-01

Smart tumor-targeted drug delivery is crucial for improving the effect of chemotherapy and reducing the adverse effects. Here, we synthesized a smart polypeptide copolymer based on n-butylamine-poly(l-lysine)-b-poly(l-cysteine) (PLL-PLC) with functionalization of folic acid (FA) and 1,2-dicarboxylic-cyclohexene anhydride (DCA) for multistage responsive tumor-targeted drug delivery. The copolymers (FA-PLL(DCA)-PLC) spontaneously crosslinked in situ to form redox and pH dual responsive FA-PLL(DCA)-PLC nanoparticles (FD-NPs), which had a reversible zeta potential around -30 mV at pH 7.4, but switched to +15 mV at pH 5.0. Moreover, FD-NPs effectively loaded DOX with a loading capacity at 15.7 wt%. At pH 7.4, only 24.5% DOX was released within 60 h. However, at pH 5.0, the presence of 10 mM DTT dramatically accelerated DOX release with over 90% of DOX released within 10 h. Although the FD-NPs only enhanced DOX uptake in FA receptor positive (FR+) cancer cells at pH 7.4, a weak acidic condition promoted FD-NP-facilitated DOX uptake in both FR+ HeLa and FR- A549 cells, as well as significantly improving cellular binding and end/lysosomal escape. In vivo studies in a HeLa cancer model demonstrated that the charge-reversible FD-NPs delivered DOX into tumors more effectively than charge-irreversible nanoparticles. Hence, these multistage responsive FD-NPs would serve as highly efficient drug vectors for targeted cancer chemotherapy.Smart tumor-targeted drug delivery is crucial for improving the effect of chemotherapy and reducing the adverse effects. Here, we synthesized a smart polypeptide copolymer based on n-butylamine-poly(l-lysine)-b-poly(l-cysteine) (PLL-PLC) with functionalization of folic acid (FA) and 1,2-dicarboxylic-cyclohexene anhydride (DCA) for multistage responsive tumor-targeted drug delivery. The copolymers (FA-PLL(DCA)-PLC) spontaneously crosslinked in situ to form redox and pH dual responsive FA-PLL(DCA)-PLC nanoparticles (FD-NPs), which had a reversible

Comparative effects on rat primary astrocytes and C6 rat glioma cells cultures after 24-h exposure to silver nanoparticles (AgNPs)

NASA Astrophysics Data System (ADS)

Salazar-García, Samuel; Silva-Ramírez, Ana Sonia; Ramirez-Lee, Manuel A.; Rosas-Hernandez, Hector; Rangel-López, Edgar; Castillo, Claudia G.; Santamaría, Abel; Martinez-Castañon, Gabriel A.; Gonzalez, Carmen

2015-11-01

The aim of this work was to compare the effects of 24-h exposure of rat primary astrocytes and C6 rat glioma cells to 7.8 nm AgNPs. Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor and current treatments lead to diverse side-effects; for this reason, it is imperative to investigate new approaches, including those alternatives provided by nanotechnology, like nanomaterials (NMs) such as silver nanoparticles. Herein, we found that C6 rat glioma cells, but no primary astrocytes, decreased cell viability after AgNPs treatment; however, both cell types diminished their proliferation. The decrease of glioma C6 cells proliferation was related with necrosis, while in primary astrocytes, the decreased proliferation was associated with the induction of apoptosis. The ionic control (AgNO3) exerted a different profile than AgNPs; the bulk form did not modify the basal effect in each determination, whereas cisplatin, a well-known antitumoral drug used as a comparative control, promoted cytotoxicity in both cell types at specific concentrations. Our findings prompt the need to determine the fine molecular and cellular mechanisms involved in the differential biological responses to AgNPs in order to develop new tools or alternatives based on nanotechnology that may contribute to the understanding, impact and use of NMs in specific targets, like glioblastoma cells.

Increased sensitivity to apoptosis induced by methotrexate is mediated by Jun N-terminal kinase

PubMed Central

Spurlock, Charles F.; Aune, Zachary T.; Tossberg, John T.; Collins, Patrick L.; Aune, Jessica P.; Huston, Joseph W.; Crooke, Philip S.; Olsen, Nancy J.; Aune, Thomas M.

