RESUMEN
Background: S-288310, a cancer peptide vaccine composed of two HLA-A*24:02-restricted peptides derived from two oncoantigens, DEP domain-containing 1 (DEPDC1) and M-phase phosphoprotein 1 (MPHOSPH1), was investigated in urothelial carcinoma (UC) of the bladder. Patients and methods: Thirty eight HLA-A*24:02-positive patients with progressive UC were enrolled in this study. In the phase I part of the study, three patients each were treated with S-288310 at 1 mg or 2 mg/peptide subcutaneously once a week to evaluate safety and tolerability. In the phase II, 32 patients were randomized to receive either 1 mg or 2 mg to evaluate the difference in cytotoxic T lymphocytes (CTL) induction and safety. Results: S-288310 was safe and well tolerated in the phase I. Of 27 patients evaluable for immune responses in the phase II, there was no difference in CTL induction rate between the 1 mg (100%) and 2 mg (80.0%) groups. Of 32 patients receiving S-288310 in the phase II, the most frequent drug-related AE was the injection site reaction that was observed in 29 patients (90.6%), but none of the patients discontinued administration due to these reactions and no dose relationship in the frequency and severity was observed. The objective response rate of the 32 patients was 6.3% and the disease control rate was 56.3%. The median overall survival (OS) rates for patients vaccinated with S-288310 after one regimen of chemotherapy, 2 regimens, or 3 or more were 14.4, 9.1 and 3.7 months, respectively, and 32.2% of patients post first-line treatment were alive at 2 years. OS of patients who showed CTL induction to both peptides was longer than that of those with CTL induction to no or one peptide. Conclusion: S-288310 was well-tolerated and effectively induced peptide-specific CTLs, which were correlated with longer survival for patients with UC of the bladder. Trial registration ID: JapicCTI-090980.
Asunto(s)
Vacunas contra el Cáncer/uso terapéutico , Carcinoma de Células Transicionales/terapia , Linfocitos T Citotóxicos/inmunología , Neoplasias de la Vejiga Urinaria/terapia , Anciano , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/uso terapéutico , Vacunas contra el Cáncer/inmunología , Supervivencia sin Enfermedad , Femenino , Antígeno HLA-A24/inmunología , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Vacunas de Subunidad/inmunología , Vacunas de Subunidad/uso terapéuticoRESUMEN
BACKGROUND: Prostaglandin (PG) D(2) is the major cylooxygenase metabolite released by mast cells upon allergen stimulation, and elicits responses through either the prostanoid DP1 receptor and/or the chemoattractant receptor homologous molecule expressed on T-helper type 2 (Th2) cells (CRTH2/DP2). Experimental evidence suggests that stimulation of one or both these receptors contributes to asthma pathophysiology. OBJECTIVE: The aim of this study was to test the hypothesis that the prostanoid DP1 receptor contributes to asthma pathophysiology by determining the efficacy of an orally active antagonist for this receptor, S-5751, on allergen-induced bronchoconstriction, airway hyperresponsiveness (AHR) and cellular inflammation in the sheep model of asthma. METHODS: PGD(2)-induced cyclic adenosine monophosphate (cAMP) production in platelet-rich plasma was used to establish the in vitro efficacy of S-5751. In vivo, sheep naturally allergic to Ascaris suum were challenged with an aerosolized antigen with and without S-5751 treatment (given 4 days before and for 6 days after the challenge). RESULTS: S-5751 inhibited PGD(2)-induced cAMP production in platelet-rich plasma with an IC(50) value of 0.12 microm. S-5751 at 30 mg/kg, but not at 3 mg/kg, reduced the early bronchoconstriction and inhibited the late bronchoconstriction. AHR and inflammatory cell infiltration in bronchoalveolar lavage fluid at days 1 and 7 were also inhibited with the 30 mg/kg dose. The responses observed with S-5751 at 30 mg/kg were comparable with those with montelukast treatment (0.15 mg/kg, twice a day, intravenous); however, S-5751 did not block inhaled leukotrieneD(4)-induced broncoconstriction. CONCLUSION: Prostanoid DP1 receptor inhibition may represent an alternative target for asthma therapy.
