Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of IL-1beta in the NOD mouse pancreas was examined following disease acceleration with cyclophosphamide (Cy). Female NOD mice were injected with Cy at day 95 and the pancreas examined immunohistochemically at days 0, 4, 7, 11, and 14 (Cy group). Cyclophosphamide was also administered to NOD mice that were given oral nicotinamide from day 21. At day 0 (Cy group), IL-1beta was expressed in selective intraislet macrophages but showed an increase from day 7 onwards in macrophages, a few beta cells, and somatostatin cells. Peak expression was seen at day 11, when it was significantly higher than in day-11 mice given nicotinamide. In the Cy group a proportion of macrophages coexpressed IL-1beta and inducible nitric oxide synthase (iNOS). IL-1beta expressed within the islet macrophages may act in concert with other cytokines, promote free radical generation including NO, and promote beta cell death during IDDM.
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PMID:IL-1beta expression in islet cells of the NOD mouse and its spatial relationship to beta cells and inducible nitric oxide synthase. 1202 Nov 4

High levels of neuropeptide Y (NPY) are found in basal ganglia where it is co-localised with somatostatin (SOM) and nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH/d) in a population of striatal GABA containing interneurones. Although alterations occur in the levels of various neuropeptides in basal ganglia in Parkinson's disease (PD), it is not known whether NPY is affected. Using in situ hybridisation immunohistochemistry, we have examined the distribution of NPY mRNA in the caudate nucleus, putamen and nucleus accumbens of normal individuals and patients with PD. NPY mRNA was weakly expressed in the caudate nucleus, putamen and nucleus accumbens in normal individuals with a scattered labelling of neurones. However, there was no regional localisation within any brain area and no obvious differences between brain regions. In PD, the number of NPY mRNA-expressing cells was increased as was the density of the silver grains overlying each positive cell. The increase was more pronounced in the nucleus accumbens and in the ventral part of the caudate nucleus. The increase in NPY mRNA expression observed in patients with PD may reflect the loss of dopaminergic tone on striatal NPY containing interneurones, although a role for chronic L-DOPA therapy cannot be ruled out.
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PMID:Increased neuropeptide Y mRNA expression in striatum in Parkinson's disease. 1259 Nov 54

The degeneration of selective and specific types of neurons is a characteristic feature in several neurodegenerative disorders. N-methyl-D-aspartate receptor (NMDAR) agonist quinolinic acid (QUIN)-induced excitotoxicity has been implicated in neurodegeneration and mimics Huntington's disease (HD) by the loss of medium-sized spiny projection neurons while sparing medium-sized aspiny interneurons in the striatum. Previous work suggests that somatostatin/neuropeptide Y (SST/NPY)-containing neurons are selectively preserved in HD due to the presence of nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) and the lack of NMDAR. In the present study, the distribution of somatostatin (SST), neuropeptide Y (NPY), nitric oxide synthase (nNOS), NMDA receptor type-1 (NR1), and the enzyme NADPH-d was determined in cultured striatal neurons with the effect of QUIN and N-methyl-D-aspartate (NMDA). SST/NPY-positive neurons, which constitute approximately 8-10% of striatal neurons, are selectively spared in QUIN/NMDA-treated cultures. nNOS and NADPH-d-positive neurons, comprising 3.8% of the neuronal population, also exhibit selective resistance to excitotoxicity. Most NR1-positive neurons, which constitute >80% of the total neuronal population, are lost in majority upon treatment with QUIN and NMDA. SST and NADPH-d-positive neurons also colocalize with Cu/Zn superoxide dismutase (Cu/Zn SOD). In conclusion, our results thus demonstrate that SST/NPY/nNOS-positive neurons are selectively spared in NMDA agonist-induced excitotoxicity, which could be attributed to the presence of Cu/Zn SOD and NADPH-d in addition to the low abundance of NMDAR on these neurons.
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PMID:Characterization of striatal cultures with the effect of QUIN and NMDA. 1509 1

Type I diabetes mellitus is caused by an autoimmune destruction of the insulin-producing beta cells. The major obstacle in using transplantation for curing the disease is the limited source of insulin-producing cells. The isolation of human embryonic stem (hES) cells introduced a new prospect for obtaining a sufficient number of beta cells for transplantation. We present here a method for forming immature islet-like clusters of insulin-producing cells derived from hES cells. The protocol consisted of several steps. Embryoid bodies were first cultured and plated in insulin-transferrin-selenium-fibronectin medium, followed by medium supplemented with N2, B27, and basic fibroblast growth factor (bFGF). Next, the glucose concentration in the medium was lowered, bFGF was withdrawn, and nicotinamide was added. Dissociating the cells and growing them in suspension resulted in the formation of clusters which exhibited higher insulin secretion and had longer durability than cells grown as monolayers. Reverse transcription-polymerase chain reaction detected an enhanced expression of pancreatic genes in the differentiated cells. Immunofluorescence and in situ hybridization analyses revealed a high percentage of insulin-expressing cells in the clusters. In addition to insulin, most cells also coexpressed glucagon or somatostatin, indicating a similarity to immature pancreatic cells. Further improvement of this insulin-producing cell protocol may lead to the formation of an unlimited source of cells suitable for transplantation.
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PMID:Differentiation of human embryonic stem cells into insulin-producing clusters. 1515 4