2011-01-01

Objective Low-dose methotrexate [MTX] is an effective therapy for rheumatoid arthritis yet its mechanism of action is incompletely understood. Here, we explored induction of apoptosis by MTX. Methods We employed flow cytometry to assess changes in levels of intracellular proteins, reactive oxygen species [ROS], and apoptosis.Quantitative polymerase chain reaction was usedtoassess changes in transcript levels of select target genes in response to MTX. Results MTX does not directly induce apoptosis but rather ‘primes’ cells for markedly increased sensitivity to apoptosis via either mitochondrial or death receptor pathways by a Jun N-terminal kinase [JNK]-dependent mechanism. Increased sensitivity to apoptosis is mediated, at least in part, by MTX-dependent production of reactive oxygen species, JNK activation and JNK-dependent induction of genes whose protein products promote apoptosis. Supplementation with tetrahydrobiopterin blocks these methotrexate-induced effects. Subjects with rheumatoid arthritis on low-dose MTX therapy express elevated levels of the JNK-target gene, JUN. Conclusions Our results support a model whereby methotrexate inhibits reduction of dihydrobiopterin to tetrahydrobiopterin resulting in increased production of ROS, increased JNK activity and increased sensitivity to apoptosis. The finding of increased JUN levels in subjects with RA taking low-dose MTX supports the notion that this pathway is activated by MTX, in vivo, and may contribute to efficacy of MTX in inflammatory disease. PMID:21618198

A critical first assessment of the new pre-market approval regime for new psychoactive substances (NPS) in New Zealand.

PubMed

Wilkins, Chris

2014-10-01

New Zealand has recently attempted to address the underlying drivers of the escalating new psychoactive substances (NPS) ('legal highs') problem by establishing the world's first pre-market approval regulatory regime for NPS. NPS products which can be shown with clinical trial data to pose a 'low risk' of harm will be approved for legal manufacture and sale. This paper critically assesses the new regime, drawing on experience of the pharmaceutical sector and legal BZP market. A number of characteristics of the recreational use of NPS may not be well addressed by standard medical clinical trials, including binge use, polydrug use, use by vulnerable groups and high-risk modes of administration. The overt advertising and covert promotion of approved NPS products on the internet may make them fairly visible to young people. The black market for unapproved NPS may be difficult to suppress given that unapproved NPS will be physically identical to approved NPS. If the legal market for NPS encourages the use of NPS, alcohol and other drugs there may be an increase in drug-related harm. Alternatively, if the legal NPS market reduces the use of more harmful drugs, there may be a considerable public health benefit. The clinical trials required for NPS products should address the characteristics of recreational NPS use. Enforcement resources and technical solutions are required to clearly distinguish legal NPS products. The impact the new NPS regime has on other drug use is a key issue and demands further study. © 2014 Society for the Study of Addiction.

Therapeutic effect of photodynamic therapy combined with targeted delivery of silencing vascular endothelial growth factor (Conference Presentation)

NASA Astrophysics Data System (ADS)

Hsu, Yih-Chih

2016-03-01

Photodynamic therapy is a novel therapeutic modality to treat cancer by using a photosensitizer which is activated by a light source to produce reactive oxygen species and mediates tumours oxygen-independent hypoxic conditions. Vascular endothelial growth factor (VEGF) is one of the primary factors that affect tumor angiogenesis. Another emerging treatment to cure cancer is the use of interference RNA to silence a specific mRNA sequence. Such treatment requires a delivery system such as liposomes. The nanoparticle size measured was about 30 nm. Cellular uptake study was performed to verify that the nanoparticles have a sigma receptor mediated pathway. Non-targeted LCP NPs did not show significant difference with or without haloperidol but has a lower intensity as than targeted LCP NPs. These results confirm that LCP NPs have a receptor mediated pathway. Cell viability was found to decrease at 25 nM of transfected VEGF siRNA. Combined therapy of PDT and VEGF siRNA showed significant response as compared with PDT and gene therapy alone. In vivo toxicity assay with mice treated with targeted LCP NPs containing control siRNA or VEGF siRNA and non-targeted LCP NPs containing VEGF siRNA did not show any significant difference with the PBS injected group which suggests that there is no toxicity with the dose. It suggests that PDT combined with targeted gene therapy has a potential mean to achieve better therapeutic outcome.

