The effects of vitamin D on different types of cells
Journal Steroids December 2023, https://doi.org/10.1016/j.steroids.2023.109350 PDF is behind paywall
Mária Janubová, Ingrid Žitňanová
Vitamin D is necessary for regulation of calcium and phosphorus metabolism in bones, affects immunity, the cardiovascular system, muscles, skin, epithelium, extracellular matrix, the central nervous system, and plays a role in prevention of aging-associated diseases. Vitamin D receptor is expressed in almost all types of cells and its activation leads to modulation of different signaling pathways. In this review, we have analysed the current knowledge of 1,25-dihydroxyvitamin D3 or 25-hydroxyvitamin D3 effects on metabolism of cells important for the function of the
- cardiovascular system (endothelial cells, vascular smooth muscle cells, cardiac cells and pericytes),
- tissue healing (fibroblasts),
- epithelium (various types of epithelial cells) and the
- central nervous system (neurons, astrocytes and microglia).
The goal of this review was to compare the effects of vitamin D on the above mentioned cells in in vitro conditions and to summarize what is known in this field of research.
Portion of the graphical abstract
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Introduction
Vitamin D belongs to the lipophilic vitamins. It exists in nature as cholecalciferol, known as vitamin D3 and ergocalciferol, known as vitamin D2. Ergocalciferol is found in mushrooms, where it is formed from ergosterol after UV-B irradiation. Cholecalciferol can be found in fish oil, cod liver, marine fish, oysters, shrimp and egg yolk. Cholecalciferol is also formed in human skin after UV-B irradiation of 7-dehydrocholesterol[98]. In the human body, vitamin D2 and D3 undergo metabolic reactions that transform them into a biologically active form known as 1,25-dihydroxyvitamin D or calcitriol. Briefly, in the liver, both forms of vitamin D are hydroxylated to 25-hydroxyvitamin D by the enzyme vitamin D-25-hydroxylase (CYP2R1). In the kidney, 25-hydroxyvitamin D undergoes a second hydroxylation by the enzyme 25-hydroxyvitamin D-1-α hydroxylase (CYP27B1) to form 1,25-dihydroxyvitamin D, which is released into circulation. Another enzyme involved in vitamin D metabolism is vitamin D-24-hydroxylase (CYP24A1). In the kidney, CYP24A1 converts 25-hydroxyvitamin D into 24,25-dihydroxyvitamin D, which is further catabolized and excreted. The formation of the active form of vitamin D (1,25-dihydroxyvitamin D) or its nonactive form (24,25-dihydroxyvitamin D) depends on the level of parathyroid hormone (PTH) (Norman et al., 2008; [64].
However, in addition to the formation in renal tubular cells, 1,25-dihydroxyvitamin D can also be formed in many other cell types. The expression of CYP27B1 gene has been detected in endothelial cells, vascular smooth muscle cells, cardiomyocytes, pericytes, fibroblasts, epithelial cells, astrocytes, neurons and microglia (Liu et al., 2014; Jiao et al., 2017; Mazzetti et al., 2018; Landel et al., 2018; [109]; Latic and Erben, 2020; Shin et al., 2019; Norman et al., 2008; Boontanrart et al., 2016). It is assumed that 1,25-dihydroxyvitamin D, formed in all the mentioned cell types except renal tubular cells, does not enter the circulation and regulates cellular metabolism in a paracrine or autocrine manner (Norman et al., 2008; Landel et al., 2018).
Vitamin D acts through the vitamin D receptor (VDR), the expression of which has been demonstrated in various types of cells, such as endothelial cells, vascular smooth muscle cells, cardiomyocytes, pericytes, neural stem cells, neurons, astrocytes, microglia, fibroblasts, osteoblasts, epithelial cells adipocytes, myocytes, monocytes and macrophages[129]; Ramirez et al., 2010; Shirazi et al., 2015; Meredith et al., 2015; Cataldi et al., 2018; Jiao et al., 2017; El-Atifi et al., 2015; Leifheit-Nestler et al., 2017; Uberti et al., 2017; Uberti et al., 2016; Costa et al., 2019; [67], [110]; Song et al, 2023; Lin et al., 2023; Boontanrart et al., 2016).
The classic VDR belongs to the nuclear receptors and directly affects gene expression, mediating the majority of vitamin D effects. However, it has been discovered that 1,25-dihydroxyvitamin D may also act through a receptor in the cytoplasmic membrane associated with a special type of lipid rafts called caveolas (Norman et al., 2008; Zanatta et al., 2012). Through the VDR in the cytoplasmic membrane, 1,25-dihydroxyvitamin D can activate some signaling pathways and elicit a rapid cellular response (Zanatta et al., 2012; Norman et al., 2008; Landel et al., 2018; Fleet 2004).
Vitamin D is necessary for the regulation of calcium and phosphorus metabolism in bones, but also affects imunity, the cardiovascular system, muscles, skin, epithelium, extracellular matrix and the central nervous system. Additionally, it plays a role in the prevention of aging-associated diseases[98]; Norman et al., 2008, Landel et al., 2018).
In this review, we have analysed the current knowledge of 1,25-dihydroxyvitamin D3 or 25-hydroxyvitamin D3 effects on cells important for the function of the cardiovascular system (endothelial cells, vascular smooth muscle cells, cardiac cells and pericytes) (Table 1, Table 2, Table 3, Table 4), tissue healing (fibroblasts) (Table 5), epithelium (various type of epithelial cells) (Table 6) and the central nervous system (neurons, astrocytes and microglia) (Table 7, Table 8, Table 9). The goal of this review is to compare the effects of vitamin D on the above mentioned cells in in vitro conditions and to summarize what is known in this field of research.
The proper function of endothelial cells is essential for maintaining vascular homeostasis. endothelial cells are important for angiogenesis, hemostasis and the regulation of vascular tone. They are also essential and active components of immune responses[134]. So not-surprisingly, endothelial dysfunction triggered by various kinds of stress is associated with the development of vascular diseases[144].
Studies investigating the effects of vitamin D on endothelial cells indicate that vitamin D is capable of protecting endothelial cells against the detrimental effects of oxidative stress, stimulates the production of NO, mitigates damage to endothelial cells induced by air-pollution or excess glucose and iron and has anti-inflammatory and anti-atherogenic effects on endothelial cells (Fig. 1).
As mentioned above, 1,25-dihydroxyvitamin D3 plays an important role in protecting endothelial cells against oxidative stress induced by radiation or chemical compounds. endothelial cells are the most radiation-sensitive cell type in the vascular wall and their damage represents the first step in the pathogenesis of radiation induced toxicities. It was shown that 1,25-dihydroxyvitamin D3 increased the number of surviving endothelial cells, reduced the number of apoptotic cells by preventing the loss of mitochondrial potential, and inhibited the subsequent release of cytochrome c from mitochondria and the activation of pro-caspase 3, 8, 9, and 10 (CAS3, 8, 9, and 10) after injury of endothelial cells by hydrogen peroxide or radiation (Marampon et al., 2016; Polidoro et al., 2013; Uberti et al., 2013). The protective effect of 1,25-dihydroxyvitamin D3 against oxidative stress generated by hydrogen peroxide included activation/phosphorylation of extracellular-signal-regulated kinase (ERK) and protein kinase B (AKT), inhibition of silent mating type information regulation 2 homolog 1 (SIRT1) down-regulation and activation of pro-autophagic beclin-1 (Polidoro et al., 2013; Uberti et al., 2013). The protective effect of 1,25-dihydroxyvitamin D3 against radiation included activation/phosphorylation of ERK and inhibition of SIRT1 down-regulation (Marampon et al., 2016).
