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At least 1,423 records · Page 79Linked to original sources
PubMed1993

A novel endogenous sodium-pump inhibitor in pig urine: purification and comparison with the inhibitor purified from bovine adrenal glands.

To clarify the chemical nature and pathophysiological significance of an endogenous, specific Na-pump inhibitor, extracts of various tissues have been examined. The activities were extracted by an Amberlite XAD-2 adsorbent and fractionated by high-performance liquid chromatography (HPLC) on an ODS column. Among many tissues and fractions tested, the extract of pig urine has been found to contain a large amount of 86Rb uptake inhibitory activities. The strongest inhibitory activity for 86Rb influx into erythrocytes also exhibited a cross-reactivity with anti-ouabain antibodies. This activity has been purified to homogeneity using five steps of reverse-phase HPLC. Although most of the dose-response curves for this purified Na-pump inhibitor, designated as uroxin, in the various assay systems paralleled those of ouabain and the inhibitor purified from bovine adrenal glands (designated as adrexin C), the cross-reactivity curve with anti-ouabain antibodies did not. The retention time of uroxin on an ODS HPLC column was also different from that of digoxin, ouabain, or adrexin C. 1H nuclear magnetic resonance spectroscopic study suggests that uroxin is a novel Na-pump inhibitor that is structurally different from any of the known cardiotonic steroids or the substances previously reported to exhibit Na-pump inhibitory activity. Thus, uroxin may be a new type of endogenous regulator for the Na pump.

Adrenal Glands↗
PubMed1995

Effects of voluntary ethanol ingestion on the POMC gene expression in the rat pituitary and on the plasma beta-endorphin content.

Studies investigating the influence of chronic ethanol treatment on the beta-endorphin content and the proopiomelanocortin (POMC) gene expression in the rat pituitary revealed contradictory results. Because of this we decided to start a more complex study to investigate the effects of isolation stress, chronic ethanol treatment and voluntary ethanol consumption on the POMC mRNA level in the rat pituitary. The immediately prepared total RNA from rat pituitaries was used in hybridization experiments (Northern- and Dot-blots). The results suggest a correlation between the POMC gene expression and the different fashions of 'living conditions' tested. So the POMC gene expression in long-term alcohol-treated animals was decreased supporting the theory of beta-endorphin deficiency in alcoholism. More interestingly, data obtained from the group of voluntary ethanol consumption suggest an inverse correlation between total ethanol ingestion and POMC gene expression. This indicates the importance of the method of ethanol administration. Consistent with a decreased POMC gene expression in the pituitary during chronic ethanol treatment are previous studies showing a decrease in the plasma beta-endorphin content in such situations. Surprisingly, in the present study the plasma beta-endorphin levels measured by radioimmunoassay were only slightly decreased in chronically ethanol-treated rats. This may be due to dysregulatory effects of ethanol on post-translational processing, degradation and/or release of beta-endorphin.

Alcohol Drinking↗
PubMed1994

Opioid peptides in the pituitary: a hormone, a paracrine modulator and a peptide in search of a function.

Endogenous opioid peptides derived from all three opioid precursors have been isolated from the pituitary of mammalian species. While beta-endorphin of the anterior lobe was soon shown to be secreted into the circulation as a hormone, the dynorphins and the enkephalins were found to occur in relative small quantities too low for export and effects in the periphery. With respect to the prodynorphin family in the neural lobe convincing evidence has been accumulated for a role of dynorphin A(1-8) in the local control of the release of the hormone oxytocin. The function of the enkephalins in the anterior and neural lobes, in spite of many efforts with in situ hybridization, immunocytochemistry, receptor autoradiography and receptor binding and bioassays, is still elusive. Research should be directed into the role of enkephalins in different physiological states, developmental stages and in non-mammalian vertebrate species.

Animals↗
PubMed1994

[The clinical significance serum N-POMC level in lung cancer patients].

