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Biomedical subjects

S M Cohen

Publications and source records attributed to S M Cohen.

At least 91 records · Page 5Linked to original sources
PubMed1998

Urinary physiologic and chemical metabolic effects on the urothelial cytotoxicity and potential DNA adducts of o-phenylphenol in male rats.

ortho-Phenylphenol (OPP), a fungicide and antibacterial agent with food residues, is carcinogenic to rat bladder. The present studies provide information on changes in urinary composition and urinary metabolites, urothelial cytotoxicity and regenerative hyperplasia, and DNA adducts in male F344 rats fed OPP. An initial experiment evaluated dietary doses of 0, 1,000, 4,000, and 12,500 ppm OPP fed for 13 weeks. There was no evidence of urinary calculi, microcrystalluria, or calcium phosphate-containing precipitate, but urothelial cytotoxicity and hyperplasia occurred at the highest dose only. In a second experiment, rats were fed dietary OPP levels of 0, 800, 4,000, 8,000, and 12,500 ppm. Urinary pH was > 7 in all groups. Urinary volume was increased at the 2 highest doses with consequent decreases in osmolality, creatinine, and other solutes. Total urinary OPP metabolite excretions were increased, mostly excreted as conjugates of OPP and of phenylhydroquinone. Free OPP or free metabolites accounted for less than 2% excreted in the urine without a dose response. Urothelial toxicity and hyperplasia occurred only at doses of 8,000 and 12,500 ppm. OPP-DNA adducts were not detected in the urothelium at any dose. In summary, OPP produces cytotoxicity and proliferation of the urothelium at dietary doses > or = 8,000 ppm without formation of urinary solids. The paucity of unconjugated metabolites and the lack of OPP-DNA adducts suggests that OPP is acting as a bladder carcinogen in male rats by inducing cytotoxicity and hyperplasia without it or its metabolites directly binding to DNA.

Administration, Oral↗
PubMed1998

Enhanced tumorigenicity of rat bladder squamous cell carcinoma cells after abrogation of gap junctional intercellular communication.

We previously demonstrated a clear tendency for actively communicating rat bladder carcinoma cell lines with elevated expression of connexin 43 mRNA to possess strong tumorigenicity. In the present study, immunohistochemical analysis established that normal bladder epithelium did not express connexin 43 protein, but bladder carcinomas often expressed the protein, particularly on the membranes of cells within areas of squamous cell differentiation. To investigate the role of connexin 43 overexpression in rat bladder carcinoma cells, an anti-sense connexin 43 expression vector was transfected into BC31 cells having a high communication capacity. In the resultant transfectants, there was little or no communication capacity and connexin 43 expression. The growth rate in vitro was not changed compared to that of cells treated with the vector alone (without the anti-sense sequence), but tumorigenicity in nude mice was dramatically enhanced. The results indicate that connexin 43 overexpression in rat bladder carcinogenesis is related to squamous cell differentiation, and the protein can have tumor suppressor characteristics, as in other organs.

Animals↗
PubMed1998

Dpp receptor levels contribute to shaping the Dpp morphogen gradient in the Drosophila wing imaginal disc.

Axis formation in the Drosophila wing depends on the localized expression of the secreted signaling molecule Decapentaplegic (Dpp). Dpp acts directly at a distance to specify discrete spatial domains, suggesting that it functions as a morphogen. Expression levels of the Dpp receptor thick veins (tkv) are not uniform along the anterior-posterior axis of the wing imaginal disc. Receptor levels are low where Dpp induces its targets Spalt and Omb in the wing pouch. Receptor levels increase in cells farther from the source of Dpp in the lateral regions of the disc. We present evidence that Dpp signaling negatively regulates tkv expression and that the level of receptor influences the effective range of the Dpp gradient. High levels of tkv sensitize cells to low levels of Dpp and also appear to limit the movement of Dpp outside the wing pouch. Thus receptor levels help to shape the Dpp gradient.

Animals↗
PubMed1998

Systematic gain-of-function genetics in Drosophila.

