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PubMed1984

[Opioid peptides].

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Amino Acid Sequence↗
PubMed1982

Brain peptides.

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Adrenocorticotropic Hormone↗
PubMedDate not supplied

New perspectives in neuropeptides. Biosynthesis from large precursors. The pro-opio-melanocortin model in the pars intermedia.

Although more and more is known about the nature of neuropeptides, there are two basic questions which need to be looked at in order for the neurophysiologists and the neuropharmacologists to have all the tools necessary for their studies. The first question is the site of biosynthesis of neuropeptides and the second is their biosynthetic pathway. We believe and propose that all neuropeptides will be formed from a larger molecular weight precursor similar to beta-LPH for beta-endorphin. All models of peptide hormones (pro-insulin, pro-PTH, pro-glucagon, beta-lipotropin etc.,) show the same characteristic preferential site of cleavage made of a double basic residue. This is also the type of cleavage recently described by Nakanishi et al. (1979). Using the rat pars intermedia, we showed that this tissue preferentially makes alpha-MSH and beta-endorphin from a large precursor, while beta-LPH and ACTH are short lived intermediates. All products of maturation were identified by chemical analyses leaving no doubt about their nature and identity. We strongly believe that the brain will biosynthesize beta-endorphin and possibly alpha-MSH in similar fashion. We also predict that our results will apply to the other neuropeptides which wil be formed from large precursors. These studies could be very useful in the interpretation of the intricate relationship between neuropeptides and behavioral effects.

Adrenocorticotropic Hormone↗
PubMed1981

Subcellular fractionation studies on the post-translational processing of pro-adrenocorticotropic hormone/endorphin in rat intermediate pituitary.

The subcellular localization of the post-translational processing steps which occur in the conversion of pro-adrenocorticotropic hormone (ACTH)/endorphin into beta-endorphin-sized molecules in rat intermediate pituitary has been studied. Primary cell cultures were incubated in radioactively labeled amino acids, and a subcellular fraction containing secretory granules was separated from a subcellular fraction containing rough endoplasmic reticulum and Golgi apparatus by centrifugation of homogenates on gradients on Percoll (Pharmacia Fine Chemicals). The radiolabeled beta-endorphin-related material in the granule and rough endoplasmic reticulum/Golgi apparatus fractions was quantitated by immunoprecipitation and sodium dodecyl sulfate polyacrylamide gel electrophoresis. A pulse-chase labeling experiment demonstrated that newly synthesized beta-endorphin-related material first appeared in the rough endoplasmic reticulum/Golgi apparatus fraction and after longer incubations (chase) appeared in the secretory granule fraction. After 2 h of chase incubation, about 85% of the beta-endorphin-related material synthesized during the 30-min pulse incubation had been transferred from the rough endoplasmic reticulum/Golgi apparatus to the secretory granule fraction. The conversion of most of the newly synthesized pro-ACTH/endorphin into beta-lipotropin occurred in the rough endoplasmic reticulum/Golgi apparatus fraction, whereas the conversion of most of the beta-lipotropin into beta-endorphin-sized molecules occurred in the secretory granule fraction.

Adrenocorticotropic Hormone↗
PubMed1981

Evidence for intragranular processing of pro-opiocortin in the mouse pituitary intermediate lobe.

Mouse pituitary neurointermediate lobes were pulse-incubated in [3H] arginine or [3H] lysine for 10 min and then chase-incubated for periods 0 to 4h. The labeled peptides from the lobes were analysed by immunoprecipitation with specific antisera, and thereafter, by acid-urea polyacrylamide gel electrophoresis. Using this paradigm, the synthesis of a prohormone common to adrenocorticotropin (ACTH) and endorphin was detected in 10 min pulse labeled lobes. Following a chase period, processing of the prohormone to several forms of ACTH (mol. wt. 25000, 23000, and 13000), beta-lipotropin and beta-endorphin was observed. To determine the intracellular site of processing of the prohormone, subcellular fractionation studies of labeled lobes were carried out. Analysis of the fractions from the pulse-labeled lobes revealed that the newly synthesized labeled prohormone was primarily localized in a granule-enriched fraction. In lobes that were pulsed and then chase-incubated for 1 h, there was a decrease in the amount of prohormone and an appearance of processed products in the granule-enriched fraction. In another paradigm, where the secretory granule-fraction was isolated from pulse-labeled lobes and then incubated in vitro for 6 h at pH 5.5, processing of the endogenous labeled prohormone within the isolated granule fraction was observed. These data suggest, that in the mouse neurointermediate lobe, the ACTH/endorphin prohormone (pro-opiocortin) is rapidly packaged into secretory granules after synthesis and processed intragranularly.

