Co-biodegradation of anthracene and naphthalene by the bacterium Acinetobacter johnsonii.

NAP (Naphthalene) and ANT (anthracene) usually co-exist in environment and possessed interactional effects on their biodegradation in environment. Presently, a strain of Acinetobacter johnsonii was employed to degrade NAP and ANT in single- and dual-substrate systems. NAP was utilized as prefer substrate by cells to accelerate ANT biodegradation. As much as 200 mg L-1 ANT could be entirely degraded with 1,500 mg L-1 NAP, which was beyond bacterial potential in single substrate system. Especially, the shortest biodegradation period (103 h) for ANT was observed with the presence of 50 mg L-1 NAP. By contrast, ANT showed strong inhibition on NAP degradation, while the peak biodegradation of 1,950 mg L-1 NAP with 50 mg L-1 ANT could still proceed. By introducing an inhibition constant parameter to fit the inhibition on cells, modeling indicated the substrate inhibition for NAP and ANT over the concentrations of 174 and 49 mg L-1, respectively. Furthermore, enzyme assay revealed the pathway of meta fission in NAP biodegradation due to the appearance of catechol 2,3-dioxygenase activity, and low-level lipase excretion was also found in both NAP and ANT biodegradation, but hardly affect NAP and ANT biodegradation in the present study. To research the interplay of NAP and ANT is conducive to targeted decontamination.

Dendrons and Multiarm Polymers with Thiol-Exchangeable Cores: A Reversible Conjugation Platform for Delivery.

Disulfide exchange reaction has emerged as a powerful tool for reversible conjugation of proteins, peptides and thiol containing molecules to polymeric supports. In particular, the pyridyl disulfide group provides an efficient handle for the site-specific conjugation of therapeutic peptides and proteins bearing cysteine moieties. In this study, novel biodegradable dendritic platforms containing a pyridyl disulfide unit at their focal point were designed. Presence of hydroxyl groups at the periphery of these dendrons allows their elaboration to multivalent initiators that yield poly(ethylene glycol) based multiarm star polymers via controlled radical polymerization. The pyridyl disulfide unit at the core of these star polymers undergoes efficient reaction with thiol functional group containing molecules such as a hydrophobic dye, namely, Bodipy-SH, glutathione, and KLAK sequence containing peptide. While conjugation of the hydrophobic fluorescent dye to the PEG-based multiarm polymer renders it water-soluble, it can be cleaved off the construct through thiol-disulfide exchange in the presence of an external thiol such as dithiothreitol. The multiarm polymer was conjugated with a thiol group containing apoptotic peptide to increase its solubility and cellular transport. In vitro cytotoxicity and apoptosis assays demonstrated that the resultant peptide-polymer conjugate had almost five times more apoptotic potential primarily through triggering apoptosis by disrupting mitochondrial membranes of human breast cancer cell line (MDA-MB-231) compared to naked peptide. The novel dendritic platform disclosed here offers an attractive template that can be modified to multiarm polymeric constructs bearing a "tag and release" characteristic.

Uptake and phytotoxicity of anthracene and benzo[k]fluoranthene applied to the leaves of celery plants (Apium graveolens var. secalinum L.).

The above-ground parts of celery plants were exposed to two polycyclic aromatic hydrocarbons (PAHs): 3-ring anthracene (ANT) and 5-ring benzo[k]fluoranthene (BkF), and the combination of ANT and BkF. After 43 days of exposure (overall dose of 1325µg/plant), celery plants retained only 1.4% of the total dose of ANT and 17.5% of the total dose of BkF. After exposure to a combination of ANT and BkF (1325µg of each compound per plant), the average ANT concentrations were more than twofold higher in/on leaf blades, whereas BkF levels were insignificantly higher. Under natural photoperiod conditions equivalent to a normal day, the combined application of ANT and BkF to the above-ground parts of celery plants slowed down physicochemical transformations of ANT. A similar effect was observed when PAHs were applied to glass surfaces. The combination of both PAHs probably led to stacking interactions, which decreased volatilization, in particular of ANT. Phytotoxicity of ANT and BkF could not be unambiguously established based on the results of this study. In all analyzed treatments, the chlorophyll content of leaf blades remained unchanged. Foliar application of ANT reduced ascorbic acid levels in all analyzed plant parts and increased the total acidity of celery leaves. In all experimental treatments, the total phenolic content of leaves increased up to 15%. Interestingly, ANT and BkF did not produce cumulative effects when applied in combination (when total PAH concentrations per plant were twofold higher).