A modular misexpression system was used to carry out systematic gain-of-function genetic screens in Drosophila. The system is based on inducible expression of genes tagged by insertion of a P-element vector carrying a GAL4-regulated promoter oriented to transcribe flanking genomic sequences. To identify genes involved in eye and wing development, the 2300 independent lines were screened for dominant phenotypes. Among many novel genes, the screen identified known genes, including hedgehog and decapentaplegic, implicated in these processes. A genetic interaction screen for suppressors of a cell migration defect in a hypomorphic slow border cells mutant identified known genes with likely roles in tyrosine kinase signaling and control of actin cytoskeleton, among many novel genes. These studies demonstrate the ability of the modular misexpression system to identify developmentally important genes and suggest that it will be generally useful for genetic interaction screens.

Animals↗
PubMed1997

Proline-induced inhibition of glutamate release in hippocampal area CA1.

Concentrations of proline typical of human CSF have been shown to potentiate transmission at Schaffer collateral-commissural synapses on CA1 pyramidal cells of the rat hippocampus. This study tested the hypothesis that proline enhances excitatory synaptic transmission by increasing glutamate release. Two concentrations of proline were used: a concentration typical of normal human CSF (3 microM) and a concentration typical of CSF in persons with the genetic disorder hyperprolinemia type II (30 microM). Continuous exposure of hippocampal slices to either concentration of proline potentiated Schaffer collateral-commissural synaptic transmission. Proline shifted the plot of field EPSP slope against fiber volley amplitude upward. Contrary to the original hypothesis, neither concentration of proline reduced paired-pulse facilitation; 30 microM proline enhanced paired-pulse facilitation, whereas 3 microM proline had no effect. In line with its enhancement of paired-pulse facilitation, 30 microM proline reduced both the K+-evoked release of glutamate and aspartate from CA1 slices and the release of glutamate and aspartate from CA1 synaptosomes evoked by 4-aminopyridine. These results suggest that the proline-induced potentiation of Schaffer collateral-commissural synaptic transmission probably involves a postsynaptic, rather than a presynaptic, mechanism. Concentrations of proline normally found in human CSF little affect glutamate release. However, proline-induced inhibition of glutamate release may contribute to the neuropsychiatric disorders associated with hyperprolinemia type II.

Animals↗
PubMed1997

Proximal-distal axis formation in the Drosophila leg.

Limb development requires the formation of a proximal-distal axis perpendicular to the main anterior-posterior and dorsal-ventral body axes. The secreted signalling proteins Decapentaplegic and Wingless act in a concentration-dependent manner to organize the proximal-distal axis. Discrete domains of proximal-distal gene expression are defined by different thresholds of Decapentaplegic and Wingless activities. Subsequent modulation of the relative sizes of these domains by growth of the leg is required to form the mature pattern.

Animals↗
PubMed1997

Proline-induced potentiation of glutamate transmission.

The amino acid proline has long been suspected to serve as a modulator of synaptic transmission in the mammalian brain, but no such function has been identified. The selective expression of high affinity proline transport by a subset of glutamate pathways suggested that proline might play a role in synaptic transmission at these sites. This idea was tested with use of one such pathway, the Schaffer collateral-commissural projection to CA1 pyramidal cells of the rat hippocampus. Proline enhanced the initial slope of the field EPSP without affecting axonal excitability or the magnitude of paired-pulse facilitation. Proline-induced potentiation far outlasted the period of proline application and required the activation of NMDA receptors. Proline enhanced Schaffer collateral-commissural synaptic transmission even when the connections between areas CA1 and CA3 had been interrupted. Potentiation was observed with a proline concentration normally present in human CSF (3 microM). A concentration typical of CSF in persons with the genetic disorder hyperprolinemia type II (30 microM) produced a somewhat greater effect. Occlusion experiments suggested that proline-induced potentiation and tetanus-induced long-term potentiation utilize largely distinct transduction mechanisms. Proline-induced potentiation could be blocked by a prior high frequency stimulus, whether or not the stimulus evoked long-term potentiation. These results suggest that endogenous extracellular proline regulates the basal function of some glutamate synapses by maintaining them in a partially potentiated state. They may also facilitate understanding of the seizures and/or mental retardation associated with genetic disorders of proline metabolism.