Exploring the Behavior and Metabolic Transformations of SeNPs in Exposed Lactic Acid Bacteria. Effect of Nanoparticles Coating Agent

PubMed Central

Palomo-Siguero, Maria; Madrid, Yolanda

2017-01-01

The behavior and transformation of selenium nanoparticles (SeNPs) in living systems such as microorganisms is largely unknown. To address this knowledge gap, we examined the effect of three types of SeNP suspensions toward Lactobacillus delbrueckii subsp. bulgaricus LB-12 using a variety of techniques. SeNPs were synthesized using three types of coating agents (chitosan (CS-SeNPs), hydroxyethyl cellulose (HEC-SeNPs) and a non-ionic surfactant, surfynol (ethoxylated-SeNPs)). Morphologies of SeNPs were all spherical. Transmission electron microscopy (TEM) was used to locate SeNPs in the bacteria. High performance liquid chromatography (HPLC) on line coupled to inductively coupled plasma mass spectrometry (ICP-MS) was applied to evaluate SeNP transformation by bacteria. Finally, flow cytometry employing the live/dead test and optical density measurements at 600 nm (OD600) were used for evaluating the percentages of bacteria viability when supplementing with SeNPs. Negligible damage was detected by flow cytometry when bacteria were exposed to HEC-SeNPs or CS-SeNPs at a level of 10 μg Se mL−1. In contrast, ethoxylated-SeNPs were found to be the most harmful nanoparticles toward bacteria. CS-SeNPs passed through the membrane without causing damage. Once inside, SeNPs were metabolically transformed to organic selenium compounds. Results evidenced the importance of capping agents when establishing the true behavior of NPs. PMID:28783048

Self-recognition of the racemic ligand in the formation of homochiral dinuclear V(V) complex: In vitro anticancer activity, DNA and HSA interaction.

PubMed

Kazemi, Zahra; Amiri Rudbari, Hadi; Mirkhani, Valiollah; Sahihi, Mehdi; Moghadam, Majid; Tangestaninejad, Shahram; Mohammadpoor-Baltork, Iraj; Kajani, Abolghasem Abbasi; Azimi, Gholamhassan

2017-07-28

The reaction of a racemic mixture of Schiff base tridentate ligand with vanadium(V) affords homochiral vanadium complex, (VO(R-L)) 2 O and (VO(S-L)) 2 O due to ligand "self-recognition" process. The formation of homochiral vanadium complex was confirmed by 1 H NMR, 13 C NMR and X-ray diffraction. The HSA- and DNA-binding of the resultant complex is assessed by absorption, fluorescence and circular dichroism (CD) spectroscopy methods. Based on the results, the HSA- and DNA-binding constant, K b , were found to be 8.0 × 10 4 and 1.9 × 10 5  M -1 , respectively. Interestingly, in vitro cytotoxicity assay revealed the potent anticancer activity of this complex on two prevalent cancer cell lines of MCF-7 (IC50 value of 14 μM) and HeLa (IC50 value of 36 μM), with considerably low toxicity on normal human fibroblast cells. The maximum cell mortality of 12.3% obtained after 48 h incubation of fibroblast cells with 100 μM of the complex. Additionally, the specific DNA- and HSA-binding was also shown using molecular docking method. The synthesized complex displayed high potential for biomedical applications especially for development of novel and efficient anticancer agents. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Epithelial cell adhesion molecule aptamer functionalized PLGA-lecithin-curcumin-PEG nanoparticles for targeted drug delivery to human colorectal adenocarcinoma cells.