Asunto(s)
Antiasmáticos/farmacología , Asma/tratamiento farmacológico , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Tiofenos/farmacología , Acetatos/farmacología , Alérgenos/toxicidad , Animales , Asma/inducido químicamente , Asma/metabolismo , Líquido del Lavado Bronquioalveolar , Broncoconstricción/efectos de los fármacos , AMP Cíclico/metabolismo , Ciclopropanos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Prostaglandina D2/metabolismo , Quinolinas/farmacología , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Sulfuros , Factores de TiempoRESUMEN
The molecular structures of several polypeptides isolated from hypothalamic tissue have been established and the synthesis of these compounds has been achieved. These polypeptides selectively stimulate or inhibit the release of anterior pituitary hormones and melanocyte-stimulating hormone. Various studies indicate their important physiological role and support the concept that some of these polypeptides are hormones. Some synthetic hypothalamic hormones and their derivatives may find important clinical and veterinary applications.
Asunto(s)
Sistema Hipotálamo-Hipofisario/fisiología , Hormonas Liberadoras de Hormona Hipofisaria/fisiología , Hormona Adrenocorticotrópica/metabolismo , Hormona Adrenocorticotrópica/fisiología , Animales , Bovinos , Hormona Liberadora de Corticotropina/fisiología , Cricetinae , Hormona Folículo Estimulante/metabolismo , Hormona Folículo Estimulante/fisiología , Hormona del Crecimiento/metabolismo , Hormona del Crecimiento/fisiología , Haplorrinos , Humanos , Sistema Hipotálamo-Hipofisario/anatomía & histología , Hormona Luteinizante/metabolismo , Hormona Luteinizante/fisiología , Hormonas Estimuladoras de los Melanocitos/metabolismo , Hormonas Estimuladoras de los Melanocitos/fisiología , Conformación Molecular , Prolactina/metabolismo , Prolactina/fisiología , Conejos , Ratas , Hormona Liberadora de Tirotropina/fisiologíaRESUMEN
A synthetic decapeptide, corresponding to the chemical structure of luteinizing hormone-releasing hormone from porcine hypothalami, was tested for the induction of ovulation in golden hamsters that had previously been treated with phenobarbital to prevent spontaneous ovulation. Subcutaneous injection of 0.089 to 0.357 nanomole of this synthetic luteinizing hormone-releasing hormone stimulated release of luteinizing hormone and induced ovulation.
Asunto(s)
Hormona Luteinizante/metabolismo , Ovulación/efectos de los fármacos , Hormonas Liberadoras de Hormona Hipofisaria/farmacología , Animales , Cricetinae , Femenino , Hipofisectomía , Inyecciones Subcutáneas , Oviductos/citología , Oviductos/efectos de los fármacos , Hormonas Liberadoras de Hormona Hipofisaria/administración & dosificación , Hormonas Liberadoras de Hormona Hipofisaria/síntesis químicaRESUMEN
Growth hormone release-inhibiting hormone (somatostatin), a hypothalamic peptide that inhibits the release of growth hormone and also the secretion of insulin glucagon, and gastrin, was found in the rat stomach and pancreas in a concentration similar to that in the hypothalamus, as measured by radioimmunoassay. Somatostatin was also found in the duodenum and jejunum, but in a smaller concentration. Gel filtration of the extracts of the pancreas and stomach on Sephadex G-25 yielded two immunoreactive peaks, one corresponding in each case to the somatostatin tetradecapeptide. The hormone was not detected in other viscera or the ovaries. The results imply that somatostatin may be synthesized in the pancreas and the stomach in addition to the brain, and may be involved in local regulatory mechanisms for pancreatic and gastric secretion as well as secretion of growth hormone.
Asunto(s)
Mucosa Gástrica/metabolismo , Páncreas/metabolismo , Somatostatina/metabolismo , Animales , Duodeno/metabolismo , Epítopos , Femenino , Radioinmunoensayo , Ratas , Somatostatina/inmunologíaRESUMEN
A substance related to luteinizing hormone-releasing hormone was demonstrated, by immunohistochemical procedures, in the cytoplasm of interstitial cells within the rat testes. In many seminiferous tubules, nuclei of spermatogonial cells were also immunopositive. Both cytoplasmic and nuclear fractions of testicular homogenates contain immunoreactive compounds, and this report identifies which cell types contain this substance. The localization of a peptide hormone within the nucleus of a target cell population may indicate its mode of action.
