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PubMed2006

Prevention of severe toxic liver injury and oxidative stress in MCP-1-deficient mice.

BACKGROUND/AIMS: Administration of carbon tetrachloride determines liver injury, inflammation and oxidative stress, but the molecular mechanisms of damage are only partially understood. In this study, we investigated the development of acute toxic damage in mice lacking monocyte chemoattractant protein-1 (MCP-1), a chemokine which recruits monocytes and activated lymphocytes. METHODS: Mice with targeted deletion of the MCP-1 gene and wild type controls were administered a single intragastric dose of carbon tetrachloride. Serum liver enzymes, histology, expression of different chemokines and cytokines, and intrahepatic levels of oxidative stress-related products were evaluated. RESULTS: Compared to wild type mice, peak aminotransferase levels were significantly lower in MCP-1-deficient animals. This was paralleled by a delayed appearance of necrosis at histology. In addition, MCP-1-deficient mice showed a shift in the pattern of infiltrating inflammatory cells, with a predominance of polymorphonuclear leukocytes. Lack of MCP-1 was also accompanied by reduced intrahepatic expression of cytokines regulating inflammation and tissue repair. The increase in tissue levels of reactive oxygen species and 4-hydroxy-nonenal following administration of the hepatotoxin was also significantly lower in animals lacking MCP-1. CONCLUSIONS: Lack of MCP-1 affords protection from damage and development of oxidative stress in a toxic model of severe acute liver injury.

Aldehydes↗
PubMed2005

Pathogenesis of nigral cell death in Parkinson's disease.

Parkinson's disease (PD) is primarily a sporadic condition which results mainly from the death of dopaminergic neurons in the substantia nigra. Its etiology remains enigmatic while its pathogenesis begins to be understood as a multifactorial cascade of deleterious factors. As of yet, most insights into PD pathogenesis are derived from toxic models of PD and show that the earlier cellular perturbations arising in dopaminergic neurons include oxidative stress and energy crisis. These alterations, rather than killing neurons, trigger subsequent death-related molecular pathways including elements of apoptosis. The fate of dopaminergic neurons in PD may also be influenced by additional factors such as excitotoxicity, emanating from the increased glutamatergic input from the subthalamic nucleus to the substantia nigra, and the glial response that arises in the striatum and the substantia nigra. In rare instances, PD can be familial, and those genetic forms have also provided clues to the pathogenesis of nigrostriatal dopaminergic neuron death including abnormalities in the mechanisms of protein folding and degradation as well as mitochondrial function. Although more remains to be elucidated about the pathogenic cascade in PD, the compilation of all of the aforementioned alterations starts to shed light on why and how nigral dopaminergic neurons may degenerate in this prominent disease, that is PD.

Cell Death↗
PubMed2005

Assessing the potential of fish cell lines as tools for the cytotoxicity testing of estuarine sediment aqueous elutriates.

In the present study, we assess the potential of fish cell lines (CHSE, EPC and RTG-2) to be used as screening tools for the ecotoxicological assessment of estuarine sediments. The processing of sediment to a form suitable for in vitro exposure is an inherent problem when using cell cultures. The approach employed in this study was to prepare aqueous elutriate extracts from whole sediments, which were subsequently used to reconstitute powdered media. This procedure allowed the exposure of cell cultures to concentrations of up to and including 100% of the original aqueous sample. Cytotoxicity was assessed using multiple endpoint measurements. Cell viability was quantified using the neutral red and alamar blue colorimetric assays, which specifically assess lysosomal and mitochondrial function, respectively. In addition, the total protein content of the cells was measured using the coomassie blue assay. Initial tests were conducted to ensure that any resultant cytotoxicity was due to sample contaminants and not osmotic stress. In addition, elutriate samples were spiked with a model toxicant to verify the ability of the cell lines to detect and respond to bioavailable contaminants. Chemical analyses were conducted on sediments from all sampling sites to assist in interpreting any observed cytotoxicity. A differential response was observed for the cytotoxicity assays following exposure treatments, which emphasises the importance of employing multiple endpoints for the determination of toxicity. Of the three cell lines utilised in this study, RTG-2 cells were the most suitable for the testing of estuarine aqueous elutriate samples on the basis of tolerance to osmolality effects. Slight toxicity was observed following exposure to the aqueous elutriates tested in this study using RTG-2 cells and the alamar blue assay. In order to fully evaluate the overall sensitivity of this cell line, further research is warranted using an extensive range of test sites incorporating more polluted sediments.

Animal Testing Alternatives↗
PubMed2003

Mitogenic properties of endogenous and pharmacological doses of macrophage inflammatory protein-2 after 70% hepatectomy in the mouse.

