Near-infrared fluorescent nanovesicles were prepared by self-assembly of block copolymer hydrophilic poly(ethylene glycol) boron-dipyrromethenes in aqueous solution. The fluorescence enhancement induced by dissociation of nanovesicles could be used as a smart imaging and diagnostic tool. This nanovesicle could encapsulate the antitumor drug, and provide a powerful platform for imaging-guided tumor-specific drug delivery and therapy.
Pontocerebellar hypoplasia (PCH) comprises a rare group of neurodegenerative disorders with variable symptoms of cerebellar ataxia. Several gene mutations have been reported to be associated with different presentations of PCH. In the present study, an extended familial case of late?onset hereditary ataxia mimicking PCH in respect of clinical manifestation, neuroradiological findings and genetic analysis is described. By means of direct sequencing, a novel heterozygous mutation was found in the TSEN54 gene by c.254A > T(+) (p.E85V), which may be a new subtype of hereditary ataxia. However, this subtype was shown to exhibit late onset, differing from PCH with prenatal onset and predominantly affecting the growth of neurons.
The objective of the present work was to explore the effect of CTS on structural, phenotypic and functional maturation of murine bone marrow derived dendritic cells (BMDCs). The maturity of BMDCs post treatment with CTS was evaluated using transmission electron microscopy (TEM) for structure changes, flow cytometry (FCM) for changes of key surface molecules, FITC-dextran bio-assay for phagocytosis, test of acid phosphatase activity (ACP) for biochemical changes and enzyme linked immunosorbent assay (ELISA) for cytokine level. We found that CTS downregulated the numbers of phagosomes inside the BMDCs, up-regulated the expression of MHC II, CD40, CD83, CD80 and CD86 molecules on BMDCs, decreased activity of ACP and phagocytosis by BMDCs, and induced production of higher levels of IL-12 and TNF-?. It was therefore confirmed that CTS could effectively promote the maturation of BMDCs. Our study provided more detailed evidence and rationale to support the application of CTS as an immune stimulator for enhancing host immunity and as an adjuvant in the design of DC-based vaccines.
Cholesterol efflux from macrophages is a critical mechanism to prevent the development of atherosclerosis. Here, we sought to investigate the effects of arctigenin, a bioactive component of Arctium lappa, on the cholesterol efflux in oxidized low-density lipoprotein (oxLDL)-loaded THP-1 macrophages. Our data showed that arctigenin significantly accelerated apolipoprotein A-I- and high-density lipoprotein-induced cholesterol efflux in both dose- and time-dependent manners. Moreover, arctigenin treatment enhanced the expression of ATP binding cassette transporter A1 (ABCA1), ABCG1, and apoE, all of which are key molecules in the initial step of cholesterol efflux, at both mRNA and protein levels. Arctigenin also caused a concentration-dependent elevation in the expression of peroxisome proliferator-activated receptor-gamma (PPAR-?) and liver X receptor-alpha (LXR-?). The arctigenin-mediated induction of ABCA1, ABCG1, and apoE was abolished by specific inhibition of PPAR-? or LXR-? using small interfering RNA technology. Our results collectively indicate that arctigenin promotes cholesterol efflux in oxLDL-loaded THP-1 macrophages through upregulation of ABCA1, ABCG1 and apoE, which is dependent on the enhanced expression of PPAR-? and LXR-?.
IR-780 iodide is a near-infrared (NIR) fluorescence dye with higher and more stable fluorescence intensity than clinically applied dye indocyanine green (ICG). Meanwhile, IR-780 can be utilized in photothermal therapy with laser irradiation. IR-780 is an important theranostic agent but its lipophilicity limited its application. In this paper, we synthesize multifunctional heparin-folic acid-IR-780 nanoparticles (HF-IR-780 NPs) by self-assembly of the heparin-folic acid conjugate and IR-780 through ultrasonic sound method. The HF-IR-780 NPs exhibit good monodispersity, significant stability, and excellent molecular targeting to folate receptor over-expressing MCF-7 cells. Furthermore, the in vivo biodistribution experiments show that the HF-IR-780 NPs are specifically targeted to the tumor and can be used for tumor imaging. The in vitro cell viability assays and in vivo photothermal therapy experiments indicate that MCF-7 cells or MCF-7 xenograft tumors could be ablated by combining HF-IR-780 NPs with irradiation of an 808 nm laser. The photothermal therapy in vivo with a single-dose treatment has not caused significant adverse effect. The resulted HF-IR-780 NPs are a potential theranostic agent for imaging-guided cancer therapy.