Pharmacokinetics and metabolism of trans-emodin dianthrones in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygonum multiflorum Thunb. (PM) is a common traditional Chinese medicine with diverse biological activities of resolving toxins, nourishing livers and promoting hairs. Nevertheless, in recent years hepatotoxic adverse reactions caused by the administration of PM have raised worldwide concerns. In our previous study, we found that emodin dianthrones showed hepatotoxicity and may be potential toxicity markers. However, the metabolic transformation and pharmacokinetic behavior of emodin dianthrones in vivo have still not been elucidated. AIM OF THE STUDY: Taking trans-emodin dianthrones (TED) as an example, the present study was conducted to investigate the pharmacokinetics and bioavailability of TED in rats and characterized its metabolic transformation in the plasma, urine and feces of rats. MATERIALS AND METHODS: A rapid and sensitive UPLC-qqq-MS/MS method was developed for accurate quantification of TED in plasma and successfully applied to the pharmacokinetic evaluation of TED in rats after intravenous and oral administration. A reliable UFLC-Q-TOF-MS high resolution mass spectrometry combined with a scientific metabolite identification strategy was used to comprehensively characterize the metabolic transformation of TED in plasma, urine and feces in rats. RESULTS: The established UPLC-qqq-MS/MS method had a linear range of 1-500 ng/mL, and the method was accurate and reliable to meet the quantitative requirements. When 20 mg/kg TED was given by gavage rats, it was rapidly absorbed into the circulatory system and had a long half-life time of 6.44 h and wide tissue distribution in vivo. While intravenous injection of 0.4 mg/kg TED in rats, it was rapidly metabolized and eliminated with a half-life time of 1.82 h. The oral absorption bioavailability of TED was only 2.83%. Furthermore with a sensitive UFLC-Q-TOF-MS technique and metabolite identification strategy, 21 metabolites were successfully identified, including 11 in plasma, 12 in urine and 18 in feces. The main Ⅰ and Ⅱ phase metabolic processes involved glucuronidation, oxidation, carbonylation, (de)methylation, sulfation and hydrogenation. CONCLUSION: TED could be rapidly absorbed into the blood circulation and widely distributed and slowly metabolized in the body and underwent extensive cleavage and metabolic transformation in vivo. The study provided a basis for in-depth elucidation of the toxicology and mechanism research of TED, but also laid the foundation for further research on the material basis of hepatotoxicity of PM.

Pharmacokinetics of the HIV integrase inhibitor S/GSK1349572 co-administered with acid-reducing agents and multivitamins in healthy volunteers.

OBJECTIVES: To evaluate the effect of pH-altering agents on S/GSK1349572 exposure in healthy subjects. METHODS: S/GSK1349572 is an unboosted, once-daily, next-generation HIV integrase inhibitor. In the first study, 16 subjects received four single-dose treatments: (i) S/GSK1349572 50 mg; (ii) S/GSK1349572 50 mg with a multivitamin (MVI; One A Day Maximum); (iii) S/GSK1349572 50 mg with a liquid antacid (Maalox Advanced Maximum Strength); and (iv) S/GSK1349572 50 mg 2 h before an antacid. In the second study, 12 subjects received a single dose of S/GSK1349572 alone and on day 5 of omeprazole. RESULTS: All treatments were well tolerated. MVI co-administration modestly decreased S/GSK1349572 AUC by 33%. Concurrent antacid co-administration reduced S/GSK1349572 AUC by 74% and staggered antacid dosing significantly diminished this interaction, with a reduction in S/GSK1349572 AUC of 26%. Omeprazole did not significantly affect S/GSK1349572 exposure. CONCLUSIONS: S/GSK1349572 can be taken with proton pump inhibitors and MVIs without dose adjustment but should be administered 2 h before or 6 h after antacids.