Recent studies show CXC chemokine elevations after hepatic resection; blockade of epithelial neutrophil-activating protein (ENA-78), a CXC chemokine, retards hepatic regeneration after resection. Additional studies demonstrate that exogenous macrophage inflammatory protein (MIP)-2, another CXC chemokine, is therapeutic in a murine acetaminophen toxicity model when other therapies fail. The current investigations study MIP-2's effects on the cellular mechanisms involved in liver regeneration in mice after 70% hepatectomy. Administration of exogenous MIP-2 after 70% hepatectomy dramatically increased hepatocyte proliferation as measured by 5-bromo-2'-deoxyuridine staining. Signal transducer and activator of transcription-3 (stat-3) was also detected in greater abundance and persisted in hepatic nuclear extracts from MIP-2-treated mice compared with control mice after hepatic resection. Further, inhibition of the MIP-2 receptor, CXCR2, decreased baseline hepatocyte proliferation and stat-3 expression in the setting of partial hepatectomy. These data show that MIP-2 is important for hepatocyte proliferation after partial hepatectomy and that pharmacological MIP-2 doses after hepatic injury accelerate hepatic regeneration.

Animals↗
PubMed2001

Toxicokinetic interactions and survival of Hyalella azteca exposed to binary mixtures of chlorpyrifos, dieldrin, and methyl mercury.

Chemical mixture interactions of chlorpyrifos, dieldrin, and methyl mercury were evaluated in Hyalella azteca. Survival of adult and juvenile organisms was evaluated following exposure to individual chemicals and in binary combinations. Binary interactions of the model chemicals on survival of adult and juvenile H. azteca were evaluated by concentration-response curve analysis as additive, synergistic, antagonistic, or independent. Chlorpyrifos and methyl mercury interacted additively, while dieldrin interacted independently with both chlorpyrifos and methyl mercury. Toxicodynamic interactions were evaluated by measuring accumulation and elimination of each model toxicant in the presence of a second toxicant. Chlorpyrifos significantly increased the amount of methyl mercury accumulated in the first 12 h of exposure. Dieldrin did not interact with chlorpyrifos or methyl mercury in the accumulation or elimination experiments. Accumulation of chlorpyrifos was not observed. Results of the current investigation demonstrate that chlorpyrifos and methyl mercury interact additively, which would otherwise be predicted to act independently.

Animals↗
PubMed2003

Acute waterborne nickel toxicity in the rainbow trout (Oncorhynchus mykiss) occurs by a respiratory rather than ionoregulatory mechanism.

The acute mechanism of toxicity of waterborne nickel (Ni) was investigated in the rainbow trout (Oncorhynchus mykiss) in moderately hard ( approximately 140 mg l(-1) as CaCO(3)) Lake Ontario water, where the 96-h LC(50) for juvenile trout (1.5-3.5 g) was 15.3 mg (12.7-19.0, 95% C.L.) dissolved Ni l(-1). No marked impact of Ni exposure on average unidirectional or net fluxes of Na(+), Cl(-), or Ca(2+) was observed in juvenile trout exposed for 48-60 h to 15.6 mg Ni l(-1) as NiSO(4). Furthermore, when adult rainbow trout (200-340 g) were fitted with indwelling dorsal aortic catheters and exposed for 117 h to 11.6 mg Ni l(-1) as NiSO(4), plasma ions (Na(+), Cl(-), Ca(2+), and Mg(2+)) were all well conserved. However, mean arterial oxygen tension dropped gradually to approximately 35% of control values. This drop in P(aO(2)) was accompanied by an acidosis primarily of respiratory origin. P(aCO(2)) rose to more than double control values with a concomitant drop in arterial pH of 0.15 units. Acute respiratory toxicity was further evidenced by a significant increase in hematocrit (Ht), and plasma lactate, and a significant decrease in spleen hemoglobin (Hb). Following 117 h of exposure to 11.6 mg Ni l(-1), the gill, intestine, plasma, kidney, stomach, and heart accumulated Ni significantly, with increases of 60, 34, 28, 11, 8, and 3-fold, respectively. Brain, white muscle, liver, and bile did not significantly accumulate Ni. Plasma Ni exhibited a remarkable linear increase with time to levels approximately 30-fold higher than controls. We conclude that in contrast to most other metals, Ni is primarily a respiratory, rather than an ionoregulatory, toxicant at exposure levels close to the 96-h LC(50). The implications of a waterborne metal as an acute respiratory toxicant (as opposed to ionoregulatory toxicants such as Cu, Ag, Cd, or Zn) with respect to toxicity modeling are discussed.