Asunto(s)
Hormona Liberadora de Gonadotropina/metabolismo , Testículo/metabolismo , Animales , Especificidad de Anticuerpos , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Hormona Liberadora de Gonadotropina/inmunología , Humanos , Técnicas Inmunológicas , Células Intersticiales del Testículo/metabolismo , Masculino , Ratas , Espermatogonias/metabolismoRESUMEN
An antagonist of luteinizing hormone-releasing hormone (LH-RH). [D-Phe2-Phe3-D-Phe6]-LH-RH (Phe, phenylalanine), suppressed luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release in male rats in response to LH-RH for at least 4 hours. Three subcutaneous injection of 1 milligram of this antagonist into rats during proestrus completely suppressed ovulation, while a single injection of 1.5 milligrams per rat inhibited 95.3 percent of the preovulatory surge of LH, 84.2 percent of the FSH surge, and suppressed ovulation by 86.4 percent.
Asunto(s)
Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Ovulación/efectos de los fármacos , Animales , Depresión Química , Femenino , Hormona Folículo Estimulante/sangre , Hormona Liberadora de Gonadotropina/farmacología , Hormona Luteinizante/sangre , Masculino , RatasRESUMEN
Free (approximately 1600 daltons) somatostatin-like immunoreactivity was identified in arterial plasma of dogs that had received a test meal. Neutralization of circulating somatostatin while the dogs were consuming a fatty meal increased the plasma concentrations of triglycerides, gastrin, pancreatic polypeptide, and insulin after the meal. It is concluded that, in the dog, somatostatin is a true hormone that regulates the movement of nutrients from the gut to the internal environment.
Asunto(s)
Ingestión de Alimentos , Hormona del Crecimiento/sangre , Somatostatina/fisiología , Triglicéridos/sangre , Animales , Perros , Gastrinas/sangre , Homeostasis , Concentración de Iones de Hidrógeno , Insulina/sangre , Polipéptido Pancreático/sangre , Somatostatina/sangreRESUMEN
A polypeptide isolated from porcine hypothalami stimulates the release of both luteinizing hormone and follicle-stimulating hormone from the pituitaries of several species. This polypeptide has been structurally identified as (pyro)Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH(2) and synthesized. The natural and synthetic materials share biological properties. It appears that this peptide represents the hypothalamic hormone regulating the secretion of both luteinizing hormone and follicle-stimulating hormone.
Asunto(s)
Hormona Folículo Estimulante/metabolismo , Hormona Luteinizante/metabolismo , Hormonas Liberadoras de Hormona Hipofisaria/farmacología , Secuencia de Aminoácidos , Animales , Anticonceptivos Orales/farmacología , Hipotálamo/análisis , Hipotálamo/fisiología , Hormona Luteinizante/sangre , Masculino , Péptidos/síntesis química , Péptidos/aislamiento & purificación , Péptidos/farmacología , Hipófisis/fisiología , Hormonas Liberadoras de Hormona Hipofisaria/síntesis química , Hormonas Liberadoras de Hormona Hipofisaria/aislamiento & purificación , Ratas , PorcinosRESUMEN
BACKGROUND: Although dry skin and T cell-dependent disease exacerbation are characteristic features of atopic dermatitis (AD), the involvement of T cells in the development of dry skin remains unclear. AIMS: We aimed to elucidate the role of T cells in the development of dry skin in DS-Nh mice as a model for AD, and to evaluate this skin condition pharmacologically. METHODS: We prepared DS-Nh mice harbouring a T-cell receptor (TCR)Vbeta(a) haplotype with a central deletion in the TCRBV gene segments, and mice harbouring a TCRVbeta(b) haplotype without any deletion. We analysed the TCRVbeta chain usage and cytokine response to antimouse CD3 monoclonal antibodies in the splenocytes from the two mouse substrains. Transepidermal water loss (TEWL) was measured, and histochemical examination of these mice was carried out. Finally, a pharmacological analysis using loratadine was also performed to evaluate the features of spontaneous dry skin in DS-Nh mice as a model of AD. RESULTS: Although the deletion of TCRBV gene segments in the TCRVbeta(a) haplotype yielded different representations of each TCRVbeta mRNA, this deletion did not evoke distinct cytokine profiles in the splenocytes compared with those of mice with the TCRVbeta(b) haplotype. Furthermore, our results indicated that the onset of dry skin occurred earlier in mice with TCRVbeta(b) than in those with TCRVbeta(a). Pharmacologically, AD-like dry skin in DS-Nh with TCRVbeta(b) mice is susceptible to an H1 blocker. CONCLUSIONS: A specific lymphocyte subpopulation bearing T-cell receptors may be responsible for loratadine-responsive dermatitis in DS-Nh mice.
