A possible neuroendocrine system in polynoid polychaetes

Within the supraesophageal ganglion of polynoids is a vertical fiber tract which has the appearance of a “Y” in transverse sections of the brain, and contains the axons of many neurosecretory cells. The granule-filled terminals of these neurosecretory fibers are found at the base of the tract where they are in contact with the inner surface of the sheath covering the ventral surface of the brain. This sheath separates these neurosecretory endings from an underlying pericapsular epithelium which is thicker in this region. Beneath this pericapsular epithelium is a coelomic sinus. The dorsal blood vessel is located within this sinus and is “innervated” by a pair of fiber bundles that pass out of the brain at the base of the vertical fiber tract. The outer surface of the vessel is covered by epithelioid cells which contact these fiber bundles and the thickened pericapsular epithelium, and sometimes contain granular cytoplasmic inclusions. The lumen of the vessel is continuous with the lumina of a pair of cellular, thickwalled structures of unknown function which are attached to the ventro-lateral margins of the brain. The relationship between neurosecretory endings, enlarged pericapsular cells, coelomic sinus and blood vessel provides morphological evidence for the hypothesis that these structures are elements of a neuroendocrine system, similar in some respects to the brain-infracerebral gland complex of nereid and nephtyid polychaetes.     

A morphological and histochemical analysis of the neuroendocrine system of the gut in Acipenser transmontanus

Morphological, histochemical and immunohistochemical data are presented to demonstrate that the enteric nervous system of the sturgeon is in part composed and arranged differently from other fish. It is composed of neurons which distribute both to the tunica propria-submucosa and tunica muscularis. Nerve cell bodies are small and nerve terminals run in bundles which are both unmyelinated and myelinated. The presence of myelinated nerve fibres in the enteric nervous system of vertebrates is infrequent. Ganglionated plexuses are only found in relation to the musculature. In contrast with the other tracts of the gut, the musculature of the oesophagus is arranged into two orthogonal layers, and the inner layer is composed of striated muscle fibres. Enzymes related to the classical neurotransmitters acetylcholine and adrenaline and some possible accessory neuromediators (CGRP-, somatostatin-, ANP-, substance P-, NPY-like peptides, and nitric oxide) were identified histochemically and immunohistochemically in components of the enteric nervous system, especially those which innervate the oesophagus. The diffuse endocrine system was limited to a gastric cell type, which synthesized a somatostatin-like peptide. Some of these special features of the enteric nervous system may possibly be related to functional properties peculiar to the sturgeon gut, which also shows aspects of morphological organization that are different to those of other fish.     

The role of glutamate and nitric oxide in the reproductive neuroendocrine system.

The preovulatory surge of gonadotropin releasing hormone (GnRH) is essential for mammalian reproduction. Recent work has implicated the neurotransmitters glutamate and nitric oxide as having a key role in this process. Large concentrations of glutamate are found in several hypothalamic nuclei known to be important for GnRH release and glutamate receptors are also located in these key hypothalamic nuclei. Administration of glutamate agonists stimulate GnRH and LH release, while glutamate receptor antagonists attenuate the steroid-induced and preovulatory LH surge. Glutamate has also been implicated in the critical processes of puberty, hormone pulsatility, and sexual behavior. Glutamate is believed to elicit many of these effects by activating the release of the gaseous neurotransmitter, nitric oxide (NO). NO potently stimulates GnRH by activating a heme containing enzyme, guanylate cyclase, which in turn leads to increased production of cGMP and GnRH release. Recent work has focused on identifying anchoring and (or) clustering proteins that target glutamate receptors to the synapse and couple the glutamate-NO neurotransmission system. The present review will discuss these new findings, as well as the role of glutamate and nitric oxide in important mammalian reproductive events, with a focus on the hypothalamic control of preovulatory GnRH release.     

The infracerebral gland--a possible neuroendocrine complex in Nereis

The infracerebral gland of Nereis consists of an epithelium covering the ventral surface of the posterior region of the brain. The thickness of the epithelium varies greatly in different species, and it appears especially well developed in Nereis limnicola. Cells of the most numerous type are in direct contact with the base of the brain. Their apical surfaces bound a coelomic sinus, below which is a blood plexus. Other cells are fuchsinophilic and contain many inclusions resembling elementary neurosecretory granules. A third type is rare and resembles glial elements. A number of nerve tracts run from the neuropil to the base of the brain in the region of the gland. Where they impinge upon the capsule they form swellings containing elementary granules and small vesicles. Some axons do not end on the capsule but pass through the capsule and then ramify among the cells of the gland. The swollen endings of other fibers, probably nervous in character, are packed with mitochondria and are scattered over the inner surface of the capsule in the region of the gland. The features described are suggestive of a neuroendocrine complex, and the relation between the brain and the infracerebral gland is in need of experimental analysis in view of the important endocrine functions presently ascribed to the brain in nereids.     