Cadmium (Cd) is toxic to plant cells. Under Cd exposure, the plant displayed leaf chlorosis, which is a typical symptom of iron (Fe) deficiency. Interactions of Cd with Fe have been reported. However, the molecular mechanisms of Cd-Fe interactions are not well understood. Here, we showed that FER-like Deficiency Induced Transcripition Factor (FIT), AtbHLH38, and AtbHLH39, three basic helix-loop-helix transcription factors involved in Fe homeostasis in plants, also play important roles in Cd tolerance. The gene expression analysis showed that the expression of FIT, AtbHLH38, and AtbHLH39 was up-regulated in the roots of plants treated with Cd. The plants overexpressing AtbHLH39 and double-overexpressing FIT/AtbHLH38 and FIT/AtbHLH39 exhibited more tolerance to Cd exposure than wild type, whereas no Cd tolerance was observed in plants overexpressing either AtbHLH38 or FIT. Further analysis revealed that co-overexpression of FIT with AtbHLH38 or AtbHLH39 constitutively activated the expression of Heavy Metal Associated3 (HMA3), Metal Tolerance Protein3 (MTP3), Iron Regulated Transporter2 (IRT2), and Iron Regulated Gene2 (IREG2), which are involved in the heavy metal detoxification in Arabidopsis (Arabidopis thaliana). Moreover, co-overexpression of FIT with AtbHLH38 or AtbHLH39 also enhanced the expression of NICOTIANAMINE SYNTHETASE1 (NAS1) and NAS2, resulting in the accumulation of nicotiananamine, a crucial chelator for Fe transportation and homeostasis. Finally, we showed that maintaining high Fe content in shoots under Cd exposure could alleviate the Cd toxicity. Our results provide new insight to understand the molecular mechanisms of Cd tolerance in plants.
The clinical application of cis-diamminedichloroplatinum(II) (DDP, cisplatin) for cancer therapy is limited by its nonspecific biodistribution and severe side effects. Here, we have developed EGFR-targeted heparin-DDP (EHDDP) nanoparticles for tumor-targeted delivery of DDP. This nanoparticle delivery system possesses the following unique properties: (i) succinic anhydride-modified heparin is biocompatible and biodegradable with no anticoagulant activity; (ii) single-chain variable fragment anti-EGFR antibody (ScFvEGFR) was conjugated to the nanoparticles as an EGFR-targeting ligand. Our results showed that EHDDP nanoparticles can significantly increase the intracellular concentrations of DDP and Pt-DNA adducts in EGFR-expressing non-small cell lung cancer H292 cells via an EGFR-mediated pathway. Compared to the free DDP, significantly prolonged blood circulation time and improved pharmacokinetics and biodistribution of Pt were observed after systemic delivery of the EHDDP nanoparticles. The new EHDDP nanoparticle delivery system significantly enhanced antitumor activity of DDP without weight loss or damage to the kidney and spleen in nude mice bearing H292 cell tumors.
In vivo behavior of nanoparticles and interactions between nanoparticles and organisms are key components of nanotoxicology. In this study, the biochemical compositions of rat serum exposed to TiO2 nanoparticles (nano-TiO2) by intratracheal instillation at low (0.8 mg/kg), medium (4 mg/kg) and high doses (20 mg/kg) were investigated using 1H-NMR techniques with pattern recognition methods. Serum biochemical assays, as well as histopathological and transmission electron microscopy (TEM) examinations of tissues were performed. 1H-NMR spectra and pattern recognition analyses of nano-TiO2 treated animals showed increased serum levels of ketone bodies, choline, low density lipoprotein (LDL), alanine and GLU, and decreased levels of lactate, creatine and pyruvate. Clinical chemistry analyses of serum showed increased levels of lactate dehydrogenase, aspartate aminotransferase, and alkaline phosphatase, as well as increased levels of blood urea nitrogen and creatinine, indicating slight liver and kidney injury. Furthermore, TEM provided an analysis of particle-related structural changes of the lungs, liver and kidneys, and revealed that the localization of nanoparticles within cells induced apoptosis. The damage to the target organs was associated with the perturbation of energy metabolism. Serum 1H-NMR spectra, in combination with pattern recognition techniques, proved to be an efficient and simple metabonomic method to depict the metabolic changes produced by intratracheally-instilled nano-TiO2.