Asunto(s)
Dermatitis Atópica/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Animales , Citocinas/metabolismo , Dermatitis Atópica/genética , Modelos Animales de Enfermedad , Haplotipos , Inmunohistoquímica , Ratones , Ratones Endogámicos , ARN Mensajero/metabolismo , Receptores de Antígenos de Linfocitos T alfa-beta/genéticaRESUMEN
BACKGROUND: Dose-escalation of epertinib (S-222611), a new potent oral EGFR/HER2 inhibitor, has established a recommended daily dose of 800 mg in patients with solid tumours. In this study, we have recruited a larger number of patients to assess further the safety, tolerability, pharmacokinetics (PKs) and antitumour activity. PATIENTS AND METHODS: Patients with solid tumours expressing EGFR or HER2 received a single dose of epertinib at 800 mg on Day 1 to assess PK over 7 days, followed by continuous once-daily dosing from Day 8. RESULTS: We treated 76 patients with breast (n = 27), upper gastrointestinal (GI; n = 30), head and neck (n = 12) or renal cancers (n = 7). Epertinib was well-tolerated with mostly grade I and II adverse events (AEs). The most frequent AE was diarrhoea, which was generally manageable with loperamide. The objective response rate (ORR) in patients with heavily pretreated breast and upper GI cancers was 16.0% (4 PRs) and 8.3% (1CR, 1PR), respectively. All six responding patients had HER2-positive tumours; the ORR for HER2-positive breast and upper GI cancer populations was 19.0% and 20.0%. Partial response in the brain disease of one breast cancer patient lasted 7.5 months. CONCLUSION: Once-daily dosing of epertinib at 800 mg was well-tolerated and demonstrated promising antitumour activity in patients with heavily pretreated HER2-positive breast and upper GI cancer, including those with brain metastases. EUDRACT NUMBER: 2009-017817-31.
Asunto(s)
Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/patología , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , Resultado del TratamientoRESUMEN
The effects of the instillation of glucose, fat, casein hydrolysate, and HCl into the gastrointestinal tract upon plasma levels of somatostatin-like immunoreactivity (SLI) in the venous effluent of the pancreas, fundus and antrum of the stomach, and in the inferior vena cava (IVC) were determined in normal laparotomized dogs. Fasting SLI levels in the effluent plasma from these sites were significantly greater than IVC levels. The intragastric administration of glucose elicited a prompt and significant rise in SLI levels in pancreatic, fundic and antral venous plasma, and in IVC plasma; intraduodenal glucose elicited smaller increments. After intragastric fat, a smaller, more gradual increase in the pancreatic and fundic effluents was observed, whereas the rise in antral SLI was minute, and IVC SLI did not rise significantly. Intraduodenal fat elicited a prompt increase in the pancreatic and antral vein SLI levels, and a small but significant increase in fundic and IVC plasma which suggests faster release of enteric factors that influence SLI secretion in the pancreas and antrum. Intragastric casein hydrolysate elicited a prompt increase in SLI in both the pancreatic and fundic veins, the latter being marked, but the antral SLI response was small; IVC SLI rose significantly within 15 min. Intragastric HCl provoked a prompt and marked rise in pancreaticoduodenal and antral vein SLI but no increase in fundic vein SLI; IVC SLI levels rose significantly within 20 min. Intraduodenal HCl elicited an even more prompt and marked pancreatic SLI response, and SLI rose significantly in both the fundic and antral venous effluents; IVC SLI also rose more promptly. In dogs with a gastric fistula that prevented intraduodenal entry of HCl, intragastric HCl elicited only a very small and transient rise in pancreaticoduodenal vein SLI, markedly stimulated the antral SLI response, but completely suppressed fundic venous SLI levels. The results indicate that all three nutrients stimulate SLI release from the pancreas and stomach. The greater SLI response to intragastric, as opposed to intraduodenal, glucose suggests that unidentified local factors are of importance. The responses to the intraduodenal instillation of HCl and fat suggest a role of enteric hormones in the release of SLI from the pancreas and fundus and antrum of the stomach. Additionally, there is evidence of direct effects of HCl upon gastric SLI release.
