| 1. |
- Halim, Md. Abdul, 1983-
(författare)
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Gut peptides in gastrointestinal motility and mucosal permeability
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Gut regulatory peptides, such as neuropeptides and incretins, play important roles in hunger, satiety and gastrointestinal motility, and possibly mucosal permeability. Many peptides secreted by myenteric nerves that regulate motor control are also produced in mucosal epithelial cells. Derangements in motility and mucosal permeability occur in many diseases. Current knowledge is fragmentary regarding gut peptide actions and mechanisms in motility and permeability.This thesis aimed to 1) develop probes and methods for gut permeability testing, 2) elucidate the role of neuropeptide S (NPS) in motility and permeability, 3) characterize nitrergic muscle relaxation and 4) characterize mechanisms of glucagon-like peptide 1 (GLP-1) and the drug ROSE-010 (GLP-1 analog) in motility inhibition.A rapid fluorescent permeability test was developed using riboflavin as a transcellular transport probe and the bisboronic acid 4,4'oBBV coupled to the fluorophore HPTS as a sensor for lactulose, a paracellular permeability probe. This yielded a lactulose:riboflavin ratio test.NPS induced muscle relaxation and increased permeability through NO-dependent mechanisms. Organ bath studies revealed that NPS induced NO-dependent muscle relaxation that was tetrodotoxin (TTX) sensitive. In addition to the epithelium, NPS and its receptor NPSR1 localized at myenteric nerves. Circulating NPS was too low to activate NPSR1, indicating NPS uses local autocrine/paracrine mechanisms.Nitrergic signaling inhibition by nitric oxide synthase inhibitor L-NMMA elicited premature duodenojejunal phase III contractions in migrating motility complex (MMC) in humans. L-NMMA shortened MMC cycle length, suppressed phase I and shifted motility towards phase II. Pre-treatment with atropine extended phase II, while ondansetron had no effect. Intestinal contractions were stimulated by L-NMMA, but not TTX. NOS immunoreactivity was detected in the myenteric plexus but not smooth muscle.Food-intake increased motility of human antrum, duodenum and jejunum. GLP-1 and ROSE-010 relaxed bethanechol-induced contractions in muscle strips. Relaxation was blocked by GLP-1 receptor antagonist exendin(9-39) amide, L-NMMA, adenylate cyclase inhibitor 2´5´-dideoxyadenosine or TTX. GLP-1R and GLP-2R were expressed in myenteric neurons, but not muscle.In conclusion, rapid chemistries for permeability were developed while physiological mechanisms of NPS, nitrergic and GLP-1 and ROSE-010 signaling were revealed. In the case of NPS, a tight synchrony between motility and permeability was found.
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| 2. |
- Abdellah, Tebani, et al.
(författare)
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Integration of molecular profiles in a longitudinal wellness profiling cohort.
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- An important aspect of precision medicine is to probe the stability in molecular profiles among healthy individuals over time. Here, we sample a longitudinal wellness cohort with 100 healthy individuals and analyze blood molecular profiles including proteomics, transcriptomics, lipidomics, metabolomics, autoantibodies andimmune cell profiling, complementedwith gut microbiota composition and routine clinical chemistry. Overall, our results show high variation between individuals across different molecular readouts, while the intra-individual baseline variation is low. The analyses show that each individual has a unique and stable plasma protein profile throughout the study period and that many individuals also show distinct profiles with regards to the other omics datasets, with strong underlying connections between the blood proteome and the clinical chemistry parameters. In conclusion, the results support an individual-based definition of health and show that comprehensive omics profiling in a longitudinal manner is a path forward for precision medicine.