Serum N-POMC level of 103 cases of lung cancer were measured in our hospital. The results were as follows: The lung cancer group, 50.5%, of patienst has an N-PONC level above the normal upper limit. The percentages of the N-POMC levels above the normal limit in lung cancers, such as: squamous-cell carcinoma, adenocarcinoma, SCLC and undifferentiated carcinoma were 52.2%, 50.0%, 47.3% and 57.1%, respectively. There was no statistically significant difference of N-POMC levels among these kinds of lung cancers, Eleven of 18 cases of SCLC patients in stage IIIb or IV, and 3 of 9 cases of SCLC patients in stage IIIa had N-POMC levels above the upper normal limit. Could serum N-POMC be one of the indexes for assisting the diagnosis and prognosis of lung cancer needs further investigation. Cases with carcinoid, thymoma and neurofibroma had higher N-POMC levels too. Six patients had Cushing syndrome.

Adenocarcinoma↗
PubMed1994

Proopiomelanocortin-derived peptides.

Cloning of the cDNA of POMC mRNA led to the characterization of the ACTH precursor and established the molecular links between ACTH, beta LPH and gamma LPH, and beta end. Further previously unidentified POMC-derived peptides were also unravelled, including the N-terminal fragment and the JP. POMC is a precursor polypeptide that contains the amino acid sequences of numerous small polypeptide products. It contains eight pairs of basic amino acids and one sequence of four basic amino acids, which are the sites of cleavage for the recently identified prohormone convertases (PC1 and PC2), which have different specificities. PC1 but not PC2 is found in corticotroph cells of the anterior pituitary and cleaves POMC to generate NT, JP, ACTH, beta LPH and small amounts of gamma LPH and beta end. In the melanotroph cells of the intermediate pituitary, both PC1 and PC2 are present. The proteolysis of POMC is thus more extensive, resulting in a series of smaller peptides including gamma MSHs, CLIP, alpha MSH, beta MSH, beta end, and beta end. Equimolar amounts (because they are all products of the same precursor) of the POMC peptides are released into the blood by exocytosis from corticotroph cells of the anterior pituitary. No physiological role has been definitively identified for any of these products other than ACTH. POMC peptides have been assayed in human blood by specific radioimmunoassay (RIA). In most circumstances, the concentrations of all these peptides are perfectly correlated. Therefore, for practical reasons, LPH RIA is widely used as an indicator of overall corticotroph function. In rare cases, the correlation between the POMC peptides is disrupted by a general disorder selectively modifying the metabolism of the different members of the family as in chronic renal failure, or in tumors where POMC processing is abnormal. Examples include pituitary macroadenomas, some silent corticotroph adenomas, and most frequently non-pituitary tumors responsible for ectopic ACTH syndrome. These pathologies can lead to the formation and secretion into blood of CLIP and beta MSH, or alternatively POMC may be underprocessed and secreted intact. An elegant approach, specific IRMA, has been developed to directly recognize unprocessed POMC in blood.

Animals↗
PubMed1994

Upregulation of the POMC gene in rats by a neurotoxicant which targets motoneurones.

Immunocytochemistry and histochemical in situ hybridisation were used to detect POMC-derived peptides (beta-endorphin and alpha-MSH) and POMC mRNA respectively, in the lumbar spinal cord of adult rats. In normal rats the incidence of ventral horn cells which expressed the peptides or mRNA was negligible. However after treatment with IDPN a neurotoxicant which targets the motoneurones the peptides and POMC mRNA were detectable in over 65% of ventral horn motoneurones. After treatment with 1,3 DNB a neurotoxicant which does not target motoneurones immunostaining for the peptides and mRNA was negligible. Thus chemical intoxication of the motoneurones causes upregulation of the POMC gene.

Animals↗
PubMed1994

Comparison of in vivo and in vitro corticotropin-releasing hormone-stimulated release of proopiomelanocortin-derived peptides in cats.

