Efficiency of butyl rubber sorbent to remove the PAH toxicity.

Large amounts of polycyclic aromatic hydrocarbons (PAHs) have been released to the marine environment as a result of oil spills and from other sources including wastewaters, surface runoff, industrial processes, atmospheric deposition, biosynthesis, and natural events such as forest fires. PAHs have been known to affect a variety of biological processes and can be potent cell mutagens/carcinogens and toxic. In this study, PAH toxicity removal was investigated by using a novel macroporous butyl rubber (BR) sorbent. To find out the toxicity removal efficiency of the sorbents, the toxicity tests with Vibrio fisheri (luminescence bacteria) and Phaeodactylum tricornutum (marine algae) were applied to the acenaphthene (Ace) and phenanthrene (Phen) solutions in seawater (Ace: 500- 1000 µg/L; Phen; 100-1000 µg/L) before and after sorbent applications. Additionally, lysosomal stability and filtration rate biomarker techniques were applied to the mussels (Mytilus galloprovincialis) exposed to 1000 µg/L Phen solution and bioaccumulation was measured. The results showed that the toxicity of the PAH solutions decreased 50-100 percent depending on the concentration of the solutions and organisms. Phaeodactylum was found as the most sensitive organism to Phen and Ace. Since the application of BR sorbent removed the Phen from the solution, the bioaccumulated Phen amount in the mussels decreased accordingly.

Acenaphtho[1,2-b]pyrrole-based selective fibroblast growth factor receptors 1 (FGFR1) inhibitors: design, synthesis, and biological activity.

A novel series of acenaphtho[1,2-b]pyrrole derivatives as potent and selective inhibitors of fibroblast growth factor receptor 1 (FGFR1) were designed and synthesized. In silico target prediction revealed that tyrosine kinases might be the potential targets of the representative compound 2, which was subsequently validated by enzyme-linked immunosorbent assay (ELISA) for its selective and active FGFR1 inhibition of various tyrosine kinases. The structure-activity relationship (SAR) analysis aided by molecular docking simulation in the ATP-binding site demonstrated that acenaphtho[1,2-b]pyrrole carboxylic acid esters (2-5) are potent inhibitors of FGFR1 with IC(50) values ranging from 19 to 77 nM. Furthermore, these compounds exhibited favorable growth inhibition property against FGFR-expressing cancer cell lines with IC(50) values ranging from micromolar to submicromolar. Western blotting analysis showed that compounds 2, 3, and 2b inhibited activation of FGFR1 and extracellular-signal regulated kinase 1/2 (Erk1/2).

Toxicity of xenobiotics during sulfate, iron, and nitrate reduction in primary sewage sludge suspensions.

The effect and persistence of six organic xenobiotics was tested under sulfate-, iron-, and nitrate-reducing conditions in primary sewage sludge suspensions. The xenobiotics tested were acenaphthene, phenanthrene, di(2-ethylhexyl)phthalate (DEHP), 4-nonylphenol (4-NP), linear alkylbenzene sulfonate (LAS), and 1,2,4-trichlorobenzene (1,2,4-TCB) added to initial analytical concentrations of 54-117 mgL(-1). The suspensions were incubated at 30 degrees C for 15 weeks and rates of sulfate, iron, and nitrate reduction were estimated from the time course of hydrogen sulfide accumulation, Fe(II) accumulation, and nitrate depletion, respectively. Chemical analysis showed that the xenobiotics were persistent under the different electron acceptor regimes for the duration of the experiment. This was partly attributed to low bioavailability and microbial toxicity of the xenobiotics. Rates of anaerobic respiration in control suspensions (without added xenobiotics) showed a weekly reduction potential of 0.84 mM SO(4)(2-), 0.92 mM Fe(III), and 9.25 mM NO(3)(-). All three processes were completely inhibited by 1,2,4-TCB (54 mgL(-1)) whereas there was no significant (P<0.05) toxicity of phenanthrene (109 mgL(-1)) and DEHP (105 mgL(-1)). Sulfate reduction was inhibited completely by LAS (105 mgL(-1)), 76% by acenaphthene (54 mgL(-1)) and 57% by 4-NP (117 mgL(-1)), and likewise iron reduction was inhibited 62% by LAS and 55% by 4-NP (the latter though at P<0.10). Nitrate reduction was not significantly inhibited by acenaphthene and 4-NP and furthermore was resistant to LAS toxicity (105 mgL(-1)). Nitrate reduction also had the highest potential for mineralization of organic matter and thus was the most robust of the tested anaerobic processes in the sewage sludge suspensions.

Novel acenaphtho[1,2-b]pyrrole-carboxylic acid family: synthesis, cytotoxicity, DNA-binding and cell cycle evaluation.

A family of 8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carboxylic acid derivatives were synthesized as a result of our efforts to modify a series of acenaphthopyrrole aromatic-heterocycle compounds that proved to be potent anticancer drugs. Among the derivatives, 3d (3-(dimethylamino-propylamino)-8-oxo-8H-acenaphtho-[1,2-b]pyrrole-9-carboxylic acid) and 3g (3-piperidine-8-oxo-8H-acenaphtho-[1,2-b]pyrrole-9-carboxylic acid) showed potential anticancer activity and different action mechanism from our previously reported compounds. UV-vis absorption, circular dichroism and viscosity measurement indicated that effect of both compounds on the advanced DNA conformation was different, although they could bind to DNA in the same way. Cell cycle analysis showed that 3d could induce S-phase arrest followed by apoptosis, while 3g induced apoptosis. The results seem to imply that different action mechanism could contribute to the dissimilitude of biological activities toward 3d and 3g.

