| 1. |
- Hedner, Charlotta, et al.
(författare)
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SATB1 is an independent prognostic factor in radically resected upper gastrointestinal tract adenocarcinoma
- 2014
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Ingår i: Virchows Archiv. - : Springer Science and Business Media LLC. - 0945-6317 .- 1432-2307. ; 465:6, s. 649-659
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Tidskriftsartikel (refereegranskat)abstract
- Gastric cancer is the second most common cause of cancer-related death worldwide, and the incidence of esophageal adenocarcinoma is rising. While some progress has been made in treatment strategies, overall survival remains very poor for patients with adenocarcinoma in the upper gastrointestinal tract. Special AT-rich sequence binding protein 1 (SATB1) is a global genome organizer that has been demonstrated to promote aggressive tumor behavior in several different types of cancer, including gastric cancer. The prognostic value of SATB1 expression in esophageal cancer has, however, not yet been described. In this study, expression of SATB1 was examined by immunohistochemistry on tissue microarrays prepared from tissue samples from 175 patients with adenocarcinoma of the esophagus, cardia, or stomach and containing normal tissue, intestinal metaplasia, primary tumors, and metastases. A well-validated antibody was used. We found SATB1 to be an independent prognostic factor in patients with a radically resected tumor, correlating with shorter overall survival as well as with shorter recurrence-free survival. SATB1 expression was also found to be significantly lower in primary tumors associated with intestinal metaplasia than those without intestinal metaplasia. This observation is of potential biological interest as it has been proposed that intestinal metaplasia-associated tumors constitute a less aggressive phenotype.
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| 2. |
- Hokfelt, Tomas, et al.
(författare)
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Neuropeptide and Small Transmitter Coexistence: Fundamental Studies and Relevance to Mental Illness
- 2018
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Ingår i: Frontiers in Neural Circuits. - : FRONTIERS MEDIA SA. - 1662-5110. ; 12
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Forskningsöversikt (refereegranskat)abstract
- Neuropeptides are auxiliary messenger molecules that always co-exist in nerve cells with one or more small molecule (classic) neurotransmitters. Neuropeptides act both as transmitters and trophic factors, and play a role particularly when the nervous system is challenged, as by injury, pain or stress. Here neuropeptides and coexistence in mammals are reviewed, but with special focus on the 29/30 amino acid galanin and its three receptors GalR1, -R2 and -R3. In particular, galanins role as a co-transmitter in both rodent and human noradrenergic locus coeruleus (LC) neurons is addressed. Extensive experimental animal data strongly suggest a role for the galanin system in depression-like behavior. The translational potential of these results was tested by studying the galanin system in postmortem human brains, first in normal brains, and then in a comparison of five regions of brains obtained from depressed people who committed suicide, and from matched controls. The distribution of galanin and the four galanin system transcripts in the normal human brain was determined, and selective and parallel changes in levels of transcripts and DNA methylation for galanin and its three receptors were assessed in depressed patients who committed suicide: upregulation of transcripts, e.g., for galanin and GalR3 in LC, paralleled by a decrease in DNA methylation, suggesting involvement of epigenetic mechanisms. It is hypothesized that, when exposed to severe stress, the noradrenergic LC neurons fire in bursts and release galanin from their soma/dendrites. Galanin then acts on somato-dendritic, inhibitory galanin autoreceptors, opening potassium channels and inhibiting firing. The purpose of these autoreceptors is to act as a brake to prevent overexcitation, a brake that is also part of resilience to stress that protects against depression. Depression then arises when the inhibition is too strong and long lasting - a maladaption, allostatic load, leading to depletion of NA levels in the forebrain. It is suggested that disinhibition by a galanin antagonist may have antidepressant activity by restoring forebrain NA levels. A role of galanin in depression is also supported by a recent candidate gene study, showing that variants in genes for galanin and its three receptors confer increased risk of depression and anxiety in people who experienced childhood adversity or recent negative life events. In summary, galanin, a neuropeptide coexisting in LC neurons, may participate in the mechanism underlying resilience against a serious and common disorder, MDD. Existing and further results may lead to an increased understanding of how this illness develops, which in turn could provide a basis for its treatment.