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| 3. |
- Bengtsson, Magnus Wilhelm, 1977-
(författare)
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Effects of Orexins, Guanylins and Feeding on Duodenal Bicarbonate Secretion and Enterocyte Intracellular Signaling
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The duodenal epithelium secretes bicarbonate ions and this is regarded as the primary defence mechanism against the acid discharged from the stomach. For an efficient protection, the duodenum must also function as a sensory organ identifying luminal factors. Enteroendocrine cells are well-established intestinal “taste” cells that express signaling peptides such as orexins and guanylins. Luminal factors affect the release of these peptides, which may modulate the activity of nearby epithelial and neural cells.The present thesis considers the effects of orexins and guanylins on duodenal bicarbonate secretion. The duodenal secretory response to the peptides was examined in anaesthetised rats in situ and the effects of orexin-A on intracellular calcium signaling by human as well as rat duodenal enterocytes were studied in vitro.Orexin-A, guanylin and uroguanylin were all stimulants of bicarbonate secretion. The stimulatory effect of orexin-A was inhibited by the OX1-receptor selective antagonist SB-334867. The muscarinic antagonist atropine on the other hand, did not affect the orexin-A-induced secretion, excluding involvement of muscarinic receptors. Orexin-A induced calcium signaling in isolated duodenocytes suggesting a direct effect at these cells. Interestingly, orexin-induced secretion and calcium signaling as well as mucosal orexin-receptor mRNA and OX1-receptor protein levels were all substantially downregulated in overnight fasted rats compared with animals with continuous access to food. Further, secretion induced by Orexin-A was shown to be dependent on an extended period of glucose priming.The uroguanylin-induced bicarbonate secretion was reduced by atropine suggesting involvement of muscarinic receptors. The melatonin receptor antagonist luzindole attenuated the secretory response to intra-arterially administered guanylins but had no effect on secretion when the guanylins were given luminally. In conclusion, the results suggest that orexin-A as well as guanylins may participate in the regulation of duodenal bicarbonate secretion. Further, the duodenal orexin system is dependent on the feeding status of the animals.
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| 4. |
- Björner, Kajsa, et al.
(författare)
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High iNOS and IL-1β immunoreactivity are features of colitis-associated colorectal cancer tumors, but fail to predict 5-year survival
- 2023
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Ingår i: Upsala Journal of Medical Sciences. - : Upsala Medical Society. - 0300-9734 .- 2000-1967. ; 128
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Inflammatory bowel disease (IBD; mainly ulcerative colitis and Crohn's disease) is associated with the development of colorectal cancer (CRC) referred to as colitis-associated colorectal cancer (CAC). In inflammatory flares of IBD, the production of luminal nitric oxide (NO) increases due to the increased inducible nitric oxide synthase (iNOS) activity in inflamed tissue. It is believed that iNOS parallels pro-inflammatory interleukin-1β (IL-1β). How these biomarkers relate to CAC pathogenesis or survival is unknown.AIM: The primary aim of this study was to investigate iNOS and IL-1β immunoreactivity in CAC tumors in comparison with CRC and normal colonic mucosa, and the secondary aim was to determine if immunoreactivity correlates with 5-year survival of CAC.METHODS: Immunohistochemistry was performed on tissue sections as follows: CAC (n = 59); sporadic CRC (sCRC) (n = 12); colonic mucosa >2 cm outside sCRC margin (normal mucosa) (n = 22); paracancerous IBD (pIBD) (n = 12). The expression of iNOS and IL-1β was quantified separately for epithelium and stroma. Data were evaluated using the Mann-Whitney U-test and the log-rank test for 5-year Kaplan-Meier survival curves. Results were compared with online mRNA databases.RESULTS: Immunoreactivity occurred predominantly in epithelial cells and to lesser extent in stroma. Compared with normal mucosa, immunoreactivity for iNOS (P < 0.01) and IL-1β (P < 0.005) was higher in CAC epithelium. In CAC stroma, iNOS immunoreactivity was lower than normal mucosa (P < 0.001), whereas IL-1β was higher (P < 0.05). Immunoreactivity differences of iNOS or IL-1β among CAC patients failed to correlate with 5-year survival. These findings were supported by online mRNA databases.CONCLUSION: Consistent with high NO production in IBD, there is more iNOS in CAC epithelium, albeit not in stroma. This immunoreactivity difference exists for IL-1β in both epithelium and stroma. The intervention of arginine or iNOS activity for CAC chemotherapy is not straightforward.