PubMed

Li, Lei; Xiang, Dongxi; Shigdar, Sarah; Yang, Wenrong; Li, Qiong; Lin, Jia; Liu, Kexin; Duan, Wei

2014-01-01

To improve the efficacy of drug delivery, active targeted nanotechnology-based drug delivery systems are gaining considerable attention as they have the potential to reduce side effects, minimize toxicity, and improve efficacy of anticancer treatment. In this work CUR-NPs (curcumin-loaded lipid-polymer-lecithin hybrid nanoparticles) were synthesized and functionalized with ribonucleic acid (RNA) Aptamers (Apts) against epithelial cell adhesion molecule (EpCAM) for targeted delivery to colorectal adenocarcinoma cells. These CUR-encapsulated bioconjugates (Apt-CUR-NPs) were characterized for particle size, zeta potential, drug encapsulation, stability, and release. The in vitro specific cell binding, cellular uptake, and cytotoxicity of Apt-CUR-NPs were also studied. The Apt-CUR-NP bioconjugates exhibited increased binding to HT29 colon cancer cells and enhancement in cellular uptake when compared to CUR-NPs functionalized with a control Apt (P<0.01). Furthermore, a substantial improvement in cytotoxicity was achieved toward HT29 cells with Apt-CUR-NP bioconjugates. The encapsulation of CUR in Apt-CUR-NPs resulted in the increased bioavailability of delivered CUR over a period of 24 hours compared to that of free CUR in vivo. These results show that the EpCAM Apt-functionalized CUR-NPs enhance the targeting and drug delivery of CUR to colorectal cancer cells. Further development of CUR-encapsulated, nanosized carriers will lead to improved targeted delivery of novel chemotherapeutic agents to colorectal cancer cells.

Cancer-targeting siRNA delivery from porous silicon nanoparticles.

PubMed

Wan, Yuan; Apostolou, Sinoula; Dronov, Roman; Kuss, Bryone; Voelcker, Nicolas H

2014-10-01

Porous silicon nanoparticles (pSiNPs) with tunable pore size are biocompatible and biodegradable, suggesting that they are suitable biomaterials as vehicles for drug delivery. Loading of small interfering RNA (siRNA) into the pores of pSiNPs can protect siRNA from degradation as well as improve the cellular uptake. We aimed to deliver MRP1 siRNA loaded into pSiNPs to glioblastoma cells, and to demonstrate downregulation of MRP1 at the mRNA and protein levels. 50-220 nm pSiNPs with an average pore size of 26 nm were prepared, followed by electrostatic adsorption of siRNA into pores. Oligonucleotide loading and release profiles were investigated; MRP1 mRNA and protein expression, cell viability and cell apoptosis were studied. Approximately 7.7 µg of siRNA was loaded per mg of pSiNPs. Cells readily took up nanoparticles after 30 min incubation. siRNA-loaded pSiNPs were able to effectively downregulate target mRNA (~40%) and protein expression (31%), and induced cell apoptosis and necrosis (33%). siRNA loaded pSiNPs downregulated mRNA and protein expression and induced cell death. This novel siRNA delivery system may pave the way towards developing more effective tumor therapies.

Modulation of hydrogel nanoparticle intracellular trafficking by multivalent surface engineering with tumor targeting peptide

NASA Astrophysics Data System (ADS)

Karamchand, Leshern; Kim, Gwangseong; Wang, Shouyan; Hah, Hoe Jin; Ray, Aniruddha; Jiddou, Ruba; Koo Lee, Yong-Eun; Philbert, Martin A.; Kopelman, Raoul

