Calcifediol: Mechanisms of Action

Donati, Simone; Palmini, Gaia; Aurilia, Cinzia; Falsetti, Irene; Marini, Francesca; Giusti, Francesca; Iantomasi, Teresa; Brandi, Maria Luisa

doi:10.3390/nu15204409

Cited by 6 publications

(2 citation statements)

References 104 publications

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“…In short, calcitriol, VDREs, and modulators bound to the heterodimer-RXR are responsible for the physiological, genetic, and cell/tissue specificities, respectively. Lastly, the VDR gene product exerts a biological response [67].…”

Section: Genomic Action Of Calcitriolmentioning

confidence: 99%

Role of Calcitriol and Vitamin D Receptor (VDR) Gene Polymorphisms in Alzheimer’s Disease

Jeong,

Sharma,

2024

IJMS

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Alzheimer’s disease (AD) is characterized by amyloid beta (Aβ) buildup and neuronal degeneration. An association between low serum vitamin D levels and an increased risk of AD has been reported in several epidemiological studies. Calcitriol (1,25-dihydroxycholecalciferol) is the active form of vitamin D, and is generated in the kidney and many other tissues/organs, including the brain. It is a steroid hormone that regulates important functions like calcium/phosphorous levels, bone mineralization, and immunomodulation, indicating its broader systemic significance. In addition, calcitriol confers neuroprotection by mitigating oxidative stress and neuroinflammation, promoting the clearance of Aβ, myelin formation, neurogenesis, neurotransmission, and autophagy. The receptors to which calcitriol binds (vitamin D receptors; VDRs) to exert its effects are distributed over many organs and tissues, representing other significant roles of calcitriol beyond sustaining bone health. The biological effects of calcitriol are manifested through genomic (classical) and non-genomic actions through different pathways. The first is a slow genomic effect involving nuclear VDR directly affecting gene transcription. The association of AD with VDR gene polymorphisms relies on the changes in vitamin D consumption, which lowers VDR expression, protein stability, and binding affinity. It leads to the altered expression of genes involved in the neuroprotective effects of calcitriol. This review summarizes the neuroprotective mechanism of calcitriol and the role of VDR polymorphisms in AD, and might help develop potential therapeutic strategies and markers for AD in the future.

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Section: Genomic Action Of Calcitriolmentioning

confidence: 99%

Role of Calcitriol and Vitamin D Receptor (VDR) Gene Polymorphisms in Alzheimer’s Disease

Jeong,

Sharma,

2024

IJMS

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“…The major form of circulating vitamin D in the body is calcifediol, which undergoes hydroxylation via an alpha-hydroxylase enzyme known as cytochrome P450 family 27 subfamily B member 1 (CYP27B1) to synthesize the active form of vitamin D, calcitriol (1,25(OH)2D3) [2]. The latter can interact with its receptor, vitamin D receptor (VDR), to govern the expression of multiple genes, including the upregulation of cathelicidin antimicrobial peptide (CAMP) [3,4]. This cascade of interactions leads up to the synthesis of cathelicidin, and ultimately its active form LL-37, which has pleiotropic immune functions including anti-inflammatory and bactericidal effects that enhance the clearance of intracellular pathogens such as mycobacteria [4,5].…”

Section: Introductionmentioning

confidence: 99%

Mycobacterium avium paratuberculosis Infection Suppresses Vitamin D Activation and Cathelicidin Production in Macrophages through Modulation of the TLR2-Dependent p38/MAPK-CYP27B1-VDR-CAMP Axis