Quantifying the vector effects of polyethylene microplastics on the accumulation of anthracene to Japanese medaka (Oryzias latipes).

To better assess the risk of microplastics (MPs) as a vector for contaminants, it is essential to understand the relative importance of MPs compared to other pathways for chemical transfer as well as the consequences of co-exposure. In this study, we exposed Japanese medaka (Oryzias latipes) to anthracene (ANT, 0.1 mg/L) in the presence or absence of pristine polyethylene MPs (PE-MPs, 106 beads/L), to quantify the vector effect of PE-MPs on ANT accumulation. Under the ANT-MPs co-exposure conditions, PE-MPs rapidly accumulated in the gastrointestinal tract of the medaka during a 14-day uptake phase, with an average bioconcentration factor of 171.4 L/kg. The PE-MPs could absorb and accumulate approximately 70 % of the ANT from the water sample. The PE-MPs changed the pharmacokinetic profile of ANT in medaka by decreasing both the uptake and depuration rate constants. The one compartment with first-order elimination model estimated that the amounts of ANT in the water phase and absorbed by PE-MPs (i.e., a vector effect) contributed about 67 % and 33 % of the ANT accumulation in medaka, respectively. At the end of the uptake (exposure) phase, however, the presence of PE-MPs did not significantly alter the final ANT concentrations in the fish body or alter the behavioral impacts of ANT. Thus, PE-MPs ingestion may act as a vector to concentrate and transfer ANT to medaka, but the presence of these particles may have limited adverse effects on fish under co-exposure systems of the type used in this study.

Bioequivalence Study Of A Fixed-Dose Combination Tablet Containing Melitracen 10 mg And Flupentixol 0.5 mg In Healthy Chinese Volunteers Under Fasted And Fed Conditions.

PURPOSE: A fixed-dose combination (FDC) tablet of melitracen/flupentixol has been widely used for depression. The purpose of this study was to assess the safety profile and the relative bioavailability of two FDC products containing 10 mg melitracen and 0.5 mg flupentixol from two different manufacturers, in order to acquire adequate pharmacokinetic evidence for registration approval of the test formulation. METHODS: The study was designed as a single-dose, randomized, open-label, 2-period crossover study under fasted or fed conditions in healthy Chinese subjects. Twenty-four subjects (16 men and 8 women) were selected for fasted study, and another 24 cases (16 men and 8 women) were in fed study. Each subject was randomized at the beginning to receive either a single dose of the reference FDC or the test FDC tablet during the first period. Following two-week washout period, all subjects received the alternate formulation during the second period. Blood samples were collected up to 144 hrs after administration. Pharmacokinetic parameters, including Cmax, Tmax, AUC0-t, AUC0-∞, t½, CL/F, and Vd/F were acquired based on the time versus concentration profiles. Then, the geometric mean ratios (GMR) and corresponding 90% CIs were calculated for the determination of bioequivalence analysis. Safety assessment included changes in vital signs and laboratory tests, physical examination findings, and incidence or reports of adverse events (AEs). RESULTS: The present study has clearly indicated the test and the reference FDC products are bioequivalent in terms of rate and extent of drug absorption. GMR of Cmax, AUC0-t, and AUC0-∞ for both flupentixol and melitracen between the two formulation FDC products, and corresponding 90% CIs, were all within the range of 80% to 125% under fasted or fed conditions. Both the test and the reference FDC products indicated good tolerance in all volunteers. Chinese Clinical Trials Registry identifier: CTR20171256.

Metabolism and mutual biotransformations of anthraquinones and anthrones in rhubarb by human intestinal flora using UPLC-Q-TOF/MS.

