Extracellular matrix coating improves the biocompatibility of polymeric heart valves.

Prosthetic heart valve replacement is an effective therapy for patients with valvular heart disease. New-type polymer materials provide potential choices of material for preparing prosthetic heart valves. In this study, we focused on enhancing the biocompatibility of polystyrene-block-isobutylene-block-styrene (SIBS) by surface modification with an extracellular matrix (ECM). Experimental results demonstrated that the ECM coating increased the adsorption resistance against protein and platelets. SIBS coated with an ECM adsorbed much less bovine serum albumin and fibrinogen (5.38 µg cm-2 and 31.53 µg cm-2, respectively) than the original material (90.84 µg cm-2 and 132.38 µg cm-2, respectively). The relative platelet adsorption of the ECM-modified SIBS was lower than that of SIBS (0.04 versus 0.10). Moreover, the surface coating could also reduce endothelial cytotoxicity, suppress the immune response, and potentially induce tissue regeneration. In conclusion, ECM coating improved the biocompatibility of SIBS effectively.

Highly Biocompatible Nanoparticles of Au@Fluorescent Polymers as Novel Contrast Agent for In Vivo Bimodality NIR Fluorescence/CT Imaging.

In this work, one kind of biocompatible and all-in-one dual-modal nanoprobe, based on Au nanoparticles and NIR emissive semiconducting fluorescence polymers, was developed by the one-step solvent-mediated self-assembly method for in vivo X-ray computed tomography (CT) and fluorescence bioimaging for the first time. After preparation, a series of comprehensive evaluations were performed, and the nanoprobe exhibited smart size and modification, good compatibility, inducement of autophagy, long blood circulation, unconspicuous in vivo toxicity, and excellent fluorescence/CT imaging effects. Overall, the studies in this work assuredly indicate that the synthesized Au@FP nanoparticles as a noninvasive contrast agent is suitable for in vivo fluorescence/X-ray CT bimodality biomedical imaging and diagnosis.

The synthesis and anticancer activity of 2-styrylquinoline derivatives. A p53 independent mechanism of action.

A series of styrylquinolines was designed and synthesized based on the four main quinoline scaffolds including oxine, chloroxine and quinolines substituted with a hydroxyl group or chlorine atom at the C4 position. All of the compounds were tested for their anticancer activity on wild-type colon cancer cells (HCT 116) and those with a p53 deletion. Analysis of SAR revealed the importance of electron-withdrawing substituents in the styryl part and chelating properties in the quinoline ring. The compounds that were more active were also tested on a panel of four cancer cell lines with mutations in TP53 tumor suppressor gene. The results suggest that styrylquinolines induce cell cycle arrest and activate a p53-independent apoptosis. The apparent mechanism of action was studied for the most promising compounds, which produced reactive oxygen species and changed the cellular redox balance.

Radical polymerization inside living cells.

Polymerization reactions conducted inside cells must be compatible with the complex intracellular environment, which contains numerous molecules and functional groups that could potentially prevent or quench polymerization reactions. Here we report a strategy for directly synthesizing unnatural polymers in cells through free radical photopolymerization using a number of biocompatible acrylic and methacrylic monomers. This offers a platform to manipulate, track and control cellular behaviour by the in cellulo generation of macromolecules that have the ability to alter cellular motility, label cells by the generation of fluorescent polymers for long-term tracking studies, as well as generate a variety of nanostructures within cells. It is remarkable that free radical polymerization chemistry can take place within such complex cellular environments. This demonstration opens up a multitude of new possibilities for how chemists can modulate cellular function and behaviour and for understanding cellular behaviour in response to the generation of free radicals.

Assessing molecular initiating events (MIEs), key events (KEs) and modulating factors (MFs) for styrene responses in mouse lungs using whole genome gene expression profiling following 1-day and multi-week exposures.