In quiescent endothelial cells, 1,25-dihydroxyvitamin D3 reduced the number of senescence-associated β-galactosidase (SA-β-gal)-positive cells and reactive oxygen species (ROS) production. It prevented the increase of p21, the phosphorylation and activation of p53, and retained the level of SIRT1, thus protecting cells against radiation-induced cell senescence (Marampon et al., 2016).
Moreover, 1,25-dihydroxyvitamin D3 reduced ROS levels that were increased by angiotensin II in endothelial cells (Dong et al., 2012).
Furthermore, 1,25-dihydroxyvitamin D3 affects the production of NO in endothelial cells both under normal conditions and during oxidative stress [103]; Uberti et al., 2013). NO is an important vasodilator that impacts cardiovascular physiology and the development of vascular disorders, such as atherosclerosis (Cines et al., 1998; [103]. Molinari et al. [103] showed that 1,25-dihydroxyvitamin D3 stimulated the phosphorylation of p38, ERK and, AKT leading to the activation of endothelial nitric oxide synthase (eNOS) and subsequently increased poduction of NO in endothelial cells. Additionally, the production of NO was increased in endothelial cells during oxidative stress induced by hydrogen peroxide after pretreatment with 1,25-dihydroxyvitamin D3 (Uberti et al., 2013).
Similarly, further experiments with endothelial cells demonstrated the anti-atherogenic properties of vitamin D. 1,25-dihydroxyvitamin D3 reduced the expression of several atherogenic parameters, including interleukin-6 (IL-6), the receptor recognising advanced glycation end products (RAGE), and certain adhesion molecules, such as intercellular adhesion molecule 1 (ICAM1) and platelet and endothelial cell adhesion molecule 1 (PECAM1) in endothelial cells. 1,25-dihydroxyvitamin D3 may possibly regulate these actions by affecting the activity of nuclear factor kappa beta (NFκβ) and p38 pathways, since in endothelial cells vitamin D reduces binding of NFκβ to DNA, decreases level of phosphorylated nuclear factor kappa beta inhibitor (Iκβ), increases level of dephosphorylated Iκβ, and decreases expression of active phosphorylated p38. Dephosphorylated Iκβ is capable of inhibiting the nuclear translocation of NFκβ (Talmor et al., 2008).
Next, 1,25-dihydroxyvitamin D3 was shown to be beneficial in preventing glucose-induced damage in endothelial cells. 1,25-dihydroxyvitamin D3 increased cell viability and mantained the blood-retinal barrier integrity in glucose-damaged retinal endothelial cells. Furthermore, 1,25-dihydroxyvitamin D3 enhanced the expression of tight junction protein zonula occludens 1 (ZO1) and adherens junction protein vascular endothelial (VE-) cadherin, which are important for the proper function of the blood-retinal barrier. Additionally, when added to glucose-damaged retinal endothelial cells, 1,25-dihydroxyvitamin D3 attenuated expression of pro-inflammatory cytokines such as interleukin-1β (IL1β), reduced NFκβ nuclear localisation and glucose-induced angiogenesis accompanied by a decrease in vascular endothelial growth factor A (VEGF-A) expression (Lazzara et al., 2022).
Glucose-induced endothelial cell damage can be associated with increased levels of ROS and malone dialdehyde (MDA), as well as the accumulation of iron inside the cells. The accumulation of iron coupled with decreased expression of oxidoreductase, especially glutathione peroxidase 4 (GPX4), and increased lipid peroxidation can lead to ferroptosis – a non-apoptotic cell death (Zhan et al., 2023; [81]. However, 25-hydroxyvitamin D3 was able to reduce ROS and MDA levels, as well as iron accumulation and increase the expression of two negative regulators of ferroptosis, GPX4 and the solute carrier family 7 member 11 (SLC7A11) in glucose-damaged retinal endothelial cells. This suggests that 25-hydroxyvitamin D3 may have an anti-ferroptotic effect (Zhan et al., 2023). The anti-ferroptotic effect of 25-hydroxyvitamin D3 is likely mediated by decreased expression of micro RNA miR-93, which is one of the key regulators of ferroptosis (Zhan et al., 2023; Liu et al., 2021).
Lai et al. (2022) studied the effect of vitamin D on endothelial cells, while simultaneously exposing them to glucose and particulate matter (PM) that simulated air pollution. The PM used in the study was composed of selected polycyclic aromatic hydrocarbon components (Lai et al., 2022). Air pollution is associated with endothelial damage, systemic inflammation, oxidative stress, and the progression of atherosclerosis (Mills et al., 2007; Lai et al., 2022). Glucose and PM significantly enhanced production of ROS, and reduced production of ATP and expression of superoxide dismutase 1 (SOD1) in endothelial cells. However, the expression of mitochondrial superoxide dismutase (SOD2) was not affected. Furthermore, mitophagy and production of the inflammatory adhesion molecules ICAM and VCAM were enhanced. However, 1,25-dihydroxyvitamin D3 treatment reversed these effects (Lai et al., 2022).
IL6 is known to stimulate inflammatory response in endothelial cells, which can lead to thrombo-inflammation (Cimmino et al., 2022). Thrombo-inflammation is a common feature of several human diseases, such as sepsis, ischemia-reperfusion injury, major trauma or severe burns[59]. endothelial cells treated with IL6 showed increased the expression and activity of tissue factor (TF), which is a key initiator of the coagulation cascade (Cimmino et al., 2022; Grover et al., 2018). The expression of adhesion molecules ICAM and VCAM, which may lead to the development of a pro-atherogenic phenotype of endothelial cells, was also increased (Cimmino et al., 2022; [40]. Furthermore, IL6 enhanced the expression of angiotensin converting enzyme 2 (ACE2) receptor, which can also bind COVID-19 virus and facilitate its entry into the cell (Cimmino et al., 2022; Shang et al., 2020). Cimmino et al. (2022) observed that 1,25-dihydroxyvitamin D3 could abrogate all these changes. The effect of 1,25-dihydroxyvitamin D3 was accompanied by an increase of cytoplasmatic IκB and decrease of signal transducer and activator of transcription 3 (STAT3) activities (Cimmino et al., 2022).
The important role of vitamin D in the metabolism of endothelial cells was confirmed through VDR deficiency in murine retinal endothelial cells. endothelial cells with VDR deficiency exhibited increased expression of several compounds participating in pro-inflammatory process, such as IL6, IL33 and the monocyte chemoattractant protein (MCP), as well as inducible nitric oxide synthase (iNOS), ICAM1, VCAM1 or PIEZO1 and 2 (Song et al., 2023). PIEZO1 and 2 are mechanically activated cation channels. PIEZO1 is essential for vascular development and mediates flow mediated increase of intracellular calcium in endothelial cells, while PIEZO2 modulates cellular cytoskeleton changes (Song et al., 2023; [3]. The pro-inflammatory response of endothelial cells with VDR deficiency was driven in part by the activation of signal transducer and activator of transcription 1 (STAT1) and NFκβ.
