Vitamin D activity is associated with the modulation of a wide variety of biological systems, in addition to its roles in calcium homeostatic mechanisms. While vitamin D is well known to promote gastrointestinal calcium absorption, vitamin D also plays a role in attenuating and/or preventing the progression of several gastrointestinal diseases including Crohn’s disease, ulcerative colitis, and colorectal cancer, and may also play a role in chemotherapy-induced intestinal mucositis. The pro-differentiation, immunomodulatory, and anti-inflammatory effects of vitamin D, which has been reported in numerous circumstances, are key potential mechanisms of action in the prevention of gastrointestinal disorders. While the debate of the effectiveness of vitamin D to treat bone pathologies continues, the clinical importance of vitamin D therapy to prevent gastrointestinal disorders should be investigated given current evidence, using both nutritional and pharmaceutical intervention approaches. Impact statement The non-skeletal functions of vitamin D play an important role in health and disease. The anti-inflammatory properties and maintenance of intestinal function fulfilled by vitamin D impact other systems in the body though downstream processing. This review provides insight into the mechanisms underpinning the potential benefits of vitamin D in both maintaining intestinal homeostasis and associated diseased states.
The regulation of vitamin D3 actions in humans occurs mainly through the Cytochrome P450 24-hydroxylase (CYP24A1) enzyme activity. CYP24A1 hydroxylates both 25-hydroxycholecalciferol (25(OH)D3) and 1,25-dihydroxycholecalciferol (1,25(OH)2D3), which is the first step of vitamin D catabolism. An abnormal status of the upregulation of CYP24A1 occurs in many diseases, including chronic kidney disease (CKD). CYP24A1 upregulation in CKD and diminished activation of vitamin D3 contribute to secondary hyperparathyroidism (SHPT), progressive bone deterioration, and soft tissue and cardiovascular calcification. Previous studies have indicated that CYP24A1 inhibition may be an effective strategy to increase endogenous vitamin D activity and decrease SHPT. This study has designed and synthesized a novel C-24 O-methyloxime analogue of vitamin D3 (VD1-6) to have specific CYP24A1 inhibitory properties. VD1-6 did not bind to the vitamin D receptor (VDR) in concentrations up to 10−7 M, assessed by a VDR binding assay. The absence of VDR binding by VD1-6 was confirmed in human embryonic kidney HEK293T cultures through the lack of CYP24A1 induction. However, in silico docking experiments demonstrated that VD1-6 was predicted to have superior binding to CYP24A1, when compared to that of 1,25(OH)2D3. The inhibition of CYP24A1 by VD1-6 was also evident by the synergistic potentiation of 1,25(OH)2D3-mediated transcription and reduced 1,25(OH)2D3 catabolism over 24 h. A further indication of CYP24A1 inhibition by VD1-6 was the reduced accumulation of the 24,25(OH)D3 , the first metabolite of 25(OH)D catabolism by CYP24A1. Our findings suggest the potent CYP24A1 inhibitory properties of VD1-6 and its potential for testing as an alternative therapeutic candidate for treating SHPT.
Purpose of review An overwhelming majority of chemotherapy agents are known to cause gastrointestinal mucositis, an unwanted side effect of cancer treatment, for which no effective treatment currently exists. The pathological processes underlying the development of gastrointestinal mucositis are many and varied, with multiple pathways thought to be involved in initiation of inflammation and apoptosis. Physiological and or biochemical-based deficiencies, such as vitamin D deficiency and gut microbiome density and population, are also thought to have an impact on mucositis severity. Recent findings Recent studies investigating inflammatory pathways, such as cytokines and apoptotic markers, do show that interleukin-blocking proteins alleviate symptoms of gastrointestinal mucositis. However, the effectiveness of these treatments varies depending on the type of anticancer agent administered, meaning blocking compounds may be limited in their application. Targeting the host's gut microbiome in preventing dysbiosis is also thought to be a potential avenue for exploration. The use of probiotic gut bacteria (i.e. Lactobacillus spp.), while beneficial in preventing chemotherapy radiotherapy-induced diarrhoea, does not seem to alleviate the physiological damage caused by gastrointestinal mucositis. Vitamin D has been widely shown to have a host of anti-inflammatory and immunomodulatory effects in the intestine, as well as anticancer properties and therefore, may reduce severity of gastrointestinal mucositis. Summary While anti-inflammatory and antiapoptotic agents have shown promise in animal models of gastrointestinal mucositis, there is still no singular mechanism allowing for the development of a therapeutic drug to prevent or cure gastrointestinal injury. A greater insight into the exact mechanistic actions of both probiotics and vitamin D might reveal how to improve their use as therapeutic treatments for gastrointestinal mucositis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.