Role of Vitamin D Receptor in the Antiproliferative Effects of Calcitriol in Tumor-Derived Endothelial Cells and Tumor Angiogenesis In vivo

Low expression of vitamin D receptor (VDR) and dysfunction of vitamin D/VDR signaling are reported in patients with inflammatory bowel disease (IBD); therefore, restoration of VDR function to control inflammation in IBD is desirable. Probiotics have been used in the treatment of IBD. However, the role of probiotics in the modulation of VDR signaling to effectively reduce inflammation is unknown. We identified a novel role of probiotics in activating VDR activity, thus inhibiting inflammation, using cell models and VDR knockout mice. We found that the probiotics Lactobacillus rhamnosus strain GG (LGG) and Lactobacillus plantarum (LP) increased VDR protein expression in both mouse and human intestinal epithelial cells. Using the VDR luciferase reporter vector, we detected increased transcriptional activity of VDR after probiotic treatment. Probiotics increased the expression of the VDR target genes, such as antimicrobial peptide cathelicidin, at the transcriptional level. Furthermore, the role of probiotics in regulating VDR signaling was tested in vivo using a Salmonella-colitis model in VDR knockout mice. Probiotic treatment conferred physiological and histologic protection from Salmonella-induced colitis in VDR+/+mice, whereas probiotics had no effects in the VDR−/−mice. Probiotic treatment also enhanced numbers of Paneth cells, which secrete AMPs for host defense. These data indicate that the VDR pathway is required for probiotic protection in colitis. Understanding how probiotics enhance VDR signaling and inhibit inflammation will allow probiotics to be used effectively, resulting in innovative approaches to the prevention and treatment of chronic inflammation.

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In Vivo Role of Vitamin D Receptor Signaling in UVB-Induced DNA Damage and Melanocyte Homeostasis

Journal of Investigative Dermatology ◽

10.1016/j.jid.2016.06.004 ◽

2016 ◽

Vol 136 (10) ◽

pp. 2108-2111 ◽

Cited By ~ 7

Author(s):

Sharmeen Chagani ◽

Sergiy Kyryachenko ◽

Yoko Yamamoto ◽

Shigeaki Kato ◽

Gitali Ganguli-Indra ◽

...

Keyword(s):

Vitamin D ◽

Dna Damage ◽

Vitamin D Receptor ◽

Receptor Signaling

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Faculty Opinions recommendation of Renoprotective role of the vitamin D receptor in diabetic nephropathy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1097755.553873 ◽

2008 ◽

Author(s):

Craig Langman

Keyword(s):

Vitamin D ◽

Diabetic Nephropathy ◽

Vitamin D Receptor

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Vitamin D as potential therapeutic anticancer agent

Journal of Cancer Science and Therapeutics ◽

10.36879/jcst.19.000106 ◽

2018 ◽

pp. 1-3

Keyword(s):

Vitamin D ◽

Anticancer Activity ◽

Anticancer Agent ◽

Antitumor Agents ◽

Metastatic Potential ◽

Anticancer Properties ◽

Chemotherapy Agents

The role of vitamin D is implicated in carcinogenesis through numerous biological processes like induction of apoptosis, modulation of immune system inhibition of inflammation and cell proliferation and promotion of cell differentiation. Its use as additional adjuvant drug with cancer treatment may be novel combination for improved outcome of different cancers. Numerous preclinical, epidemiological and clinical studies support the role of vitamin D as an anticancer agent. Anticancer properties of vitamin D have been studied widely (both in vivo and in vitro) among various cancers and found to have promising results. There are considerable data that indicate synergistic potential of calcitriol and antitumor agents. Possible mechanisms for modulatory anticancer activity of vitamin D include its antiproliferative, prodifferentiating, and anti-angiogenic and apoptic properties. Calcitriol reduces invasiveness and metastatic potential of many cancer cells by inhibiting angiogenesis and regulating expression of the key molecules involved in invasion and metastasis. Anticancer activity of vitamin D is synergistic or additive with the antineoplastic actions of several drugs including cytotoxic chemotherapy agents like paclitaxel, docetaxel, platinum base compounds and mitoxantrone. Benefits of addition of vitamin D should be weighed against the risk of its toxicity.

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Role of genetic variants of Vitamin D receptor, Toll-like receptor 2 and Toll-like receptor 4 in extrapulmonary tuberculosis

Microbial Pathogenesis ◽

10.1016/j.micpath.2021.104911 ◽

2021 ◽

pp. 104911

Author(s):

Bilal Ahmad Wani ◽

Faheem Shehjar ◽

Sonaullah Shah ◽

Ajaz Koul ◽

Adfar Yusuf ◽

...