Asunto(s)
Alimentos , Mucosa Gástrica/metabolismo , Ácido Clorhídrico/farmacología , Páncreas/metabolismo , Somatostatina/metabolismo , Animales , Caseínas/farmacología , Grasas de la Dieta/administración & dosificación , Perros , Glucosa/farmacología , Somatostatina/sangreRESUMEN
The effects of glucose, amino acids, pancreozymin-cholecystokinin, and tolbutamide upon the release of immunoreactive somatostatin (IRS) from the isolated perfused pancreas were studied. In seven experiments in which glucose was perfused either at a concentration of 100 or 350 mg/dl or at 25 mg/dl, IRS levels were significantly greater at the higher glucose concentrations. In three dose-response experiments in which the perfusing glucose concentration was increased at 30-min intervals from an initial concentration of 25 mg/dl to a final concentration of 300 mg/dl, progressive increases in IRS release were noted at glucose concentrations of 100 mg/dl and above. Perfusion of a 20 mM mixture of 10 amino acids also elicited a prompt and significant biphasic IRS rise in each of six experiments. In five experiments, 20 mM leucine evoked a similar response in mean IRS. Perfusion with 0.075 Ivy U/ml of pancreozymin-cholecystokinin, with or without the presence of a 1 mM 10-amino acid mixture, elicited a prompt rise in IRS with a pattern resembling that of insulin in a total of six experiments. Tolbutamide (0.75 mg/min) also stimulated IRS release in five of six challenges. The IRS responses to nutrients and to pancreozymin and their similarity to the insulin responses raise the possibility that, like insulin, pancreatic somatostatin may have an endocrine role related to nutrient homeostasis.
Asunto(s)
Aminoácidos/farmacología , Glucosa/farmacología , Islotes Pancreáticos/efectos de los fármacos , Somatostatina/metabolismo , Animales , Antígenos , Colecistoquinina/farmacología , Perros , Islotes Pancreáticos/metabolismo , Leucina/farmacología , Masculino , Tolbutamida/farmacologíaRESUMEN
The effects of gastrin, gastric inhibitory polypeptide, secretin, and the octapeptide of pancreozymin-cholecystokinin on immunoreactive somatostatin release were studied in the isolated perfused dog pancreas. Gastrin at a concentration of 65 ng/ml and the octapeptide of pancreozymin-cholecystokinin at a concentration of 25 ng/ml produced a prompt, but transient statistically significant, twofold rise in mean somatostatin concentration. Secretion at a concentration of 0.3 U/ml and gastric inhibitory polypeptide concentration of 58 ng/ml produced a prompt two- to threefold rise in mean somatostatin release, which persisted throughout the perfusion period. With all four polypeptides the pattern of the somatostatin response resembled that of insulin. It appears that pancreatic somatostatin release is stimulated by gastrointestinal hormones that influence the secretion of insulin and glucagon.
Asunto(s)
Colecistoquinina/análogos & derivados , Polipéptido Inhibidor Gástrico/farmacología , Gastrinas/farmacología , Hormonas Gastrointestinales/farmacología , Páncreas/efectos de los fármacos , Secretina/farmacología , Somatostatina/metabolismo , Animales , Colecistoquinina/farmacología , Perros , Técnicas In Vitro , Páncreas/metabolismo , PerfusiónRESUMEN
Ten peptides were isolated from porcine hypothalami and structurally elucidated. These included four dipeptides Arg-Phe, Phe-Tyr, Val-Trp, and Tyr-Phe; a tripeptide Lys-Phe-Tyr; two tetrapeptides Gly-Lys-Val-Asn and Phe-Glu-His-Glu, a nonapeptide Val-Val-Tyr-Pro-Trp-Thr-Gln-Arg-Phe; a decapeptide Leu-Val-Val-Tyr-Pro-Trp-Thr-Gln-Arg-Phe and a hexadecapeptide Phe-Leu-Gly-Phe-Pro-Thr-Thr-Lys-Thr-Tyr-Phe-Pro-His-Phe-Asn-Leu. The tetrapeptide Gly-Lys-Val-Asn, the nonapeptide, the decapeptide and the hexadecapeptide most probably represent artifact fragments of alpha- and beta-chains of porcine hemoglobin. The natural or synthetic Gly-Lys-Val-Asn and Phe-Glu-His-Glu had some growth hormone releasing activity while Val-Trp, Tyr-Phe and Lys-Phe-Tyr had slight prolactin releasing activity. The biological activities of other peptides have not been determined yet.