In 6 cats, the effect of IV administration of various concentrations of ovine corticotropin-releasing hormone (oCRH) on plasma concentrations of cortisol, alpha-melanocyte-stimulating hormone (alpha-MSH), and adrenocorticotropic hormone (ACTH) was measured. After administration of 1.0 microgram of oCRH/kg of body weight, significant (P < 0.05) increases in plasma cortisol, alpha-MSH, and ACTH concentrations were observed. After administration of 0.1 microgram of oCRH/kg, significant increases were found only for cortisol and ACTH concentrations. In vitro release of ACTH from dispersed feline pars distalis cells in primary culture stimulated by oCRH and arginine vasopressin (AVP) was dose-dependent. Maximal stimulation was achieved by 1 nM oCRH or 100 nM AVP. The oCRH-stimulated ACTH release was partially inhibited by dexamethasone, and AVP-induced release was completely inhibited. Pars intermedia cells released 20 times as much alpha-MSH as ACTH. A dose-dependent inhibition of alpha-MSH release was induced by the dopamine agonist, bromocriptine. This inhibition could be partially abolished by coincubation with haloperidol. Bromocriptine had no effect on release of ACTH. In conclusion, oCRH stimulates the pars distalis and pars intermedia of the pituitary gland of cats. Release of ACTH is stimulated by a direct effect on the pars distalis. In addition, in cats, oCRH is a more potent secretagogue than is AVP. The MSH release from the pars intermedia is sensitive to dopaminergic inhibition, indicating that dopamine may have a central role in regulation of MSH secretion in cats.

Adrenocorticotropic Hormone↗
PubMed1993

Quantitative and sensitive northern blot hybridization using PCR-generated DNA probes labeled with digoxigenin by nick translation.

Northern blot hybridization is one of the most convenient methods of detecting an mRNA. Nonradioactive Northern blotting using digoxigenin (DIG) is becoming widely applied because it is rapid and safe. Previous studies have indicated that DIG-labeled RNA probes are suitable for Northern blot hybridization. Here, the application of PCR-generated double-stranded DNA probes labeled with DIG by nick translation is described. DNA probes were synthesized by PCR, then labeled with DIG by nick translation. Northern blot hybridization was performed using the DIG-labeled DNA probes, and the signals were detected by means of a chemiluminescent reaction. A low amount of DIG-dUTP in the labeling reaction resulted in excellent Northern blots with low background. Densitometric analysis of the blots showed that the mRNA concentrations could be determined by densitometric analysis. The sensitivity of the DIG-Northern system was comparable to Northern blotting using 32P and was sufficiently sensitive to detect low-abundance mRNA.

Animals↗
PubMed1994

Cyclic AMP and ethanol interact to control apoptosis and differentiation in hypothalamic beta-endorphin neurons.

In this study we have determined the role of cyclic AMP on the function and differentiation of beta-endorphin (beta-EP) neurons in rat fetal hypothalamic cell cultures. Addition of Bt2cAMP or the cAMP elevating agent, forskolin, in cultures, dose and time dependently increased beta-endorphin secretion. The increased beta-EP secretion after Bt2cAMP or forskolin treatment was associated with proopiomelanocortin gene expression, enhanced neurite growth, and increased neuronal viability. Determination of internucleosomal cleavage of DNA by agarose gel electrophoresis revealed that apoptosis occurred in hypothalamic neurons during the first 6-8 days in culture. Addition of Bt2cAMP during this developmental period inhibited DNA degradation in hypothalamic neurons. Furthermore, incubation with various doses of ethanol, which is known to reduce intracellular levels of Bt2cAMP, increased DNA degradation in these cells. Ethanol-induced DNA degradation was blocked by concomitant incubation with Bt2cAMP. Histochemical identification of apoptotic cells following ethanol and Bt2cAMP treatments further revealed that apoptosis occurred in beta-EP neurons during the developmental period, and that ethanol increased and Bt2cAMP reduced apoptotic beta-EP cell numbers. These results suggest that ethanol neurotoxicity on beta-EP neurons during early neuronal differentiation involves an apoptotic process and that the cAMP signaling system plays an important role in controlling apoptosis and differentiation of the beta-EP neuronal system.

Animals↗
PubMed1994

Effect of POMC-derived peptides on corticosterone secretion during the stress hypo-responsive period in rat.