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| 5. |
- Sjöblom, Markus, 1973-
(författare)
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The Duodenal Mucosal Bicarbonate Secretion : Role of Melatonin in Neurohumoral Control and Cellular Signaling
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The duodenal lumen is exposed to aggressive factors with a high potential to cause damage to the mucosa. Bicarbonate secretion by the duodenal mucosa is accepted as the primary important defense mechanism against the hydrochloric acid intermittently expelled from the stomach.The present thesis concerns the influence of the central nervous system and the effects of the hormone melatonin on bicarbonate secretion in anesthetized rats in vivo. Effects of melatonin on intracellular calcium signaling by duodenal enterocyte in vitro were examined in tissues of both human and rat origin. The main findings were as follows:Melatonin is a potent stimulant of duodenal mucosal bicarbonate secretion and also seems to be involved in the acid-induced stimulation of the secretion. Stimulation elicited in the central nervous system by the α1-adrenoceptor agonist phenylephrine induced release of melatonin from the intestinal mucosa and a four-fold increase in alkaline secretion. The melatonin antagonist luzindole abolished the duodenal secretory response to administered melatonin and to central nervous phenylephrine but did not influence the release of intestinal melatonin. Central nervous stimulation was also abolished by synchronous ligation of the vagal trunks and the sympathetic chains at the sub-laryngeal level. Melatonin induced release of calcium from intracellular stores and also influx of extracellular calcium in isolated duodenal enterocytes. Enterocytes in clusters functioned as a syncytium.Overnight fasting rapidly and profoundly down-regulated the responses to the duodenal secretagogues orexin-A and bethanechol but not those to melatonin or vasoactive intestinal polypeptide.In conclusion, the results strongly suggest that intestinal melatonin plays an important role in central nervous elicited stimulation of duodenal mucosal bicarbonate secretion. Sensitivity of this alkaline secretion to some peripheral stimulators markedly depends on the feeding status.
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| 6. |
- Tsapournas, Georgios, 1977-, et al.
(författare)
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Diagnostic accuracy of a quantitative faecal immunochemical test vs. symptoms suspected for colorectal cancer in patients referred for colonoscopy
- 2020
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Ingår i: Scandinavian Journal of Gastroenterology. - : Taylor & Francis. - 0036-5521 .- 1502-7708. ; 55:2, s. 184-192
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Determine diagnostic accuracy of a quantitative faecal immunochemical haemoglobin test (QuikRead go® FIT, Orion Diagnostica Oy) in symptomatic patients referred for colonoscopy, at various cut-offs and for one or two tests.Methods: Patients referred to four endoscopy units in mid-Sweden between 2013 and 2017 provided information on lower abdominal symptoms and faecal samples from two separate days prior to colonoscopy.Results: In all, 5.4% (13/242) patients had colorectal cancer (CRC). For one FIT at cut-off 10 µg Hb/g faeces, sensitivity for CRC was 92% (95% CI 78-100%) and specificity 77% (95% CI 72-83%); equal to 74%; 95% CI 68-80 (178/242) colonoscopies potentially avoidable and one CRC missed. Based on the maximal outcome of two FITs, sensitivity was 100%, specificity 71% (66-77%) and 68%; 95% CI 62-74 (160/237) colonoscopies potentially avoidable. Among 17% (42/242) patients with one FIT of >200 µg Hb/g faeces, 85% (11/13) had CRC. Positive predictive values of FIT varied 16.9-26.2% depending on cut-off and one or two FITs, whereas NPVs were 99% and above in all scenarios.In 60 patients reporting rectal bleeding, one FIT at cut-off 10 µg Hb/g discriminated well between CRC and other conditions (p = .001). In regression models, FIT was more important than age, sex and all symptoms.Conclusion: One or two FITs in symptomatic patients referred for colonoscopy imply powerful risk stratification abilities for CRC, even among patients reporting rectal bleeding. Larger studies in various settings will clarify how to make the best use of this opportunity.Trial registration: Clinicaltrails.gov NCT02491593.
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