Styrene increased lung tumors in mice at chronic inhalation exposures of 20ppm and greater. MIEs, KEs and MFs were examined using gene expression in three strains of male mice (the parental C57BL/6 strain, a CYP2F2(-/-) knock out and a CYP2F2(-/-) transgenic containing human CYP2F1, 2A13 and 2B6). Exposures were for 1-day and 1, 4 and 26weeks. After 1-day exposures at 1, 5, 10, 20, 40 and 120ppm significant increases in differentially expressed genes (DEGs) occurred only in parental strain lungs where there was already an increase in DEGs at 5ppm and then many thousands of DEGs by 120ppm. Enrichment for 1-day and 1-week exposures included cell cycle, mitotic M-M/G1 phases, DNA-synthesis and metabolism of lipids and lipoproteins pathways. The numbers of DEGs decreased steadily over time with no DEGs meeting both statistical significance and fold-change criteria at 26weeks. At 4 and 26weeks, some key transcription factors (TFs) - Nr1d1, Nr1d2, Dbp, Tef, Hlf, Per3, Per2 and Bhlhe40 - were upregulated (|FC|>1.5), while others - Npas, Arntl, Nfil3, Nr4a1, Nr4a2, and Nr4a3 - were down-regulated. At all times, consistent changes in gene expression only occurred in the parental strain. Our results support a MIE for styrene of direct mitogenicity from mouse-specific CYP2F2-mediated metabolites activating Nr4a signaling. Longer-term MFs include down-regulation of Nr4a genes and shifts in both circadian clock TFs and other TFs, linking circadian clock to cellular metabolism. We found no gene expression changes indicative of cytotoxicity or activation of p53-mediated DNA-damage pathways.

Cytotoxic and Antimicrobial Activity of Dehydrozingerone based Cyclopropyl Derivatives.

A small series of 1-acetyl-2-(4-alkoxy-3-methoxyphenyl)cyclopropanes was prepared, starting from dehydrozingerone (4-(4-hydroxy-3-methoxyphenyl)-3-buten-2-one) and its O-alkyl derivatives. Their microbiological activities toward some strains of bacteria and fungi were tested, as well as their in vitro cytotoxic activity against some cancer cell lines (HeLa, LS174 and A549). All synthesized compounds showed significant antimicrobial activity and expressed cytotoxic activity against tested carcinoma cell lines, but they showed no significant influence on normal cell line (MRC5). Butyl derivative is the most active on HeLa cells (IC50 = 8.63 µm), while benzyl one is active against LS174 and A549 cell lines (IC50 = 10.17 and 12.15 µm, respectively).

Photocrosslinking of styrene-butadiene-styrene (SBS) networks formed by thiol-ene reactions and their influence on cell survival.

Styrene-butadiene-styrene (SBS) triblock copolymer has been conventionally used as synthetic rubber. However, the potential of SBS for biomedical applications has only been considered in limited earlier reports. Here, we demonstrate an effective approach to designing a photocrosslinked SBS network. Rheological analysis has been conducted for the investigation of the storage modulus of the resultant network. Crosslinked SBS networks were synthesized and characterized through optical and electron microscope imaging. The crosslink density of the network, calculated from swelling experiments, was 643 mol m(-3), where higher swelling in a hydrophobic medium was observed compared to the swelling measured in water. Cell survival analysis with HeLa cells and NIH/3T3 fibroblasts revealed that these networks are non-toxic, and that they could be considered for a variety of biomedical applications.

A comprehensive review of occupational and general population cancer risk: 1,3-Butadiene exposure-response modeling for all leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, myeloid neoplasm and lymphoid neoplasm.

Excess cancer risks associated with 1,3-butadiene (BD) inhalation exposures are calculated using an extensive data set developed by the University of Alabama at Birmingham (UAB) from an epidemiology study of North American workers in the styrene butadiene rubber (SBR) industry. While the UAB study followed SBR workers, risk calculations can be adapted to estimate both occupational and general population risks. The data from the UAB SBR study offer an opportunity to quantitatively evaluate the association between cumulative exposure to BD and different types of cancer, accounting for the number of tasks involving high-intensity exposures to BD as well as confounding associated with the exposures to the multiple other chemicals in the SBR industry. Quantitative associations of BD exposure and cancer, specifically leukemia, can be further characterized by leukemia type, including potential associations with acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML), and the groups of lymphoid and myeloid neoplasms. Collectively, these multiple evaluations lead to a comprehensive analysis that makes use of all of the available information and is consistent with the risk assessment goals of the USEPA and other regulatory agencies, and in line with the recommendations of the USEPA Science Advisory Board. While a range of cancer risk values can result from these multiple factors, a preferred case for occupational and general population risk is highlighted. Cox proportional hazards models are used to fit exposure-response models to the most recent UAB data. The slope of the model with cumulative BD ppm-years as the predictor variable is not statistically significantly greater than zero for CML, AML, or, when any one of eight exposure covariates is added to the model, for all leukemias combined. The slope for CLL is statistically significantly different from zero. The slope for myeloid neoplasms is not statistically significantly greater than zero while the slope for lymphoid neoplasms is statistically significantly greater than zero. The excess risk for the general population is largest for lymphoid neoplasms. The best estimates of the environmental concentrations (ECs) associated with an excess risk of 1/100,000 by age 70 years for lymphoid neoplasms, all leukemias, and CLL are EC(1/100,000)'s equal to 0.06, 0.16 and 0.38 ppm, respectively. The best estimates of the occupational BD exposure from 20 to 65 years of age associated with an excess risk of 1/10,000 by age 70 years for lymphoid neoplasms, all leukemias, and CLL are the EC(1/10,000)'s of 2.7, 7.3 and 15.1 ppm, respectively.