Asunto(s)
Hormonas Hipotalámicas/aislamiento & purificación , Hipotálamo/análisis , Péptidos/aislamiento & purificación , Secuencia de Aminoácidos , Animales , Células Cultivadas , Hormona Liberadora de Hormona del Crecimiento , Oligopéptidos/aislamiento & purificación , Péptidos/farmacología , Hipófisis/efectos de los fármacos , Ratas , Porcinos , Hormona Liberadora de TirotropinaRESUMEN
The human gene encoding pituitary adenylate cyclase activating polypeptide (PACAP) was isolated and its nucleotide sequence was determined. By comparison with a human PACAP cDNA, the exon/intron organization of PACAP gene was determined. The last exon encoded the longer form of PACAP, PACAP38 and 3'-untranslated sequences, suggesting that the shorter form of PACAP, PACAP27 is not generated by alternative splicing mechanisms. The 5'-flanking region of the PACAP gene contains several sequence motifs homologous to CRE, TRE, and GHF-1. On the basis of DNA isolated from mouse A9 microcell hybrid clone containing a single human chromosome, the PACAP gene was assigned to human chromosome 18. Furthermore, we determined the locus of the gene to be 18p11 by the chromosomal in situ hybridization technique.
Asunto(s)
Neuropéptidos/genética , Secuencia de Aminoácidos , Secuencia de Bases , Mapeo Cromosómico , Codón , ADN , Exones , Biblioteca Genómica , Humanos , Intrones , Datos de Secuencia Molecular , Hibridación de Ácido Nucleico , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Precursores de Proteínas/genética , Secuencias Reguladoras de Ácidos NucleicosRESUMEN
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a new member of the secretin glucagon-vasoactive intestinal peptide (VIP) family of peptides, being most homologous to VIP. PACAP exists in two amidated forms with 38 residues (PACAP38) and 27 residues (PACAP27), respectively. PACAP38 is the major form in tissues. There are two types of high-affinity receptors for PACAP: type I, which specifically binds to both PACAPs, and type II, which is shared with VIP. Type I PACAP receptors appear to have two subtypes: type IA, which binds to both PACAP38 and PACAP27, with slight preference for the latter, and type IB, with greater preference for PACAP38. Distribution of the type I PACAP receptor is different from that of VIP, and it is found in high concentrations in brain, spinal cord, anterior pituitary, adrenal medulla, spermatogonia at certain stages, mature spermatozoa, and some cell lines. Type II PACAP receptors are found in lung, liver, intestine, and other tissues, and their distribution is similar to that of the VIP receptor. Type II PACAP receptor might be similar to or identical with the VIP receptor.
RESUMEN
Pituitary adenylate cyclase-activating polypeptide (PACAP) is abundant not only in the brain, but also in the testis. Immunohistochemical studies have shown that PACAP-LI in rat testis is expressed stage specifically in spermatids. This suggests that testicular PACAP participates in the regulatory mechanism of spermatogenesis. Additionally, the ovary contains a relatively small amount of PACAP, conceivably involved in the regulation of folliculogenesis. PACAP is synthesized as a preprohormone and is processed by prohormone convertases, such as PC1, PC2, and PC4. PC4 is expressed only in the testis and ovary, where neither PC1 nor PC2 is expressed. However, whether PC4 is the sole endoprotease for the PACAP precursor in the gonads remains unknown. Recent studies using PC4-transgenic mice revealed that male PC4-null mice exhibited severely impaired fertility, although spermatogenesis appeared to be normal. The female PC4-null mice exhibited delayed folliculogenesis in the ovaries. To examine whether PC4 is the sole processing enzyme for the PACAP precursor in the gonads, we analyzed testicular and ovarian extracts from the PC4-null and wild-type mice for PACAP (PACAP38 and PACAP27) and its messenger RNA using reverse phase HPLC combined with specific RIAs and ribonuclease protection assay, respectively. For RIAs, three different polyclonal antisera with different recognition sites were used to identify PACAP38, PACAP27, and its precursor. Neither the testis nor the ovary from the PC4-null mice expressed PACAP38 or PACAP27, but the levels of PACAP transcripts in the testis and ovary of homozygous PC4-deficient mice were considerably elevated compared with those of the wild-type and heterozygous animals. The findings indicate that PC4 is the sole processing enzyme for the precursor of PACAP in the testis and ovary of mice. The possibility that the absence of bioactive PACAP in the testis and ovary of PC4-null mice caused severely impaired fertility in the males and delayed folliculogenesis in females warrants investigation.