Anthraquinones and anthrones are the main active components of rhubarb. To investigate the metabolism and possible mutual biotransformations pathways of anthraquinones and anthrones by human intestinal flora, 9 representative constituents (aloe-emodin, rhein, emodin, chrysophanol, physcion, sennosides A, B, C and D) were studied. An ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) with mass spectrometryElevated Energy (MSE) technology was employed to separate and identify their metabolites. As a result, a total of 64 metabolites were identified or characterized from 9 components. Among them, 12 of them were identified by compared with the reference substances, 52 of them were tentatively identified. The results indicated that reduction, hydrolysis, acetylation, oxidation, demethylation, methylation, hydroxylation, dehydroxylation and the bond cleavage of CO and CC were likely to be the metabolic pathways involved in the generation of these metabolites. Moreover, mutual biotransformations existed among the nine representative constituents in rhubarb by human intestinal flora. This study will provide evidences that intestinal flora may play an important role in mediating the bioactivities in vivo of anthraquinones and anthrones in rhubarb.

Enhancing Radiotherapeutic Effect With Nanoparticle-Mediated Radiosensitizer Delivery Guided By Focused Gamma Rays In Lewis Lung Carcinoma-Bearing Mouse Brain Tumor Models.

BACKGROUND: Targeting radiosensitizer-incorporated nanoparticles to a tumor could allow for less normal tissue toxicity with more efficient drug release, thus improving the efficacy and safety of radiation treatment. The aim of this study was to improve tumor-specific delivery and bioavailability of a nanoparticle-mediated radiosensitizer in mouse brain tumor models. METHODS: A pH-sensitive nanoparticle, chitoPEGAcHIS, was conjugated to recombinant peptide HVGGSSV that could bind to tax-interaction protein 1 (TIP-1) as a radiation-inducible receptor. Then the c-Jun N-terminal kinase (JNK) inhibitor, SP600125 was incorporated into this copolymer to fabricate a HVGGSSV-chitoPEGAcHIS-SP600125 (HVSP-NP) nanoradiosensitizer. In vitro and in vivo radiation treatment were performed using a Gamma Knife unit. The tumor targetability of HVSP-NP was estimated by optical bioluminescence. Synergistic therapeutic effects of radiation treatment and HVSP-NP were investigated in Lewis lung carcinoma (LLC) cell-bearing mouse brain tumor models. RESULTS: The SP600125 JNK inhibitor effectively reduced DNA damage repair to irradiated LLC cells. A pH sensitivity assay indicated that HVSP-NP swelled at acidic pH and increased in diameter, and its release rate gradually increased. Optical bioluminescence assay showed that radiation induced TIP-1 expression in mouse brain tumor and that the nanoradiosensitizer selectively targeted irradiated tumors. Radiation treatment with HVSP-NP induced greater apoptosis and significantly inhibited tumor growth compared to radiation alone. CONCLUSION: As a novel nanoradiosensitizer, HVSP-NP was found to be able to selectively target irradiated tumors and significantly increase tumor growth delay in LLC-bearing mouse brain tumor models. This research shows that delivering a pH-sensitive nanoradiosensitizer to a brain tumor in which TIP-1 is induced by radiation can result in improved radiosensitizer-release in an acidic microenvironment of tumor tissue and in created synergistic effects in radiation treatment.

Validation of a sensitive LC/MS/MS method for simultaneous quantitation of flupentixol and melitracene in human plasma.

A sensitive method has been developed and validated, using LC/ESI-MS/MS, for simultaneous quantitation of flupentixol and melitracen--antidepressant drugs, in human plasma. The quantitation of the target compounds was determined in a positive ion mode and multiple reaction monitoring (MRM). The method involved a repeated liquid-liquid extraction with diethyl ether and analytes were chromatographed on a C(8) chromatographic column by elution with acetonitrile-water-formic acid (36:64:1, v/v/v) and analyzed by tandem mass spectrometry. The method was validated over the concentration ranges of 26.1-2090 pg/ml for flupentixol and 0.206-4120 ng/ml for melitracen. The correlation coefficients of both analyst were >0.998 for six sets of calibration curves. The recovery was 60.9-75.1% for flupentixol, melitracen and internal standard. The lower limit of quantitation (LLOQ) detection was 26.1 pg/ml for flupentixol and 0.206 ng/ml for melitracen. Intra- and inter-day precision of the assay at three concentrations were 2.15-5.92% with accuracy of 97.6-103.0% for flupentixol and 0.5-6.36% with accuracy of 98.7-101.7% for melitracen. Stability of compounds was established in a battery of stability studies, i.e., bench-top, autosampler and long-term storage stability as well as freeze/thaw cycles. The method proved to be suitable for bioequivalence study of flupentixol and melitracen in healthy human male volunteers.