High throughput HPLC-ESI(-)-MS/MS methodology for mercapturic acid metabolites of 1,3-butadiene: Biomarkers of exposure and bioactivation.

1,3-Butadiene (BD) is an important industrial and environmental carcinogen present in cigarette smoke, automobile exhaust, and urban air. The major urinary metabolites of BD in humans are 2-(N-acetyl-L-cystein-S-yl)-1-hydroxybut-3-ene/1-(N-acetyl-L-cystein-S-yl)-2-hydroxybut-3-ene (MHBMA), 4-(N-acetyl-L-cystein-S-yl)-1,2-dihydroxybutane (DHBMA), and 4-(N-acetyl-L-cystein-S-yl)-1,2,3-trihydroxybutyl mercapturic acid (THBMA), which are formed from the electrophilic metabolites of BD, 3,4-epoxy-1-butene (EB), hydroxymethyl vinyl ketone (HMVK), and 3,4-epoxy-1,2-diol (EBD), respectively. In the present work, a sensitive high-throughput HPLC-ESI(-)-MS/MS method was developed for simultaneous quantification of MHBMA and DHBMA in small volumes of human urine (200 µl). The method employs a 96 well Oasis HLB SPE enrichment step, followed by isotope dilution HPLC-ESI(-)-MS/MS analysis on a triple quadrupole mass spectrometer. The validated method was used to quantify MHBMA and DHBMA in urine of workers from a BD monomer and styrene-butadiene rubber production facility (40 controls and 32 occupationally exposed to BD). Urinary THBMA concentrations were also determined in the same samples. The concentrations of all three BD-mercapturic acids and the metabolic ratio (MHBMA/(MHBMA+DHBMA+THBMA)) were significantly higher in the occupationally exposed group as compared to controls and correlated with BD exposure, with each other, and with BD-hemoglobin biomarkers. This improved high throughput methodology for MHBMA and DHBMA will be useful for future epidemiological studies in smokers and occupationally exposed workers.

Synthesis and biological evaluation of 5-nitropyrimidine-2,4-dione analogues as inhibitors of nitric oxide and iNOS activity.

Fifty two compounds based on 5-nitropyrimidine-2,4-dione moiety have been synthesized and evaluated for their inhibitory potency on the production of nitric oxide. Among them, compound 36 inhibited the production of nitric oxide (IC50 : 8.6 µm) on lipopolysaccharide-induced RAW 264.7 cells and inducible nitric oxide synthase activity (IC50 : 6.2 µm), as well as exerted no potential cytotoxicity (IC50 > 80.0 µm). Docking study confirmed that compound 36 was an inducible nitric oxide synthase inhibitor with perfect binding to the active site of inducible nitric oxide synthase. At a dose of 10 mg/kg, oral administration of 36 possessed protective properties in carrageenan-induced paw edema of male ICR mice.

Risk of cancer in workers exposed to styrene at eight British companies making glass-reinforced plastics.

OBJECTIVES: To provide further information on the risks of lymphohaematopoietic (LH) and other cancers associated with styrene. METHODS: We extended follow-up to December 2012 for 7970 workers at eight companies in England which used styrene in the manufacture of glass-reinforced plastics. Mortality was compared with that for England and Wales by the person-years method, and summarised by SMRs with 95% CIs. A supplementary nested case-control analysis compared styrene exposures, lagged by 5 years, in 122 incident or fatal cases of LH cancer and 1138 matched controls. RESULTS: A total of 3121 cohort members had died (2022 since the last follow-up). No elevation of mortality was observed for LH cancer, either in the full cohort (62 deaths, SMR 0.90, 95% CI 0.69 to 1.15), or in those with more than background exposure to styrene (38 deaths, SMR 0.82, 95% CI 0.58 to 1.14). Nor did the case-control analysis suggest any association with LH cancer. In comparison with background exposure, the OR for non-Hodgkin's lymphoma/chronic lymphocytic leukaemia in workers with high exposure (estimated 8-h time-weighted average of 40-100 ppm) for ≥1 year was 0.54 (95% CI 0.23 to 1.27). Mortality from lung cancer was significantly elevated, and risk increased progressively across exposure categories, with an SMR of 1.44 (95% CI 1.10 to 1.86) in workers highly exposed for ≥1 year. CONCLUSIONS: We found no evidence that styrene causes LH cancer. An association with lung cancer is not consistently supported by other studies. It may have been confounded by smoking, but would be worth checking further.