Inflammation is a primary event in atherogenesis. Oleoylethanolamide (OEA), a naturally occurring fatty-acid ethanolamide, lowers lipid levels in liver and blood through activation of the nuclear receptor, peroxisome proliferator-activated receptor-alpha (PPAR?). We designed and synthesized (Z)-(S)-9-octadecenamide, N-(2-hydroxyethyl, 1-methyl) (OPA), an OEA analog. The present study investigated the effect of OPA on the expression of adhesion molecules in human umbilical vein endothelial cells (HUVEC). OPA inhibited expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) stimulated by Tumor Necrosis Factor-? (TNF-?) via activation of PPAR?. This inhibition of VCAM-1 and ICAM-1 expression decreased adhesion of monocyte-like cells to stimulated endothelial cells. These results demonstrate that OPA may have anti-inflammatory properties. Our results thus provide new insights into possible future therapeutic approaches to the treatment of atherosclerosis.
Accidental ingestion or injection of household products sometimes occurs due to their accessibility, but the toxic manifestations have not been well characterized when they are internally administered. The aim of this study was to investigate the toxic effects induced by ingestion or injection of different ionic surfactants and disinfectants in rats. The test drugs involved benzalkonium and benzethonium (BZK and BZT, both cationic surfactants used as disinfectants), alkyldiaminoethylglycine (AEG, an amphoteric surfactant used as a disinfectant), linear alkylbenzenesulfonate (LAS, an anionic surfactant), polyoxyethylene cetylether (PEC, a nonionic surfactant), chlorhexidine (CHX, not a surfactant but a disinfectant) and saline (control). Male Sprague-Dawley rats were administered one of the test drugs orally (p.o.), intravenously (i.v.) or intraarterially (i.a.). The fatal effects appeared rapidly (<30?min) in i.v.-administered rats, while taking hours (>5?h) in i.a./p.o.-administered rats after a dose of around LD(50) , although the progress and degree of toxic effects varied among the drugs tested. In intravascular administration, BZK and BZT were fatal at doses of 15-20?mg kg(-1) . Higher concentrations in lung and kidney than in blood were determined. CHX showed a high toxic effect compared with cationic surfactants. The rats administered anionic (LAS) or amphoteric (AEG) surfactant died in less than 24?h at doses over 100?mg kg(-1) . In p.o. administration, the toxic effects were concentration/dose-dependent, and all rats administered high doses of surfactants except for PEC died at 5-20?h. The overall toxic ranks could be: cationic surfactant/CHX> anionic/amphoteric surfactant > nonionic surfactant.
Chlorhexidine (CHX) is a cationic biguanide compound that has been widely used for disinfection of skin, mucous membranes, and medical instruments. Poisoning has been occurred occasionally due to its easy accessibility. Some fatal cases developed acute respiratory distress syndrome (ARDS) from aspiration of CHX directly into the lung. There is no preclinical information about the pulmonary toxicity of CHX available since the products of CHX are usually developed for disinfection by topical use. In this study, the acute pulmonary toxic effects of CHX following an intratracheal instillation in rats were investigated. Rats were exposed either to CHX at concentrations of 0.02% and 0.2% or to distilled water at a volume of 500 ?l/kg b.w. CHX at concentration of 0.2% caused changes in hematological and biochemical values including white blood cell count (WBC), total protein (TP), albumin (ALB), lactate dehydrogenase (LDH), blood urea nitrogen (BUN) and creatinine (CRE), and induced inflammatory reactions including intra-alveolar edema and hemorrhages, as well as resulted in the target organ concentration in lungs at the level of about 1.0 ?g/g and maintained for more than 1 week, when administered intratracheally in rats. The cytotoxic action of CHX might induce those detrimental reactions in rats.
To enhance site-specific intracellular delivery against folate receptor, heparin-PEG-folate (H-PEG-F) containing succinylated-heparin conjugated with folate via PEG 1000/3000 spacers has been prepared. Due to covalent strategy, H-PEG-F displays amphiphilic property, which is capable of entrapping a hydrophobic agent, like taxol, to form heparin-PEG-folate-taxol nanoparticles (H-PEG-F-T NPs) in aqueous solution. Hydrophobic agents can be entrapped within the core, while the H-PEG-F conjugates can stabilize the nanoparticles with exposing folate moieties on the surface. The structure of carrier and naoparticles has been characterized by(1)H NMR, and the content of folate and taxol has been quantitatively analyzed by UV method. The morphology and size of H-PEG-F-T NPs have been measured by field emission scanning electron microscopy (FESEM) and dynamic lighting scatter (DLS). All the NPs are in spherical shape and the sizes are less than 200 nm. The sizes of the NPs increases with increasing PEG segment length. By employing the flow cytomery method, the extent of cellular uptake has been comparatively evaluated under various conditions. The results of cellular uptake demonstrate that the cellular uptake of the carrier and the NPs is exceedingly higher for KB-3-1 cells (folate receptor overexpressing cell line) than for A549 cells (folate receptor deficiency cell line); H-PEG-F-T NPs show far greater extent of cellular uptake than that of H-PEG-F conjugates against A549 cells; when the content of folate is fixed at the same value, the extent of cellular uptake for the carrier and NPs ascends with the increase of PEG chain length against KB-3-1 cells. It suggests folate-receptor-mediated endocytosis and formation of nanoparticle and spacer length are considered to coaffect the cellular uptake efficiency of H-PEG-F-T NPs and H-PEG-F conjugates. Flow cytometry analysis depicts that KB-3-1 cells treated with H-PEG-F-T are arrested in the G(2)/M phase of the cell cycle, which states the similar inhibition mechanism as taxol. The strategy based on the formation of H-PEG-F-T NPs could be potentially applied for cancer cell targeted delivery of various therapeutic agents.