Antidiabetic effects of dietary administration of Aloe arborescens Miller components on multiple low-dose streptozotocin-induced diabetes in mice: investigation on hypoglycemic action and systemic absorption dynamics of aloe components.

We carried out three experimental trials to determine antidiabetic effects of Aloe arborescens Miller components. Firstly, ICR mice which received frequent injections of streptozotocin (Sz) in small doses (low-dose Sz-induced diabetes mice) were fed ad libitum with basal diets supplemented with components of Aloe arborescens Miller var. natalensis Berger (Kidachi aloe) and Aloe vera Linne from 31 days before to 73 days after the Sz injections. Variation in blood glucose levels, incidence rates of insulitis and blood insulin levels were examined during the trial. As a result, groups receiving diets supplemented at the rate of 2% with whole leaf of Kidachi aloe and 10 KDa fraction powder (a fraction with less than 10 KDa molecular weight derived from Kidachi aloe leaf skin juice by ultra filtration) significantly suppressed the elevation of blood sugar as compared to a control group receiving basal diet. In contrast, there was no significant effect with Aloe vera leaf pulp powder. Insulitis emerged at the rate of 87% in the basal diet group. On the contrary, the whole aloe leaf and 10 KDa fraction groups significantly decreased the incidence of insulitis and incidence rates of whole aloe leaf and 10 KDa fraction powder were 51 and 38%, respectively. While insulin levels in the basal diet group averaged at 0.05 ng, more than four times the insulin level was observed in the 10 KDa group relative to the basal diet group. Secondary, the inhibitory effects of test materials on intestinal glucose absorption were observed using the jejunum of rats. A strong inhibitory action on intestinal glucose absorption was observed in the 10 KDa fraction powder group. Thirdly, phenol compounds derived from aloe in the blood serum and organs were quantitatively measured by a HPLC following forced administration of aloe components to rats to determine absorption kinetics of aloe components inside the body. The primary component of aloe phenol compounds is the same component of the 10 KDa fraction powder and it was found in the pancreas and liver in addition to in the blood serum. The above results indicate that fore and aft when Sz injections could cause selective toxicity to B cells of islets, the dietary administration of 10 KDa fraction powder to mice would lead to the persistence of aloe phenol compound having an antioxidant activity in the pancreas and blood, which could protect islets of Langerhans from the destruction caused by methyl radical derived from Sz. The results also suggested the possibility of the 10 KDa fraction powder to alleviate the burden of insulin secretion as it has an inhibitory action on glucose absorption in the jejunum of rats.

Phase I and clinical pharmacology trial of 502U83 using a monthly single dose schedule.

502U83 is an arylmethylaminopropanediol derivative exhibiting significant antineoplastic activity in a number of murine and human tumor models. In this Phase I trial, a 1-h or 4-h infusion of the agent was administered i.v. in 250 ml of 5% dextrose in water every 28 days. Fifty-three courses at doses of 25 to 2000 mg/m2 were administered to 36 patients with refractory solid tumors. Prolongation of the PR, QRS, and QT intervals on electrocardiograms was dose limiting at 2000 mg/m2. This prolongation appeared dose related and was reversible upon discontinuation of the infusion. No hematological toxicity was observed. Other toxicities included only sporadic and mild to moderate nausea and vomiting. No tumor responses were noted. 502U83 plasma concentrations were determined by high-pressure liquid chromatography. Complete pharmacokinetic profiles were obtained for 21 of the 36 patients. After infusion, plasma concentrations declined in a biexponential or in a triexponential manner with a harmonic mean terminal t 1/2 of 8.83 h. Using a three-compartment model, the mean apparent volume of distribution at steady state and total-body clearance were 195 liters/m2 and 42.5 liters/h/m2, respectively, indicative of extensive tissue distribution. No correlation could be found between the pharmacokinetic parameters and prolongation of the cardiac conduction intervals. Because of the cardiac effects with the drug, the schedule of administration of 502U83 used in this study cannot be recommended.