2-Amino-5-phosphonovalerate↗
PubMed1997

Sodium-dependent proline and glutamate uptake by hippocampal synaptosomes during postnatal development.

NA(+)-dependent uptake of proline and glutamate by hippocampal synaptosomes was studied during postnatal development. At all ages from 9 days to adulthood, hippocampal synaptosomes transported proline by both a high-affinity and a low-affinity process, whereas glutamate was always transported predominantly by a high-affinity process. During the period of rapid synaptogenesis, the KT for high-affinity proline transport overshot the adult value, whereas the KT for glutamate transport increased steadily toward the adult value. The ratio of KT values for proline and glutamate was 2-3 times the adult value between 12 and 24 days of age. Although high-affinity transporters for proline and glutamate are expressed by nearly the same hippocampal pathways, they are differentially regulated during postnatal development.

Animals↗
PubMed1997

Evolutionary origin of insect wings from ancestral gills.

Two hypotheses have been proposed for the origin of insect wings. One holds that wings evolved by modification of limb branches that were already present in multibranched ancestral appendages and probably functioned as gills. The second proposes that wings arose as novel outgrowths of the body wall, not directly related to any pre-existing limbs. If wings derive from dorsal structures of multibranched appendages, we expect that some of their distinctive features will have been built on genetic functions that were already present in the structural progenitors of insect wings, and in homologous structures of other arthropod limbs. We have isolated crustacean homologues of two genes that have wing-specific functions in insects, pdm (nubbin) and apterous. Their expression patterns support the hypothesis that insect wings evolved from gill-like appendages that were already present in the aquatic ancestors of both crustaceans and insects.

Amino Acid Sequence↗
PubMed1997

Tributyl phosphate effects on urine and bladder epithelium in male Sprague-Dawley rats.

Tributyl phosphate (TBP) produces tumors of the bladder urothelium in rats at high doses (700 and 3000 ppm), with greater effects in males than in females. TBP does not produce tumors in mice and it is nongenotoxic. The dose response of TBP effects on urine and urothelium was evaluated in male Sprague-Dawley rats at 0, 200, 700, and 3000 ppm of the diet, 10 rats per group, for 10 weeks. Another group received 3000 ppm TBP plus 12,300 ppm NH4Cl to evaluate the effect of urinary acidification. An additional group of 10 rats received 12,300 ppm NH4Cl. A high-dose recovery group (10 weeks 3000 ppm TBP, then 10 weeks control diet) was included to evaluate reversibility. Urine chemistries for control and TBP-treated animals were similar except for a slight decrease in osmolality and creatinine at the highest dose. Scanning electron microscopic examination of the urine of TBP-treated rats showed no increased or abnormal crystalluria, urinary precipitate, or calculi. The urothelial effects were seen at the two highest doses, but were most severe at 3000 ppm TBP, with ulceration and hemorrhage into the bladder lumen and consequent diffuse papillary and nodular hyperplasia. Dietary NH4Cl acidified the urine but did not prevent the urothelial toxicity and regeneration. The bladder epithelial changes were reversible, but the ulcer repair process was accompanied by submucosal fibrosis. TBP at high doses appears to produce urothelial cytotoxicity with marked regenerative hyperplasia which is reversible upon withdrawal of treatment. The cytotoxicity is likely due to the direct effect of TBP or its metabolites rather than an indirect consequence of urinary changes.

Administration, Oral↗
PubMed1997

Effects of diet on urinary bladder carcinogenesis and cancer prevention.

Urine plays a major role in bladder carcinogenesis, acting as a transport mechanism for carcinogens, containing several growth factors stimulating cell proliferation, and indirectly affecting chemicals by alterations in concentrations of normal urinary components such as electrolytes, water and proteins. These latter effects are greatly modified by diet composition and consumption and also by water consumption. Several examples of these effects are presented.

Animals↗
PubMed1997

Attenuation of acute lung injury caused by hind-limb ischemia-reperfusion injury by butyrolactone anti-inflammatory agent FL1003.

