Current Medicinal Chemistry - Volume 24, Issue 9, 2017

Crohn's disease (CD) and ulcerative colitis (UC) are classified under inflammatory bowel disease (IBD) which has been linked to a multifaceted etiology involving both environmental and genetic factors that intersect with the vitamin D pathway. Dysfunctions in innate immune defense mechanisms in the epithelial compartment of the intestine play a crucial role in the pathogenesis of IBD. Symptoms of IBD are caused by excessive immune responses to luminal bacteria, and vitamin D has been shown to play a role in intestinal defense by aiding in the suppression of microbial invasion into the epithelium. Vitamin D, as an immunomodulator, can modify the innate immune response of the body. Vitamin D attenuates the transcription of pro-inflammatory cytokines that are upregulated in the event of epithelial stress common in patients with IBD. Vitamin D deficiency was identified in 82% of IBD patients compared to the 31% national average and has been linked to defective epithelial processes at both genomic and proteomic levels. Mucosal damage and an impaired immune response are at the center of IBD, and vitamin D aids in sustaining the structural integrity of epithelial cells while enhancing innate immune responses in the mucosa. Here we provide a systematic review of the pathophysiological effects of cytokines in IBD in the presence of vitamin D deficiency. Also, analysis of the immunomodulatory effect of vitamin D in regulating immunopathogenic factors like chemokines, growth factors, and human defensins will enhance knowledge of the underlying molecular mechanisms of the therapeutic role of vitamin D in IBD and thus aid in the development of better patient management strategies.

Vitamin D deficiency and insufficiency are associated with an increased risk of cancer, autoimmune disease, inflammation, infection, cardiovascular disease and metabolic disease, as well as bone and mineral disorders. The vitamin D receptor (VDR), a member of the nuclear receptor superfamily, is a receptor for the active form of vitamin D, 1α ,25-dihydroxyvitamin D3 [1,25(OH)2D3], and mediates vitamin D regulation of specific target gene expression. The secondary bile acid lithocholic acid, which is produced by intestinal bacteria, is another natural VDR ligand. VDR signaling has been suggested to be involved in reciprocal communication between intestinal cells, including immune and epithelial cells, and intestinal microflora. In addition to epidemiological studies on vitamin D status, genome-wide analyses and cellular and animal experiments have shown that VDR is involved in the prevention of inflammatory bowel disease (IBD) and colorectal cancer (CRC). VDR deletion in mice exaggerates colitis and colon tumorigenesis in experimental models, and treatment of mice with synthetic vitamin D analogues ameliorates pathological changes in these diseases. Several VDR ligands are less active in increasing serum calcium levels, showing higher therapeutic efficiency than the natural hormone 1,25(OH)2D3. VDR plays a role in intestinal homeostasis and in protection against IBD and CRC. The development of VDR ligands with reduced or no calcemic activity will be necessary to expand clinical application of VDRtargeting therapy.

Vitamin D is an important factor in regulating inflammation, immune responses, and carcinoma inhibition via action of its receptor, vitamin D receptor (VDR). Recent studies have demonstrated the role of vitamin D/VDR in regulating host-bacterial interactions. Probiotics are beneficial bacteria with the power of supporting or favoring life on the host. In the current review, we will discuss the recent progress on the roles of vitamin D/VDR in gut microbiome and inflammation. We will summarize evidence of probiotics in modulating vitamin D/VDR and balancing gut microbiota in health and gastrointestinal diseases. Moreover, we will review the clinical application of probiotics in prevention and therapy of IBD or colon cancer. Despite of the gains, there remain several barriers to advocate broad use of probiotics in clinical therapy. We will also discuss the limits and future direction in scientific understanding of probiotics, vitamin D/VDR, and host responses.

Vitamin D is an important hormone that regulates many physiological processes related to human health. Through its nuclear receptor, VDR, vitamin D controls gene expression through genetic and epigenetic mechanisms. Increasing data have demonstrated the anti-cancer activities of vitamin D in various cancers, including colon cancer. This review summarizes the recent progresses in our understanding of the molecular mechanisms of vitamin D and its interaction with the epigenetic machinery in colon cancer. Vitamin D changes the status of DNA methylation and histone modifications, resulting in the activation of tumor suppressors and inhibition of oncogenes. In addition, vitamin D activates the expression of tumor suppressing miRNAs, which contribute to the tumor suppressive activity. Further understanding of the epigenetic action of vitamin D will help the development of therapeutic strategies targeting the vitamin D signaling pathway without inducing the hypercalcemic side effects.

Vitamin D exerts an anti-inflammatory effect in both health and disease. The importance of vitamin D in protection against various inflammatory and metabolic diseases, including inflammatory bowel diseases (IBDs), has been discussed. Considerable data indicate a role for vitamin D in the activation of autophagy, an intracellular renewal system that maintains homeostasis by eliminating large protein aggregates and damaged organelles. Recent studies have demonstrated an intricate interplay between autophagy and the regulation of inflammation, suggesting that autophagy-modulating agents could be used to treat IBDs. This review focuses on the role and mechanisms of vitamin D in autophagy and the regulation of intestinal inflammation. Vitamin D shows promise for the prevention and amelioration of pathologic responses in IBD, an effect that is mediated, at least in part, by the induction and modulation of autophagy.