DNA double helix unwinding triggers transcription block-dependent apoptosis: a semiquantitative probe of the response of ATM, RNAPII, and p53 to two DNA intercalators.

We have previously shown the binding modes of two DNA interacting analogues (1)a {3-(4-methyl-piperazin)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile} and (3)a {3-(3-dimethylamino-propylamino)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile} with the DNA double helix. In this study, we have determined the notably different DNA damage signal pathway elicited by (1)a and (3)a due to the different extents to which they unwind the DNA double helix. First, we have identified that ataxia-telangiectasia-mutated (ATM) protein kinase can respond to DNA double helix unwinding caused by both (1)a and (3)a. In addition, the amount of ATM activation is consistent with the degree to which the DNA double helix was unwound. Consequently, we used (1)a and (3)a to semiquantitatively probe the response of RNA polymerase II (RNAPII) and p53 toward DNA double helix unwinding in vivo. By means of flow cytometry, immunocytochemistry, ChIP, quantitative real-time polymerase chain reaction, and Western blot analyses, we measured the level of p53 and RNAPII phosphorylation, in addition to the dynamics of the RNAPII distribution along the c-Myc gene. These results provided novel evidence for the impact of subtle DNA structural changes on the activity of RNAPII and p53. Moreover, DNA double helix conformational damage-dependent apoptosis was studied for the first time. These results indicated that (1)a can induce transcriptional blockage following a shift of the unphosphorylated IIa form of RNAPII to the phosphorylated IIo form, while (3)a is unable to induce the same effect. Subsequently, p53 accumulation and phosphorylation events occur that lead to apoptosis in the case of (1)a exposure. This suggests that the transcriptional blockage is also correlated to the degree of double helix unwinding. Furthermore, we found that the degree of DNA conformational damage determines whether or not apoptosis occurs through transcriptional blockage. Under our experimental conditions, ATM does not participate in the downstream events even when it has been activated. Thus, p53-mediated apoptosis may be independently triggered by transcriptional blockage.

An environmental quinoid polycyclic aromatic hydrocarbon, acenaphthenequinone, modulates cyclooxygenase-2 expression through reactive oxygen species generation and nuclear factor kappa B activation in A549 cells.

Diesel exhaust particles (DEPs) contain oxygen-containing polycyclic aromatic hydrocarbons (PAHs) called quinoid PAHs. Some quinoid PAHs generate free radicals as they undergo enzymatic and nonenzymatic redox cycling with their corresponding semiquinone radicals. Reactive oxygen species (ROS) produced by these reactions can cause severe oxidative stress connected with inflammatory processing. Although humans and animals are continuously exposed to these chemicals in the environment, little is known about which quinoid PAHs are active. In this study, we estimated the intracellular ROS production and nuclear factor kappa B (NF-kappaB) translocation in A549 cells exposed to isomers of quinoid PAHs having two to four rings. We found that both acenaphthenequinone (AcQ) and 9,10-phenanthrenequinone (PQ) enhanced ROS generation and that AcQ translocated NF-kappaB from the cytosol to the nucleus. However, PQ, which has been reported to induce apoptosis, did not influence NF-kappaB activation. In addition, AcQ induced cyclooxygenase-2 (COX-2) expression which is a key enzyme in the inflammatory processing involved in the activation of NF-kappaB. Upregulation of NF-kappaB and COX-2 expression by AcQ treatment was suppressed by the antioxidant N-acetylcysteine (NAC). These results provide that AcQ might play an important role in human lung inflammatory diseases as an air pollutant.

Ability of 16 priority PAHs to be directly cytotoxic to a cell line from the rainbow trout gill.

Sixteen polycyclic aromatic hydrocarbons (PAHs) were screened for their ability to be directly cytotoxic to a cell line from the rainbow trout gill, RTgill-W1. Exposure times of 2 h or less were sufficient for direct cytotoxicity to be detected, which appeared to be caused by a common mechanism, the general perturbation of membranes. This was judged by the similarity of results obtained for three fluorescent indicator dyes, alamar Blue, 5-carboxyfluorescein diacetate acetoxymethyl ester (CFDA-AM) and neutral red. Among the 16 PAHs tested, just two- and three-ring PAHs were found to be directly cytotoxic. These were naphthalene approximately = acenaphthylene approximately = acenaphthene > fluorene approximately = phenanthrene. The results suggest that water solubility and lipophilicity are the critical properties determining the direct cytotoxicity of PAHs and that they do so by influencing PAH accumulation in membranes. Only naphthalene was effective at concentrations well below its water solubility limit. Therefore, direct cytotoxicity is likely to be most environmentally relevant only with naphthalene.

Assessment of the mutagenic activity of some acenaphtho(1,2-b)quinolines.

The mutagenic activity of four substituted acenaphtho(1,2-b)quinolines were evaluated using the Ames test (Salmonella assay). The compounds tested were acenaphtho(1,2-b)quinoline (1) and its 10-methoxy (2), 10-methyl (3) and 10-nitro (4) derivatives. Compounds 1 and 3 were found to be non-mutagenic, but compound 2 was found to be mutagenic with metabolic activation only. However, compound 4 was found to be very active with or without activation.