During the stress hyporesponsive period (postnatal days 2-10), the stimulation of corticosterone secretion by ACTH is very low. In our study, we have observed that administration of ACTH during 3 consecutive days is followed by a striking increase in corticosterone response to an acute ACTH test. A comparable potentiation of corticosterone secretion was observed after a similar treatment with Lys gamma 3-MSH. The 3 day-treatment with each peptide induced an increase in adrenal weight. Similar data were obtained with alpha-MSH. However, corticosterone response to ACTH was not significantly altered following the same pattern of alpha-MSH administration.

Adrenal Cortex↗
PubMed1994

The proopiomelanocortin (POMC) gene expression of AtT20 mouse pituitary cells is dependent on cell culture conditions.

We have compared the properties of AtT20 cells cultivated in a Dulbecco's modified Eagles medium containing 10% fetal calf serum (FCS) and of AtT20 cells adapted to a chemically better defined medium with transferrin, albumin, insulin, sodium selenit and 0.2% FCS. Our interest was focused on the hypothalamo-pituitary-adrenal axis (HPA) involved adrenocorticotropic hormone (ACTH) and the potent opioid peptide beta-endorphin (beta-END). There were no differences in basal secretion of ACTH and beta-END by cells cultivated in medium containing 10% or 0.2% serum, respectively. In combination to the decreased proliferation activity of AtT20 cells, grown in the serum-reduced medium we found a strongly enhanced ACTH secretion activity stimulated by the corticotropin releasing hormone (CRH) in contrast to normally cultivated AtT20 cells (10% serum). In addition, the proopiomelanocortin (POMC) gene expression was significantly down regulated in serum-reduced medium and was normalized again after further cultivation in a 10% serum containing medium. This leads to the conclusion that under standard conditions (10% serum) the gene transcription is increased by hitherto uncharacterized modulators present in the serum. The unexpected unchanged amounts of ACTH and beta-End could be the result of increased protein convertases activities. These enzymes are responsible for the POMC precursor processing into beta-End and ACTH.

Animals↗
PubMed1994

Endoproteolytic processing of proopiomelanocortin and prohormone convertases 1 and 2 in neuroendocrine cells overexpressing prohormone convertases 1 or 2.

AtT-20 mouse corticotrope tumor cell lines overexpressing the prohormone convertases PC1 or PC2 were established and used to examine prohormone and prohormone convertase biosynthetic processing. On a molar basis, wild-type AtT-20 cells synthesize about 20% as much PC1 as the endogenous prohormone, proopiomelanocortin (POMC). Kinetic, oligosaccharide, and temperature blockade analyses established that proPC1 is converted to PC1 in the endoplasmic reticulum at a rate independent of the level of PC1 or PC2 expression. In contrast, proPC2 is converted to PC2 primarily in a post-trans-Golgi compartment. PC1 is further shortened from its COOH-terminal end in a post-trans-Golgi compartment in a step that is accelerated at higher levels of PC1 expression, but unaltered by PC2 overexpression. The initial steps in POMC processing are speeded up by overexpression of PC1, and overexpression of PC1 leads to more extensive cleavage of POMC to smaller products. However, even when the rate of PC1 synthesis exceeds that for POMC by 2-fold, PC1 does not cleave the Lys-Lys or Arg-Lys bonds cleaved upon overexpression of PC2.

Animals↗
PubMed1994

Plasma concentrations of immunoreactive proopiomelanocortin peptides and cortisol in clinically normal cats.

