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Special Issue "Recent Advances in Environmental Health Research: Health Disparities, Toxicology and Carcinogenesis. Part III"

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (30 June 2002)

Published Papers (7 papers)

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Research

Open AccessArticle Neurotoxic Activity of the HIV-1 Envelope Glycoprotein: Activation of Protein Kinase C in Rat Astrocytes
Int. J. Mol. Sci. 2002, 3(11), 1105-1116; doi:10.3390/i3111105
Received: 7 June 2002 / Accepted: 30 October 2002 / Published: 30 November 2002
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Abstract
Envelope glycoprotein (gp120) of the human immunodeficiency virus type one (HIV-1), has adverse effects on glial cells and neurons. This study reports on the direct effect of recombinant gp120 (r-gp120) produced from different expression systems on protein kinase C, as a measure of
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Envelope glycoprotein (gp120) of the human immunodeficiency virus type one (HIV-1), has adverse effects on glial cells and neurons. This study reports on the direct effect of recombinant gp120 (r-gp120) produced from different expression systems on protein kinase C, as a measure of relative neurotoxicity. Brain cells were grown in vitro from explants of the cerebral cortex of newborn rats, and recombinant gp120 preparations expressed in mammalian cell/vaccinia virus and insect cell/baculovirus systems were applied to astrocyte-enriched cultures. The gp120 preparations activated protein kinase C (PKC) to similar levels in these cells. Mutant recombinant gp120 lacking the amino-terminal 29 amino acids produced from the mammalian and insect cells also activated PKC to similar levels as did the full-length protein. The recombinant proteins specifically activated PKC β and ζ, suggesting that they are able to induce both Ca2+-dependent and Ca2+-independent isoforms of this enzyme. Alteration of PKC activity in astrocytes by gp120 indicates its ability to modulate gene expression, which is associated with the neurotoxicity of this protein. Furthermore, the results suggest that the deletion of the first 29 residues of NH2-terminal end of the gp120 does not affect the functional activity of this protein with regard to modulation of signal transduction in astrocytes. Full article
Open AccessArticle Differential Cytotoxicity and Gene Expression in Human Liver Carcinoma (HepG2) Cells Exposed to Arsenic Trioxide, and Monosodium Acid Methanearsonate (MSMA)
Int. J. Mol. Sci. 2002, 3(11), 1117-1132; doi:10.3390/i3111117
Received: 7 June 2002 / Accepted: 30 October 2002 / Published: 30 November 2002
Cited by 14 | PDF Full-text (210 KB) | HTML Full-text | XML Full-text
Abstract
Research in our laboratory has demonstrated that a trivalent form of arsenic such as arsenic trioxide (AT) has the ability to cause significant cytotoxicity, and induction of a significant number of stress genes in human liver carcinoma cells (HepG2). However, the literature also
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Research in our laboratory has demonstrated that a trivalent form of arsenic such as arsenic trioxide (AT) has the ability to cause significant cytotoxicity, and induction of a significant number of stress genes in human liver carcinoma cells (HepG2). However, the literature also indicates that the toxicity of arsenic depends on its chemical form. To test this hypothesis, we further evaluated the cellular and molecular responses of HepG2 cells following exposure to monosodium acid methanearsonate (MSMA), a pentavalent and organic form of arsenic. Cytotoxicity was evaluated using the MTT-assay for cell viability, while the gene profile assay was performed to measure the degree of gene induction in 13 different recombinant cell lines generated from a parental HepG2 cell line. Cytotoxicity experiments yielded LC50 values of 11.9 + 2.6 μg/mL for AT, and 257.3 + 51.4μg/mL for MSMA; indicating that AT was about 20 times more toxic than MSMA. Exposure of HepG2 cells to MSMA also resulted in a significant reduction (p < 0.05) in the number of stress genes induced, compared to AT. Upon MSMA exposure, only 2 (HMTIIA and HSP70) out of the 13 constructs evaluated yielded inductions to statistically significant levels (p < 0.05), compared to 11 (GSTYa, XRE, HMTIIA, c-fos, NF-kBRE, HSP70, p53RE, GADD153, GADD45, and GRP78) for AT. These results greatly support the hypothesis that the toxicity of arsenic compounds highly depends on their chemical forms; with the inorganic forms being more potent than the organic ones. Full article
Open AccessArticle Influence of Humic Acid on 1-Aminopyrene Ecotoxicity During Solar Photolysis Process
Int. J. Mol. Sci. 2002, 3(11), 1133-1144; doi:10.3390/i3111133
Received: 7 June 2002 / Accepted: 30 October 2002 / Published: 30 November 2002
Cited by 3 | PDF Full-text (197 KB) | HTML Full-text | XML Full-text
Abstract
1-Aminopyrene (1-AP), a polycyclic aromatic hydrocarbons (PAH) compound, is a major metabolite during biotransformation of 1-nitropyrene by microflora in natural environment and in the guts of animals and humans. Under UV-A irradiation, 1-AP has been shown to cause light-induced DNA single strand cleavage.