Further, these cells also produced higher protein levels of some extracellular matrix components, such as of osteopontin, osteonestin (also known as the secreted protein acidic and rich in cysteine – SPARC), and thrombospondin 2 (TSP2), and lower protein level of thrombospondin 1 (TSP1) (Song et al., 2023). Osteopontin, SPARC, and TSP1 play important roles in inflammatory responses, thus changes in their protein levels correlate with alteration in immune response of endothelial cells with VDR deficiency (Song et al., 2023; Lok and Lyle, 2019).
Moreover, endothelial cells with VDR deficiency were less migratory and more adherent to various extracellular components, such as fibronectin or collagen 4 (COL4). Next, VDR deficiency affected metabolism of iron in retinal endothelial cells. Expression of hepcidin was enhanced, whereas expression of ferroportin was reduced in retinal endothelial cells with VDR deficiency (Song et al., 2023). Because of blood-retinal barrier, iron metabolism in retina is mainly modulated by local production of iron regulators including hepcidin[112]. Hepcidin is produced in retinal endothelial cells after stimulation with the bone morphogenetic protein 6 (BMP6), which expression was also increased in retinal endothelial cells with VDR deficiency. Consequently, retinal endothelial cells with VDR deficiency were more sensitive to ROS (Song et al., 2023).
In addition, 1,25-dihydroxyvitamin D3 affects angiogenesis in endothelial colony forming cells (ECFCs). ECFCs are endothelial-like cells important to blood vessel formation and repair [128]. ECFCs develop from circulating endothelial progenitor cells (EPCs). Reduced number of EPCs is observed in patients with various cardiovascular risk factors[5]. In in vitro studies, ECFSs treated with 1,25-dihydroxyvitamin D3 showed higher proliferation rate, increased expression of vascular endothelial growth factor (VEGF), and enhanced activty and secretion of promatrixmetalloproteinase 2 (pro-MMP2), which led to improved angiogenesis of ECFCs (Grundmann et al., 2012).
Vascular smooth muscle cells (VSMCs) are an essential component of the medial layer of arteries. The main function of VSMCs is the regulation of blood vessel tone, blood stream, and blood pressure (Shi et al., 2020; [118]. The mature VSMCs exhibit a phenotype characterized by an extremely low rate of proliferation and expression of specific contractile proteins, such as smooth muscle myosin heavy chain. However, upon vascular injury, VSMCs change their phenotype, enhance the rate of proliferation and migration, increase the production of extracellular matrix components and reduce the production of VSMC-specific markers. This changed phenotype contributes to the development of various cardiovascular diseases (Shi et al., 2020).
Vitamin D has been shown to decrease senescence of VSMC, affect metabolism of calcium in VSMC, stimulate production of prostacyclins in VSMCs, reduce abnormal proliferation of VSMCs, and inhibit osteogenic transdifferentiation of VSMCs. However, prolonged incubation of VSMCs with vitamin D can induce their calcification (Fig. 2).
Specifically, VSMCs isolated from mice with vitamin D receptor knockout, produced more angiotensin II and cathepsin D and expressed more angiotensin II type 1 receptor at the mRNA and protein levels than VSMCs isolated from wild type mice[140]. Cathepsin D is an enzyme with renin-like activity[51]. Moreover, VSMCs isolated from mice with vitamin D receptor knockout showed several markers of premature senescence, such as higher production of ROS, bigger size and flattened shape, increased activity of SA-β-galactosidase and impaired proliferation[140]. In another experiment, 1,25-dihydroxyvitamin D3 added to VSMCs led to diminished angiotensin II induced cell contractility. More specifically, VSMCs treated with 1,25-dihydroxyvitamin D3 contained higher level of the myosin phosphatase regulatory target unit 1 (MYPT1) phosphorylated at serine 507. MYPT1 phosphorylated at serine 507 can activate the myosin light chain phosphatase (MLCP), which is essential for smooth mucle cell relaxation [62].
1,25-dihydroxyvitamin D3 is also able to stimulate activity of Ca2+-ATPase[66], increase cellular uptake of Ca2+ [57], raise cytosolic Ca2+ concentration [121]and increase the synthesis of prostacyclins (PGI2) in VSMCs[143], thereby affecting arterial tone.
In quiescent, as well as in non-quiescent VSMCs, 1,25-dihydroxyvitamin D3 induces increase in proliferation (Cardus et al., 2006; [102]. However, vitamin D diminishes mitogenic effect of thrombin in non-quiescent VSMCs. In non-quiescent VSMCs, transcription of cellular Myc (c-MYC) was inhibited, whereas transcription of c-MYC in quiescent VSMCs was enhanced after incubation with 1,25-dihydroxyvitamin D3 and thrombin [102]. Similarly, 1,25-dihydroxyvitamin D3 was able to inhibit endothelin-induced VSMCs proliferation through the induction of a decrease in cell division control 25 phosphatase (CDC25) expression and activity [20]. The abnormal proliferation of VSMCs is one of the main cause of the development of atherosclerosis (Zhou et al., 2022).
Further, RBP4-glucose-induced abnormal proliferation of VSMCs was prevented by 1,25-dihydroxyvitamin D3 through inhibition of the JAK-STAT3 signaling pathway (Zhou et al., 2022). RBP4 (the retinol binding protein 4) is an adipokine derived from adipocytes and hepatocytes, which is responsible for transporting retinol to systemic tissues. However, elevated circulating RBP4 levels may contribute to insulin resistance and the development of type 2 diabetes mellitus and cardiovascular diseases (Young et al., 2005; Aust et al., 2011; Llombart et al., 2016)
Advanced glycation end products (AGE) can induce osteogenic trans-differentiation of VSMCs[135]. AGE significantly increase migration of VSMCs, expression of collagen 1 (COL1) and the Runt related transcription factor 2 (RUNX2), which is an osteogenic transcription factor, enhance activity of alkaline phosphatase and production of ROS in VSMCs and inhibit expression of α-actin, which is a marker of VSMCs. After addition of 1,25-dihydroxyvitamin D3 to VSMCs, production of ROS and migration of VSMCs was diminished, as well as the expression of COL1 and RUNX2 (Molinuevo et al., 2017).
However, Cardus et al. (2007) have observed that prolonged incubation with excessive amounts of 1,25-dihydroxyvitamin D3 (100 nM and 300 nM/5 days) can lead to VSMC calcification, that is accompanied by increased mRNA and protein expression of the receptor activator of nuclear factor kappa-beta ligand (RANKL) (Fig. 9) (Cardus et al., 2007). RANKL is normally highly expressed in osteoblasts and undetectable in normal VSMCs but its expression increases in calcified arterial lesions (Schoppet et al., 2004).
Furthermore, metabolism of vitamin D in VSMCs can be regulated by PTH. Human VSMCs treated wκth PTH have shown an increase of CYP27B1 mRNA expression and formation of 1,25-dihydroxyvitamin D3 [129].
cardiac cells include cardiomyoblasts (cardiomyocyte precursors) and cardiomyocytes (Jahanifar et al., 2019; Guo et al., 2020). Cardiomyocytes are the building blocks of the heart muscle, having the lifelong responsibility of remaining healthy and contractile to keep the heart pumping blood throughout the body, as humans generate limited amounts of heart muscle after birth. The recent estimates suggest that more than half of the cardiomyocytes in a 70-year-old healthy human are remnants of embryogenesis (Daiou et al., 2022).
It has been observed that vitamin D can protect cardiac cells against glucose induced damage, inhibit certain types of hypertrophy of cardiac cells, affect contractile function and viability of cardiac cells. Similarly as in VSMCs, prolonged incubation of cardiac cells with vitamin D induces calcification of cardiac cells (Fig. 3).