Evaluation of arylmethylaminopropanediols by a novel in vitro pharmacodynamic assay: correlation with antitumor activity in vivo.

The pharmacodynamics of a new series of antitumor DNA intercalators, known as arylmethylaminopropanediols (AMAPs), has been evaluated in vitro against adherent (MCF-7 human breast cancer) and nonadherent (P388 murine leukemia) cell lines. Previous work had shown that the in vitro antitumor activity of the model AMAP crisnatol was a function of exposure (Cn x T), rather than concentration alone. A unique exposure parameter, the minimum C x T, was proposed as an end point for antitumor activity in cell culture. Comparison of crisnatol to several established agents by the minimum C x T versus the standard concentration producing 10% survival indicated that these end points were not equivalent. The current work examined the validity of the pharmacodynamic approach using AMAP isomers from three different ring systems that were known to exhibit a spectrum of activity against the P388 tumor in vivo. The results indicated that antiproliferative, but not cytotoxic, activity of AMAPs in the pharmacodynamic assay correlated with their differential activity in vivo, expressed as percentage of increase in life span. In contrast, the concentration producing 10% survival either at 1 h or after continuous exposure did not show a similar correlation. The pharmacodynamic assay also revealed that certain AMAPs, while equipotent by concentration alone, required significantly less time and therefore less overall exposure for efficacy. Finally, the activity of AMAP isomers in P388 cells differed from that in MCF-7 cells, which may indicate AMAP selectivity for certain tumor types. Since AMAP action was a function of exposure, drug effects on cellular targets could likewise depend on exposure rather than concentration. These findings emphasize the importance of relating drug mechanisms to the pharmacodynamics of anticancer agents.

Pharmacokinetic and tissue distribution studies of 1,9-pyrazoloanthrone, a c-Jun-N-terminal kinase inhibitor in Wistar rats by a simple and sensitive HPLC method.

JNK pathway activates c-Jun(s) which are responsible for cell apoptosis; as a result, inhibitors of JNK pathway have the potential to prevent dopaminergic neurons from death and decrease the loss of dopamine in substantia nigra pars compacta (SNpc). Recent in-vitro studies show that 1,9-pyrazoloanthrone (1,9-P) a potent JNK-3 inhibitor prevents the apoptosis of dopaminergic cells of brain. In the present study we formulated liposomes to increase the bioavailability of 1,9-P in the brain and developed a simple, sensitive and selective high performance liquid chromatographic method and validated for the estimation of 1,9-P in Wistar rat plasma and tissue samples. Plasma and tissue samples were extracted by protein precipitation technique using acetonitrile (ACN) and rasagiline as the internal standards. Chromatography was performed on Hibar C18 column with mobile phase of ammonium acetate (10mM, pH 8.0 adjusted with ammonia) and ACN at a flow rate of 1mL/min. The lower limit of quantification of the developed method was found to be 2.0ng/mL and 4.0ng/g in plasma and tissue samples respectively. The liposomes of 1,9-P administered to animals at the dose equivalent to 15mg/kg orally demonstrated remarkable absorption into the systemic circulation with maximum concentration (∼7500ng/mL) within 2.0h. The order of the area under curve was found to be kidney>liver>brain>lungs>spleen>heart. The liposomes of 1,9-P were rapidly taken up into brain and showed a good brain concentration after 2.0h; sustenance up to 4.0h was achieved which is better than 1,9-P solution.

Effects of Glycosylation on Biodistribution and Imaging Quality of Necrotic Myocardium of Iodine-131-Labeled Sennidins.