[Styrylquinolines-type synthetic compounds with leishmanicidal and cytotoxic activities]. / Compuestos sintéticos del tipo de estirilquinolinas con actividades leishmanicida y citotóxica.

INTRODUCTION: Leishmaniasis is a major public health problem faced by many countries, including Colombia. Its treatment has limitations such as the toxicity of the drugs used, the emergence of resistant strains, and prolonged and expensive treatments. Thus, there is an urgent need to find alternative solutions. OBJECTIVE: To evaluate the leishmanicidal and cytotoxic activities of three 2-styrylquinolines type compounds: 2-[(E)-2-(2,3-diacetyloxyphenyl)ethenyl]quinolin-8-yl-acetate, E1; 2-[(E)-2-(4-acetyloxy-3-methoxyphenyl)ethenyl] quinoline, E2, and 2-[(E)-2-(2,3-diacetyloxyphenyl)ethenyl] quinoline, E3. MATERIALS AND METHODS: The 2-styrylquinolines were obtained by organic synthesis using Perkin-type condensation reaction from 8-hydroxy quinaldine or quinaldine and aromatic aldehydes. The leishmanicidal activity was evaluated on intracellular amastigotes of Leishmania (Viannia) panamensis by flow cytometry. The results were expressed as lethal concentration 50 (LC 50 ) for cytotoxicity and effective concentration 50 (EC 50 ) for leishmanicidal activity, calculated by the Probit method. RESULTS: E3 showed high activity against L. (V) panamensis with a calculated EC 50 value of 1.4 µg/ml, and a selectivity index of 3.9; E1 and E2 showed higher EC 50 values of 5.6 and 68.1 µg/ml, respectively. For cytotoxicity, LC 50 values ranging from 5.4 to 68.1 µg/ml were calculated. E2 was moderately toxic, showing an LC 50 very similar to that of amphotericin B, a substance used as cytotoxic control. CONCLUSION: The styrylquinoline E3 is a promising compound against L. (V) panamensis , as it was able to significantly inhibit amastigotes inside the cell, reducing infection despite its toxicity.

Compuestos sintéticos del tipo de estirilquinolinas con actividades leishmanicida y citotóxica / Styrylquinolines-type synthetic compounds with leishmanicidal and cytotoxic activities

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New biomaterial as a promising alternative to silicone breast implants.

One in eight American women develops breast cancer. Of the many patients requiring mastectomy yearly as a consequence, most elect some form of breast reconstruction. Since 2006, only silicone breast implants have been approved by the FDA for the public use. Unfortunately, over one-third of women with these implants experience complications as a result of tissue-material biocompatibility issues, which may include capsular contracture, calcification, hematoma, necrosis and implant rupture. Our group has been working on developing alternatives to silicone. Linear triblock poly(styrene-b-isobutylene-b-styrene) (SIBS) polymers are self-assembling nanostructured thermoplastic rubbers, already in clinical practice as drug eluting stent coatings. New generations with a branched (arborescent or dendritic) polyisobutylene core show promising potential as a biomaterial alternative to silicone rubber. The purpose of this pre-clinical research was to evaluate the material-tissue interactions of a new arborescent block copolymer (TPE1) in a rabbit implantation model compared to a linear SIBS (SIBSTAR 103T) and silicone rubber. This study is the first to compare the molecular weight and molecular weight distribution, tensile properties and histological evaluation of arborescent SIBS-type materials with silicone rubber before implantation and after explantation.

Real-time cellular analysis as a novel approach for in vitro cytotoxicity testing of medical device extracts.

Cytotoxicity measurements are often performed to evaluate the biocompatibility of medical device materials. Here, we describe the use of a real-time cell analyzer (RTCA) system for the investigation of biocompatibility of medical devices by comparing RTCA results to two distinct methods described in the International Organization for Standardization (ISO) guidelines. Mouse L-929 fibroblast proliferation was assessed every 15 min from 24 to 100 h during the pretreatment and postextract addition period. Simultaneously, we performed quantitative cytotoxicity analyses using water-soluble tetrazolium salt (WST-1) and qualitatively scored cytotoxicity by examining changes in morphology at 24-h intervals. The RTCA uses electrical impedance to measure cell viability quantified as a normalized cellular index (CI) which was converted in this study to a reactivity grade. Results from microscopic analyses were expressed as a reactivity grade, based on morphology as defined by the ISO 10993-5:2009. There was a clear correlation between addition of cytotoxic agents and, both, decreased normalized CI and concomitant cell layer destruction observed by microscopy. Results obtained from the colorimetric WST-1 assays also correlated with normalized CI at various time points tested. The results indicate that RTCA allows for automated and accurate assessment of biocompatibility of medical devices and biomaterials.