Glucose is capable of inducing autophagy, accompanied by increased apoptosis. However, addition of 1,25-dihydroxyvitamin D3 to glucose-treated cardiomyoblasts can suppress glucose-induced damage. 1,25-dihydroxyvitamin D3 led to a decrease in the microtubule associated proteins 1 light chain 3β II/I (LC3II/LC3I) ratio, as well as BAX/BCL2 ratio. Autophagy in cardiomyoblasts was decreased by the inhibition of forkhead box transcription factor 1 (FOXO1) nuclear translocation induced by 1,25-dihydroxyvitamin D3 (Guo et al., 2020).
Other effects of Vitamin D on cardiomyocytes include prevention of hypertrophy induced by fibroblast growth factor 23 (FGF23) or angiotensin II (Leifheit-Nestler et al., 2017; Jahanifar et al., 2019). FGF23 induces hypertrophic growth of cardiomyocytes via FGFR-dependent activation of phospholipase C gamma (PLCγ)/calcineurin/NFAT signaling pathway (Faul et al., 2011). 1,25-dihydroxyvitamin D3 blocked FGF23-induced activation of fibroblast growth factor receptor 24 (FGFR4) by inhibiting the interaction of FGFR4 with PLCγ.
On the other hand, 1,25-dihydroxyvitamin D3 had no effect on the development of hypertrophy induced by fibroblast growth factor 2 (FGF2) in cardiomyocytes (Leifheit-Nestler et al., 2017). FGF2 induces hypertrophy of cardiomyocytes by activating another signaling pathway, namely RAS/ mitogen activated protein kinase (MAPK) signaling pathway (Faul et al., 2011).
Addition of 1,25-dihydroxyvitamin D3 to angiotensin II-induced hypertrophic cardiomyoblasts was accompanied with decreased expression of the atrial natriuretic peptide (ANP) and did not affect expression of silent mating type information regulation 2 homolog 3 (SIRT3). SIRT3 is an endogenous negative regulator of cardiac hypertrophy (Jahanifar et al., 2019). ANP is a counter-regulator of RAS and its production is stimulated by cell growth in stressful conditions (Clerico et al., 2006).
Further, 1,25-dihydroxyvitamin D3 has been shown to increase expression of myotrophin and decrease expression of ANP and c-MYC in cardiomyocytes (Nibbelink et al., 2007). Myotrophin plays an important role in cardiomyocyte development (McMurray et al., 2003).
Moreover, addition of 1,25-dihydroxyvitamin D3 to cardiomyocytes can lead to a decrease in peak shortening and an increase in the rate of contraction and relaxation, which is mediated by proteinkinase C (PKC) activation (Zhao and Simpson, 2010; Tishkoff et al., 2008; Green et al., 2006). Acute exposure (15 or 60 minutes) of cardiomyocytes to 1,25-dihydroxyvitamin D3 was accompanied with an increase in phosphorylation of Ca2+ regulatory proteins – phospholamban and cardiac troponin I, whereas chronic exposure of cardiomyocytes to 1,25-dihydroxyvitamin D3 (1 or 2 days) was not associated with an increase in phosphorylation of phospholamban or cardiac troponin I (Green et al., 2006).
Next, 1,25-dihydroxyvitamin D3 in different concentrations improves viability of cardiomyoblasts. However, prolonged incubation with 1,25-dihydroxyvitamin D3 in excess concentration (300 nM / 7days) has been found to increase calcification of cardiomyoblasts (Fig. 9). Besides that, 1,25-dihydroxyvitamin D3 (300 nM / 48 hours) increased proliferation of cardiomyoblasts (Pacini et al., 2013).
pericytes are perivascular supporting cells that mediate vascular stability, control proliferation and survival of endothelial cells, play important roles during angiogenesis and contribute to the formation of both the blood-brain and blood-retina barriers (Caporarello et al., 2019; Jamali et al., 2019).
Vitamin D is capable of regulating angiogenic activity of retinal pericytes and production of anti-inflammatory compounds in brain pericytes (Jamali et al., 2019; [109].
1,25-dihydroxyvitamin D3 increased production of VEGF that played a role in a decrease of proliferation and migration of retinal pericytes. In accordance with that, incubation of retinal pericytes with 1,25-dihydroxyvitamin D3 was associated with increased adhesion of retinal pericytes to extracellular matrix proteins (COL1 and 4 and fibronectin) and increased expression of integrin α4 and α5β1, which play an important part in adhesion to extracellular matrix. VEGF can act through its receptor VEGF-R2.
Retinal pericytes incubated with 1,25-dihydroxyvitamin D3 showed increased colocalisation of VEGF-R2 with platelet-derived growth factor receptor beta (PDGF-Rβ) (Jamali et al., 2019). However, activation of PDGF-Rβ results in proliferation of pericytes and cytoskeletal rearrangements facilitating migration (Winkler et al., 2014). Interaction of PDGF-Rβ with VEGF-R2 probably led to attenuation of PDGF-Rβ signalling.
Further, incubation of retinal pericytes with 1,25-dihydroxyvitamin D3 led to increased expression of ERK (Jamali et al., 2019). ERK activation is necessary for cell cycle promotion but ERK overactivation can have a negative effect on the cell cycle progression by promoting accumulation of cell cycle inhibitors such as p21 (Chambard et al., 2007).
fibroblasts are the principal cell type of connective tissue, that secrete extracellular matrix components. Fibroblast are necessary for tissue development, homeostasis and repair, and they also play an important role in cancer development (Lendahl et al., 2022). During tissue repair, fibroblasts can be converted to myofibroblasts, which secrete large amounts of matrix proteins and form a collagen-based scar. However, prolonged activation of myofibroblasts is responsible for the development of fibrosis and subsequent organ failure (Venugopal et al., 2022).
It has been observed that vitamin D can reduce transdifferentiation of fibroblasts into myofibroblasts, stimulate fibroblast repair functions, has an anti-inflammatory and anti-tumour effects on fibroblasts and mitigates the negative effect of oncogenic ras activation and ionising radiation on fibroblasts (Fig. 4).
As mentioned above, vitamin D has been shown to have an anti-fibrotic effect on fibroblasts. Lung fibroblasts cultivated in the presence of 1,25-dihydroxyvitamin D3 were characterised by reduced proliferation and expressed less transforming growth factor beta 1 (TGFβ1)-induced pro-fibrotic markers, such as α-smooth muscle actin (αSMA), procollagen 1 and collagen 3 (COL3), fibronectin and plasminogen activator inhibitor-1 (PAI1). Moreover, 1,25-dihydroxyvitamin D3 inhibited organisation of αSMA into the tubular structure of the actin cytoskeleton, which is typical for transdifferentiation fibroblasts into myofibroblasts (Ramirez et al., 2010). TGFβ is a pro-fibrotic cytokine consistently found in fibrotic tissues and has the ability to stimulate cell proliferation and expression of extracellular matrix components in fibroblasts[8].
Similarly, 1,25-dihydroxyvitamin D3 prevented TGFβ1-induced development of fibrosis in cardiac fibroblasts. Specifically, 1,25-dihydroxyvitamin D3 reduced TGFβ1-induced expression of αSMA, as well as the incorporation of αSMA into stress fibers. TGFβ1-driven contractility of cardiac fibroblasts was also reduced. 1,25-dihydroxyvitamin D3 inhibited signals through decreased activation of SMAD family member 2 (SMAD2) (Meredith et al., 2015).
