Toxicity bioassays in core sediments from the Bay of Santander, northern Spain

The use of Vibrio fischeri as luminescence bacteria is particularly effective in evaluating contaminated sediment. In this study, the ecotoxicity of five core sediments from the Bay of Santander, northern Spain, utilising V. fischeri as marine bacterium, was carried out. Different toxicity assay procedures were applied in order to study the influence of the mobility and bioavailability of the pollutants. Basic Solid Phase Test (BSPT) in whole sediment and acute toxicity test, using pore water and three leaching test procedures as liquid extracts, were applied. In addition, the study of the influence of the pH value on the toxicity results of the leaching tests was conducted. The obtained results show toxicity units (TU50) values in BSPT test ranging from 0.42 to 39.06 with a decrease with depth as general trend and TU50 values from 0.010 to 0.389 in the liquid extracts, where TU50 is calculated as the inverse of EC50 (%). The obtained data show the historical toxicity trends of the Bay of Santander and provides a technical database for the management of contaminated sediments. Moreover, these results showed evidence that each sediment test procedure provided independent and complementary ecotoxicological responses useful for a sediment classification. In order to analyse the correlations between chemical parameters (both organic and inorganic) and the toxicity results, the self-organising map (SOM) neural network and regression equations were applied. Satisfactory correlations (R=0.93) between chemical concentrations of sum of five heavy metals and 16 PAHs and BSPT toxicity were obtained.     

SPF32629A and SPF32629B: enantioselective synthesis, determination of absolute configuration, cytotoxicity and antibacterial evaluation

We report herein an efficient enantioselective synthesis of SPF32629A and SPF32629B through one-pot enantioselective reduction and protecting-group-free regioselective O-acylation strategy. The absolute configuration of the enantiomerically pure isomers was established by Mosher ester analysis. The inhibitory potencies of the synthesized compounds were assayed in vitro against a panel of microorganisms and against A549 human lung adenocarcinoma cell line. Compounds 2, 11 and 12 displayed moderate to potent antibacterial activity against all the tested strains and compounds 7, 8, 2, 11 and 12 exhibited significant cytotoxicity in a dose-dependent manner with an IC₅₀ values ranging from 2.92 to 4.14 μg/ml and 8-11 μM.     

Synthesis and cytotoxicity of 2-phenylquinazolin-4(3H)-one derivatives

Thirty 2-phenylquinazolin-4(3H)-one derivatives were prepared and their cytotoxic activities were tested in five human tumor cell lines. Some compounds (5e, 5k, 5t, 6c and 6f) showed relatively high cytotoxic activity. Especially, compound 6c showed the most cytotoxicity against all cell lines tested among the synthesized derivatives, and the inhibitory activity of 6c against HeLa cell was higher than that of adriamycin. The putative mechanism of antitumor action in apoptotic cell death was cell cycle arrest in the G0/G1 phase by compounds 5k, 5v, 5m, 6c, and 6f in HeLa cells. These compounds showed relatively high cytotoxicity in this cell type.     

Investigations on cytotoxicity and anti-inflammatory potency of licofelone derivatives

A series of C5-substituted licofelone ([2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetic acid) derivatives were developed by a parallel synthesis approach and investigated for cytotoxicity against MCF-7 and MDA-MB-231 cells as well as for anti-inflammatory potency in vitro and in vivo. Dependent on the C5-substituent, the compounds showed high selectivity for MCF-7 cells. Especially 2-oxoethyl benzoate derivatives were inactive at the MDA-MB-231 cell line and as active as 5-FU at MCF-7 cells. C5-acetyl (8a), -2-oxoethyl formiate (8e), -2-oxoethyl acetate (8f) and -2-oxoethyl propionate (8g) derivatives showed growth inhibition at both cell lines, comparable with cisplatin. Modifications significantly reduced the inhibitory potency at COX-1 and COX-2 in vitro and in the xylene-induced ear swelling assay in mice. Only compound 8a was equipotent to licofelone, ibuprofen and celecoxibe in vivo.     