Acid-Base Equilibrium↗
PubMed2000

Sensitivity of characteristic riverine insects, the caddisfly Cyrnus trimaculatus and the mayfly Ephoron virgo, to copper and diazinon.

This study reports the effects of two model toxicants, copper and diazinon, on two characteristic riverine insect species, the caddisfly Cyrnus trimaculatus and the mayfly Ephoron virgo. It was demonstrated that these species are very sensitive to both compounds in comparison with aquatic insects traditionally used in ecotoxicity tests. For diazinon, the 96-h LC(50) value of Cyrnus trimaculatus (1.1 microg/l) is lower than for any other insect species known from the literature and for copper it was demonstrated that Ephoron virgo is among the most sensitive aquatic insect species. The observed low LC(50) values stress the importance of using these indigenous species in assessing the risk of environmental contaminants in large European rivers and in defining conditions for ecological recovery.

Journal Article↗
PubMed2002

Neuroprotective effect of the monoamine oxidase inhibitor PF 9601N [N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine] on rat nigral neurons after 6-hydroxydopamine-striatal lesion.

Monoamine oxidase B (MAO-B) inhibitors are potentially useful in the therapeutic treatment of Parkinson's disease. L-Deprenyl has been shown to slow nigrostriatal tract degeneration in human idiopathic Parkinsonism and to be an effective neuroprotector in experimental 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity models. However, L-amphetamine and (-)methamphetamine, the metabolites generated by L-deprenyl, can have adverse and severe side-effects. Therefore, the search for new MAO-B inhibitors without potential amphetamine-like properties is a matter of great therapeutic interest. The present report is the first to describe the neuroprotective effect--following chronic intraperitoneal (i.p.) treatment--of a novel and non-amphetaminic MAO-B inhibitor, [N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine] (PF 9601N), on the neurodegeneration of nigral dopaminergic neurons caused by administration of intrastriatal 6-hydroxydopamine (6-OHDA). Two groups of six animals were unilaterally injected with 6-OHDA in the right striatum. One group was treated daily with 60 mg/kg PF 9601N i.p., starting before stereotaxic lesion and continuing for 18 days thereafter. The other group was treated with vehicle solution. Coronal slabs including the substantia nigra pars compacta (SNpc) were processed for tyrosine hydroxylase immunohistochemistry (TH). The number of TH positive (TH+) neurons in the SNpc was 60% lower in 6-OHDA lesioned rats. However, the loss of TH+ neurons in the SNpc was only 30% in PF 9601N i.p.-treated animals. Therefore, treatment with the specific MAO-B inhibitor significantly reduced the 6-OHDA-induced degeneration to about 50%.

Animals↗
PubMed2003

Practicing cementing technique with a toy: Play-Doh.

Cementing technique has direct impact on the longevity of a total hip arthroplasty, and the proper technique can only be acquired by practice. Using acrylic bone cement to practice cementing technique in a bioskill workshop is expensive and can cause occupational hazards. In this article, we describe a toy that can replace acrylic bone cement in a bioskill workshop. Play-Doh (Hasbro Inc, Pawtucket, RI) is an inexpensive, reusable and non-toxic modeling toy that mimics the doughy phase of acrylic bone cement.

Arthroplasty, Replacement, Hip↗
PubMed2005

A comparative study of unrelaxed surfaces on quartz and kaolinite, using the periodic density functional theory.

To investigate surface properties of fractured silica particles, which are commonly connected to the etiology of silica toxicity, models of low-index unrelaxed surfaces of quartz and kaolinite were constructed and analyzed using the periodic density functional theory calculations. The models were used to investigate surface sites that emerge in the processes of heterolytic and homolytic cleavage of quartz. It is found that the quartz surface is stabilized by two types of interactions. One, due to a more even charge distribution of sites, was characterized by surface energies of up to 0.025 eV x A(-2) and the other, due to a more even oxygen distribution between complementary surfaces, was up to 0.036 eV x A(-2). The total specific surface energies of unrelaxed surfaces ranged from 0.161 to 0.200 eV x A(-2) for quartz and from 0.017 to 0.158 eV x A(-2) for kaolinite. For the conchoidal fracture of quartz an average specific surface energy of 0.187 eV x A(-2) was obtained. These results provide a foundation for further characterization of the surface properties of mechanically comminuted respirable silica particulate and for reduction of occupational health hazards due to pulverized silica.

Chemistry, Physical↗
PubMed2006

Identification of early proteomic markers for hepatic steatosis.