Further, vitamin D was able to attenuate isoproterenol-induced fibrosis in cardiac fibroblasts. In this case, the development of fibrosis was inhibited through downregulation of integrin β3 and suppression of phosphorylation of focal adhesion kinase (FAK) and AKT, leading to decreased isoproterenol-induced proliferation (Wang et al., 2023).
Besides its anti-fibrotic effect, vitamin D also plays a role in stimulating fibroblast repair functions by inhibiting the production of prostaglandin E2 (PGE2) in fibroblasts, which is known to inhibit fibroblast repair functions. 25-hydroxyvitamin D3, as well as 1,25-dihydroxyvitamin D3, inhibited expression of microsomal prostaglandin E (mPGE) synthase 1 and stimulated expression of 15-hydroxy prostaglandin dehydrogenase (15-PGDH) that degrades PGE2 (Liu et al., 2014).
It has also been shown that vitamin D could have a slightly protective role in inflammatory responses in synovial fibroblasts. Synovial fibroblasts obtained from patients with rheumatoid arthritis treated with 1,25-dihydroxyvitamin D3 exhibited decreased expression of Toll-like receptors 1 and 4 (TLR1 and TLR4) but not affected expression of Toll-like receptor 2 (TLR2) and matrixmetalloproteinase (MMPs) (Sakalyte et al., 2022). Activation of TLR can trigger uncontrolled local inflammation, that can lead to a pathological immune response and the development of inflammatory or autoimmune disorders [84]; Sakalyte et al., 2022). MMPs directly contribute to degradation of cartilage components[58].
Anti-tumor activity of vitamin D in fibroblasts has also been observed. 1,25-dihydroxyvitamin D3 reduced pro-tumor properties, such as proliferation and migration in different types of fibroblasts (human colon myofibroblasts, human lung fibroblasts, human foreskin fibroblasts). Surprisingly, Wnt family member 3A (WNT3A), that usually promotes the development of a pro-tumor phenotype in fibroblasts, also led to decreased proliferation and migration in these types of fibroblasts (Lam et al., 2011, Ferrer-Mayorga et al., 2019). Moreover, in case of human colon myofibroblasts, the affect of 1,25-dihydroxyvitamin D3 and WNT3A on reduction of proliferation was additive (Ferrer-Mayorga et al., 2019).
Next, vitamin D affects oncogene ras-induced senescence in fibroblasts. Ras expression led to decreased expression of breast cancer type 1 susceptibility protein (BRCA1) and increased cathepsin L mediated degradation of tumor suppressor P53-binding protein 1 (53BP1) (Graziano et al., 2016). BRCA 1 is a key factor in DNA DSBs repair by homologous recombination, whereas 53BP1 is important for DNA DSBs repair by non-homologous end joining (Cao et al., 2009). Addition of 1,25-dihydroxyvitamin D3 to ras expressing fibroblasts increased mRNA expresson of BRCA-1 but had no effect on mRNA expression of 53BP1. It also increased BRCA-1 and 53BP1 protein levels and foci formation, while decreasing cathepsin L protein levels. These results indicate that 1,25-dihydroxyvitamin D3 can improve DNA repair in ras-induced senescent cells and protect them against further accumulation of DNA damage, which could promote malignant transformation (Graziano et al., 2016).
epithelial cells are a fundamental type of cells found throughout the human body. epithelial cells form the lining of many organs, cavities, and surfaces within the body, creating protective barriers and facilitating important functions, such as absorption, secretion, and sensory perception (Larsen et al., 2020).
Vitamin D has been observed to affect various types of epithelial cells. Vitamin D is capable of stimulating wound healing in alveolar epithelial cells and keratinocytes, inhibiting epithelial to mesenchymal transition in lung epithelial cells including alveolar epithelial cells and protecting fallopian epithelial cells, bronchial epithelial cells, keratinocytes, gastric mucosa epithelial cells and intestinal epithelial cells against various types of damage. Furthermore, vitamin D has an anti-inflammatory effect on keratinocytes and bronchial epithelial cells (Fig. 5).
1,25-dihydroxyvitamin D3 as well as 25-hydroxyvitamin D3 added to human alveolar type II cells (ATII) or human keratinocytes stimulated wound healing after the cells were physically wounded with a pipette tip (Zheng et al., 2020; Cataldi et al., 2022). This wound repair can happen because of migration and proliferation of cells. Increased proliferation of ATII cells after addition of 1,25-dihydroxyvitamin D3 was promoted by phosphorylation of AKT. Further, 1,25-dihydroxyvitamin D3 was able to reduce Fas ligand protein (FasL)-induced apoptosis of ATII cells by inhibition of CAS3 cleavage and activation.
Finally, 1,25-dihydroxyvitamin D3 inhibited TGFβ-induced epithelial-mesenchymal transition of ATII cells which was confirmed by increased expression of epithelial cell marker epithelial (E-)cadherin and decreased expression of mesenchymal cell markers neural (N-)cadherin, vimentin, COL1, SNAIL family zinc finger 2 protein (SLUG) and αSMA (Zheng et al., 2020).
In another study, Ramirez et al. (2010) have similarly shown that 1,25-dihydroxyvitamin D3 was able to abrogate TGFβ-induced abnormal expression of E-cadherin and two other markers of epithelial cells – cytokeratin and ZO1 in rat lung epithelial cells. Moreover, 1,25-dihydroxyvitamin D3 mitigated TGFβ-induced organisation of αSMA into stress fibers, expression of procollagen 1 and secretion of fibronectin in rat lung epithelial cells (Ramirez et al., 2010).
Further, vitamin D has been observed to have protective effects against epithelial cell damage induced by various stress conditions.
Protective effect of vitamin D against Fe3+ -induced cell damage has been observed in epithelial secretory cells from fimbriae of fallopian tubes (FSEC). Fe3+ led to increased cell growth, ROS formation and increased expression of oncogenes c-MYC and pan-RAS, marker of cell division protein Ki67 and tumor suppressor p53 in FSEC. 1,25-dihydroxyvitamin D3 was able to counteract these changes (Uberti et al., 2016). FSEC are greatly exposed to catalytic iron derived from menstrual reflux and are also the cells where most serious ovarian cancers develop (Kuhn et al., 2013).
Furthermore, 1,25-dihydroxyvitamin D3 increased viability and protected bronchial epithelial cells exposed to nitrogen mustard by activating nuclear factor erythroid 2 related factor 2 (NRF2)/SIRT3 signaling pathway. Activation of NRF2/SIRT3 signaling pathway led to decreased acetylation of mitochondrial SOD2 and reduced production of ROS (Yu et al., 2022). Acetylation of SOD2 results in a loss of dismutase activity and a gain of peroxidase activity. The peroxidase activity of SOD2 is capable of increasing oxidative damage in cells (Hjelmeland and Patel, 2019). ROS have been found to significantly participate in mustard-induced damage to respiratory system [55], [77].
Chronic arsenic exposure causes a variety of diseases including skin cancer[133]; Yajima et al., 2022). Yajima et al. (2022) observed that keratinocytes exposed to arsenic exhibited enhanced proliferation and activation of ERK, MAP kinase kinase (MEK) and AKT. However, 1,25-dihydroxyvitamin D3 added to keratinocytes exposed to arsenic led to suppression of activation of ERK, MEK and AKT and increased expression of p21 – a well known cell cycle inhibitor. Moreover, 1,25-dihydroxyvitamin D3 decreased expression of aquaporines 7 and 9, which was accompanied with reduced uptake of arsenic in keratinocytes (Yajima et al., 2022).