A possible role for gut GLI: an inhibitor of lipolysis

Duck gut GLI was incubated a) alone and b) with the lipolytically active duck pancreatic GLI and the intestinal factors peak 2 and 3, and the glycerol released from duck adipocytes measured. Intestinal GLI was non-lipolytic, but not inert: it reduced the lipolysis induced by pancreatic GLI and peak 2.     

Intrauterine growth retardation in experimental diabetes: possible role of the placenta

Fetal growth disorders are common in pregnancy complicated by diabetes. Whereas macrosomia often occurs in infants of diabetic women, growth retardation is almost a rule in spontaneous and experimental diabetes in animals. However, it is not clear when during development growth inhibition starts and how placental pathology might affect fetal growth in maternal diabetes. In this study pregnant Wistar rats were injected (ip) with a single dose of 50 mg/kg of streptozotocin (STZ) on gestation day (GD) 2 and a blood glucose level of 200 mg/dl or more determined 24 hrs later indicated diabetes. The controls were non-treated, buffer treated or, following confirmation of diabetes, injected with a single dose of 2--6 IU of insulin (Novo Ultralente) once daily. Fetuses and placentae were collected from GD 14--20. Intrauterine growth retardation (IUGR) in STZ group was significant as early as GD 15 and persisted to GD 20. Insulin produced a significant recovery in fetal weight gain. The placentas of STZ-treated group were significantly heavier than those of the control groups. The reduction in cord length of the STZ group became apparent on GD 16 and remained so to term. The placenta of GD 14 STZ group had a thicker decidua basalis and dilated maternal sinusoids. By GD 16, the decidua basalis contained glycogen-containing decidual cells and scattered glycogen cells confirmed by Best's carmine with or without diastase. The glycogen cells of the basal zone were more abundant, and had degenerated in some sites leaving behind cysts with eosinophilic mass. The giant cells had proliferated enormously. The labyrinthine zone appeared spongy with persistent fetal mesenchyme, peri-vascular fibrosis, and enhanced placental barrier. The trophoblasts of the labyrinths also contained traces of glycogen unlike the controls. By GD 18, the decidua basalis of the STZ group was thinner than that of the controls and contained necrotic giant cells and lymphocytic aggregations. In the basal zone, the giant cells had proliferated further; more glycogen cells had degenerated. Perivascular fibrosis was still extensive in the labyrinthine zone. Bloodless maternal sinusoids, extensive vacuolization, degeneration of glycogen islands and formation of cysts characterized the labyrinthine zone. These changes varied in intensity from one area to another in the same placenta and between placentas of the same and of different litters. The development of the upper and lower jaws, elevation and fusion of palatal shelves, reduction of physiological umbilical hernia, descent of the testes, fusion of the urethral folds and separation of digits of the paws were significantly delayed in the STZ group. The consistent association of placental pathology with fetal growth retardation is suggestive of an alteration in placental function possibly contributing to IUGR in STZ-induced diabetes in rats.     

The presence of a galanin-like peptide in the gut neuroendocrine system of Lampetra fluviatilis and Acipenser transmontanus: an immunohistochemical study

Galanin is a brain-gut neuropeptide present in the central and peripheral nervous systems of vertebrates. In the present survey, the galaninergic and the diffuse endocrine systems of the alimentary canal of the river lamprey, Lampetra fluviatilis, and the white sturgeon, Acipenser transmontanus, were studied by immunohistochemistry. The results show the presence of galanin-like immunoreactive endocrine cells in the gut of L. fluviatilis. In addition, a galanin-like immunoreactivity was detected in enteric intramural neurons of both species. It is conceivable that the galaninergic system plays in both species a role in the regulation of the gut muscle contractility and in the modulation of mucosal secretive/absorptive processes. In A. transmontanus, the presence of galanin-like immunoreactive nerve fibres associated with components of the gut associated-lymphoid tissue is possibly correlated with a control of the defensive events at this site. The presence of a galanin-like immunoreactivity in the neuroendocrine system of these two ancient fishes confirms the hypothesis on the early occurrence of this regulative molecule in the gastro-enteric system of vertebrates.     

