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E A Duell

Publications and source records attributed to E A Duell.

At least 55 records · Page 3Linked to original sources

Regulation of cell cycles.

Of the major achievements in cell biology during the last 25 years, none is more important than the understanding of regulation of cell cycles. In 1953 two fundamental observations concerning DNA were made. Watson and Crick suggested that the three-dimensional structure of DNA exists as a double helix with specific base pairings, and Howard and Pelc observed that DNA is replicated during a specific phase in the mitotic cycle. Thus developed the theory of cell cycles. Next, investigators explored which events occur during each phase of the cycle and what controls the readout of the genes of proliferation or differentiation. In 1961, Jacob and Monod proposed that for prokaryotic cells the operon is the mechanism which controls the readout of the genes; and by the end of the 1960s, several investigators had defined the role of cyclic AMP and its mechanism of action at the gene level. The control mechanisms of eukaryotic cells are less well defined. Basically there are two types of regulatory molecules: those that arrive at the cell surface and send messages inside the cell; and those that enter the cell, bind to receptors, and then enter the nucleus to interact with the genes. During the past five to ten years, the cell surface and its receptors have received considerable attention as the recognition and control areas for cell proliferation and differentiation, and currently the role of the cyclic nucleotides and prostaglandins is being investigated. Various model systems are now available for detailed studies of these control mechanisms.

Animals↗

Cyclic AMP and cyclic GMP in epidermal physiology and pathophysiology.

The second messengers cyclic AMP and cyclic GMP in several organs appear to coordinate those molecular events which are responsible for specialized organ function. As a result of balanced cell proliferation and specialization, epidermis functions by terminal specialization which provides a barrier between man and environment. Since the epidermal component of psoriasis is a classic example of deranged epidermal homeostasis, which has a low level of cyclic AMP and a high level of cyclic GMP, it seems reasonable that rebalancing these cyclic nucleotides might ultimately be a safe and effective therapy for psoriasis and other proliferative skin diseases.

3',5'-Cyclic-AMP Phosphodiesterases↗

Increased concentrations of nonesterified arachidonic acid, 12L-hydroxy-5,8,10,14-eicosatetraenoic acid, prostaglandin E2, and prostaglandin F2alpha in epidermis of psoriasis.

Lesional epidermis of psoriasis has a probable reduction in the cyclic AMP/cyclic GMP ratio. This altered ratio may in part be responsible for the characteristic glycogen storage, rapid cell proliferation, and reduced differentiation in lesional epidermis. The concentrations of prostaglandins E2 and F2alpha, free arachidonic acid, and 12L-hydroxy-5,8,10,14-eicosatetrawnoic acid in specimens of uninvolved and involved epidermis of psoriasis were measured with deuterium-labeled carriers and multiple ion analysis. Snap frozen specimens contained: 1.4 +/- 0.4 mug/g (wet weight) of arachidonic acid in uninvolved in contrast to 36.3 +/- 16.7 mug/g in involved epidermis (P = 0.015); less than 0.05 +/- 0.01 mug/g of hydroxyeicosatetraenoic acid in uninvolved in contrast to 4.1 +/- 1.9 mug/g in involved epidermis (P = 0.015); 23.6 +/- 5.0 ng/g of prostaglandin E2 in uninvolved in contrast to 33.1 +/- 5.7 ng/g in involved epidermis (P less than 0.01); and 21.0 +/- 4.4 ng/g of prostaglandin F2alpha in uninvolved in contrast to 39.0 +/- 5.9 ng/g in involved epidermis (P less than 0.01). The arachidonic acid and hydroxyeicosatetraenoic acid levels in involved epidermis were strongly correlated (r = 0.97). The increased levels of arachidonic acid and 12L-hydroxy-5,8,10,14-eicosatetraenoic acid in involved epidermis may have diagnostic and pathophysiological importance.

Arachidonic Acids↗

Papaverine: its effects on cyclic AMP in vitro and psoriasis in vivo.

Psoriatic epidermis shows excessive cell proliferation, incomplete morphogenesis, and glycogen accumulation. These three features may result from coordinate misregulation by the previously reported abnormal lesional ratio of cyclic AMP/cyclic GMP. If so, it is possible that psoriasis might improve by topical application of an agent known to alter cellular levels of cyclic nucleotides. In the present study papaverine (3.0 x 10-4 m) produced a 210percent increase (.02 smaller than p smaller than .05) in epidermal cyclic AMP levels in vitro. Therefore, 1 percent papaverine cream (approximately 2.7 x 10-2m papaverine) was chosen to establish whether a cyclic AMP elevating agent could improve a soriatic lesion. A double-blind comparison of 1 percent papaverine cream versus cream alone was conducted on matched lesions in 45 patients. Of those patients showing differential improvement (i.e., only one lesion of the pair improved), 81 percent (p=0.011) of those showing a response in the center of the lesion and 77 percent (p=0.046) of those improving at the edge had applied papaverine. Although no attempts were made to develop a papaverine formulation with immediate therapeutic utility, the numerically significant papaverine results suggest future therapeutic developments.

Animals↗

Epidermal chalone--past to present concept.

How the constantly renewing epidermis maintains its homeostatic state remains a mystery. A "negative feedback" mechanism of control with chalone, a tissue-specific, species-nonspecific inhibitor of mitosis, has been suggested by Bullough and Laurence. Progress in isolating, purifying, and characterizing epidermal chalone has been slow and difficult because of the lack of a fast, assurate, and meaningful assay system. A G2 assay (depending upon mitotic counts) was used to obtain the data which served as the basis for postulating the existence of chalone. Since a control point with the G1 phase of the cell cycle is considered to be the one with physiologic implications, in vivo and in vitro assays with pure primary epidermal cell cultures have been used to investigate a G1 block. The incorporation of tritiated thymidine into DNA is often used as a measure of the rate of prokiferation. However, inhibition of thymidine transport and phosphorylation have been encountered in several systems and negate this method as an accurate measure of cell proliferation.

Animals↗

Cyclic AMP, cyclic GMP, and glucocorticoids as potential metabolic regulators of epidermal proliferation and differentiation.

The two cyclic nucleotides, cyclic AMP and cyclic GMP, appear to be central to the metabolic regulation of cell proliferation and differentiation in various cells. Moreover, in many systems glucocorticoids appear to act in concert with or parallel to cyclic AMP. The available evidence suggests that these three molecular species--cyclic AMP, cyclic GMP, and glucocorticoids--may be essential to the normal regulation of epidermal proliferation and differentiation. In 1970, we suggested that perturbed epidermal homeostasis, exemplified by psoriasis, might be associated with low cellular levels of cyclic AMP and, in 1972, with high levels of cyclic GMP as well. Subsequent measurements of these two cyclic nucleotides in our laboratory showed a probable reduction in the cyclic AMP/cyclic GMP ratio in lesional psoriatic tissue. This led to the hypothesis that the cardinal features of psoriatic epidermis--glycogen accumulation, excessive proliferation, and reduced cell specialization--are the results of this reduced ratio. A corollary of this hypothesis was that a psoriatic lesion could not begin or exist without this altered cyclic nucleotide ratio. Recently, four different agents--lithium, a beta adrenergic blocking agent, antimalarials, and iodide--have been found to exacerbate psoriasis and to reduce the formation of cyclic AMP in various tissues. Consequently we believe that cyclic nucleotides are of central importance in the pathogenesis of the epidermal component of psoriasis.

Animals↗