We measured immunoreactive (IR) plasma concentrations of the proopiomelanocortin (POMC)-derived peptides (adrenocorticotropic hormone [ACTH]; beta-endorphin/beta-lipotropin [beta END/beta LPH]; and alpha-melanocyte stimulating hormone [alpha MSH]) and of cortisol in 100 clinically normal cats. Median plasma concentration of IR-ACTH was 2.7 pmol/L (range, < or = 1.1 to 22 pmol/L), of beta END/beta LPH was 28 pmol/L (range, 3.8 to 130 pmol/L), of alpha MSH was 36 pmol/L (range, < or = 3.6 to 200 pmol/L), and of cortisol was 35 nmol/L (range, 5 to 140 nmol/L). Plasma concentrations of IR-ACTH, alpha MSH, and beta END/beta LPH were at or below the assay sensitivity in 34, 3, and 0% of the cats, respectively. We did not detect a correlation between plasma concentrations of IR-ACTH and beta END/beta LPH (r = 0.23) or between plasma concentrations of IR-ACTH and alpha MSH (r = 0.19). However, there was a significant (P < 0.001) correlation between plasma concentrations of IR-beta END/beta LPH and alpha MSH (r = 0.81). There was not a significant correlation between plasma concentration of cortisol and plasma concentration of any of the IR-POMC peptides. High plasma concentrations of IR-alpha MSH and beta END, POMC peptides secreted predominantly by melanotrophs in other species, indicate that clinically normal cats have an actively secreting pars intermedia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1993

Post-translational processing of proopiomelanocortin (POMC) in mouse pituitary melanotroph tumors induced by a POMC-simian virus 40 large T antigen transgene.

Mice harboring a transgene composed of proopiomelanocortin (POMC) gene promoter sequences (nucleotides -706 to +64) ligated to the simian virus (SV) 40 early gene encoding large T antigen developed large POMC-expressing pituitary tumors. Histologically the tumors arose from the intermediate lobe, contained nuclear SV40 T antigen and POMC peptides, but did not express other pituitary hormones. POMC processing in the pituitary tumors was indistinguishable from normal mouse intermediate lobe melanotrophs and was characterized by high proportions of acetylated and carboxyl-terminal shortened beta-endorphins, and amino-terminal acetylated alpha-melanocyte-stimulating hormone, and virtually no adrenocorticotropic hormone (ACTH)(1-39), beta-lipotropin, or POMC. The tumors contained abundant levels of mRNA for the prohormone convertase PC2 and undetectable levels of PC1. Normal mouse neurointermediate lobe also has a high ratio of PC2/PC1 expression that is distinct from the relative abundance of PC1 in anterior lobe and AtT-20 corticotroph cells. In contrast, extracts from tumors transplanted subcutaneously in nude mice contained predominantly nonacetylated forms of beta-endorphin(1-31) and -(1-27), very little ACTH(1-39), almost no corticotropin-like intermediate peptide or alpha-melanocyte-stimulating hormone, and higher proportions of intact POMC. Surprisingly, despite the less efficient proteolytic cleavage, a transplanted tumor expressed both PC1 and PC2. These studies are the first biochemical documentation of a melanotroph pituitary tumor in a rodent species and provide a new model for the investigation of pituitary oncogenesis and the molecular basis of tissue-specific prohormone post-translational processing.

Adrenocorticotropic Hormone↗
PubMed1993

Detection of proopiomelanocortin-derived antigens in normal and pathologic human skin.

We investigated the presence of proopiomelanocortin (POMC) products in sections of skin from normal subjects and patients with neoplastic and non-neoplastic cutaneous disorders. Antibodies specific against adrenocorticotropin, beta-melanotropin, and beta-endorphin were used for detection and characterization of cell types bearing POMC peptides. POMC products were not observed in sections of normal skin from the corporal (non-scalp) areas (six cases), whereas the hair follicles of scalp skin exhibited positive immunostains that were readily apparent (four cases). POMC products were frequently detected in corporal skin affected by diseases (13 of 26 cases), for example, psoriatic keratinocytes, the inflammatory infiltrate in scarring alopecia, nevocytes, the epithelial cell nests of basal cell carcinoma, and melanoma cells. Further tests were performed in keloids, a primary reactive skin disorder, to evaluate whether POMC accumulation represented a disease-related phenomenon or an expression of normal cutaneous reactivity. POMC products were consistently detected (10 of 11 cases) in the keratinocytes and mononuclear cells at keloid lesions. Thus these observations indicate that POMC products may accumulate locally in lesional skin representing, presumably, a novel cutaneous response to injury. The broad spectrum of POMC products detected suggests that these arise from production in situ (expression of the POMC gene itself) by human skin.

Adrenocorticotropic Hormone↗