2013-10-01

Surface engineering of a hydrogel nanoparticle (NP) with the tumor-targeting ligand, F3 peptide, enhances both the NP's binding affinity for, and internalization by, nucleolin overexpressing tumor cells. Remarkably, the F3-functionalized NPs consistently exhibited significantly lower trafficking to the degradative lysosomes than the non-functionalized NPs, in the tumor cells, after internalization. This is attributed to the non-functionalized NPs, but not the F3-functionalized NPs, being co-internalized with Lysosome-associated Membrane Protein-1 (LAMP1) from the surface of the tumor cells. Furthermore, it is shown that the intracellular trafficking of the F3-functionalized NPs differs significantly from that of the molecular F3 peptides (untethered to NPs). This has important implications for designing effective, chemically-responsive, controlled-release and multifunctional nanodrugs for multi-drug-resistant cancers.Surface engineering of a hydrogel nanoparticle (NP) with the tumor-targeting ligand, F3 peptide, enhances both the NP's binding affinity for, and internalization by, nucleolin overexpressing tumor cells. Remarkably, the F3-functionalized NPs consistently exhibited significantly lower trafficking to the degradative lysosomes than the non-functionalized NPs, in the tumor cells, after internalization. This is attributed to the non-functionalized NPs, but not the F3-functionalized NPs, being co-internalized with Lysosome-associated Membrane Protein-1 (LAMP1) from the surface of the tumor cells. Furthermore, it is shown that the intracellular trafficking of the F3-functionalized NPs differs significantly from that of the molecular F3 peptides (untethered to NPs). This has important implications for designing effective, chemically-responsive, controlled-release and multifunctional nanodrugs for multi-drug-resistant cancers. Electronic supplementary information (ESI) available: Effect of Potassium depletion on F3 peptide subcellular localization, MTT

Sodium selenite/selenium nanoparticles (SeNPs) protect cardiomyoblasts and zebrafish embryos against ethanol induced oxidative stress.

PubMed

Kalishwaralal, Kalimuthu; Jeyabharathi, Subhaschandrabose; Sundar, Krishnan; Muthukumaran, Azhaguchamy

2015-10-01

Alcoholic cardiomyopathy is the damage caused to the heart muscles due to high level of alcohol consumption resulting in enlargement and inflammation of the heart. Selenium is an important trace element that is beneficial to human health. Selenium protects the cells by preventing the formation of free radicals in the body. In the present study, protein mediated synthesis of SeNPs was investigated. Two different sizes of SeNPs were synthesized using BSA and keratin. The synthesized SeNPs were characterized by scanning electron microscopy (SEM) with elemental composition analysis Energy Dispersive X-ray spectroscopy(EDX) and X-ray diffraction (XRD). This study demonstrates the in vitro and in vivo antioxidative effects of sodium selenite and SeNPs. Further selenium and SeNPs were evaluated for their ability to protect against 1% ethanol induced oxidative stress in H9C2 cell line. The selenium and SeNPs were found to reduce the 1% ethanol-induced oxidative damage through scavenging intracellular reactive oxygen species. The selenium and SeNPs could also prevent pericardial edema induced ethanol treatment and reduced apoptosis and cell death in zebrafish embryos. The results indicate that selenium and SeNPs could potentially be used as an additive in alcoholic beverage industry to control the cardiomyopathy. Copyright © 2015 Elsevier GmbH. All rights reserved.

Functionalized gold nanoparticles for topical delivery of methotrexate for the possible treatment of psoriasis.

PubMed

Bessar, Hagar; Venditti, Iole; Benassi, Luisa; Vaschieri, Cristina; Azzoni, Paola; Pellacani, Giovanni; Magnoni, Cristina; Botti, Elisabetta; Casagrande, Viviana; Federici, Massimo; Costanzo, Antonio; Fontana, Laura; Testa, Giovanna; Mostafa, Fawzia Farag; Ibrahim, Samia Ali; Russo, Maria Vittoria; Fratoddi, Ilaria