The identification of biomarkers for disease state, drug efficacy, and toxicity is becoming increasingly important for drug discovery and development. We have used two-dimensional differential in-gel electrophoresis and mass spectrometry to identify proteomic markers associated with hepatocellular steatosis in rats after dosing with a compound (CDA) in preclinical development. Rats were dosed daily for up to 5 days with CDA for measurement of blood biochemical parameters, histological, and proteomic analysis. Alterations in plasma glucose and liver transaminases were detected from dosing day 3 onward, and livers showed trace levels of hepatocellular vacuolation from 6 h which increased in extent and severity over the 5 day time course. The number of significantly altered protein spots increased over the 5 day time course, and Ingenuity Pathway Analysis showed that the predominant functions altered by CDA treatment were cell death and cellular assembly and organization. This included alterations in secreted proteins, endoplasmic reticulum and mitochondrial chaperones, antioxidant proteins, and enzymes involved in fatty acid biosynthesis. Comparative in vitro dosing studies showed similar alterations to the proteome, neutral lipid accumulation, and mitochondrial dehydrogenase activity in response to CDA treatment of cultured rat hepatocytes. The finding that several proteins showed significant changes in abundance before the onset of overt toxicity in vivo suggested that these could serve as predictive biomarkers of compounds with a propensity to induce liver steatosis. These markers underwent further direct analysis in the in vitro hepatocyte toxicity model to determine their utility in the development of high throughput assays for drug-induced steatosis.

Animals↗
PubMed2003

Hepatoprotective and free radical scavenging effects of Nelumbo nucifera.

Ethanol extracts from Nelumbo nucifera (ENN) seeds were studied for possible antioxidative and hepatoprotective effects. Antioxidative effects were measured spectrophotometrically by reduction of 2,2'-Diphenyl-1-picrylhydrazyl (DPPH) radicals. Hepatoprotective effects were tested using carbon tetrachloride (CCl4) and aflatoxin B1 (AFB1)-induced hepatocyte toxicity models. ENN showed potent free radical scavenging effects with a median inhibition concentration of 6.49 microg/ml. Treatment of hepatocytes with ENN inhibited both the production of serum enzymes and cytotoxicity by CCl4. The genotoxic and cytotoxic effects of AFB1 were also inhibited by ENN in dose-dependent manners. These hepatoprotective effects of ENN against CCl4 and AFB1 might result from its potent antioxidative properties.

Aflatoxin B1↗
PubMed2001

Dynamic mimicry in an Indo-Malayan octopus.

During research dives in Indonesia (Sulawesi and Bali), we filmed a distinctive long-armed octopus, which is new to science. Diving over 24 h periods revealed that the 'mimic octopus' emerges during daylight hours to forage on sand substrates in full view of pelagic fish predators. We observed nine individuals of this species displaying a repertoire of postures and body patterns, several of which are clearly impersonations of venomous animals co-occurring in this habitat. This 'dynamic mimicry' avoids the genetic constraints that may limit the diversity of genetically polymorphic mimics but has the same effect of decreasing the frequency with which predators encounter particular mimics. Additionally, our observations suggest that the octopus makes decisions about the most appropriate form of mimicry to use, allowing it to enhance further the benefits of mimicking toxic models by employing mimicry according to the nature of perceived threats.

Animals↗
PubMed2001

Preclinical in vivo antitumor efficacy of nedaplatin with gemcitabine against human lung cancer.

The antitumor efficacy of the combination of nedaplatin (NDP) with gemcitabine (GEM) was evaluated. We also compared the antitumor activity of NDP plus GEM with that of cisplatin (CDDP) plus GEM or carboplatin (CBDCA) plus GEM. Ma44, which is a human lung cancer sensitive to GEM, and NCI-H460, which is a human lung cancer refractory to GEM, were used in this study. GEM was injected i.v. once followed by i.v. injection of NDP at an interval of approximately 30 min into tumor-bearing athymic mice. GEM was administered again 3 or 4 days thereafter. Combined dosing of NDP with GEM resulted in synergistically enhanced inhibition of tumor growth in the Ma44 tumor model. NDP plus GEM was also effective against Ma44 cells when given late in the therapy, a model for advanced disease. Potent augmentation of growth inhibition by NDP with GEM was also found with the NCI-H460 tumor model. The combination effect of NDP plus GEM appeared to be superior to that of CDDP plus GEM or CBDCA plus GEM in both tumor models. Toxicity in terms of blood cell numbers was not enhanced by the combination of NDP with GEM. These results suggest the effectiveness of combination of NDP with GEM for clinical therapy.

Animals↗
PubMed2002

Ensaculin (KA-672 HCl): a multitransmitter approach to dementia treatment.