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1-Aminopyrene (1-AP), a polycyclic aromatic hydrocarbons (PAH) compound, is a major metabolite during biotransformation of 1-nitropyrene by microflora in natural environment and in the guts of animals and humans. Under UV-A irradiation, 1-AP has been shown to cause light-induced DNA single strand cleavage. Humic acids (HA) in aquatic ecosystems can influence the bioavailability, toxicity, and fate of organic xenobiotics. Therefore, photochemical fate and effect of PAH in natural aquatic environment may differ significantly across sites. The objectives of this study are to assess the time course (TC; 18 and 90 minutes) influence of HA (0, 20, and 60 ppm) on microbial ecotoxicity of 1-AP (0 and 10 μM) during solar photolysis process (PP). Microbial ecotoxicity of 1-AP during different time courses in the presence and absence of HA was measured with spread plate counting and microbial mineralization of 14C-D-glucose. The experimental results were analyzed as factorial arrangements of treatment in a complete randomized design using General Linear Model by SAS. LSMEANS was used to separate means or combination of means. Significant effect on glucose mineralization was found by the following treatment interactions 1-AP*TC, 1-AP*PP, TC*PP, HA*1-AP*TC, HA*1-AP*PP, and HA*1-AP*TC*PP. The treatment interaction HA*1-AP was the only one affecting spread plate counting. In the groups exposed to 1-AP (10 μM), microbial heterotrophic mineralization of 14C-D-glucose was significantly inhibited in the presence of HA in light and in darkness. Exposure to HA in light and darkness, however, did not necessarily inhibit bacterial viability at the HA concentration range assayed. Therefore, inhibition on microbial activity could have been caused by multiple factors, instead of toxicity of HA alone. Full article
Open AccessArticle Bioorganic Studies in AIDS: Synthetic Antifungals Against Pneumocystis carinii Based on the Multivalency Concept
Int. J. Mol. Sci. 2002, 3(11), 1145-1161; doi:10.3390/i3111145
Received: 7 June 2002 / Accepted: 30 October 2002 / Published: 30 November 2002
Cited by 7 | PDF Full-text (330 KB) | HTML Full-text | XML Full-text
Abstract
We report the syntheses of antifungals containing the novel pharmacophores: oxaziridines, sulfonyloxaziridines, nitrones and nitronyl nitroxides. We hypothesized that multiple copies of the pharmacophore per molecule might be a prerequisite to enhance efficacy against the opportunistic pathogen, Pneumocystis carinii. Therefore structural optimization of
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We report the syntheses of antifungals containing the novel pharmacophores: oxaziridines, sulfonyloxaziridines, nitrones and nitronyl nitroxides. We hypothesized that multiple copies of the pharmacophore per molecule might be a prerequisite to enhance efficacy against the opportunistic pathogen, Pneumocystis carinii. Therefore structural optimization of the leads was based on this new “multivalency” approach. All bisoxaziridines were inactive, but a trisoxaziridine caused ca. 50% reduction of the number of P. carinii tropozoites, compared to TMP-SMX, and a hexaoxaziridine at 1 μg/ml showed activity comparable to the currently used drug, TMP-SMX. Insertion of three units of the nitronyl nitroxide pharmacophore per molecule afforded an antifungal triradical with activity comparable to TMP-SMX at 1 μg/ml; at 25 μg/ml and at 10 μg/ml the triradical was better. The results lend further support to the oxidoredox pharmacophore hypothesis, and the enhancement of activities observed demonstrates the high potential and benefits of applying the concept of multivalency to drug development. Full article
Open AccessArticle Differential Gene Expression of Fibroblasts: Keloid versus Normal
Int. J. Mol. Sci. 2002, 3(11), 1162-1176; doi:10.3390/i3111162
Received: 7 June 2002 / Accepted: 30 October 2002 / Published: 30 November 2002
Cited by 2 | PDF Full-text (324 KB) | HTML Full-text | XML Full-text
Abstract
This study investigated gene regulation and unique gene products in both keloid (KDF) and normal (NDF) dermal fibroblasts in established cell lines. For gene regulation, NDF versus KDF were compared using Clontech's Atlas™ Human cDNA Expression Array while unique gene products were studied
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This study investigated gene regulation and unique gene products in both keloid (KDF) and normal (NDF) dermal fibroblasts in established cell lines. For gene regulation, NDF versus KDF were compared using Clontech's Atlas™ Human cDNA Expression Array while unique gene products were studied using RNA Fingerprinting Kit. RNA from each sample was converted to cDNA using oligo-dT primers. Down-regulated genes using Atlas Array in KDF were 1) 60 S ribosomal protein, 2) Thioredoxin dependent peroxidase, 3) Nuclease sensitive element DNA binding protein, 4) c-myc purine-binding transcription factor, 5) c-AMP dependent protein kinase, and, 6) Heat Shock Protein 90 kDa. Genes that are up regulated in KDF were 1) Tubulin and 2) Heat Shock Protein 27 kDa. With the differential display, we found 17 bands unique to both KDF and NDF. The specific gene and the manner in which they were differentially regulated have direct implications to understanding keloid fibroblast proliferation. Full article