New approach to the ecotoxicological risk assessment of artificial outdoor sporting grounds.

Artificial surfaces for outdoor sporting grounds may pose environmental and health hazards that are difficult to assess due to their complex chemical composition. Ecotoxicity tests can indicate general hazardous impacts. We conducted growth inhibition (Pseudokirchneriella subcapitata) and acute toxicity tests (Daphnia magna) with leachates obtained from batch tests of granular infill material and column tests of complete sporting ground assemblies. Ethylene propylene diene monomer rubber (EPDM) leachate showed the highest effect on Daphnia magna (EC(50) < 0.4% leachate) and the leachate of scrap tires made of styrene butadiene rubber (SBR) had the highest effect on P. subcapitata (EC(10) = 4.2% leachate; EC(50) = 15.6% leachate). We found no correlations between ecotoxicity potential of leachates and zinc and PAH concentrations. Leachates obtained from column tests revealed lower ecotoxicological potential. Leachates of column tests of complete assemblies may be used for a reliable risk assessment of artificial sporting grounds.

Structure-toxicity relationship study of para-halogenated styrene analogues in CYP2E1 transgenic cells.

Styrene is one of the most important industrial intermediates consumed in the world and is mainly used as a monomer for reinforced plastics and rubber. Styrene has been found to be hepatotoxic and pneumotoxic in humans and experimental animals. The toxicity of styrene is suggested to be metabolism-dependent. Styrene-7,8-oxide has been considered as the major metabolite responsible for styrene-induced cytotoxicity. The objective of the study was to investigate the correlation between cytotoxicity of styrene and chemical and biochemical properties of the vinyl group of styrene by development of structure activity relationships (SAR). 4-Fluorostyrene, 4-chlorostyrene and 4-bromostyrene were selected for the SAR study. Cytotoxicity of styrene and the halogenated styrene derivatives with an order of 4-bromostyrene>4-chlorostyrene>4-fluorostyrene≈styrene was observed in CYP2E1 transgenic cells. Similar orders in the efficiency of the metabolism of styrene and the halogenated styrene analogues to their oxides and in the electrophilicity of the corresponding oxides were observed. Additionally, the order of the potency of cellular glutathione depletion and the degree of protein adduction induced by styrene and the halogenated styrenes were consistent with that of their cytotoxicities. The wild-type cells were less susceptible to the toxicity of the corresponding model compounds than CYP2E1 cells. The present study provided insight into the roles of the biochemical and chemical properties of styrene in its cytotoxicity.

Genotoxicity of styrene-acrylonitrile trimer in brain, liver, and blood cells of weanling F344 rats.

Styrene-acrylonitrile Trimer (SAN Trimer), a by-product in production of acrylonitrile styrene plastics, was identified at a Superfund site in Dover Township, NJ, where childhood cancer incidence rates were elevated for a period of several years. SAN Trimer was therefore tested by the National Toxicology Program in a 2-year perinatal carcinogenicity study in F344/N rats and a bacterial mutagenicity assay; both studies gave negative results. To further characterize its genotoxicity, SAN Trimer was subsequently evaluated in a combined micronucleus (MN)/Comet assay in juvenile male and female F344 rats. SAN Trimer (37.5, 75, 150, or 300 mg/kg/day) was administered by gavage once daily for 4 days. Micronucleated reticulocyte (MN-RET) frequencies in blood were determined by flow cytometry, and DNA damage in blood, liver, and brain cells was assessed using the Comet assay. Highly significant dose-related increases (P < 0.0001) in MN-RET were measured in both male and female rats administered SAN Trimer. The RET population was reduced in high dose male rats, suggesting chemical-related bone marrow toxicity. Results of the Comet assay showed significant, dose-related increases in DNA damage in brain cells of male (P < 0.0074) and female (P < 0.0001) rats; increased levels of DNA damage were also measured in liver cells and leukocytes of treated rats. Chemical-related cytotoxicity was not indicated in any of the tissues examined for DNA damage. The results of this subacute MN/Comet assay indicate induction of significant genetic damage in multiple tissues of weanling F344 male and female rats after oral exposure to SAN Trimer.