OBJECTIVE: Activation of systemic inflammation after reperfusion of ischemic tissue results in severe acute lung injury. Neutrophil activation and oxygen radical generation have been implicated in the pathogenesis. This study tested the hypothesis that treatment with FL1003, a butyrolactone with in vitro antioxidant properties, will down-regulate this response and abrogate acute lung injury. METHODS: Male Sprague-Dawley rats (n = 16) were divided into a surgical sham group (n = 4), a group that received 2 hours of ischemia by infrarenal aortic clip followed by 1 hour of reperfusion (n = 7), and an ischemia-reperfusion (I/R) group that received FL1003 100 mg/kg intravenously before ischemia (n = 5). After reperfusion, the heart and lungs were excised en bloc in an isolated lung perfusion apparatus for 1.5 hours of perfusion, while pulmonary artery pressures were held between 5 and 12 mm Hg and venous effluent was collected. Bronchoalveolar lavage fluid and both lungs were harvested at death for determination of tissue water content, pulmonary microvascular permeability, and indicators of neutrophil activation and tissue oxidation. RESULTS: After I/R, there were significant (p < 0.05) increases in intravenous fluid (IVF) requirements (18 +/- 1.2 mL) to maintain hemodynamic stability, wet weight/dry weight ratio of lung tissue, and isolated-lung lavage Ficoll concentrations (0.58 +/- 0.02 microg/mL) compared with sham animals (IVF, 0 mL; Ficoll concentration, 0.08 +/- 0.03 microg/mL). In addition, lung myeloperoxidase activity (0.60 +/- 0.03 vs. 0.12 +/- 0.02 units/g of tissue) and levels of lipid-conjugated dienes (0.042 +/- 0.012 vs. 0.018 +/- 0.006 optical density of 233 nm (OD233)/mL) were significantly higher (p < 0.05) compared with the sham group. In I/R animals treated with FL1003, the IVF requirement (8.5 +/- 1.0 mL), wet weight/dry weight ratio, lung tissue Ficoll concentration (0.21 +/- 0.02 microg/mL), myeloperoxidase concentration (0.217 +/- 0.02 units/g), and lipid-conjugated diene levels (0.012 +/- 0.005 OD233/ mL) were all significantly lower (p < 0.05) than after untreated I/R. CONCLUSION: A pulmonary microvascular permeability defect with pulmonary edema, neutrophil aggregation, and cell membrane damage resulted from ischemia and reperfusion. Treatment of animals with FL1003 significantly attenuated the inflammatory response associated with acute lung injury.

4-Butyrolactone↗
PubMed1997

Cell cycle progression, growth and patterning in imaginal discs despite inhibition of cell division after inactivation of Drosophila Cdc2 kinase.

During larval development, Drosophila imaginal discs increase in size about 1000-fold and cells are instructed to acquire distinct fates as a function of their position. The secreted signaling molecules Wingless and Decapentaplegic have been implicated as sources of positional information that globally control growth and patterning. Evidence has also been presented that local cell interactions play an important role in controlling cell proliferation in imaginal discs. As a first step to understanding how patterning cues influence growth we investigated the effects of blocking cell division at different times and in spatially controlled manner by inactivation of the mitotic kinase Cdc2 in developing imaginal discs. We find that cell growth continues after inactivation of Cdc2, with little effect on overall patterning. The mechanisms that regulate size of the disc therefore do not function by regulating cell division, but appear to act primarily by regulating size in terms of physical distance or tissue volume.

Animals↗
PubMed1997

A Hedgehog activity gradient contributes to AP axial patterning of the Drosophila wing.

The secreted protein Hedgehog (Hh) transmits a signal from posterior to anterior cells that is essential for limb development in insects and vertebrates. In Drosophila, Hh has been thought to act primarily to induce localized expression of Decapentaplegic and Wingless which in turn relay patterning cues at long range. We report here that Hh plays an additional role in patterning the wing. By replacing endogenous Hh activity with that of a membrane-tethered form of Hh, we show that Hh acts directly to pattern the central region of the wing, in addition to its role as an inducer of Dpp. Comparing the biological activities of secreted and membrane-tethered Hh provides evidence that Hh forms a local concentration gradient and functions as a concentration-dependent morphogen in the fly wing.

Animals↗