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| 3. |
- Kuteeva, Eugenia
(författare)
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Brain galanin sytems and their role in depression-like behaviour
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of the present thesis was to investigate the role of the neuropeptide galanin and galanin receptor subtypes in behavioural functions with a particular focus on depression-like behaviour. In agreement with its wide distribution in the central nervous system, galanin has been implicated in various functions, including regulation of reproduction, endocrine functions, antinociception, attention, learning and memory as well as regulation of mood. Under normal circumstances the levels of galanin expression in several neuronal systems, including dorsal root ganglia, hippocampus and cerebral cortex, are low. However, they may be markedly upregulated following, for example, lesions and/or colchicine treatment. Moreover, in Alzheimer s disease, galanin levels are elevated in the cerebral cortex, hippocampus and basal forebrain. To further analyse the functional roles of galanin in the central and peripheral nervous systems, mice overexpressing galanin (GalOE) under the platelet-derived growth factor B (PDGF-B) promoter were generated and characterised both morphologically and behaviourally. In GalOE mice, a large proportion of sympathetic and sensory ganglia neurons as well as spinal motor neurons were galanin-positive. Expression of galanin in the brain of GalOE mice was more abundant than in wild type controls. A particularly high expression was observed in the olfactory bulb, cerebral cortex, hippocampus and some motor brainstem nuclei. GalOE mice showed an attenuated plasma extravasation in response to mustard oil, an increase in pain response in the formalin test, and changes in muscle physiology. This suggests that overexpressed galanin can be released and influence physiological processes via a receptor-mediated action. Young adult GalOE mice showed a slight increase in the spontaneous locomotor activity, but a decreased response to D-amphetamine treatment. Anxiety-like behaviour as well as spatial and emotional learning and memory were not affected in the GalOE mice. However, GalOE mice displayed an increased time of immobility in the forced swim test, suggesting that an increase in galanin levels may lead to a higher stress-susceptibility evidenced by the development of depression-like behaviour. In support, GalOE mice displayed a significantly higher increase of hippocampal noradrenaline and serotonin release in response to repeated forced swimming as measured by in vivo microdialysis, suggesting that hippocampal afferents of GalOE mice are hypersensitive to stressful stimuli. Intracerebroventricular infusion of galanin to rats resulted in an increased time of immobility in the forced swim test, indicative of depression-like behaviour. This effect was blocked by co-administration of the galanin antagonist M35, while M35 alone caused a decrease of immobility time. These results indicate a potential involvement of galanin in depression-like behaviour and suggest that galanin antagonists may have antidepressant properties. Intracerebroventricular infusion of the galanin receptor GalR1 agonist M617 significantly increased immobility time, similar to galanin itself. In contrast, the GalR2 agonist M1896 decreased, while the GalR2 antagonist M871 increased, time of immobility. These results indicate that galanin receptor subtypes have a differential role in modulation of depression-like behaviour. Galanin may mediate its pro-depressive action via GalR1 subtype, while GalR2 may mediate the putative antidepressant action of galanin. In situ hybridisation studies, performed following exposure to swim stress and galaninergic ligands infusion, showed that the combination of injection and swim stress upregulated tyrosine hydroxylase and galanin mRNA expression in the locus coeruleus, but not tryptophan hydroxylase 2 and galanin mRNA expression in the dorsal raphe. In contrast, following intracerebroventricular galanin infusion, galanin mRNA levels were upregulated both in the locus coeruleus and the dorsal raphe. The levels of the 5-HT1A receptor mRNA were reduced in the dorsal raphe following galanin infusion, and both in the dorsal and median raphe following infusion of the GalR2 agonist M1896. In contrast, serotonin transporter mRNA levels were not affected by any treatment. In summary, these results give evidence for an important role of the neuropeptide galanin in regulation of depressionlike behaviour in rodents. Physiological mechanisms underlying the action of galanin are probably mediated via alterations in neuronal activity of the locus coeruleus and the raphe nuclei, as indicated by changes in gene expression of neuronal markers relevant for noradrenaline, serotonin and galanin transmission. Galanin mechanisms may thus be relevant for mood disorders and galanin ligands may be useful in antidepressant therapy.
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| 4. |
- Kuteeva, Eugenia, et al.