PURPOSE: Sennidins are necrosis-avid agents for noninvasive assessment of myocardial viability which is important for patients with myocardial infarction (MI). However, high accumulation of radioactivity in the liver interferes with the assessment of myocardial viability. In this study, we compared sennidins with sennosides to investigate the effects of glycosylation on biodistribution and imaging quality of sennidins. PROCEDURES: Sennidin A (SA), sennidin B (SB), sennoside A (SSA), and sennoside B (SSB) were labeled with I-131. In vitro binding to necrotic cells and hepatic cells and in vivo biodistribution in rats with muscular necrosis were evaluated by gamma counting, autoradiography, and histopathology. Single photon emission computed tomography/computed tomography (SPECT/CT) images were acquired in rats with acute MI. RESULTS: The uptake of [131I]SA, [131I]SSA, [131I]SB, and [131I]SSB in necrotic cells was significantly higher than that in viable cells (p < 0.05). Hepatic cells uptake of [131I]SSA and [131I]SSB were 7-fold and 10-fold lower than that of corresponding [131I]SA and [131I]SB, respectively. The biodistribution data showed that the radioactivities in the liver and feces were significantly lower with [131I]sennosides than those with [131I]sennidins (p < 0.01). Autoradiography showed preferential accumulation of these four radiotracers in necrotic areas of muscle, confirmed by histopathology. SPECT/CT imaging studies showed better image quality with [131I]SSB than with [131I]SB due to less liver interference. CONCLUSIONS: Glycosylation significantly decreased the liver uptake and improved the quality of cardiac imaging. [131I]SSB may serve as a promising necrosis-avid agent for noninvasive assessment of myocardial viability.

Surface functionalization superparamagnetic nanoparticles conjugated with thermoresponsive poly(epsilon-lysine) dendrons tethered with carboxybetaine for the mild hyperthermia-controlled delivery of VEGF.

UNLABELLED: Vascular endothelial growth factor (VEGF) is the growth factor responsible for the triggering of angiogenesis, the process of blood vessel formation supporting the long-term viability of any repaired or regenerated tissue. As the growth factor is effective only when concentration gradients are generated, new shuttles need to be developed that ensure both the control of gradients at the site of tissue repair and the release of VEGF at physiological levels. Magnetic hyperthermia is the production of heat induced by magnetic materials through their exposure to an external oscillating magnetic field. In this paper, magnetic nanoparticles capable of generating controllable hyperthermia were functionalised with hyperbranched poly(epsilon-lysine) peptides integrating in their core parallel thermoresponsive elastin-like peptide sequences and presenting an uppermost branching generation tethered by the zwitterionic amino acid carboxybetaine. The results show that these functionalised magnetic nanoparticles avidly bind VEGF and release it only upon generation of mild-hyperthermic pulses generated by oscillating magnetic filed. The VEGF release occurred in a temperature range at which the elastin-like peptides collapse. It is proposed that, through the application of an external magnetic field, these magnetic carriers could generated gradients of VEGF in vivo and allow its tuned delivery in a number of clinical applications. STATEMENT OF SIGNIFICANCE: The present paper for the first time reveals the possibility to control the delivery of VEGF through mild hyperthermia stimuli generated by a oscillating magnetic field. To this purpose, magnetic nanoparticles of high size homogeneity and coated with a thin coating of poly(acrylic acid) were functionalised with a novel class of poly(epsilon lysine) dendrimers integrating in their structure a thermoresponsive amino acid sequence mimicking elastin and exposing at high density a zwitterionic modified amino acid, the carboxybetaine, known to be able to bind macromolecules. Physicochemical and biochemical characterisation elegantly show the link between the thermal properties of the nanoparticles and of the dendrimer change of conformation and how this enable the release of VEGF at temperature values compatible with the growth factor stability.

Molecular conformational analysis, vibrational spectra, NBO, NLO, HOMO-LUMO and molecular docking studies of ethyl 3-(E)-(anthracen-9-yl)prop-2-enoate based on density functional theory calculations.

FT-IR and FT-Raman spectra of ethyl 3-(E)-(anthracen-9-yl)prop-2-enoate were recorded and analyzed. The conformational behavior of the molecule was also investigated. The vibrational wavenumbers were calculated using DFT quantum chemical calculations. The data obtained from the wavenumber calculations were used to assign vibrational bands obtained experimentally. The geometrical parameters are in agreement with XRD data. The stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been analyzed using NBO analysis. The HOMO and LUMO analysis were used to determine the charge transfer within the molecule and quantum chemical parameters related to the title compound. From the MEP analysis, it is clear that the negative electrostatic potential regions are mainly localized over the carbonyl groups and anthracene ring and are possible sites for electrophilic attack and the positive regions are localized at all the hydrogen atoms as possible sites for nucleophilic attack. NLO and NMR studies are also reported. Molecular docking studies suggest that the title compound might exhibit inhibitory activity against IDE and may act as an insulysin inhibitor. Conformational analysis is also reported.