Primary dystonia is a common movement disorder with an unknown pathophysiology, but basal ganglia dysfunctions seem to play a critical role. Previous studies in the dtsz mutant hamster, an animal model of primary paroxysmal dystonia, demonstrated a deficit of striatal gamma-amino-butyric acid (GABA) containing interneurons, which normalized at the age of the spontaneous remission of the symptoms. Whereas the reduction of striatal parvalbumin-reactive interneurons is thought to be critically involved in the pathogenesis of dystonia in the hamster mutant, the impact of a reduced density of nitric oxide synthase (NOS) reactive interneurons within the striatum is still unclear. Beside GABA, these interneurons contain somatostatin, neuropeptide Y, nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) and neuronal NOS, an enzyme which produces NO after the activation of the interneurons. In order to clarify if the reduced density of NOS-reactive interneurons contributes by an altered striatal production of nitric oxide (NO) to the occurrence of dystonic attacks in the hamster mutant, we performed microinjections of the NOS inhibitors 7-nitroindazole (7-NI) and Nomega-propyl-L-arginine (NPLA) and of the precursor of NO, L-arginine, into the striata of dtsz hamsters. Neither 7-NI (0.1 and 0.4 microg per hemisphere) and NPLA (2.5, 5 and 7.5 microg per hemisphere) nor L-arginine (9 and 18 microg per hemisphere) exerted any effects on the severity of dystonic movements in the dtsz mutant. Therefore, a critical involvement of striatal changes of NO in the pathophysiology of dystonic attacks in the dtsz hamster cannot be confirmed by the results of these pharmacological examinations. In view of the ontogenetic reduction of the other types of GABAergic interneurons, the deficit of NOS-reactive interneurons is possibly due to the same underlying unknown mechanism, but is less important for the pathophysiology of primary paroxysmal dystonia in the dtsz hamster mutant.
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PMID:Striatal microinjections of nitric oxide synthase inhibitors and L-arginine fail to exert effects on paroxysmal dystonia in the dtsz mutant. 1642 62

We recently found that pancreatic acinar cells isolated from normal adult mouse can transdifferentiate into insulin-secreting cells in vitro. Using two different animal models of type 1 diabetes, we show here that insulin-secreting cells can also be generated from pancreatic acinar cells of rodents in the diabetic state with absolute insulin deficiency. When pancreatic acinar cells of streptozotocin-treated mice were cultured in suspension in the presence of epidermal growth factor and nicotinamide under low-serum condition, expressions of insulin genes gradually increased. In addition, expressions of other pancreatic hormones, including glucagon, somatostatin, and pancreatic polypeptide, were also induced. Analysis by the Cre/loxP-based direct cell lineage tracing system revealed that these newly made cells originated from amylase-expressing pancreatic acinar cells. Insulin secretion from the newly made cells was significantly stimulated by high glucose and other secretagogues. In addition, insulin-secreting cells were generated from pancreatic acinar cells of Komeda diabetes-prone rats, another animal model of type 1 diabetes. The present study demonstrates that insulin-secreting cells can be generated by transdifferentiation from pancreatic acinar cells of rodents in the diabetic state and further suggests that pancreatic acinar cells represent a potential source of autologous transplantable insulin-secreting cells for treatment of type 1 diabetes.
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PMID:Generation of insulin-secreting cells from pancreatic acinar cells of animal models of type 1 diabetes. 1692 84

Embryonic stem (ES) cells offer great potential for cell replacement and tissue engineering therapies because of their almost unlimited proliferation capacity and the potential to differentiate into cellular derivatives of all three primary germ layers. This chapter describes a strategy for the in vitro differentiation of mouse ES cells into insulin-producing cells. The three-step protocol does not select for nestin-expressing cells as performed in previous differentiation systems. It includes (1) the spontaneous differentiation of ES cells via embryoid bodies and (2) the formation of progenitor cells of all three primary germ layers (multilineage progenitors) followed by (3) directed differentiation into the pancreatic lineage. The application of growth and extracellular matrix factors, including laminin, nicotinamide, and insulin, leads to the development of committed pancreatic progenitors, which subsequently differentiate into islet-like clusters that release insulin in response to glucose. During differentiation, transcript levels of pancreas-specific transcription factors (i.e., Pdx1, Pax4) and of genes specific for early and mature beta cells, including insulin, islet amyloid pancreatic peptide, somatostatin, and glucagon, are upregulated. C-peptide/insulin-positive islet-like clusters are formed, which release insulin in response to high glucose concentrations at terminal stages. The differentiated cells reveal functional properties with respect to voltage-activated Na+ and ATP-modulated K+ channels and normalize blood glucose levels in streptozotocin-treated diabetic mice. In conclusion, we demonstrate the efficient differentiation of murine ES cells into insulin-producing cells, which may help in the future to establish ES cell-based therapies in diabetes mellitus.
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PMID:Insulin-producing cells. 1714 Oct 44