Long-term noise exposure and the risk for type 2 diabetes: A meta-analysis

Diabetes mellitus is one of the leading causes for disability and mortality in modern societies. Apart from personal factors its incidence might be influenced by environmental risks such as air pollution and noise. This paper reports a systematic review and meta-analysis on the risk for type 2 diabetes due to long-term noise exposure. Electronic searches in MEDLINE, EMBASE and the Internet yielded 9 relevant studies (5 for residential and 4 for occupational exposure). They were checked against a predefined list of safeguards against bias producing individual quality scores, which were then fed to MetaXL to conduct a quality effects meta-analysis. People exposed at their homes to roughly L_den > 60 dB had 22% higher risk (95% confidence interval [CI]: 1.09-1.37) for type 2 diabetes in comparison to those exposed to L_den < 64 dB; when studies reporting contentious exposure categories were excluded, there was still 19% risk (95% CI: 1.05-1.35) for L_den = 60-70 dB versus L_den < 60 dB. In occupational environment there was not significant risk (relative risk [RR] = 0.91, 95% CI: 0.78-1.06) for < 85 dB versus >85 dB. There was no heterogeneity in the two groups (I² = 0.00). The results should be interpreted with caution due to methodological discrepancies across the studies; however, they are indicative of the close links that noise pollution might have not only to cardiovascular diseases but to endocrine dysfunction as well.     

Synthesis of 4H-chromene, coumarin, 12H-chromeno[2,3-d]pyrimidine derivatives and some of their antimicrobial and cytotoxicity activities

Condensation of 3-N,N-diethylaminophenol (1) with α-cyanocinnamonitriles (2a-c) and ethyl α-cyanocinnamates (2d-f) provided compounds 3a-f and 4a-c. 12H-Chromeno[2,3-d]pyrimidine derivatives 6, 11-13 and 16 were obtained by treatment of 4H-chromene compounds (3) with different electrophiles followed by nucleophilic reagents. Structures of these compounds were established on the basis of IR, UV, ¹H NMR, ¹³C NMR and MS data. Some of the new compounds were evaluated for antimicrobial and cytotoxicity activities.     

Polymorphisms in Iron Homeostasis Genes and Urinary Cadmium Concentrations among Nonsmoking Women in Argentina and Bangladesh

Background: Cadmium (Cd) is a human toxicant and carcinogen. Genetic variation might affect long-term accumulation. Cd is absorbed via iron transporters.Objectives: We evaluated the impact of iron homeostasis genes [divalent metal transporter 1 (SLC11A2), transferrin (TF), transferrin receptors (TFR2 and TFRC), and ferroportin (SLC40A1)] on Cd accumulation.Methods: Subjects were nonsmoking women living in the Argentinean Andes [n = 172; median urinary Cd (U-Cd) = 0.24 µg/L] and Bangladesh (n = 359; U-Cd = 0.54 µg/L) with Cd exposure mainly from food. Concentrations of U-Cd and Cd in whole blood or in erythrocytes (Ery-Cd) were measured by inductively coupled plasma mass spectrometry. Fifty polymorphisms were genotyped by Sequenom. Gene expression was measured in whole blood (n = 72) with Illumina DirectHyb HumanHT-12 v4.0.Results: TFRC rs3804141 was consistently associated with U-Cd. In the Andean women, mean U-Cd concentrations were 22% (95% CI: –2, 51%), and they were 56% (95% CI: 10, 120%) higher in women with GA and AA genotypes, respectively, relative to women with the GG genotype. In the Bangladeshi women, mean U-Cd concentrations were 22% (95% CI: 1, 48%), and they were 58% (95% CI: –3, 157%) higher in women with GA and AA versus GG genotype, respectively [adjusted for age and plasma ferritin in both groups; p_trend = 0.006 (Andes) and 0.009 (Bangladesh)]. TFRC expression in blood was negatively correlated with plasma ferritin (r_S = –0.33, p = 0.006), and positively correlated with Ery-Cd (significant at ferritin concentrations of < 30 µg/L only, r_S = 0.40, p = 0.046). Rs3804141 did not modify these associations or predict TFRC expression. Cd was not consistently associated with any of the other polymorphisms evaluated.Conclusions: One TFRC polymorphism was associated with urine Cd concentration, a marker of Cd accumulation in the kidney, in two very different populations. The consistency of the findings supports the possibility of a causal association.     

Expansion of Achatina fulica in Brazil and potential increased risk for angiostrongyliasis

The explosive introduction of the snail Achatina fulica in Brazil illustrates the current concern with global changes favouring dissemination of infectious diseases. The mollusc is an important host for Angiostrongylus cantonensis, which occurs in Asia and the Pacific Islands and is a causative agent for eosinophilic meningoencephalitis. In the Americas there is another metastrongylid worm, An. costaricensis, that causes abdominal disease and may also be transmitted by Ac. fulica. Although both infections may occur in focal outbreaks and with low morbidity, very severe complicated clinical courses pose a challenge for diagnosis and treatment. Data on abdominal angiostrongyliasis are briefly reviewed.     