(författare)
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Differential Role of Galanin Receptors in the Regulation of Depression-Like Behavior and Monoamine/Stress-Related Genes at the Cell Body Level
- 2008
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Ingår i: Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 0893-133X .- 1740-634X. ; 33:11, s. 2573-2585
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Tidskriftsartikel (refereegranskat)abstract
- The present study on rat examined the role of galanin receptor subtypes in regulation of depression-like behavior as well as potential molecular mechanisms involved in the locus coeruleus (LC) and dorsal raphe (DR). The effect of intracerebroventricular (i.c.v.) infusion of galanin or galanin receptor GalR1- and GalR2-selective ligands was studied in the forced swim test, followed by quantitative in situ hybridization studies. Naive control, non-treated (swim control), saline-and fluoxetine-treated rats were used as controls in the behavioral and in situ hybridization studies. Subchronic treatment with fluoxetine reduced immobility and climbing time. Intracerebroventricular infusion of galanin, the GalR1 agonist M617 or the GalR2 antagonist M871 increased, while the GalR2(R3) agonist AR-M1896 decreased, immobility time compared to the aCSF-treated animals. Galanin also decreased the time of climbing. Galanin mRNA levels were upregulated by the combination of injection + swim stress in the saline-and the fluoxetine-treated groups in the LC, but not in the DR. Also tyrosine hydroxylase levels in the LC were increased following injection + swim stress in the saline-and fluoxetine-treated rats. Tryptophan hydroxylase 2 and serotonin transporter mRNAs were not significantly affected by any treatment. 5-HT(1A) mRNA levels were downregulated following i.c.v. galanin, M617 or AR-M1896 infusion. These results indicate a differential role of galanin receptor subtypes in depression-like behavior in rodents: GalR1 subtype may mediate 'prodepressive' and GalR2 'antidepressant' effects of galanin. Galanin has a role in behavioral adaptation to stressful events involving changes of molecules important for noradrenaline and/or serotonin transmission.
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| 5. |
- Kuteeva, Eugenia, et al.
(författare)
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Distribution of galanin and galanin transcript in the brain of a galanin-overexpressing transgenic mouse
- 2004
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Ingår i: Journal of Chemical Neuroanatomy. - : Elsevier BV. - 0891-0618 .- 1873-6300. ; 28:4, s. 185-216
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Tidskriftsartikel (refereegranskat)abstract
- The distribution of galanin mRNA-expressing cells and galanin-immunoreactive (IR) cell bodies and processes was studied in the brain of mice overexpressing galanin under the PDGF-B promoter (GalOE mice) and of wild type (WT) mice, both in colchicine-treated and non-treated animals. In this abstract, we only describe the results in GalOE mouse. A widespread ectopic expression of galanin (both mRNA and peptide) was found, that is a situation when neither transcript nor peptide could be seen in WT mice, not even after colchicine treatment. However, in some regions, such as claustrum, basolateral amygdala, thalamus, CA1 pyramidal cells, and Purkinje cells only galanin mRNA could be detected. In the forebrain galanin was seen in the mitral cells of the olfactory bulb, throughout the cortex, in the basolateral amygdaloid nucleus, claustrum, granular and pyramidal cell layers of the hippocampus, subiculum and presubiculum. In the thalamus, the anterodorsal, mediodorsal, intermediodorsal and mediodorsal lateral nuclei, the reuniens and reticular nuclei showed ectopic expression of galanin. Within the hypothalamus, neurons of the suprachiasmatic nucleus contained galanin. In the mesencephalon, the geniculate nucleus, nucleus ruber, the mesencephalic trigeminal and reticulotegmental nuclei ectopically expressed galanin. In the cerebellum, galanin was observed in the Purkinje cells and in the lateral and interposed cerebellar nuclei. In the pons, sensory and motor nuclei of the trigeminal nerve, the laterodorsal and dorsal tegmental nuclei, the pontine, reticulotegmental and gigantocellular reticular nuclei expressed galanin. Within the medulla oblongata, labeled cells were detected in the facial, ambiguus, prepositus, lateral paragigantocellular and lateral reticular nuclei, and spinal trigeminal nucleus. High densities of galanin-IR fibers were found in the axonal terminals of the lateral olfactory tract, the hippocampal and presumably the cerebellar mossy fibers system, in several thalamic and hypothalamic regions and the lower brain stem. Possible functional consequences of galanin overexpression are discussed.
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| 6. |
- Larsson, Anna H., et al.