The ventricular system in neuroendocrine mechanisms

Summary This investigation has utilized a correlative scanning-transmission electron microscopic technique in the analysis of the primate cerebral ventricular system. This approach has demonstrated a complex network of supraependymal cellular elements upon the walls of the third cerebral ventricle in direct contact with the ventricular lumen. Type I neuronal-like cells and type II histiocytic-like cells with potential phagocytic capabilities have been observed in large numbers throughout the third ventricle. Type I neuron-like cells are discussed in the context that they may represent a population of receptor-cells which serve to assess ambient changes in the composition of bioactive peptides in the cerebrospinal fluid and may serve as a supraependymal network that integrates the endocrine hypothalamus with other circumventricular organs which may also be sites of neuroendocrine transduction.Supported by USPHS Program Project Grant NS-11642Career Development Awardee GM K04 70001     

The immune system in neuroendocrine tumors

During the last 30 years the incidence of neuroendocrine tumors has increased considerably and the overall 5-year survival rate has not changed substantially. Conventional therapeutic approaches appear to show an unsatisfactory effect in the more insidious forms of malignancies. Hence, attempts were made to direct the patient's own immune system against cancer by vaccinating against different tumor antigens. Up to date, only sporadic achievements were demonstrated in the majority cases of vaccination trials. One of the main hindrances to a successful vaccination comprises tumor-immune-escape mechanisms. This review focuses on the current knowledge concerning tumor immunoevasion strategies and the immune system in neuroendocrine tumors.     

Proliferative activity of well differentiated neuroendocrine tumours of the gut

Neuroendocrine tumours of the gastrointestinal tract are relatively uncommon neoplasms with, in spite of their characteristic morphology, relatively unpredictable biological behaviour. In some sites, notably the appendix, these tumours are largely benign whereas at other localisations, such as the small bowel, metastases occur and the outcome is less favourable. Given the lack of discriminative power of histological parameters, immunohistochemical parameters have been proposed. Of these the Ki-67 index, as an indicator of proliferative activity, has shown some promise. In order to assess their proliferative activity and the potential contribution of this parameter to defining biological behaviour, we performed Ki-67 immunostaining of a series of 64 well differentiated neuroendocrine tumours of the gut (stomach, small bowel, appendix, colon and rectum). Ki-67 labeling index, based upon counting of up to 5000 cells, ranged between 0 and 6.1%. No difference was found according to age, gender, size, location or TNM classification. Ki-67 labeling index of midgut endocrine tumours of long term surviving patients did not differ from patients that died. We conclude that Ki-67 labeling index as an indicator of proliferative activity of well differentiated neuroendocrine tumours of the digestive tract does not correlate with size nor site nor stage. Even though only small numbers of tumours could be analysed, which hampered appropriate statistical analysis, it seems unlikely that proliferative activity has potential as an independent prognostic parameter for this type of tumour.     

The cellulolytic system of the termite gut

The demand for the usage of natural renewable polymeric material is increasing in order to satisfy the future needs for energy and chemical precursors. Important steps in the hydrolysis of polymeric material and bioconversion can be performed by microorganisms. Over about 150 million years, termites have optimized their intestinal polysaccharide-degrading symbiosis. In the ecosystem of the “termite gut,” polysaccharides are degraded from lignocellulose, such as cellulose and hemicelluloses, in 1 day, while lignin is only weakly attacked. The understanding of the principles of cellulose degradation in this natural polymer-degrading ecosystem could be helpful for the improvement of the biotechnological hydrolysis and conversion of cellulose, e.g., in the case of biogas production from natural renewable plant material in biogas plants. This review focuses on the present knowledge of the cellulose degradation in the termite gut.     

The role of enteric glia in gut inflammation

A neuro-glia interaction is part of gut inflammation and essential for the integrity of the bowel. A loss of enteric glia cells (EGCs) led to a fatal haemorrhagic jejuno-ileitis and death in a few days. Although a diminished EGC network is postulated in inflammatory bowel disease and enteric glia pathology is described in Chagas' disease the role of EGCs in the onset of these disease complexes is not definitely clear. Several lines of evidence implicate that the secretion of different factors by enteric glia may be the key for modulating gut homeostasis. As mucosal integrity might be important for remission in Crohn's disease and inflammation of the enteric nervous system is part of the pathology in Chagas' disease, the role of EGCs during gut inflammation could be part of the key to understand these diseases.     