Helicobacter pylori is a common human pathogen colonising human gastrointestinal mucosa, which can lead to gastritis, peptic ulcers, tumors and adenocarcinoma (Burucoa and Axon, 2017). Gastric mucosa epithelial cells infected with Helicobacter pylori are characterised by decreased viability, increased cytochrome c release from mitochondria, increased expression of BCL2 associated X protein (BAX) and CAS3, 6 and 9, consequently enhanced apoptosis. Importantly, 1,25-dihydroxyvitamin D3 was able to abbrogate all these effects of Helicobacter pylori through activation of cellular RAF serin/threonine kinase (c-RAF)/MEK/ERK pathway in gastric mucosa epithelial cells (Zhao et al., 2022).
Next, vitamin D has been shown to have beneficial effects on intestinal epithelial cells exposed to ionizing radiation. Pretreatment of intestinal epithelial cells with 1,25-dihydroxyvitamin D3 increased viability and decreased apoptosis after exposition of cells to ionizing radiation (Lin et al., 2023). 1,25-dihydroxyvitamin D3 pretreatment also enhanced expression of ZO1 and claudin 1, both of which are important components of tight junctions (Lin et al., 2023; Zihni et al., 2016). Moreover, expression of β-catenin, which is essential for maintenance of homeostasis and function of intestinal epithelial cells, was increased after 1,25-dihydroxyvitamin D3 pretreatment (Lin et al., 2023; Fevr et al., 2007). 1,25-dihydroxyvitamin D3 probably mitigates the effect of ionising radiation by activating the hypoxia inducible factor/phosphoinositide dependent kinase 1 (HIF/PDK1) signaling pathway (Lin et al., 2023).
Excesive UVB radiation is responsible for many of the deleterious effects of sun exposure on humans, including the development of skin cancer (Difey et al., 2004; [113]. Excessive UVB irradiation can increase production of ROS and DNA damage, trigger inflammation, apoptosis and endoplasmic reticulum stress in keratinocytes (Mera et al., 2010; Chen et al., 2022). However, 1,25-dihydroxyvitamin D3 has been revealed as a promising agent that can protect keratinocytes against UVB-induced damages mentioned above. 1,25-dihydroxyvitamin D3 was able to decrease ROS production, enhance expression of NRF2 and several antioxidant enzymes, which can be induced by NRF2, such as catalase (CAT), SOD1, SOD2, glutathione reductase (GR), heme oxygenase 1 (HMOX1) and thioredoxin reductase (TRXR) in UVB irradiated keratinocytes (Chen et al., 2022; Chaiprasongsuk et al., 2019). Further, 1,25-dihydroxyvitamin D3 reduced production of cyclobutane-pyrimidine dimers and increased repair of 6-4 pyrimidine photoproducts, which are the major type of DNA damage induced by UVB irradation (Chaiprasongsuk et al., 2019; Lo et al., 2005).
Anti-inflammatory effect of vitamin D on UVB-irradiated keratinocytes was assesed by decreased expression of NFκβ and phosphorylation of Iκβ. The effect of 1,25-dihydroxyvitamin D3 on endoplasmic reticulum stress in UVB-irradiated keratinocytes was determined by detecting the expression and activation of two proteins – a HSP70 molecular chaperone located in the lumen of the endoplasmatic reticulum (BIP) and protein kinase R like endoplasmic reticulum kinase (PERK), which are typical endoplasmatic reticulum stress-related molecules (Chen et al., 2022; Liu et al., 2015). After 1,25-dihydroxyvitamin D3 administration, expression of BIP and phosphorylation/activation of PERK were reduced. Anti-inflammatory, anti-apoptotic and preventive endoplasmatic reticulum stress effects of 1,25-dihydroxyvitamin D3 were enhanced when 1,25-dihydroxyvitamin D3 was added to UVB-irradiated keratinocytes along with TLR4 inhibitor (Chen et al., 2022). TLR4 activation leads to the majority of the UVB-induced damage to keratinocytes (Ahmad et al., 2014; Chen et al., 2022).
Anti-inflammatory effects of 1,25-dihydroxyvitamin D3 on epithelial cells can be also mediated by suppression of hypoxia inducible factor 1 alpha (HIF1α)/GATA1/STING/IFNβ molecular pathway. Increased expressions of GATA binding factor 1 (GATA-1), stimulator of interferon genes protein (STING) and interferon β (IFNβ) were observed in the oral keratinocytes from patients suffering from oral lichen planus (Ge et al., 2022). Ge et al. (2022) revealed that 1,25-dihydroxyvitamin D3 can succesfully reduce the expression of GATA-1, STING, and IFNβ in lipopolysaccharides- (LPS-) stimulated keratinocytes. Moreover, HIF1α overexpression led to the enhancement of GATA1 expression, and HIF1α knockdown was accompanied by reduced expression of STING and IFNβ (Ge et al., 2022).
Interestingly, vitamin D could improve the effectiveness of unsatisfactory glucocorticoid therapy. When 1,25-dihydroxyvitamin D3 was added to LPS-stimulated human nasal or human bronchial epithelial cells along with dexamethasone, it decreased the production of the pro-inflammatory cytokine IL6, reduced LPS-induced expression of TLR4, myeloid differentiation primary response 88 protein (MYD88), and NFκB signaling [144]. TLR4 is a transmembrane receptor, whose activation leads to a pro-inflammatory cytokine production, and MYD88 is an an essential signal transducer in TLR signaling pathways (Furman et al., 1996; Deuguine and Barton, 2014; Jiao et al., 2017).
On the other hand, prolonged incubation with 1,25-dihydroxyvitamin D3 can lead to increased expression of matrixmetalloproteinase 1 (MMP1) in human primary keratinocytes. Furthermore, UV-irradiated primary keratinocytes (42.8% UV-A and 56.7% UV-B) exhibited lower expression of MMP1 after transfection with CYP27B1 siRNA compared to UV-irradiated non-transfected cells (Shin et al., 2019).
neurons are highly differentiated postmitotic cells, and the lifespan of the majority of neurons in the postnatal period is equal to the lifespan of the entire organism. Therefore, the maintenance of healthy neurons is vital for brain health (Sikora et al., 2021).
The results of the research focusing on the effetcs of vitamin D on neural cells have shown that vitamin D plays a role in neuronal development and plasticity, reduces the negative effects of hypoxia on neural cells and stimulates the proliferation and differentiation of neural progenitor/stem cells (Fig. 6).
In murine hippocampal neurons 1,25-dihydroxyvitamin D3 administration increased the expresssion of microtubule associated protein 2 (MAP2) and neurofilament heavy polypeptide (NEFH), which are associated with neurite elongation (Cataldi et al., 2018). Expression of N-cadherin, which is a major adhesion molecule involved in the neuron interaction, development and plasticity of the nervous system, was also enhanced (Cataldi et al., 2018; Lelievre et al., 2012). However, 1,25-dihydroxyvitamin D3 is not probably involved in the regulation of an important neuroprotective molecule – peroxisome proliferator-activated receptor gamma (PPARγ) in neurons (Cataldi et al., 2018).