(författare)
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Significant association and synergistic adverse prognostic effect of podocalyxin-like protein and epidermal growth factor receptor expression in colorectal cancer
- 2016
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Ingår i: Journal of Translational Medicine. - : BioMed Central. - 1479-5876 .- 1479-5876. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Background: Podocalyxin-like 1 (PODXL) is an anti-adhesive transmembrane protein that has been demonstrated to be an independent factor of poor prognosis in colorectal cancer (CRC). The gene encoding PODXL is located to chromosome 7, which also harbours the gene for the epidermal growth factor receptor (EGFR). The aim of this study was to examine the associations between PODXL and EGFR expression in CRC in vitro and in vivo. Methods: EGFR expression was analysed in tumours from three independent patient cohorts; cohort 1 (n = 533), cohort 2 (n = 259) and cohort 3 (n = 310), previously analysed for immunohistochemical PODXL expression and KRAS and BRAF mutations (cohort 1 and 3). Levels of EGFR and PODXL were determined by western blot in six different CRC cell lines. Results: High expression of PODXL was significantly associated with high EGFR expression (p < 0.001) in all three cohorts, and with BRAF mutation (p < 0.001) in cohort 1 and 3. High EGFR expression correlated with BRAF mutation (p < 0.001) in cohort 1. High EGFR expression was associated with adverse clinicopathological factors and independently predicted a reduced 5-year overall survival (OS) in cohort 1 (HR 1.77; 95 % CI 1.27-2.46), cohort 2 (HR 1.58; 95 % CI 1.05-2.38) and cohort 3 (HR 1.83; 95 % CI 1.19-2.81). The highest risk of death within 5 years was observed in patients with tumours displaying high expression of both EGFR and PODXL in cohort 1 and 3 (HR 1.97; 95 % CI 1.18-3.28 and HR 3.56; 95 % CI 1.75-7.22, respectively). Western blot analysis showed a uniform expression of PODXL and EGFR in all six examined CRC cell lines. Conclusions: The results from this study demonstrate that high expression of EGFR is an independent factor of poor prognosis in CRC. Moreover, strong links have been uncovered between expression of the recently proposed biomarker candidate PODXL with EGFR expression in CRC in vivo and in vitro, and with BRAF mutation in vivo. High expression of both PODXL and EGFR may also have a synergistic adverse effect on survival. These findings suggest a potential functional link in CRC between PODXL, EGFR and BRAF, all originating from chromosome 7, which may be highly relevant in the clinical setting and therefore merit future in-depth study.
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| 7. |
- Schlifke, Irene, et al.
(författare)
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Galanin expressed in the excitatory fibers attenuates synaptic strength and generalized seizures in the piriform cortex of mice.
- 2006
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 200:2, s. 398-406
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Tidskriftsartikel (refereegranskat)abstract
- The neuropeptide galanin is considered to be an endogenous antiepileptic agent, presumably acting via inhibition of glutamate release. Previously, we have demonstrated that in mice ectopically overexpressing galanin in cortical and hippocampal neurons, particularly in granule cells and their axons, the mossy fibers, hippocampal kindling epileptogenesis is suppressed and is associated with attenuated frequency facilitation in mossy fiber-CA3 cell synapses. We hypothesized that changes in synaptic transmission might occur also in other excitatory synapses of the galanin overexpressing (GalOE) mouse, contributing to seizure suppression. Lateral olfactory tract (LOT) synapses, formed by axons of olfactory bulb (013) mitral cells and targeting piriform cortex (PC) pyramidal cells, ectopically express galanin in GalOE mice. Using whole-cell patch-clamp recordings, we found that excitatory synaptic responses recorded in PC pyramidal cells during high frequency stimulation of the LOT were attenuated in GalOE mice as compared to wild-type controls. This effect was mimicked by bath application of galanin or its agonist galnon to wild-type slices, supporting the notion of ectopic galanin action. Since the high frequency activation induced in vitro resembles epileptic seizures in vivo, we asked whether the observed synaptic inhibition would result in altered epileptogenesis when animals were kindled via the same synapses. In male GalOE mice, we found that the latency to convulsions was prolonged, and once animals had experienced the first stage 5 seizure, generalized seizures were less sustainable. These data indicate that the PC is a possible target for epilepsy treatment by ectopically overexpressing galanin to modulate seizure activity. (c) 2006 Elsevier Inc. All rights reserved.