Drug-lead synthesis through rapid construction of chiral molecular complexity around the biologically relevant framework using a highly efficient strategy is a key goal of organic synthesis. Molecules bearing a spirooxindole-type framework exhibit important bioactivities. Herein, we present a highly efficient and convenient strategy that allows rapid construction of unique optically active spiro[oxazoline-3,3-oxindole]s through the organocatalyzed asymmetric synthesis of spirocyclic thiocarbamates via an aldol reaction. Preliminary biological evaluation of several of the spirooxazolines using a model of acute neuroinflammation revealed promising antipyretic activity and provided an opportunity to discover new antipyretic agents.
The targeted delivery of nanoparticles to solid tumors is one of the most important and challenging problems in cancer nanomedicine, but the detailed delivery mechanisms and design principles are still not well understood. Here we report quantitative tumor uptake studies for a class of elongated gold nanocrystals (called nanorods) that are covalently conjugated to tumor-targeting peptides. A major advantage in using gold as a "tracer" is that the accumulated gold in tumors and other organs can be quantitatively determined by elemental mass spectrometry (gold is not a natural element found in animals). Thus, colloidal gold nanorods are stabilized with a layer of polyethylene glycols (PEGs) and are conjugated to three different ligands: (i) a single-chain variable fragment (ScFv) peptide that recognizes the epidermal growth factor receptor (EGFR); (ii) an amino terminal fragment (ATF) peptide that recognizes the urokinase plasminogen activator receptor (uPAR); and (iii) a cyclic RGD peptide that recognizes the a(v)?(3) integrin receptor. Quantitative pharmacokinetic and biodistribution data show that these targeting ligands only marginally improve the total gold accumulation in xenograft tumor models in comparison with nontargeted controls, but their use could greatly alter the intracellular and extracellular nanoparticle distributions. When the gold nanorods are administered via intravenous injection, we also find that active molecular targeting of the tumor microenvironments (e.g., fibroblasts, macrophages, and vasculatures) does not significantly influence the tumor nanoparticle uptake. These results suggest that for photothermal cancer therapy, the preferred route of gold nanorod administration is intratumoral injection instead of intravenous injection.
A novel real-time in situ detection method for the investigation of cellulase-cellulose interactions based on fluorescence resonance energy transfer (FRET) has been developed. FRET has been widely used in biological and biophysical fields for studies related to proteins, nucleic acids, and small biological molecules. Here, we report the efficient labeling of carboxymethyl cellulose (CMC) with donor dye 5-(aminomethyl)fluorescein and its use as a donor in a FRET assay together with an Alexa Fluor 594 (AF594, acceptor)-cellulase conjugate as acceptor. This methodology was successfully employed to investigate the temperature dependency of cellulase binding to cellulose at a molecular level by monitoring the fluorescence emission change of donor (or acceptor) in a homogeneous liquid environment. It also provides a sound base for ongoing cellulase-cellulose study using cellulosic fiber.
There are various types of coronary artery fistula (CAF) with complex shapes; therefore, it is important to obtain a correct diagnosis and to understand its relations to the adjacent structures before surgery. This study evaluated echocardiography and 64-multislice computed tomography (64-MSCT) angiography in diagnosing CAF.
