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5-fluorouracil (5FU) is associated with significant GI side-effects. Randomized trials have shown a 50% reduction in severe diarrhea with chrono-chemotherapy versus conventional regimens at similar doses. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in 5FU breakdown. We hypothesized that DPD has a circadian expression pattern, accounting for the reduced GI side effects of chrono-modulated...
The intestinal sodium–glucose cotransporter 1 (SGLT1) is responsible for all secondary active transport of dietary glucose, and it presents a potential therapeutic target for obesity and diabetes. SGLT1 expression varies with a profound diurnal rhythm, matching expression to nutrient intake. The mechanisms entraining this rhythm remain unknown. We investigated the role of local nutrient signals in...
The sodium glucose cotransporter (SGLT1) is responsible for all active intestinal glucose uptake. Hepatocyte nuclear factors 1 α and β (HNF1α and HNF1β) activate the SGLT1 promoter, whereas GATA-binding protein 5 (GATA-5) and caudal-type homeobox protein 2 (CDX2) regulate transcription of other intestinal genes. We investigated SGLT1 regulation by these transcription factors using promoter studies...
Intestinal transport exhibits distinct diurnal rhythmicity. Understanding the mechanisms behind this may reveal new therapeutic strategies to modulate intestinal function in disease states such as diabetes and obesity, as well as short bowel syndrome. Although diurnal rhythms have been amply documented for several intestinal transporters, the complexity of transepithelial transport has precluded definitive...
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