Adrenocorticotropic Hormone↗
PubMed1982

Multiple cellular forms of corticotrophs in surgically removed pituitary adenomas and periadenomatous tissue in Cushing's disease.

Transsphenoidally removed samples of pituitary adenomas from 14 patients with Cushing's disease and 5 patients with Nelson's syndrome always contained groups of uniform small ACTH-cells. Antibodies against the pro-opiocortin precursor fragments beta-endorphin, ACTH, and 16k-peptide recognized material in typical adenoma cells. A subpopulation of these cells, varying in number from sample to sample, specifically exhibited alpha-melanotropin immunoreactivity. Most periadenomatous samples showed signs of severe degeneration. Typical Crooke cells only occurred in samples from patients with Cushing's syndrome, but, with this exception, no clear differences between pituitaries of patients with Cushing's and Nelson's syndromes could be discerned. Two other forms of ACTH-immunoreactive cells were observed: rare, single, highly immunoreactive cells, with characteristics of both normal and Crooke cells, and numerous syncytial groups of cells in an advanced state of disintegration, presumably the remnants of hyperplastic follicles. The four different corticotrophs are characterized according to their fine structure and immunoreactivity in this study.

Adenoma↗
PubMed1982

[ACTH, beta-endorphin, lipotropins, and other pro-opiocortin-derived peptides: a new family of hormones (author's transl)].

beta-Endorphin, a pituitary morphino-mimetic peptide, was identified in a culture medium derived from a human corticotropic adenoma. Secretion products from cultured human cells derived from a small-cell carcinoma of the lung were shown to contain a high molecular weight precursor analagous to pro-opiocortin: this molecule is a polypeptide of the order of 28,000 daltons the enzymatic processing of which leads to the coordinated and simultaneous release of different peptide fragments: ACTH, beta- and gamma-lipotropins, beta-endorphin, fragment 16 K and gamma 3-MSH. All these peptides have been identified in human plasma, and pituitary and non-pituitary tumor extracts. Their plasma concentrations vary in a parallel manner, beta-endorphin and a peptide very similar to beta-MSH have been detected in human hypothalamus.

Adenoma↗
PubMed1982

[Ontogenesis of pro-opio-melano-cortin neurons in the rat].

Immunocytochemical study of the pro-opio-melano-cortin neurones in rat fetuses and newborns indicates that: 1) they appear precociously in the mediobasal hypothalamus, as early as day 13 of fetal development, that is to say 3 days before pro-opio-melano-cortin-containing pituitary cells; 2) between day 13 and day 17 they display synchronous changes in their intracellular patterns of immunoreactivity, arguing in favour of their cyclic secreting activity, which precedes the establishing of their projections; 3) beginning with day 18 until birth, the somatal immunoreactivity disappears transitorily; during the same period and the first postnatal days, their immunoreactive fibres extend in various brain regions.

Adrenocorticotropic Hormone↗
PubMed1982

Structural organization of the corticotropin-beta-lipotropin precursor gene.

The human and the bovine corticotropin (ACTH)-beta-lipotropin (LPH) precursor gene have been isolated and characterized. Both genes consist of three exons which are divided by two large introns at exactly the same positions. One of the introns is inserted within the segment transcribed into the 5'-untranslated region of the mRNA, and the other interrupts the protein-coding sequence near the signal peptide region. The largest exon encodes most of the protein sequence which includes the three repeated melanotropin (MSH) peptides and other biologically active peptides such as ACTH and beta-endorphin. Thus, there is no apparent correspondence between the repetitive structure of the precursor protein and the structural organization of its gene. Comparison of the nucleotide sequences of the human and the bovine gene reveals that three regions are highly conserved, i.e., the region extending from the signal peptide to gamma-MSH, the ACTH region and the beta-MSH/beta-endorphin region. This suggests that the peptide(s) in the amino-terminal region, including gamma-MSH, may be of physiological importance, as is the case for ACTH and beta-endorphin. The different biologically active component peptides of the ACTH-beta-LPH precursor, encoded by a single gene, seem to be involved in the defense mechanism of the living organism by acting coordinately in the central nervous system as well as in peripheral tissues. The identification of the mRNA encoding the ACTH-beta-LPH precursor in a human ectopic ACTH-producing tumor is also reported.