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| 8. |
- Stanic, Davor, et al.
(författare)
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Characterization of CGRP protein expression in "satellite-like" cells and dendritic arbours of the mouse olfactory bulb
- 2010
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Ingår i: Journal of Comparative Neurology. - : Wiley. - 0021-9967 .- 1096-9861. ; 518:6, s. 770-784
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Tidskriftsartikel (refereegranskat)abstract
- The main olfactory bulb (OB) is made up of several concentric layers, forming circuitries often involving dendro-dendritic synapses. Important interactions between OB neurons occur in the external plexiform layer (EPL), where dendrites of tufted and Van Gehuchten cells form synapses with dendrites of deeper lying mitral, tufted, and granule cells. OB neurons display a variety of neurotransmitters. Here, the focus is on calcitonin gene-related peptide (CGRP), a 37-amino acid neuropeptide transmitter that is widely distributed in the central and peripheral nervous system. In the OB, CGRP-immunoreactive (ir) cell bodies were mostly observed in the mitral cell layer (MCL) of normal mice, and their number increased following colchicine treatment. Sparsely distributed CGRP-ir cell bodies were also found in the EPL and granular cell layer. Double-immunofluorescence experiments revealed a lack of co-localization between CGRP-like immunoreactivity (LI) and corticotropin-releasing factor- or galanin-LI, two markers for mitral cells, and no CGRP-LI was found in cholecystokinin-, parvalbumin-, or vasoactive intestinal polypeptide-ir tufted/Van Gehuchten cells. CGRP-ir cell bodies were not found to co-localize glutamic acid decarboxylase 67 (GAD67)-green fluorescence protein, gamma-aminobutyric acid (GABA)-, or calretinin-LI, although the possibility remains that CGRP-ir cells may contain low levels of GABA and/or GAD67 not detected by our methodology. Dendrites of CGRP-ir cells extensively ramified deep in the EPL and double-immunofluorescence revealed them to be adjacent with, often apparently contacting, dendrites of granule, mitral, tufted, and Van Gehuchten cells. We propose that these CGRP-ir cell bodies in the mouse OB are "satellite-like" cells within and, occasionally, close to the MCL.
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| 9. |
- Yoshitake, Shimako, et al.
(författare)
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Correlation between the effects of local and intracerebroventricular infusions of galanin on 5-HT release studied by microdialysis, and distribution of galanin and galanin receptors in prefrontal cortex, ventral hippocampus, amygdala, hypothalamus, and striatum of awake rats
- 2014
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Ingår i: Synapse. - : John Wiley & Sons. - 0887-4476 .- 1098-2396. ; 68:5, s. 179-193
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Tidskriftsartikel (refereegranskat)abstract
- The neuropeptide galanin is implicated in regulation of affective behavior, including modulation of 5-HT signaling. Here, we investigated, by use of microdialysis in freely moving rats, the effects of intracerebral (i.c.) and intracerebroventricular (i.c.v.) infusions of galanin on basal extracellular 5-HT levels in medial prefrontal cortex (mPFC), CA1 area of ventral hippocampus (vHPC), central amygdaloid nucleus (CeA), ventromedial hypothalamic nucleus ventrolateral part (VMHvl), and ventromedial caudate putamen (CPu). These results were compared with a parallel immunohistochemical analysis of the distribution of galanin, 5-HT, and noradrenaline (NA) nerve terminals, and with data on galanin receptors. Galanin i.c.v. significantly decreased the 5-HT levels in mPFC to 79% and in vHPC to 72%. Local infusions of galanin caused a long-lasting decrease in 5-HT levels in vHPC to 88%, and a moderate decrease in CeA, whereas the 5-HT levels in mPFC significantly increased to 121%. These effects of i.c. galanin correlated well with the density of 5-HT and galanin nerve terminals and galanin receptors autoradiography in mPFC, vHPC, and CeA. No effects of i.c. or i.c.v. galanin on 5-HT levels were observed in CPu or VMHvl, in agreement with the low numbers of galanin-positive terminals and low/moderate galanin receptor density. Galanin was often found to coexist in NA, but could never be detected in 5-HT terminals. Together the results show a neuroanatomical correlation between the effects of galanin infusions on 5-HT release and distribution of galanin and its receptors, and that i.c.v. and i.c. administration can give opposite effects on 5-HT release.
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