Hypoxia is a serious pathological condition that interferes with energy metabolism and may result in cell death. neurons belong to the cells, which are the most vulnerable to hypoxia, and neuronal injury induced by hypoxia forms the basis of many neurological disorders, such as stroke[2]; Cui et al., 2020). 1,25-dihydroxyvitamin D3 has been shown to counteract hypoxia-induced damage in neural cells, probably by reducing dual oxidase 1 (DUOX1) expression (Cui et al., 2020). DUOX1 is Ca2+-dependent NADPH oxidase that leads to ROS production and promotes activation of NFκβ signaling pathways[65], [70]. Addition of 1,25-dihydroxyvitamin D3 to neural cells overexpressed DUOX1 was accompanied with less ROS production, lower MDA level, reduced apoptosis and NFκβ nuclear signaling (Cui et al., 2020).
Regarding neural progenitor cells, vitamin D has been shown to increase the proliferation of murine neural progenitor cells. 1,25-dihydroxyvitamin D3 significantly enhanced the percentage of Ki67-positive cells, the ratio of proliferating cell nuclear antigen (PCNA)/actin and the number of cells in S phase. However, the differentiation of murine neural progenitor cells into neurons was not affected by 1,25-dihydroxyvitamin D3. 1,25-dihydroxyvitamin D3 neither triggered differentiation nor affected the differentiation of murine neural progenitor cells (Morello et al., 2018). Neural progenitor cells modify their shape, flatten and adhere to the culture support, and exhibit a G1 cell cycle arrest during differentiation (Millet et al., 2005). After three days of treatment with 1,25-dihydroxyvitamin D3, no change was detected in the modifying neurosphere shape or their cell cycle, that indicates an absence of 1,25-dihydroxyvitamin D3 pro-differentiation direct effect on neural progenitor cells. Next, the unchanged percentage of neural progenitor cells expressing nestin or microtubule associated protein 2 (MAP2) suggested that neuronal differentiation was not affected by 1,25-dihydroxyvitamin D3 after 7 days of treatment (Morello et al., 2018).
On the other hand, 1,25-dihydroxyvitamin D3 has been observed to enhance proliferation, as well as differentiation of neural stem cells into neurons and oligodendrocytes after 14 days of treatment. Addition of 1,25-dihydroxyvitamin D3 to murine neural stem cells also led to increased expression of neurotrophin 3 (NT3), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF), which are important for neural differentiation (Shirazi et al., 2015).
astrocytes are the most abundant cells in the brain. They perform many important functions, which are essential for normal neuronal development, synapse formation, and proper propagation of action potentials (Chen et al., 2023).
Vitamin D has been detected to affect the expression of neural growth factors in astrocytes, favour anti-inflammatory phenotype of astrocytes, protect astrocytes against various kinds of stress and affects steroid synthesis in astrocytes (Fig. 7).
Specifically, 1,25-dihydroxyvitamin D3 enhanced the expression of nerve growth factor and neurotrophin 3, and sligthly downregulated the expression of neurotrophin 4 (NT4) in primary astrocytes (Neveu et al., 1994a; Neveu et al., 1994b).
In studies observing the effect of vitamin D on astrocyte immune response, addition of 1,25-dihydroxyvitamin D3 to LPS-stimulated astrocytes led to the decreased expression of various proinflammatory cytokines, such as tumor necrosis factor alpha (TNFα), macrophage colony-stimulating factor (M-CSF), VEGF, IL1β, and also TLR4 – a transmembrane receptor, the activation of which leads to the production of pro-inflammatory cytokines (Furman et al., 1996; Jiao et al., 2017). Activated astrocytes, also known as reactive astrocytes, form in response to injuries, diseases or infections in the central nervous system, undergoing morphological, molecular, and functional remodeling. These activated astrocytes can also have harmful effects on the central nervous system by augmenting the inflammatory response in neurodegeneration and brain injury (Liddelow and Barres, 2017).
ROS modulate cellular mechanisms and lead to various cell damages and the production of pro-inflammatory cytokines that contribute to brain aging (Nakano et al., 2005; Molinari et al., 2019). 1,25-dihydroxyvitamin D3 added to astrocytes exposed to ROS improved mitochondrial functions, reduced oxidative stress and amyloid precursor protein formation, decreased activity of p53 and increased cell viability (Molinari et al., 2019). Signaling pathways that play a crucial role in regulating the survival of brain cells are ERK/MAPK and phosphoinositide 3 kinase (PI3K)/AKT pathways. Molinari et al. (2019) showed that 1,25-dihydroxyvitamin D3 enhanced ERK and AKT activity in astrocytes exposed to ROS. Moreover, 1,25-dihydroxyvitamin D3 administration was asscociated with enhanced proteinkinase A (PKA) phosphorylation, which is an important anti-inflammatory marker (Dwidedi et al., 2011; Molinari et al., 2019).
1,25-dihydroxyvitamin D3 also prevented mitochondrial dysfunction and improved astrocyte viability in astrocytes exposed to rotenone. Beneficial effects of 1,25-dihydroxyvitamin D3 included the decrease of ROS levels and expressions of NFkβ and NRF2, and the increase of glutathione (GSH) level (de Siqueira et al., 2023).
Iron is known to accumulate in the brain during normal aging, especially in neurodegenerative diseases, iron can be stored in excess (Ward et al., 2014). Iron accumulation is usually associated with oxidative stress and cellular damage and can also influence the production, accumulation, and aggregation of amyloid precursor protein (Ward et al., 2014; Molinari et al., 2019). 1,25-dihydroxyvitamin D3 was able to reduce oxidative stress induced by catalytic iron in astrocytes, decreased activity of p53 and led to increased viability of astrocytes exposed to catalytic iron. astrocytes treated with 1,25-dihydroxyvitamin D3 stored significantly less iron than astrocytes non-treated with 1,25-dihydroxyvitamin D3 (Molinari et al., 2019). Molinari et al. also observed that the effect of 1,25-dihydroxyvitamin D3 on astrocytes was enhanced by cotreatment with α-lipoic acid (50 μM), which belongs to important antioxidants (Molinari et al., 2019; Grasso et al., 2014).
Regarding the regulation of steroid synthesis, 1,25-dihydroxyvitamin D3 suppressed activity and mRNA expression of cytochrome-P450 17α-hydroxylase (CYP17A1) and 3β-hydroxysteroid dehydrogenase (3β-HSD). The effect of 1,25-dihydroxyvitamin D3 on mRNA expression was considerably stronger (Emanuelsson et al., 2018). CYP17A1 is required to form sex hormones and 3β-HSD is important in all basic steroidogenic pathways (Emanuelsson et al., 2018; Labrie et al., 1992).
Microglia are resident macrophages of the central nervous system, playing a crucial role in brain development and overall brain health. Microglia continuously survey the central nervous system environment, sensing changes in their microenvironment. Upon inflammatory and pathophysiological stimuli microglia can be transform into activated microglia producing pro-inflammatory cytokines (Borst et al., 2021). Sustained and strongly activated microglia are known to induce neuronal damage, potentially contributing to the development of neurodegenerative diseases (Borst et al., 2021; Hur et al., 2014).
However, vitamin D has been detected to suppress pro-inflammatory responses of microglia and favour anti-inflammatory responses of microglia (Fig. 8).