Open AccessArticle Expression of Chemokines, MIP-1alpha and RANTES in Caprine Lentiviral Infection and Their Influence on Viral Replication
Int. J. Mol. Sci. 2002, 3(11), 1177-1187; doi:10.3390/i3111177
Received: 7 June 2002 / Accepted: 30 October 2002 / Published: 30 November 2002
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Abstract
Chemokines belong to a super family of inducible and secreted, pro-inflammatory cytokines. They act primarily as chemoattractants and activators of specific types of leukocytes and are involved in a variety of immune and inflammatory responses. The status and role of chemokines, macrophage inflammatory
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Chemokines belong to a super family of inducible and secreted, pro-inflammatory cytokines. They act primarily as chemoattractants and activators of specific types of leukocytes and are involved in a variety of immune and inflammatory responses. The status and role of chemokines, macrophage inflammatory protein (MIP-1α) and RANTES (Regulated upon Activation Normal T-cell Expressed and Secreted) in the immunopathogenesis by caprine arthritis-encephalitis virus (CAEV) are not fully elucidated. The objectives of this study were to, 1) determine the expression MIP-1α in goat synovial membrane cells (GSM cells) infected in vitro, and peripheral blood mononuclear cells (PBMC) of CAEV infected goats by RT-PCR, and 2) effect of exogenous MIP-1α and on replication of CAEV in GSM cells in vitro. RT-PCR results indicated higher expression of MIP-1α in PBMC of CAEV-infected goats as compared to controls. Similarly, higher expression of MIP-1α was observed in GSMC infected in vitro with CAEV as compared to that in uninfected cells. Exogenous MIP-1α (20 ng/ml) and RANTES (20 ng/ml) significantly inhibited CAEV replication in GSM cells by 75% and 65%, respectively as compared to the replication in GSM cells not treated with the chemokines. Results of this study suggest that CAEV infection may alter the expression of chemokines in goats, which may suppress the replication of the virus. Full article
Open AccessArticle Interaction Energy Analysis of Nonclassical Antifolates with Pneumocystis carinii Dihydrofolate Reductase
Int. J. Mol. Sci. 2002, 3(11), 1188-1202; doi:10.3390/i3111188
Received: 7 June 2002 / Accepted: 30 October 2002 / Published: 30 November 2002
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Abstract
The x-ray structure of the Pneumocystis carinii dihydrofolate reductase (DHFR):trimethoprim:NADPH ternary complex obtained from the Protein Databank was used as a structural template to generate models for the following complexes: P. carinii DHFR:piritrexim:NADPH, P. carinii DHFR:epiroprim:NADPH, and P. carinii DHFR:trimetrexate:NADPH. Each of these
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The x-ray structure of the Pneumocystis carinii dihydrofolate reductase (DHFR):trimethoprim:NADPH ternary complex obtained from the Protein Databank was used as a structural template to generate models for the following complexes: P. carinii DHFR:piritrexim:NADPH, P. carinii DHFR:epiroprim:NADPH, and P. carinii DHFR:trimetrexate:NADPH. Each of these complexes, including the original trimethoprim complex was then modeled in 60 angstrom cubes of explicit water and minimized to a rms gradient between 1.0 to 3.0 x 10-5 kcal/angstrom. Subsequently, each antifolate structure was subdivided into distinct substructural regions. The minimized complexes were used to calculate interaction energies for each intact antifolate and its corresponding substructural regions with the P. carinii DHFR binding site residues, the DHFR protein, the solvated complex ( which consists of P. carinii DHFR, NADPH, and solvent water), solvent water alone, and NADPH. Antifolate substructural regions which contained nitrogen and carbon atoms in an aromatic environment (i. e. the pteridyl, pyridopyrimidinyl, and diaminopyrimidinyl subregions) contributed most to the stability of antifolate interactions, while interaction energies for the hydrocarbon aromatic rings, methoxy, and ethoxy groups were much less stable. Additionally, interaction energy analyses were calculated for carbon and nitrogen atoms of the pteridyl, pyridopyrimidinyl, and diaminopyrimidinyl subregions and for the carbon and oxygen atoms of methoxy and ethoxy subregions. The contributions of hydrogen atoms were included with those of the carbon, nitrogen and oxygen atoms to which they are attached. These analyses revealed that the carbon atoms of the pteridyl, pyridopyrimidinyl, and diaminopyrimidinyl subregions generally contributed most to the stability of those regions. Carbon atoms also contributed favorably to the stability of the methoxy group interactions. Those substructural regions which exhibit relatively unfavorable interaction energies may constitute important modification targets in the design of improved P. carinii DHFR inhibitors. Interaction energies for different groups of atoms within the substructural regions suggest strategies for modification of the substructural regions. Full article

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