One-pot microwave assisted synthesis under green chemistry conditions, antioxidant screening, and cytotoxicity assessments of benzimidazole Schiff bases and pyrimido[1,2-a]benzimidazol-3(4H)-ones

The synthesis of a number of benzimidazole Schiff bases 3 and 3-oxo-pyrimido[1,2-a]benzimidazoles 4 in excellent yields by a one-step sequence from the reaction of 2-aminobenzimidazole under green chemistry conditions is described. Structural assignments of the new compounds as well as complete assignment of ¹H and ¹³C NMR signals have been unambiguously achieved based on the analysis of their ¹H and ¹³C NMR (1D and 2D), IR, MS and elemental analysis data. To the synthesized Schiff bases the E-configuration was assigned on the basis of comparison of experimental and calculated (DFT) ¹³C NMR chemical shifts. Compounds 3 and 4 were evaluated as inhibitors of lipoxygenase (LOX) and of lipid peroxidation (LPO). All the tested derivatives showed inhibition of lipid peroxidation, whereas most of them were found to have higher activation than the reference compound trolox; The Schiff bases 3e, 3h, and 3i, and the pyrimidobenzimidazoles 4a, 4e and 4f were found to be the most potent. The most potent LOX inhibitor within the subset of Schiff bases was found compound 3i, followed by 3f, whereas compounds 4a and 4g were found the most potent of the 3-oxo-pyrimido[1,2-a]benzimidazole group. Moreover, some cytotoxicity assessments were undertaken, whereupon it was found that Schiff base 3i and pyrimidobenzimidazoles 4e and 4f did not exhibit cytotoxicity at similar concentrations resembling thus the inhibitory activity of lipid peroxidation. The most cytotoxic Schiff base and pyrimidobenzimidazole were found to be 3d and 4c, respectively.     

Synthesis, evaluation against Leishmania amazonensis and cytotoxicity assays in macrophages of sixteen new congeners Morita-Baylis-Hillman adducts

We report the design, synthesis, in vitro evaluation against Leishmania amazonensis (IC₅₀), cytotoxicity assays in macrophages (CC₅₀), and selectivity index (SICC₅₀/IC₅₀) of sixteen new congeners aromatic Morita-Baylis-Hillman adducts 1-16. The 1-16 were prepared in good to excellent yields (58%-97%) from the “one pot” Morita-Baylis-Hillman Reaction between the aldehydes 29-36 and the acrylates 27 or 28 under DABCO as promoter. The MBHA 2-[Hydroxy(2-nitrophenyl)propyl] propanoate (1, IC₅₀ = 7.52 μg/mL or 28.38 μM; CC₅₀ = 35.77 μg/mL or 134.98 μM; SI = 4.75) and 2-[Hydroxy(2-nitrophenyl)hydroxyethyl] propanoate (9, IC₅₀ = 5.48 μg/mL or 20.52 μM; CC₅₀ = 29.81 μg/mL or 111.64c μM and, SI = 5.43) were the most effective and safe evaluated compounds.     

Synthesis of 3-heteroarylthioquinoline derivatives and their in vitro antituberculosis and cytotoxicity studies

A series of 3-heteroarylthioquinoline derivatives has been synthesized by the Friedlander annulation of 2-[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanyl]-1-aryl-1-ethanone/2-(1,3-benzothiazol-2-ylsulfanyl)-1-aryl-1-ethanone/1-aryl-2-[(2-phenyl-2H-1,2,3,4-tetraazol-5-yl)sulfanyl]-1-ethanone with 2-aminobenzophenone in good yields using YbCl₃ as the catalyst. These compounds have been screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) and among the 21 compounds screened, 2-[2-(4-bromophenyl)-4-phenyl-3-quinolyl]sulfanyl-5-methyl-1,3,4-thiadiazole (5d) and 2-[2-(4-chlorophenyl)-4-phenyl-3-quinolyl]sulfanyl-5-methyl-1,3,4-thiadiazole (5c) were found to be the most active compounds with MIC of 3.2 and 3.5 μM respectively against MTB. The cytotoxic effects against mouse fibroblasts (NIH 3T3) in vitro were evaluated for 5c and 5d, which displayed no toxic effects (IC₅₀ > 1000 μM) against the mouse fibroblast cell line NIH 3T3.     