Hepatic oval cells (OC) are considered to be facultative liver stem cells and, because they may undergo differentiation into a variety of cell lineages, they might have the potential to be used in cellular therapy. Signals delivered by extracellular matrix (ECM) proteins take part in cellular differentiation in cooperation with signals from growth factors; indeed, some ECM proteins, such as laminin (LAM) and fibronectin (FN), have been shown to contribute to beta-cell differentiation and islet development, respectively. Since no previous studies have investigated the effect of ECM proteins on the expression of islet cell markers by cultured OC, the purpose of the present study was to evaluate whether FN and LAM modulate the expression of genes related to the endocrine pancreas in these liver cells. OC proliferation was induced in Wistar rats by prolonged treatment with 2-acetoaminofluorene/allyl alcohol and confirmed by reverse transcription/polymerase chain reaction and hepatic immunocytochemical and histopathological analyses. OC isolation was performed by Ficoll gradient and magnetic-activated cell sorting. OC were cultured for 1 and 2 months under several conditions with specific growth factors, over a FN or LAM substrate or in high glucose, nicotinamide and fetal calf serum. OC cultured on FN substrate expressed Pdx-1, Pax-6, insulin 2 and glucagon. LAM also induced the expression of Pdx-1, insulin 1 and insulin 2, glucagon, somatostatin and GLUT-2. Our results suggest that these ECM proteins can be used in protocols of OC transdifferentiation aimed at reducing the period necessary for complete transdifferentiation.
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PMID:Fibronectin and laminin induce expression of islet cell markers in hepatic oval cells in culture. 1714 94

Neocortical gamma-aminobutyric acid (GABA)ergic neurons have been previously described as largely involved in local intracortical circuitry. However, our recent findings in the murine model described select neocortical GABAergic neurons that project to both neighboring and more distant neocortical regions. Here, we investigated whether such GABAergic projection neurons are also found in the cat neocortex. Wheat germ agglutinin-conjugated horseradish peroxidase (WGA-HRP) was injected into the visual, auditory, or somatosensory cortex, in order to label efferent cortical neurons retrogradely and to label axons and terminals orthogradely. Staining for nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d), an enzyme involved in nitric oxide synthesis, was employed, and co-localization with WGA-HRP was determined by means of both polarizing and brightfield microscopy. We concluded that neurons double-labeled with WGA-HRP and NADPH-d in a distant region from the WGA-HRP-injection site are GABAergic neurons with long-range projection axons. All double-labeled neurons were found in cortical layers VIa and VIb and in the white matter. Neurons with intense NADPH-d reactivity (type I) were determined to be neuronal nitric oxide synthase (nNOS) positive in all cases. However, weakly NADPH-d-reactive neurons (type II) lacked nNOS immunoreactivity. Moreover, nNOS often co-localized with GABA, neuropeptide-Y, and somatostatin in the cat neocortex. In summary, the GABAergic neurons described here projected in a manner similar to that previously described for neocortical principal neurons, although some unique GABAergic long-range projections were also demonstrated.
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PMID:Long-range GABAergic projection neurons in the cat neocortex. 1750 78

Recent success in pancreatic islet transplantation has energized the field to discover an alternative source of stem cells with differentiation potential to beta cells. Generation of glucose-responsive, insulin-producing beta cells from self-renewing, pluripotent human ESCs (hESCs) has immense potential for diabetes treatment. We report here the development of a novel serum-free protocol to generate insulin-producing islet-like clusters (ILCs) from hESCs grown under feeder-free conditions. In this 36-day protocol, hESCs were treated with sodium butyrate and activin A to generate definitive endoderm coexpressing CXCR4 and Sox17, and CXCR4 and Foxa2. The endoderm population was then converted into cellular aggregates and further differentiated to Pdx1-expressing pancreatic endoderm in the presence of epidermal growth factor, basic fibroblast growth factor, and noggin. Soon thereafter, expression of Ptf1a and Ngn3 was detected, indicative of further pancreatic differentiation. The aggregates were finally matured in the presence of insulin-like growth factor II and nicotinamide. The temporal pattern of pancreas-specific gene expression in the hESC-derived ILCs showed considerable similarity to in vivo pancreas development, and the final population contained representatives of the ductal, exocrine, and endocrine pancreas. The hESC-derived ILCs contained 2%-8% human C-peptide-positive cells, as well as glucagon- and somatostatin-positive cells. Insulin content as high as 70 ng of insulin/mug of DNA was measured in the ILCs, representing levels higher than that of human fetal islets. In addition, the hESC-derived ILCs contained numerous secretory granules, as determined by electron microscopy, and secreted human C-peptide in a glucose-dependent manner. Disclosure of potential conflicts of interest is found at the end of this article.
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PMID:Generation of insulin-producing islet-like clusters from human embryonic stem cells. 1751 Feb 17


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