2016-05-01

Gold nanoparticles (AuNPs) represent an effective choice for topical drug delivery systems thanks to their small size, general non-toxicity, ease of functionalization and high surface to volume ratio. Even if systemic, methotrexate still plays an important role in psoriasis treatment: its topical use shows insufficient percutaneus penetration owing to limited passive diffusion, high molecular weight and dissociation at physiological pH. The aim of our study was to design a new drug delivery nanocarrier for Methotrexate and to improve its solubility, stability and biodistribution. AuNPs were on purpose prepared with a hydrophilic stabilizing layer, in order to improve the colloidal stability in water. Water-soluble gold nanoparticles functionalized by sodium 3-mercapto-1-propansulfonate (Au-3MPS) were prepared and loaded with methotrexate (MTX). The loading efficiency of MTX on Au-3MPS was assessed in the range 70-80%, with a fast release (80% in one hour). The release was studied up to 24h reaching the value of 95%. The Au-3MPS@MTX conjugate was fully characterized by spectroscopic techniques (UV-vis, FTIR) and DLS. Preliminary toxicity tests in the presence of keratinocytes monolayers allowed to assess that the used Au-3MPS are not toxic. The conjugate was then topically used on C57BL/6 mouse normal skin in order to trace the absorption behavior. STEM images clearly revealed the distribution of gold nanoparticles inside the cells. In vitro studies showed that Methotrexate conjugated with Au-3MPS is much more efficient than Methotrexate alone. Moreover, DL50, based on MTT analysis, is 20 folds reduced at 48 h, by the presence of nanoparticles conjugation. UV-vis spectra for in vivo tracing of the conjugate on bare mouse skin after 24h of application, show increased delivery of Methotrexate in the epidermis and dermis using Au-3MPS@MTX conjugate, compared to MTX alone. Moreover we observed absence of the Au-3MPS in the dermis and in the epidermis, suggesting that

Systemic delivery of siRNA by hyaluronan-functionalized calcium phosphate nanoparticles for tumor-targeted therapy

NASA Astrophysics Data System (ADS)

Qiu, Chong; Wei, Wei; Sun, Jing; Zhang, Hai-Tao; Ding, Jing-Song; Wang, Jian-Cheng; Zhang, Qiang

2016-06-01

In this study, hyaluronan (HA)-functionalized calcium phosphate nanoparticles (CaP-AHA/siRNA NPs) were developed for an injectable and targetable delivery of siRNA, which were prepared by coating the alendronate-hyaluronan graft polymer (AHA) around the surface of calcium phosphate-siRNA co-precipitates. The prepared CaP-AHA/siRNA NPs had a uniform spherical core-shell morphology with an approximate size of 170 nm and zeta potential of -12 mV. The coating of hydrophilic HA improved the physical stability of nanoparticles over one month due to the strong interactions between phosphonate and calcium. In vitro experiments demonstrated that the negatively charged CaP-AHA/siRNA NPs could effectively deliver EGFR-targeted siRNA into A549 cells through CD44-mediated endocytosis and significantly down-regulate the level of EGFR expression. Also, the internalized CaP-AHA/siRNA NPs exhibited a pH-responsive release of siRNA, indicating that the acidification of lysosomes probably facilitated the disassembling of nanoparticles and the resultant ions sharply increased the inner osmotic pressure and thus expedited the release of siRNA from late lysosomes into the cytoplasm. Furthermore, in vivo tumor therapy demonstrated that high accumulation of CaP-AHA/siEGFR NPs in tumor led to a significant tumor growth inhibition with a specific EGFR gene silencing effect after intravenous administration in nude mice xenografted with A549 tumor, along with a negligible body weight loss. These results suggested that the CaP-AHA/siRNA NPs could be an effective and safe systemic siRNA delivery system for a RNAi-based tumor targeted therapy strategy.In this study, hyaluronan (HA)-functionalized calcium phosphate nanoparticles (CaP-AHA/siRNA NPs) were developed for an injectable and targetable delivery of siRNA, which were prepared by coating the alendronate-hyaluronan graft polymer (AHA) around the surface of calcium phosphate-siRNA co-precipitates. The prepared CaP-AHA/siRNA NPs had a uniform

Highly selective luminescent nanostructures for mitochondrial imaging and targeting

NASA Astrophysics Data System (ADS)

Fanizza, E.; Iacobazzi, R. M.; Laquintana, V.; Valente, G.; Caliandro, G.; Striccoli, M.; Agostiano, A.; Cutrignelli, A.; Lopedota, A.; Curri, M. L.; Franco, M.; Depalo, N.; Denora, N.