Synthesis and biological evaluation of novel Mannich bases of 2-arylimidazo[2,1-b]benzothiazoles as potential anti-cancer agents

A new series of Mannich bases of 2-arylimidazo[2,1-b]benzothiazoles were synthesized and evaluated for their anti-cancer activity. These compounds showed better cytotoxicity activity with IC₅₀ values ranging from 2.8 to 8.0 μM in HepG2, MCF-7 and HeLa cell lines. Further mechanism aspects responsible for the anti-cancer activity of two promising compounds 3c and 3f in HepG2 cell line were studied. Interestingly, 3c, 3f induced G2/M cell cycle arrest with down regulation of cyclin B and up regulation of Chk2 protein. Moreover, compounds 3c, 3f also showed the characteristic features of apoptosis such as enhancement in the levels of caspase-3. Treatments with compounds led to a decrease in levels of vital cell proliferation proteins such as Jun (C-Jun, JunB), p38 MAPK, p-JNK and PKCα. The compound 3f of the series could be considered as the potential lead for its development as a novel anti-cancer agent.     

Novel naphthalimide derivatives as potential apoptosis-inducing agents: Design, synthesis and biological evaluation

A series of novel naphthalimide derivatives with flexible alkyl/aryl moieties were designed and synthesized. Their antitumor activities were evaluated against HeLa, A549, P388, HL-60, MCF-7, HCT-8 and A375 cancer cell lines in vitro. The preliminary results showed that most of the derivatives had comparable antitumor activities over Amonafide with the IC₅₀ values of 10⁻⁶ to 10⁻⁵ M. More importantly, flow cytometric analysis indicated that the derivatives could effectively induce G₂/M arrest and progress to apoptosis in HL-60 cell line after double staining with annexin V–FITC and propidium iodide. The present work provided a novel class of naphthalimide-based derivatives with potent apoptosis-inducing and antitumor activities for further optimization.     

Chemopreventive properties of trans-resveratrol against the cytotoxicity of chloroacetanilide herbicides in vitro

The beneficial effect of trans-resveratrol (RESV) on health is well documented. Our aim was to study the putative preventive effect of RESV on the cytotoxicity of frequently used herbicides (alachlor, acetochlor). Estrogen receptor positive (ER+) MCF-7 human mammary carcinoma, HepG2 (ER+) human hepatocellular carcinoma and VERO estrogen receptor negative (ER-) non-transformed monkey fibroblast cell lines were treated with alachlor and acetochlor (2-500 microg/ml) as toxic agents, and RESV (10 microM) as preventive agent. The MTT dye reduction assay was performed to test cytotoxicity, and flow cytometry to test cell proliferation and apoptosis. RESV is not cytotoxic in the concentration range of 1-100 microM on neither cell lines examined after 24 h, but cytotoxic on Vero and MCF-7 cells at 100 microM after 48h, and on all three cell lines after 72 h. On both ER+ cell lines a stimulation of viability occurs in the low concentration range (0.5-12.5 microM) as detected by the MTT assay. Cell cycle analysis of the culture shows a significant increase of S-phase cells at low concentrations of RESV (10-50 microM) and a decrease in the 100-200 microM concentration range. The ratio of apoptotic cells significantly increases after the administration of 50 microM RESV, depending on the incubation time. The cytotoxicity of 20-65 microg/ml alachlor and 10-65 microg/ml acetochlor was significantly decreased by the addition of 10 microM RESV in Vero ER- cells whereas no significant change was detected on ER+ cell lines MCF-7 and HepG2. These results show that RESV protects non-transformed ER- cells, but has no such effect on ER+ tumor cells.     

Genotoxicity and oxidative stress biomarkers in Carassius gibelio as endpoints for toxicity testing of Ukrainian polluted river waters

This study aimed to assess oxidative stress and genotoxicity biomarkers in Prussian carp Carassius gibelio laboratory-exposed to water from polluted Ukrainian rivers in order to evaluate their usefulness as endpoints in a short-term bioassay for toxicity testing of freshwaters. The micronucleus (MN) test and the frequency of cells with double nuclei (DN) in erythrocytes and gill cells were used as indicators of chromosome aberrations and abnormalities in cell divisions, respectively. Cellular antioxidant defenses i.e. antioxidant enzyme activities (catalase, Se-dependent glutathione peroxidase, total glutathione peroxidase and glutathione-S-transferase) and oxidative damage, i.e. lipid peroxidation (measured as thiobarbituric acid reactive substances) in the fish liver were used as biomarkers of oxidative stress. Exposure to the polluted river water samples for 96 h resulted in significantly increased MN and DN frequencies, limited increases in antioxidant enzyme activities and no changes in lipid peroxidation. Results suggest that MN and DN frequencies in C gibelio are useful endpoints in a short-term bioassay for genotoxicity testing of environmental water samples in contrast to the oxidative stress biomarkers applied that showed low potential for assessing sublethal effects after a 96 h exposure.     