It is well accepted that inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, is one of high risk factors for colorectal cancer (CRC). This supports the notion that inflammation plays a key role in cancer development. Epidemiologic studies have shown that vitamin D (Vit D) deficiency is associated with IBD and various types of cancer including colorectal cancer. Clinical trials and mouse models have shown that Vit D is beneficial in preventing or ameliorating inflammation and carcinogenesis. Mechanism studies show that Vit D played wide-spectrum roles in anti-inflammation, immunoregulation, and anti-cancer activities. In this review, we summarized and updated the findings on Vit D, IBD and colitis-associated colorectal cancer (CAC) with the emphasis on the effects of Vit D on anti-inflammation, EMT and cancer stem cells (CSC).

Vitamin D has been widely used as a dietary supplement for the prevention and treatment of bone disorders. Epidemiological and preclinical studies demonstrated the anticancer action of vitamin D in a variety of cancers including those in the gastrointestinal (GI) tract. In these studies the inhibitory action of vitamin D on cancer stem cells (CSCs) has been a focus and is also an important subject to revolutionize the therapeutic potential of vitamin D on cancer treatment. Here, we summarize the involvement of CSC markers and factors and also their signaling pathways in the development of cancers in the esophagus, stomach, colon, pancreas and also liver. It is also evidenced that vitamin D could inhibit these markers and factors and their related signaling pathways to suppress tumor progression. All these information could provide new strategies in repurposing vitamin D as therapeutic agent to inhibit cancers in the GI tract.

Background: The body of biomedical literature on Vitamin D effector mechanisms in gastrointestinal biology and pathophysiology is rapidly expanding. Accordingly, new possibilities of vitamin D biology-based therapeutical intervention in gastroenterological disease are being identified. However, the literature lacks a concise review on these developments, hampering comprehension of the possibilities involved for many in the community. Results: Genetic vitamin D receptor (VDR) polymorphisms and other VDR biology regulation are involved in predisposition to gastrointestinal cancers and might allow tailored strategies for managing those individuals especially at risk, e.g. through vitamin D supplementation. Likewise, modulation of Hedgehog signaling by vitamin D analogues may have promise in combating gastrointestinal cancers or improving barrier function in IBD, but shortage in vitamin D levels may also influence inflammatory conditions of the gut through direct interaction with the mucosal immune system. Evidence justifying population-wide monitoring for vitamin D status is accumulating. Conclusion: There is kaleidoscopic interaction of vitamin D biology with many aspects of gastrointestinal tract biology. Vitamin D appears an attractive target for personalized approaches like precision and P4 medicine.

Prior to senescence, erythrocytes may experience injury, which compromises their integrity and thus triggers suicidal erythrocyte death or eryptosis. This mechanism is characterised by cell shrinkage, cell membrane blebbing, and cell membrane phospholipid scrambling after phosphatidylserine exposure on the cell surface that is identified by macrophages, which engulf and degrade the eryptotic cells. The term eryptosis also includes typical mechanisms, which contribute to the triggering of this process, such as oxidative stress, Ca2+ entry with an increase in cytosolic Ca2+ activity ([Ca ]i) and the activation of p38 kinase, which is a kinase expressed in human erythrocytes and activated after hyperosmotic shock. Enhanced eryptosis has been observed in several clinical conditions such as diabetes, renal insufficiency, haemolytic uremic syndrome, sepsis, mycoplasma infection, malaria, iron deficiency, sickle cell anaemia, beta-thalassemia, glucose-6-phosphate dehydrogenase-(G6PD) deficiency, hereditary spherocytosis, paroxysmal nocturnal haemoglobinuria, Wilson's disease, myelodysplastic syndrome, and phosphate depletion. Therefore, eryptosis may be considered as a useful mechanism of removal of defective erythrocytes to prevent haemolysis. Moreover, the clearance of infected erythrocytes in diseases such as malaria may counteract parasitemia. Indeed it is known that sickle-cell trait, beta-thalassemia trait, glucose-6-phosphate dehydrogenase (G6PD)- deficiency and iron deficiency confer some protection against a severe course of malaria. Importantly, strategies to control Plasmodium infection by inducing eryptosis are not expected to generate resistance of the pathogen, as the proteins involved in suicidal death of the host cell are not encoded by the pathogen and thus cannot be modified by mutations of its genes. However, excessive eryptosis could compromise microcirculation and lead to anemia.

Background: Aging is a phenomenon in which the functions, adaptability and resistance of an organism decrease over time. With the global population aging at an accelerating pace, delaying the negative aspects of aging is vital for advancing the human life span and quality of life. The aging of multiple organs can lead to many diseases, and the cardiovascular system is no exception. Indeed, one of the primary risk factors for cardiovascular diseases is aging because of altered cardiovascular metabolism resulting in metabolic disorders and inflammation. Methods: We attempted an organized search of bibliographic databases for peer-reviewed research papers by searching featured reviews using inclusion/exclusion criteria. The collected papers were assessed by standard tools for quality control. Results: Forty-six papers were admitted to the review, and most papers featured recent research results (44) and reviewed the research field (8). We discuss these papers along with the recent progress of our work. In this review, we examine the relationship of oxidative stress with aging and the FoxO proteins, which are essential anti-aging factors in the cardiovascular system. Conclusion: The observations of this review suggest that anti-aging signaling mediated by FoxO proteins is important for understanding cardiovascular aging and the design of medicinal approaches.