Adrenocorticotropic Hormone↗
PubMed1983

A DNA polymorphism in close physical linkage with the proopiomelanocortin gene.

Cellular DNAs from a panel of 20 unrelated individuals were screened for restriction fragment length polymorphisms (RFLP) with a DNA probe containing the first exon of the proopiomelanocortin gene (POMC), which has been assigned to chromosome 2p23-25. Digestion with the restriction endonuclease Sst 1 revealed a high frequency RFLP. The two alleles that were found are fragments of 10- and 15-kilobase (kb) length and are in Hardy-Weinberg equilibrium with frequencies of 72.6% and 27.4%, respectively. Informative families were tested for linkage between POMC/Sst 1 RFLP and other polymorphic markers of chromosome 2. Linkage was excluded to AcP-1 (2p23-25) at 15% recombination, which is still consistent with the chromosomal assignments for these genes. The close physical linkage (10 kb) of the polymorphic locus to the POMC gene makes this RFLP a suitable marker for future linkage studies involving the POMC gene.

Chromosome Mapping↗
PubMed1984

Endorphins and psychiatry: pre-clinical perspectives.

The chemical relationships among the 3 major families of endorphins are summarized, and the CNS distribution and possible circuit functions are discussed. The overlapping distributions of enkephalin and dynorphin pathways is intriguing, and their existence in classical hippocampal pathways has implications for limbic function which are not understood. Functionally the predominant effect of these systems is 'disenabling', in contrast with the 'enabling' effects of monoamines, although specific and reversible excitatory responses in hippocampal pyramidal neurons may have important behavioral implications. The complex theoretical and methodological issues that arise in attempting to establish transmitter correlates of psychiatric disorders defy simplistic hypotheses. Endorphin research, where well established agonists and antagonists are available, illustrates the problems facing other areas of peptide research in conceptualizing a peptide related pathophysiology of the major psychoses. The structural, functional and chemical indices of hypothetical forms of endorphin pathology, and the reliability of various radio-immunoassays used now to quantify known endorphins are discussed. The complex range of behaviors produced in animals by endorphin antagonists continue to make research in this area important to psychiatry.

Animals↗
PubMed1983

Methods for evaluating response to treatment in adult acute leukemia.

The criteria for evaluating response to treatment for patients with adult acute leukemia are objective, quantitative, and effective. The first objective of treatment is to achieve a complete clinical and hematological remission, since in the absence of such response the disease has a rapidly progressive and inevitably fatal outcome. Logistic regression analysis and the generation of models for predicting the probability of response for each patient have proven to be extremely useful techniques for evaluating new candidates for front-line treatment in acute leukemia. In prospective tests, such modeling procedures have proven to predict accurately for response. It is evident that this methodology will be highly effective for selecting treatment for individual patients and for detecting improved treatments for patients who respond poorly to conventional treatment. For patients who achieve complete remission, the duration of that remission can also be evaluated by logistic regression analysis. Variables which predict for duration of remission have proven to be different from those variables which predict for probability of response. In addition, variables which predict for prolonged remission--that is, beyond 2 and 3 years--have proven to be different from variables which predict for relapse in the first year of remission. Therefore, the models which estimate risk of relapse per unit of time at risk should prove most valuable for evaluating not only the choice of treatments to be used during remission, but the duration of treatment and the strategy of treatment, that is, whether intensive treatment or low-dose intermittent treatment should be chosen. Finally, the demonstration that a significant fraction of the patients in complete remission will have long term disease-free and treatment-free survival makes the identification of such patients even more important. Evaluation of innovative higher-risk strategies for treatment of the patient in remission should be offered primarily to patients who have a low probability of having already been cured with conventional treatment. Thus, the rapid evolution of effective treatment for adult acute leukemia over the last 15 years has necessitated the development of more precise and more effective methods for evaluating the effects of those treatments on patients with this disease.

Acute Disease↗