Exploring diagnostic potentials of radioiodinated sennidin A in rat model of reperfused myocardial infarction.

Non-invasive "hot spot imaging" and localization of necrotic tissue may be helpful for definitive diagnosis of myocardial viability, which is essential for clinical management of ischemic heart disease. We labeled Sennidin A (SA), a naturally occurring median dianthrone compound, with (131)I and evaluated (131)I SA as a potential necrosis-avid diagnostic tracer agent in rat model of reperfused myocardial infarction. Magnetic resonance imaging (MRI) was performed to determine the location and dimension of infarction. (131)I-SA was evaluated in rat model of 24-hour old reperfused myocardial infarction using single-photon emission computed tomography/computed tomography (SPECT/CT), biodistribution, triphenyltetrazolium chloride (TTC) histochemical staining, serial sectional autoradiography and microscopy. Gamma counting revealed high uptake and prolonged retention of (131)I SA in necrotic myocardium and fast clearance from non-targeted tissues. On SPECT/CT images, myocardial infarction was persistently visualized as well-defined hotspots over 24h, which was confirmed by perfect matches of images from post-mortem TTC staining and autoradiography. Radioactivity concentration in infarcted myocardium was over 9 times higher than that of the normal myocardium at 24h. With favorable hydrophilicity and stability, radioiodinated SA may serve as a necrosis-avid diagnostic agent for assessment of myocardial viability.

2-Fluoro-4-pyridinylmethyl analogues of linopirdine as orally active acetylcholine release-enhancing agents with good efficacy and duration of action.

In an effort to improve the pharmacokinetic and pharmacodynamic properties of the cognition-enhancer linopirdine (DuP 996), a number of core structure analogues were prepared in which the 4-pyridyl pendant group was systematically replaced with 2-fluoro-4-pyridyl. This strategy resulted in the discovery of several compounds with improved activity in acetylcholine (ACh) release-enhancing assays, in vitro and in vivo. The most effective compound resulting from these studies, 10, 10-bis[(2-fluoro-4-pyridinyl)methyl]-9(10H)-anthracenone (9), is between 10 and 20 times more potent than linopirdine in increasing extracellular hippocampal ACh levels in the rat with a minimum effective dose of 1 mg/kg. In addition to superior potency, 9 possesses an improved pharmacokinetic profile compared to that of linopirdine. The half-life of 9 (2 h) in rats is 4-fold greater than that of linopirdine (0.5 h), and it showed a 6-fold improvement in brain-plasma distribution over linopirdine. On the basis of its pharmacologic, pharmacokinetic, absorption, and distribution properties, 9 (DMP543) has been advanced for clinical evaluation as a potential palliative therapeutic for treatment of Alzheimer's disease.

Potent tumorigenicity of 7-chlorobenz[a]anthracene and 7-bromobenz[a]anthracene in the neonatal B6C3F (1) male mouse.

The tumorigenicity of 7-chlorobenz[a]anthracene (7-Cl-BA, and environmental contaminant, and 7 bromobenz[a]anthracene (7-Br-BA) was determines in the male B6C3F(1) newborn mouse. Mice receiving 7-Cl-BA and 7-Br-BA by i.p. injections at a dose of 1600 nmol per mouse on 1, 8, and 15 days after birth developed 92 and 96% hepatocellular adenomas, and 100 and 83% hepatocellular carcinoma, respectively. Metabolism by liver microsomes of 15-day-old mice each produced the corresponding trans-3,4-dihydrodiol. Analysis by (32)P-postlabeling/HPLC indicated the presence of DNA adducts derived from 7-Cl-BA trans-3,4-dihydrodiol and 7-Br-BA trans-3,4-dihydrodiol. Our results indicate that both 7-Cl-BA and 7-Br-BA are potent carcinogens and that bay-region diol epoxides are the ultimate metabolites that lead to DNA adduct formation and tumor initiation.