2016-02-01

Here a luminescent hybrid nanostructure based on functionalized quantum dots (QDs) is used as a fluorescent imaging agent able to target selectively mitochondria thanks to the molecular recognition of the translocator protein (TSPO). The selective targeting of such an 18 kDa protein mainly located in the outer mitochondrial membrane and overexpressed in several pathological states including neurodegenerative diseases and cancers may provide valuable information for the early diagnosis and therapy of human disorders. In particular, the rational design of amino functionalized luminescent silica coated QD nanoparticles (QD@SiO2 NPs) provides a versatile nanoplatform to anchor a potent and selective TSPO ligand, characterized by a 2-phenyl-imidazo[1,2-a]pyridine acetamide structure along with a derivatizable carboxylic end group, useful to conjugate the TSPO ligand and achieve TSPO-QD@SiO2 NPs by means of a covalent amide bond. The colloidal stability and optical properties of the proposed nanomaterials are comprehensively investigated and their potential as mitochondrial imaging agents is fully assessed. Sub-cellular fractionation, together with confocal laser scanning fluorescence microscopy and co-localization analysis of targeted TSPO-QD@SiO2 NPs in C6 glioma cells overexpressing the TSPO, proves the great potential of these multifunctional nanosystems as in vitro selective mitochondrial imaging agents.Here a luminescent hybrid nanostructure based on functionalized quantum dots (QDs) is used as a fluorescent imaging agent able to target selectively mitochondria thanks to the molecular recognition of the translocator protein (TSPO). The selective targeting of such an 18 kDa protein mainly located in the outer mitochondrial membrane and overexpressed in several pathological states including neurodegenerative diseases and cancers may provide valuable information for the early diagnosis and therapy of human disorders. In particular, the rational design of amino

Synthesis and structure elucidation of a copper(II) Schiff-base complex: in vitro DNA binding, pBR322 plasmid cleavage and HSA binding studies.

PubMed

Tabassum, Sartaj; Ahmad, Musheer; Afzal, Mohd; Zaki, Mehvash; Bharadwaj, Parimal K

2014-11-01

New copper(II) complex with Schiff base ligand 4-[(2-Hydroxy-3-methoxy-benzylidene)-amino]-benzoic acid (H₂L) was synthesized and characterized by spectroscopic and analytical and single crystal X-ray diffraction studies which revealed that the complex 1 exist in a distorted octahedral environment. In vitro CT-DNA binding studies were performed by employing different biophysical technique which indicated that the 1 strongly binds to DNA in comparison to ligand via electrostatic binding mode. Complex 1 cleaves pBR322 DNA via hydrolytic pathway and recognizes minor groove of DNA double helix. The HSA binding results showed that ligand and complex 1 has ability to quench the fluorescence emission intensity of Trp 214 residue available in the subdomain IIA of HSA. Copyright © 2014 Elsevier B.V. All rights reserved.

MgO NPs synthesis, capping and enhanced free radical effect on the bacteria and its cell morphology

NASA Astrophysics Data System (ADS)

Kushwaha, Amisha; Bagchi, T.

2018-05-01

Magnesium Oxide Nanoparticles (MgO NPs) commonly known as Magnesia is a white powder, hygroscopic material. MgO NPs were synthesized through four methods Co-precipitation method (Co-PM), Solution combustion (S-CoM) and Sol-gel method with starch (So-GSM) and CTAB (So-GCM), classified as template dependent and template independent method using magnesium nitrate hexahydrate (Mg(NO3).6H2O) as the precursor and comparative analysis was done through DLS. The order of hydrodynamic diameters of four different synthesis method of MgO NPs is Co-PMNPs considered for the further studies and characterized through UV/Visible spectroscopy, DLS and FTIR spectroscopy and particle size was confirmed with transmission electron microscopy (TEM), crystal lattice was estimated by XRD spectroscopy, morphology was confirmed with SEM and surface absorbed free radicals were analysed with electron spin resonance (ESR). Subsequently, MgO NPs were capped with Lauric acid (LA). Further, antibacterial assay of MgO NPs, LA capped MgO NPs (LA-MgO) and LA studied against bacteria through Minimum Inhibitory Concentration (MIC). In the antibacterial test the Ascending order for bactericidal activity responding against Bacillus pumilus was resultant as LA> LA-MgO NPs> MgO NPs responding.

n vivo retention of ingested Au NPs by Daphnia magna: No evidence for trans-epithelial alimentary uptake