Nonspecific distribution of chemotherapeutic drugs (such as paclitaxel) is a major factor contributing to side effects and poor clinical outcomes in the treatment of human head and neck cancer. To develop novel drug delivery systems with enhanced efficacy and minimized adverse effects, we synthesized a ternary conjugate heparin-folic acid-paclitaxel (HFT), loaded with additional paclitaxel (T). The resulting nanoparticle, HFT-T, is expected to retain the antitumor activity of paclitaxel and specifically target folate receptor (FR)-expressing tumors, thereby increasing the bioavailability and efficacy of paclitaxel. In vitro experiments found that HFT-T selectively recognizes FR-positive human head and neck cancer cell line KB-3-1, displaying higher cytotoxicity compared to the free form of paclitaxel. In a subcutaneous KB-3-1 xenograft model, HFT-T administration enhanced the specific delivery of paclitaxel into tumor tissues and remarkably improved antitumor efficacy of paclitaxel. The average tumor volume in the HFT-T treatment group was 92.9 +/- 78.2 mm(3) vs 1670.3 +/- 286.1 mm(3) in the mice treated with free paclitaxel. Furthermore, paclitaxel tumors showed a resurgence of growth after several weeks of treatment, but this was not observed with HFT-T. This indicates that HFT-T could be more effective in preventing tumors from developing drug resistance. No significant acute in vivo toxicity was observed. These results indicate that specific delivery of paclitaxel with a ternary structured nanoparticle (HFT-T) targeting FR-positive tumor is a promising strategy to enhance chemotherapy efficacy and minimize adverse effects.
To evaluate the therapeutic results of oxygen-ozone combined collagenase injection for the treatment of lumbar disc herniation compared to the surgery. And to explore the role of this minimally invasive treatment as an alternative to disc surgery.
Recent developments in nanotechnology offer researchers opportunities to significantly transform cancer therapeutics. This technology has enabled the manipulation of the biological and physicochemical properties of nanomaterials to facilitate more efficient drug targeting and delivery. Clinical investigations suggest that therapeutic nanoparticles can enhance efficacy and reduced side effects compared with conventional cancer therapeutic drugs. Encouraged by rapid and promising progress in cancer nanotechnology, researchers continue to develop novel and efficacious nanoparticles for drug delivery. The use of therapeutic nanoparticles as unique drug delivery systems will be a significant addition to current cancer therapeutics.
Coronary artery fistulas are rare, and the further development of mitral valvular insufficiency and endocarditis is even more uncommon. We report a case of endocarditis secondary to a congenital coronary artery fistula arising from the right coronary artery and draining into the left ventricle. Vegetations were found on the mitral valve leaflet. The fistula was successfully treated with surgery, and the endocarditis, with antibiotic therapy. Surgical repair is the optimal treatment for coronary artery fistula, even in asymptomatic patients.
Surveillance is critical for the prevention and control of infectious disease. Chinas real-time web-based infectious disease reporting system is a distinguished achievement. However, many aspects of the current China Infectious Disease Surveillance System do not yet meet the demand for timely outbreak detection and identification of emerging infectious disease. PulseNet, the national molecular typing network for foodborne disease surveillance was first established by the Centers for Disease Control and Prevention of the United States in 1995 and has proven valuable in the early detection of outbreaks and tracing the pathogen source. Since 2001, the China CDC laboratory for bacterial pathogen analysis has been a member of the PulseNet International family; and has been adapting the idea and methodology of PulseNet to develop a model for a future national laboratory-based surveillance system for all bacterial infectious disease.We summarized the development progress for the PulseNet China system and discussed it as a model for the future of Chinas national laboratory-based surveillance system.
A biologically inspired compound-eye structure, which composes of ~5,867 honeycomb-patterned microlenses, was fabricated on a hemispherical shell. The fabrication process was simple and low-cost, which involves a femtosecond laser-enhanced wet etching and casting process followed by a thermomechanical process to convert the film into a hemispherical surface. By optimizing the parameters of thermomechanical process to form the curvilinear surface, the experimental result shows that the microlenses are omnidirectionally aligned on the dome with lens diameters of ~85 µm and the angle between two lens of ~2°, and the individual microlenses have rudimentary focusing and imaging properties. The artificial compound-eye structure fabricated by this method has great potential applications in scale-invariant processing, robot vision, and fast motion detection.
The determination of cellulase distribution on the surface of cellulose fiber is an important parameter to understand when determining the interaction between cellulase and cellulose and/or the cooperation of different types of cellulases during the enzymatic hydrolysis of cellulose. In this communication, a strategy is presented to quantitatively determine the cellulase colocalization using the fluorescence resonance energy transfer (FRET) methodology, which is based on acceptor photobleaching and spectrally unmixing fluorescence microscopy. FRET monitoring of cellulase colocalization was achieved by labeling cellulases with an appropriate pair of FRET dyes and by adopting an appropriate FRET model. We describe here that the adapted acceptor photobleaching FRET method can be successfully used to quantify cellulase colocalization regarding their binding to a cellulose fiber at a resolution <10 nm. This developed quantitative FRET method is promising for further studying the interactions between cellulase and cellulose and between different types of cellulases.
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