Ensaculin, a novel benzopyranone substituted with a piperazine moiety, showed memory-enhancing effects in paradigms of passive and conditioned avoidance in both normal and artificially amnesic rodents. It exhibited neuroprotective activities in an NMDA toxicity model and neurotrophic effects in primary cultured rat brain cells. The compound could be characterized as a weak NMDA receptor-operated channel blocker. In receptor-binding studies, ensaculin was found to have high affinities to serotonergic 5-HT(1A) and 5-HT(7) receptors, adrenergic alpha(1), and dopaminergic D(2) and D(3) receptors. Due to its unique pharmacodynamic profile, ensaculin may have potential as an antidementia agent acting on various transmitter systems.

Animals↗
PubMed1987

Marker exchange mutagenesis of the aerolysin determinant in Aeromonas hydrophila demonstrates the role of aerolysin in A. hydrophila-associated systemic infections.

We report here on the isolation of isogenic strains of Aeromonas hydrophila AB3 deleted for a segment of the aerolysin gene. All aer mutants obtained lacked the 49-kilodalton aerolysin gene product and were neither hemolytic for blood erythrocytes nor cytotoxic for Chinese hamster ovary tissue culture cells. One such mutant, AB3-5, was used in a mouse toxicity model to evaluate the role of aerolysin in the pathogenesis of A. hydrophila infections. The strain had a 50% lethal dose (LD50) of greater than 10(9) as compared with the parental strain which had an LD50 of 5 X 10(7). Reintegration of the deleted segment into AB3-5 resulted in an LD50 of 6 X 10(7) cells for this revertant. Furthermore, all mice injected with a sublethal dose of the parental strains developed necrotic lesions; this was never obtained with the aerolysin-deficient strain AB3-5. More importantly, specific neutralizing antibody to aerolysin was detected in mice surviving A. hydrophila infection, demonstrating that aerolysin is produced during the course of systemic A. hydrophila infections.

Aeromonas↗
PubMed2003

Stx2-specific human monoclonal antibodies protect mice against lethal infection with Escherichia coli expressing Stx2 variants.

Shiga toxin-producing Escherichia coli (STEC) strains are responsible for causing hemolytic-uremic syndrome (HUS), and systemic administration of Shiga toxin (Stx)-specific human monoclonal antibodies (HuMAbs) is considered a promising approach for prevention or treatment of the disease in children. The goal of the present study was to investigate the ability of Stx2-specific HuMAbs to protect against infections with STEC strains that produce Stx2 variants. Dose-response studies on five HuMAbs, using the mouse toxicity model, revealed that only the three directed against the A subunit were protective against Stx2 variants, and 5C12 was the most effective among the three tested. Two HuMAbs directed against the B subunit, while highly effective against Stx2, were ineffective against Stx2 variants. In a streptomycin-treated mouse model, parenteral administration of 5C12 significantly protected mice up to 48 h after oral bacterial challenge. We conclude that 5C12, reactive against the Stx2 A subunit, is an excellent candidate for immunotherapy against HUS and that antibodies directed against the A subunit of Stx2 have broad-spectrum activity that includes Stx2 variants, compared with those directed against the B subunit.

Animals↗
PubMed2005

Characterization of a human monoclonal antibody against Shiga toxin 2 expressed in Chinese hamster ovary cells.

Shiga toxin-producing Escherichia coli infections can often lead to the development of hemolytic-uremic syndrome (HUS) in a small percentage of infected humans. Patients with HUS receive only supportive treatment as the benefit of antibiotic therapy remains uncertain. We have previously reported the generation and preclinical evaluation of neutralizing human monoclonal antibodies (HuMAbs) against the Shiga toxins (Stx). In this paper, we describe the expression in Chinese hamster ovary (CHO) cells of 5C12 HuMAb, which is directed against the A subunit of Stx2. The cDNAs of the light and heavy chain immunoglobulin (Ig) variable regions of 5C12 HuMAb were isolated and cloned into an expression vector containing human IgG1 constant regions. The vector was transfected into CHO cells, and transfectants secreting Stx2-specific antibody were screened by an Stx2-specific enzyme-linked immunosorbent assay. The CHO-produced recombinant 5C12 (r5C12) showed similar specificity and binding affinity to Stx2 as the parent hybridoma-produced 5C12. More significantly, the r5C12 displayed the same neutralizing activity as the parent 5C12 in vitro and in vivo. In the mouse toxicity model, both antibodies significantly and equally prolonged survival at a dose of 0.312 microg/mouse. The data showed that since r5C12, produced in CHO cells, was equally effective as the parent 5C12, it is our choice candidate as a potential prophylactic or therapeutic agent against hemolytic-uremic syndrome.

Amino Acid Sequence↗