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- Ehrström, Marcus
(författare)
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Studies on the effect of orexin on upper gastrointestinal function in rats and man
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aims: To define the morphological localisation of orexin A (OXA) in the gut, and study the effect of endogenous and peripherally administered OXA on fasting small bowel motility, gastric emptying and acid secretion, hormones involved in glucose homeostasis and pharmacokinetic profile of OXA in rats and humans. Methods: The distribution of OXA, orexin receptors 1 and 2 (OX1 R, OX2R), neuronal nitric oxide synthase (nNOS) and various peptides were studied with immunocytochemistry in rat and human gut. In rats, the migrating myoelectric complex (MMC) was studied during intravenous (IV) infusion of OXA or the selective OX1 R-antagonist SB-334867-A. In separate sets of experiments, the rats were pretreated with vagotomy or the NOS-antagonist Nomeganitro-L-arginine (L-NNA). Gastric acid secretion and emptying of a 51Cr-labelled liquid nutrient or non-nutrient were studied in rats equipped with a gastric fistula and subjected to IV infusion of OXA or SB-334867-A. In humans, gastric emptying was studied of a 99mTclabelled omelette during IV infusion of OXA. Simultaneously, appetite ratings were measured using visual analogue scale (VAS) ratings. Plasma concentrations of OXA, leptin, insulin, glucagon, gastrin and glucose were analysed with radioimmunoassay (RIA). Results: OXA- and OXRs-like immunoreactivity were found in nerve fibres and neurones in myenteric and submucosal ganglia, the circular muscle, the mucosa and endocrine cells in the stomach, duodenum and pancreas in both rats and humans. OXA was co-expressed with nNOS in myenteric neurons and circular muscle in rats and humans. IV OXA inhibited fasting small bowel motility in rats through OX1 R and nitric oxide (NO), independent of the vagus nerve. SB-334867-A inhibited gastric emptying and acid secretion independent of gastrin in rats. Gastric retention in humans increased during IV infusion of OXA without affecting appetite ratings. Plasma levels of leptin decreased and insulin increased in humans and OXA has a half-life in plasma of 27.1 min in rats. Conclusions: Peripheral IV OXA affects upper gastrointestinal function in rats and humans. The activity of peripheral OXA may involve several pathways, including the central nervous system (CNS), intrinsic circuits of the enteric nervous system (ENS), vago-vagal reflexes or interactions with other gut hormones and NO. In humans, IV OXA affects hormones implicated in the regulation of glucose and energy homeostasis. The long half-life of OXA in plasma needs to be taken into account when interpreting results on metabolic and gut function after peripheral administration of OXA. Antagonists against OXRs may become a target in the treatment of obesity, diabetes and motility disorders of the gut.
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| 2. |
- Li, Xi, et al.
(författare)
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MicroRNA-132 with Therapeutic Potential in Chronic Wounds.
- 2017
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 137:12, s. 2630-2638
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Tidskriftsartikel (refereegranskat)abstract
- Chronic wounds represent a major and rising health and economic burden worldwide. There is a continued search toward more effective wound therapy. We found significantly reduced microRNA-132 (miR-132) expression in human diabetic ulcers compared with normal skin wounds and also in skin wounds of leptin receptor-deficient (db/db) diabetic mice compared with wild-type mice. Local replenishment of miR-132 in the wounds of db/db mice accelerated wound closure effectively, which was accompanied by increased proliferation of wound edge keratinocytes and reduced inflammation. The pro-healing effect of miR-132 was further supported by global transcriptome analysis, which showed that several inflammation-related signaling pathways (e.g., NF-κB, NOD-like receptor, toll-like receptor, and tumor necrosis factor signaling pathways) were the top ones regulated by miR-132 in vivo. Moreover, we topically applied liposome-formulated miR-132 mimics mixed with pluronic F-127 gel on human ex vivo skin wounds, which promoted re-epithelialization. Together, our study showed the therapeutic potential of miR-132 in chronic wounds, which warrants further evaluation in controlled clinical trials.
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