Experimental Disruption of Intestinal Mucosal Homeostasis: Exploring the Protective Potential of Melatonin and Misoprostol

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Peters, KarstenUppsala universitet,Institutionen för medicinsk cellbiologi,Institutionen för farmaceutisk biovetenskap (författare)

Experimental Disruption of Intestinal Mucosal Homeostasis : Exploring the Protective Potential of Melatonin and Misoprostol

BokEngelska2023

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Uppsala :Acta Universitatis Upsaliensis,2023
49 s.
electronicrdacarrier

Nummerbeteckningar

LIBRIS-ID:oai:DiVA.org:uu-516607
ISBN:9789151319780
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-516607URI

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Språk:engelska
Sammanfattning på:engelska &language:-1_t

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Ämneskategori:vet swepub-contenttype
Ämneskategori:dok swepub-publicationtype

Serie

Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine,1651-6206 ;1997

Anmärkningar

The intestinal mucosa serves as a protective layer that separates the intestinal contents from the underlying tissues. It restricts harmful substances, pathogens, and undigested particles from entering the bloodstream. This mucosa also facilitates selective absorption of nutrients, electrolytes, and fluids, allowing essential substances to pass while maintaining a defense against potential threats. The integrity of the mucosa can be disrupted, such as in diseases or by off-target toxicities of chemotherapeutic drugs. A dysfunctional intestinal mucosa can result in inflammation, altered epithelial secretory and absorptive functions, as well as an increased mucosal permeability that may enable bacterial translocation. Chemotherapy-induced intestinal side effects may lead to dose reduction or even discontinuation of the treatment, but also decreasing the patient’s quality of life. The aim of this thesis was to explore the protective potential of melatonin and misoprostol on experimental disruption of small intestinal mucosal permeability and chemotherapy-induced mucositis. In Papers I and II an increase in intestinal mucosal permeability was induced by perfusing the jejunal segment with the surfactant sodium dodecyl sulfate (SDS) in rats. Melatonin and misoprostol were found to mitigate the induced increase in permeability. In Paper II it was shown that the melatonin receptor antagonist luzindole completely abolished the protective effect of melatonin on SDS-induced increase in mucosal permeability, showing that the effect of melatonin is receptor-mediated. In Papers III and IV off-target intestinal toxicity of the chemotherapeutic agents doxorubicin (DOX) and 5-fluorouracil (5-FU) were evaluated. In Paper III the progression of intestinal mucositis during seven consecutive days after a single injection of DOX was monitored. It was found that villus atrophy was most distinct after three days. In addition, within the first 24 hours after administration of DOX the most pronounced effect on a decrease in cell proliferation and an increase in crypt cell apoptosis was observed. In Paper IV it was found that daily administration of melatonin fully prevented villus atrophy and reduced the number of apoptotic crypts cells induced by a single injection of 5-FU. Administration of misoprostol increased colonic water contents but had no effect on 5-FU-induced villus atrophy or apoptosis. Furthermore, melatonin reduced 5-FU-induced cytotoxicity in murine intestinal organoids.In conclusion, the results suggest that melatonin might be a potential candidate for supportive therapy in diseases affecting the small intestinal mucosal barrier and in chemotherapy-induced mucositis.

Ämnesord och genrebeteckningar

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Gastroenterologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Gastroenterology and Hepatology hsv//eng
Intestinal barrier dysfunction
intestinal permeability
chemotherapy-induced mucositis
doxorubicin
5-fluorouracil
apoptosis
proliferation
melatonin
misoprostol
Medicinsk vetenskap
Medical Science

Biuppslag (personer, institutioner, konferenser, titlar ...)

Sjöblom, Markus,Associate Professor,1973-Uppsala universitet,Forskargrupp Markus Sjöblom/Olof Nylander(Swepub:uu)msj20812 (preses)
Lennernäs, Hans,ProfessorUppsala universitet,Institutionen för farmaci,Läkemedelsdesign och läkemedelsutveckling,Institutionen för farmaceutisk biovetenskap(Swepub:uu)hanslenn (preses)
Dahlgren, David,Associate ProfessorUppsala universitet,Institutionen för farmaci,Läkemedelsdesign och läkemedelsutveckling,Institutionen för farmaceutisk biovetenskap(Swepub:uu)davda219 (preses)
Keita, Åsa,Senior Associate ProfessorDepartment of Biomedical and Clinical Sciences, Divsion of Surgery, Orthopedics and Oncology, Linköping University (opponent)
Uppsala universitetInstitutionen för medicinsk cellbiologi (creator_code:org_t)

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