Asunto(s)
Neuropéptidos/metabolismo , Ovario/metabolismo , Profármacos/metabolismo , Serina Endopeptidasas/metabolismo , Testículo/metabolismo , Animales , Femenino , Masculino , Ratones , Mutación/fisiología , Neuropéptidos/genética , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Proproteína Convertasas , ARN Mensajero/metabolismo , Serina Endopeptidasas/deficiencia , Serina Endopeptidasas/genética , SubtilisinasRESUMEN
Passive immunization of rats with an antiserum to synthetic somatostatin caused a 250% elevation of basal serum TSH levels and a nearly 200% increase in TSH-response to TRH. These findings strongly support the concept that pituitary thyrotrophs are regulated by endogenous somatostatin as well as by TRH and thyroid hormones. Serum GH levels in the antiserum-treated rats were considerably higher than those in rats which received normal serum. No clearcut influence on prolactin secretion was observed.
Asunto(s)
Somatostatina/fisiología , Hormona Liberadora de Tirotropina/sangre , Tirotropina/sangre , Animales , Anticuerpos , Hormona del Crecimiento/sangre , Inmunidad Materno-Adquirida , Masculino , Prolactina/sangre , Ratas , Somatostatina/inmunologíaRESUMEN
GH-releasing factor (GRF) is a hypothalamic peptide that stimulates the secretion of pituitary GH. The possibility of feedback effects of GRF within the central nervous system was studied in conscious freely moving male rats with indwelling iv and intracerebroventricular (icv) cannulae. Animals were injected icv or iv with 10 ng-10 micrograms human (h) GRF(1-40)-OH (hGRF-40) or GRF(1-44)-NH2 (hGRF-44), and blood samples were obtained every 10-20 min from 1000-1400 h. GH secretion was pulsatile, with major secretory peaks at around 1200 h in most control animals. When 10 ng hGRF-40 were injected icv at 1100 h, immediately before the expected onset of the spontaneous GH secretory burst, GH secretion was suppressed during the following 2-h period. An iv injection of 10 ng hGRF-40 was without effect. In contrast, when 1 microgram hGRF-40 was injected icv or iv, plasma GH levels peaked at 20 and 10 min, respectively, and returned toward baseline shortly thereafter. The spontaneous GH secretory pulse after 1 microgram hGRF-40 (icv or iv) was suppressed in proportion to the magnitude of the GH secretory response to GRF (r = 0.78, p less than 0.01), and the prolongation of the interval between the injection of GRF and the subsequent spontaneous GH surge was directly related to the GH response to GRF (r = 0.85, p less than 0.001). The icv or iv injection of a larger dose of either hGRF-40 or hGRF-44 (10 micrograms) at 1100 h also resulted in marked and comparable increases in plasma GH levels, with peaks at 20 min (icv) and 10 min (iv) after injection. No changes in behavior or plasma glucose were observed up to 3 h after icv injection of any of the doses of hGRF-40 or of hGRF-44. The suppressive effect of centrally administered hGRF-40 (10 ng) on GH secretion was blocked by the iv administration of a specific antisomatostatin serum immediately before the injection of hGRF. These results demonstrate a dual action of GRF on spontaneous GH secretion and indicate the presence of an inhibitory feedback system within the central nervous system for the regulation of GH secretion which is mediated by hypothalamic somatostatin.