The Vitamin D endocrine system of the gut--its possible role in colorectal cancer prevention

While Vitamin D insufficiency in the US and European population is rising, epidemiological studies suggest an inverse correlation between low serum levels of 25-hydroxyvitamin D(3) (25-OH-D(3)) and colorectal cancer incidence. The antimitotic, prodifferentiating and proapoptotic active metabolite 1alpha,25-dihydroxyvitamin D(3) (1,25-(OH)(2)-D(3)) is synthesized also by colonocytes, since these possess Vitamin D synthesizing (CYP27B1) and catabolic (CYP24) hydroxylases similar to the kidney. Early during colon tumor progression, expression of CYP27B1 and of the Vitamin D receptor increases, suggesting an autocrine/paracrine growth control in colon tissue as a physiological restriction against tumor progression. However, in human adenocarcinomas expression of the catabolic CYP24 is also enhanced when compared with adjacent normal mucosa. Therefore, to maintain colonic accumulation of 1,25-(OH)(2)-D(3) its catabolism needs to be restricted. Our studies in mice show that low nutritional calcium causes hyperproliferation of colon crypts and significant elevation of CYP24 expression, which can be completely abrogated by soy feeding. We suggest that phytoestrogens in soy, known to be estrogen receptor modulators, are responsible for decreased CYP24 expression. These results and our observation that 17beta-estradiol can elevate CYP27B1 expression in rectal tissue of postmenopausal women, may underlie the observed protective effect of estrogens against colorectal cancer in females.     

The role of the gut flora in the metabolism of cyclamate

1. [(14)C]Cyclamate was not metabolized when incubated with the liver, spleen, kidney or blood of rats of rabbits kept on a cyclamate-containing diet, and that had become converters of cyclamate into cyclohexylamine. 2. [(14)C]Cyclamate was converted into cyclohexylamine when incubated under anaerobic conditions with the contents of the caecum, colon or rectum or with the faeces of cyclamate-pretreated rats. Similar results were obtained with cyclamate-pretreated rabbits. With cyclamate-pretreated guinea pigs, which did not readily convert cyclamate into cyclohexylamine, the colon contents showed only low activity in this respect. 3. The faeces of a human converter of [(14)C]cyclamate into cyclohexylamine were also very active, but became less active when cyclamate was removed from his diet. 4. On subculturing the organisms from the contents of the colon and rectum of rats, the ability to convert cyclamate into cyclohexylamine was lost during three subcultures, but the loss of the activity was considerably decreased by subculturing in the presence of cyclamate. 5. Incubation of rat faeces in broths containing cyclamate increased their ability to metabolize cyclamate, but similar treatment of rabbit and human faeces suppressed this activity. 6. When rats are kept on a cyclamate diet the number of clostridia in the faeces increased considerably. In human dietary cyclamate did not appear to alter the counts of various faecal micro-organisms. 7. The gut organisms that appear to develop the ability to convert cyclamate into cyclohexylamine are clostridia in rats, enterobacteria in rabbits and enterococci in man. 8. [(14)C]Cyclohexylamine injected into the caecum or colon of rats is readily absorbed and excreted in the urine. 9. It appears that on continued intake of cyclamate the gut flora develop the ability to convert cyclamate into cyclohexylamine, which is then absorbed and excreted mainly in the urine, although a small proportion is metabolized to other compounds.     

The formation of lipid droplets: possible role in the development of insulin resistance/type 2 diabetes

Neutral lipids are stored in so-called lipid droplets, which are formed as small primordial droplets at microsomal membranes and increase in size by a fusion process. The fusion is catalyzed by the SNARE proteins SNAP23, syntaxin-5 and VAMP4. SNAP23 is involved in the insulin dependent translocation of GLUT4 to the plasma membrane, and has an important role in the development of insulin resistance. Thus fatty acids relocalize SNAP23 from the plasma membrane (and the translocation of GLUT 4) to the interior of the cell giving rise to insulin resistance. Moreover this relocalization is seen in skeletal muscles biopsies from patients with type 2 diabetes compared to matched control. Thus a missorting of SNAP23 is essential for the development of insulin resistance.