Keyword(s):

Vitamin D ◽

Vitamin D Receptor ◽

Genetic Variants ◽

Extrapulmonary Tuberculosis ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Toll Like Receptor 2

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Hyperglycaemia up-regulates placental growth factor (PlGF) expression and secretion in endothelial cells via suppression of PI3 kinase-Akt signalling and activation of FOXO1

Scientific Reports ◽

10.1038/s41598-021-95511-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Samir Sissaoui ◽

Stuart Egginton ◽

Ling Ting ◽

Asif Ahmed ◽

Peter W. Hewett

Keyword(s):

Endothelial Cells ◽

Growth Factor ◽

Endothelial Dysfunction ◽

Akt Activation ◽

Forkhead Box ◽

Pi3k Activity ◽

Binding Sequence

AbstractPlacenta growth factor (PlGF) is a pro-inflammatory angiogenic mediator that promotes many pathologies including diabetic complications and atherosclerosis. Widespread endothelial dysfunction precedes the onset of these conditions. As very little is known of the mechanism(s) controlling PlGF expression in pathology we investigated the role of hyperglycaemia in the regulation of PlGF production in endothelial cells. Hyperglycaemia stimulated PlGF secretion in cultured primary endothelial cells, which was suppressed by IGF-1-mediated PI3K/Akt activation. Inhibition of PI3K activity resulted in significant PlGF mRNA up-regulation and protein secretion. Similarly, loss or inhibition of Akt activity significantly increased basal PlGF expression and prevented any further PlGF secretion in hyperglycaemia. Conversely, constitutive Akt activation blocked PlGF secretion irrespective of upstream PI3K activity demonstrating that Akt is a central regulator of PlGF expression. Knock-down of the Forkhead box O-1 (FOXO1) transcription factor, which is negatively regulated by Akt, suppressed both basal and hyperglycaemia-induced PlGF secretion, whilst FOXO1 gain-of-function up-regulated PlGF in vitro and in vivo. FOXO1 association to a FOXO binding sequence identified in the PlGF promoter also increased in hyperglycaemia. This study identifies the PI3K/Akt/FOXO1 signalling axis as a key regulator of PlGF expression and unifying pathway by which PlGF may contribute to common disorders characterised by endothelial dysfunction, providing a target for therapy.

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FRAP analysis of nucleocytoplasmic dynamics of the vitamin D receptor splice variant VDRB1: preferential targeting to nuclear speckles

Biochemical Journal ◽

10.1042/bj20042040 ◽

2005 ◽

Vol 388 (2) ◽

pp. 509-514 ◽

Cited By ~ 10

Author(s):

Kathryn L. SUNN ◽

John A. EISMAN ◽

Edith M. GARDINER ◽

David A. JANS

Keyword(s):

Vitamin D ◽

Vitamin D Receptor ◽

Nuclear Import ◽

Protein Import ◽

Nucleocytoplasmic Transport ◽

Nuclear Speckles ◽

Nuclear Targeting ◽

Nuclear Retention ◽

First Time

Although the key components of the cellular nuclear transport machinery have largely been characterized through extensive efforts in recent years, in vivo measurements of the kinetics of nuclear protein import/export are patently few. The present study applies the approach of FRAP (fluorescence recovery after photobleaching) to examine the nucleocytoplasmic flux of a novel human VDRB1 (vitamin D receptor B1) isoform in living cells. Through an N-terminal extension containing a consensus nuclear targeting sequence, VDRB1 is capable of localizing in nuclear speckles adjacent to SC-35 (35 kDa splicing component)-containing speckles as well as in the nucleoplasm, dependent on ligand. Investigation of VDRB1 nucleocytoplasmic transport using FRAP indicates for the first time that the VDRB1 has a serum-modulated, active nuclear import mechanism. There is no evidence of an efficient, active export mechanism for VDRB1, probably as a result of nuclear retention. VDRB1 nuclear import in the absence of serum occurred more rapidly and to a greater extent to nuclear speckles compared with import to other nuclear sites. This preferential transport from the cytoplasm to and accumulation within nuclear speckles is consistent with the idea that the latter represent dynamic centres of VDRB1 interaction with other nuclear proteins. The results are consistent with the existence of specialized pathways to target proteins to nuclear subdomains.

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Peroxiredoxin 6 is required for blood vessel integrity in wounded skin

The Journal of Cell Biology ◽

10.1083/jcb.200706090 ◽

2007 ◽

Vol 179 (4) ◽

pp. 747-760 ◽

Cited By ~ 51

Author(s):

Angelika Kümin ◽

Matthias Schäfer ◽

Nikolas Epp ◽

Philippe Bugnon ◽

Christiane Born-Berclaz ◽

...

Keyword(s):

Oxidative Stress ◽

Wound Healing ◽

Endothelial Cells ◽

Ultrastructural Level ◽

Peroxiredoxin 6 ◽

Severe Hemorrhage ◽

Vessel Integrity ◽

Knockout Animals

Peroxiredoxin 6 (Prdx6) is a cytoprotective enzyme with largely unknown in vivo functions. Here, we use Prdx6 knockout mice to determine its role in UV protection and wound healing. UV-mediated keratinocyte apoptosis is enhanced in Prdx6-deficient mice. Upon skin injury, we observe a severe hemorrhage in the granulation tissue of knockout animals, which correlates with the extent of oxidative stress. At the ultrastructural level endothelial cells appear highly damaged, and their rate of apoptosis is enhanced. Knock-down of Prdx6 in cultured endothelial cells also increases their susceptibility to oxidative stress, thus confirming the sensitivity of this cell type to loss of Prdx6. Wound healing studies in bone marrow chimeric mice demonstrate that Prdx6-deficient inflammatory and endothelial cells contribute to the hemorrhage phenotype. These results provide insight into the cross-talk between hematopoietic and resident cells at the wound site and the role of reactive oxygen species in this interplay.

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