Talafha,

Qasem,

Naser

2024

Nutrients

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Background: Vitamin D plays a vital role in modulating both innate and adaptive immune systems. Therefore, vitamin D deficiency has been associated with higher levels of autoimmune response and increased susceptibility to infections. CYP27B1 encodes a member of the cytochrome P450 superfamily of enzymes. It is instrumental in the conversion of circulating vitamin D (calcifediol) to active vitamin D (calcitriol). This is a crucial step for macrophages to express Cathelicidin Anti-microbial Peptide (CAMP), an anti-bacterial factor released during the immune response. Our recent study indicated that a Crohn’s disease (CD)-associated pathogen known as Mycobacterium avium paratuberculosis (MAP) decreases vitamin D activation in macrophages, thereby impeding cathelicidin production and MAP infection clearance. The mechanism by which MAP infection exerts these effects on the vitamin D metabolic axis remains elusive. Methods: We used two cell culture models of THP-1 macrophages and Caco-2 monolayers to establish the effects of MAP infection on the vitamin D metabolic axis. We also tested the effects of Calcifediol, Calcitriol, and SB203580 treatments on the relative expression of the vitamin D metabolic genes, oxidative stress biomarkers, and inflammatory cytokines profile. Results: In this study, we found that MAP infection interferes with vitamin D activation inside THP-1 macrophages by reducing levels of CYP27B1 and vitamin D receptor (VDR) gene expression via interaction with the TLR2-dependent p38/MAPK pathway. MAP infection exerts its effects in a time-dependent manner, with the maximal inhibition observed at 24 h post-infection. We also demonstrated the necessity to have toll-like receptor 2 (TLR2) for MAP infection to influence CYP27B1 and CAMP expression, as TLR2 gene knockdown resulted in an average increase of 7.78 ± 0.88 and 13.90 ± 3.5 folds in their expression, respectively. MAP infection also clearly decreased the levels of p38 phosphorylation and showed dependency on the p38/MAPK pathway to influence the expression of CYP27B1, VDR, and CAMP which was evident by the average fold increase of 1.93 ± 0.28, 1.86 ± 0.27, and 6.34 ± 0.51 in their expression, respectively, following p38 antagonism. Finally, we showed that calcitriol treatment and p38/MAPK blockade reduce cellular oxidative stress and inflammatory markers in Caco-2 monolayers following macrophage-mediated MAP infection. Conclusions: This study characterized the primary mechanism by which MAP infection leads to diminished levels of active vitamin D and cathelicidin in CD patients, which may explain the exacerbated vitamin D deficiency state in these cases.

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The prevalence and outcomes of pre‐admission vitamin D levels in the management of proximal femur fractures

Rajeev,

Hunter,

Krishnan

et al. 2024

Aging Medicine

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ObjectivesThe prevalence of low Vitamin D levels (<30 nmol/L) is about 15.7% globally. The aim of this study was to examine the prevalence of vitamin D deficiency in elderly patients with fragility fractures of the hip by estimating 25‐hydroxyvitamin D levels and to assess whether low vitamin D levels at the time of admission affect functional outcomes at 3 months and mortality at 28 days and 1 year.MethodsWe conducted a retrospective study of all patients admitted with a fracture of the neck of the femur between January 2018 and March 2022. Data were obtained from the National Hip Fracture Database (NHFD) and Medway software. A total of 1440 patients were included. Patient demographics, including age, sex, fracture pattern, vitamin D levels at the time of admission, functional status at 120 days, and mortality at 1 month and 1 year, were analyzed.ResultsThe average age of the patients was 81.91 years (range 60–108). Of the patients, 1009 (70%) were female and 431 (30%) were male. Vitamin D levels were low in 796 patients (55.3%). Mobility significantly declined in patients with vitamin D deficiency within 3 months after surgery for proximal femur fractures. The 28‐day and one‐year mortality rates were 6.7% and 30.3%, respectively, in patients with low vitamin D levels, compared to 4.7% and 22.3% in those with normal levels. Patients with low vitamin D levels at the time of admission had higher mortality rates at both 28 days and 1 year compared to those with normal levels.ConclusionOur study demonstrates that low vitamin D levels at the time of admission for proximal femur fractures are associated with poorer functional mobility and higher perioperative and 1‐year mortality rates.

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Calcifediol: Mechanisms of Action

Cited by 6 publications

References 104 publications

Role of Calcitriol and Vitamin D Receptor (VDR) Gene Polymorphisms in Alzheimer’s Disease

Role of Calcitriol and Vitamin D Receptor (VDR) Gene Polymorphisms in Alzheimer’s Disease

Mycobacterium avium paratuberculosis Infection Suppresses Vitamin D Activation and Cathelicidin Production in Macrophages through Modulation of the TLR2-Dependent p38/MAPK-CYP27B1-VDR-CAMP Axis

The prevalence and outcomes of pre‐admission vitamin D levels in the management of proximal femur fractures

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