Synthesis and cytotoxic activity of benzo[a]acronycine and benzo[b]acronycine substituted on the A ring

The impact of substitutions at position 10 in the A ring of the cytotoxic benzo[a]acronycine and benzo[b]acronycine series has been explored. 10-Bromobenzo[a] and 10-bromobenzo[b]acronycine were prepared in 12% and 15% yield respectively from commercially available chemicals. Their 1,2-dihydro-1,2-dihydroxy diesters were synthesized. The different derivatives were tested against two cell lines KB-3-1 and L1210. Their cytotoxic activities were found in the same range of magnitude as their non-substituted counterparts. These structure-activity relationships permitted to conclude that the introduction of a substituent at position 10 maintains the activity in both the benzo[a] and [b]acronycine series and open the way to further pharmacomodulations.     

Ecofriendly degradation, decolorization and detoxification of textile effluent by a developed bacterial consortium

Present study illustrates the effectual decolorization and degradation of the textile effluent using a developed bacterial consortium SDS, consisted of bacterial species Providencia sp. SDS and Pseudomonas aeuroginosa strain BCH, originally isolated from dye contaminated soil. The intensive metabolic activity of the consortium SDS led to complete decolorization of textile effluent within 20 h at pH 7 and temperature 30 °C. Significant induction in the activities of veratryl alcohol oxidase, laccase, azoreductase and DCIP reductase were observed during decolorization, which indicates their involvement in decolorization and degradation process. The decolorization and biodegradation was monitored using UV-vis spectroscopy, IR spectroscopy, HPLC and HPTLC analysis. Toxicological analysis of effluent before and after treatment was performed using classical Allium cepa test. Investigations of various toxicological parameters viz, oxidative stress response, cytotoxicity, genotoxicity and phytotoxicity, collectively concludes that, the toxicity of effluent reduces significantly after treatment with consortium SDS.     

Generation of an attenuated Salmonella-delivery strains expressing adhesin and toxin antigens for progressive atrophic rhinitis,and evaluation of its immune responses in a murine model

An expression/secretion plasmid containing genes encoding the FimA, CP39, PtfA, ToxA and F1P2 antigens associated with porcine pneumonic pasteurellosis and progressive atrophic rhinitis (PAR) was constructed and harbored in an attenuated Salmonella Typhimurium, which was used as the vaccine candidate. The immune responses induced by this delivery strain were investigated in a murine model. Each antigen secreted from the delivery strain was confirmed by Western blot analysis. Thirty BALB/c mice were divided equally into two groups; group A were intranasally inoculated with the mixture of the five delivery strains, and group B were inoculated with sterile PBS. In group A, all antigen-specific serum IgG were significantly increased compared to those of group B from the 2nd week post-inoculation (WPI) till the 8th WPI. All antigen-specific mucosal IgA in group A were also significantly greater than those of group B. In addition, the significant splenic lymphocyte proliferative responses, the elevations of CD3⁺CD4⁺, CD3⁺CD8⁺ and B-cell populations, and the induction of IFN-γ expression in group A were observed. In conclusion, the mixture of five delivery strains expressing specific antigen for these diseases was found to be capable of inducing significant humoral and cellular immune responses.     

A virosomal vaccine against candidal vaginitis: immunogenicity, efficacy and safety profile in animal models

A novel vaccine (PEV7) consisting of a truncated, recombinant aspartyl proteinase-2 of Candida albicans incorporated into influenza virosomes was studied. This vaccine candidate generated a potent serum antibody response in mouse and rat following intramuscular immunization. Anti-Sap2 IgG and IgA were also detected in the vaginal fluid of rats following intravaginal or intramuscular plus intravaginal administration. In a rat model of candidal vaginitis, PEV7 induced significant, long-lasting, likely antibody-mediated, protection following intravaginal route of immunization. PEV7 was also found to be safe in a repeated-dose toxicological study in rats. Overall, these data provide a sound basis to envisage the clinical development of this new candidate vaccine against candidal vaginitis.