Activated microglia treated with 25-dihydroxyvitamin D3, as well as with 1,25-dihydroxyvitamin D3 expressed less pro-inflammatory cytokines IL6, interleukin-12 (IL12) and TNFα, and more anti-inflammatory cytokine interleukin-10 (IL10) (Boontanrart et al., 2016). IL10 is known to reduce the expression of pro-inflammatory cytokines by inducing the suppressor of cytokine signaling 3 (SOCS3) (Qin et al., 2006). Boontanrart et al (2016) observed that both 25-dihydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 increased the expression of SOCS3 in activated microglia. Furthermore, it has been revealed that 1,25-dihydroxyvitamin D3 increased the expression of SOCS3 in an IL10-dependent manner (Boontanrart et al., 2016).
Similar results have been obtained by culturing activated microglia in medium from neurons treated with 1,25-dihydroxyvitamin D3. These microglia expressed more IL34, arginase 1 (ARG1) and HMOX1 associated with anti-inflammatory microglia and less IL6, NADPH oxidase 2 (NOX2) and major histocompatibility complex II (MHCII), which are associated with pro-inflammatory microglia. IL34 is considered to be a survival factor for microglia. However, blocking of IL34 mRNA had reverse effect only on IL6 expression (Lee et al., 2020).
Vitamin D also leads to reduced production of NO and inhibition of MAPKs in LPS-stimulated microglia (Hur et al., 2014; Dulla et al., 2016). MAPK cascade is included in the downstream signaling pathways activated by LPS-stimulation of TLR in microglia (Lampron et al., 2013). 1,25-dihydroxyvitamin D3 significantly attenuated phopshorylation of ERK1/2 – a clasical type of MAPKs in LPS-stimulated microglia. In another study, 25-dihydroxyvitamin D3 inhibited phosporylation of p38 – a type of MAPK activated mainly in stress conditions (Hur et al., 2014). Moreover, translocation of p65 – a subunit of NFκβ was inhibited by 1,25-dihydroxyvitamin D3 in LPS-stimulated microglia (Dulla et al., 2016). NFκβ is recruited in response to TLR stimulation by LPS and mediates the expression of various pro-inflammatory cytokines (Kopitar-Jerala, 2015).
Vitamin D has been also observed to play an anti-inflammatory role after stimulation of microglia by Staphylococcal enterotoxin B (SEB). SEB is an enterotoxin produced by the gram-positive bacteria Staphylococcus aureus and functions as a superantigen, initiating inflammation (Yang et al., 2013). SEB is able to increase expression of pro-inflammatory cytokine TNFα in microglia. 1,25-dihydroxyvitamin D3 abrogated this effect of SEB on TNFα (He et al., 2017).
Recently, heptapeptide of renin-angiotensin system – angiotensin (1–7) has been discovered. Angiotensin (1–7) has protective effects against inflammation and oxidative damage through binding with Mas receptor (MASR), probably counteracting the deleterious effects of ACE/angiotensin II/Angiotensin II receptor type 1 (AT1) pathway. Angiotensin (1–7) formation is catalyzed by angiotensin converting enzyme 2 (ACE2) from angiotensin II (Gironacci et al., 2014). 1,25-dihydroxyvitamin D3 has been detected to enhance expression of ACE2 in microglial BV2 cells and also expression of MASR in microglial BV2 cells cotreated with angiotensin II. Further, 1,25-dihydroxyvitamin D3 attenuated angiotensin-II-induced expression of NOX2, phosphorylation of p47, as well as the activity of NADPH-oxidase in microglial BV2 cells. Subsequently, angiotensin II-induced formation of ROS was significantly decreased. Moreover, angiotensin-II-induced M1 polarization of microglial BV2 cells was shifted to M2 polarization after addition of 1,25-dihydroxyvitamin D3. All these protective effects of 1,25-dihydroxyvitamin D3 were depended on MASR (Cui et al., 2019). M1 macrophages promote tissue inflammation, while M2 macrophages have anti-inflammatory effects and mediate tissue repair (Davies and Taylor, 2015).
Section snippets
Discussion and Conclusion
1,25-dihydroxyvitamin D3 has been shown to protect various cells against the detrimental effects of different kinds of stress. Briefly, endothelial cells were protected against hydrogene peroxide-induced stress, angiotensin-II-induced stress, radiation, high glucose and air pollution. VSMCs were protected against AGE-induced damage. cardiac cells resisted high glucose-induced stress. epithelial cells exhibited less damage induced by stressors such as arsenic, nitrogen mustard, radiation, iron, . . . . .
Some of the 158 References
- I. Ahmad et al. Toll-like receptor-4 deficiency enhances repair of UVR-induced cutaneous DNA damage by nucleotide excision repair mechanism J Invest Dermatol. (2014 Jun)
- G. Aust et al. Circulating Nampt and RBP4 levels in patients with carotid stenosis undergoing carotid endarterectomy (CEA) Clin Chim Acta. (2011 Jun 11)
- C.M. Best et al. Vitamin D in human serum and adipose tissue after supplementation Am J Clin Nutr. (2021 Jan 4)
M. Boontanrart et al.
Vitamin D3 alters microglia immune activation by an IL-10 dependent SOCS3 mechanism
J Neuroimmunol.
(2016 Mar)
K. Borst et al.
microglia: Immune and non-immune functions
Immunity.
(2021 Oct 12)
L. Cao et al.
A selective requirement for 53BP1 in the biological response to genomic instability induced by Brca1 deficiency
Mol Cell.
(2009 Aug 28)
A. Chaiprasongsuk et al.
Protective effects of novel derivatives of vitamin D3 and lumisterol against UVB-induced damage in human keratinocytes involve activation of Nrf2 and p53 defense mechanisms
Redox Biol.
(2019 Jun)
J.C. Chambard et al.
ERK implication in cell cycle regulation
Biochim Biophys Acta.
(2007 Aug)
P. Chen et al.
Effects of Combination of 1,25(OH) 2D 3 and TLR-4 Inhibitor on the Damage to HaCaT Cells Caused by UVB Irradiation
Biomed Environ Sci.
(2022 Nov 20)
S. Chen et al.
A role for the cell cycle phosphatase Cdc25a in vitamin D-dependent inhibition of adult rat vascular smooth muscle cell proliferation
J Steroid Biochem Mol Biol.
(2010)
D.B. Cines et al.
endothelial cells in physiology and in the pathophysiology of vascular disorders
Blood.
(1998 May 15)
C. Cui et al.
Vitamin D receptor activation regulates microglia polarization and oxidative stress in spontaneously hypertensive rats and angiotensin II-exposed microglial cells: Role of renin-angiotensin system
Redox Biol.
(2019 Sep)
Y. Dwivedi et al.
Elucidating biological risk factors in suicide: role of protein kinase A
Prog Neuropsychopharmacol Biol Psychiatry.
(2011 Jun 1)
I. Emanuelsson et al.
Expression and regulation of CYP17A1 and 3β-hydroxysteroid dehydrogenase in cells of the nervous system: Potential effects of vitamin D on brain steroidogenesis
Neurochem Int.
(2018 Feb)
J.C. Fleet
Rapid, membrane-initiated actions of 1,25 dihydroxyvitamin D: what are they and what do they mean?
J Nutr.
(2004 Dec)
S.E. Gould et al.
BMP-7 regulates chemokine, cytokine, and hemodynamic gene expression in proximal tubule cells
Kidney International.
(2002)
J.J. Green et al.
Calcitriol modulation of cardiac contractile performance via protein kinase C
J Mol Cell Cardiol.
(2006 Aug)
X. Guo et al.
1,25-Dihydroxyvitamin D attenuates diabetic cardiac autophagy and damage by vitamin D receptor-mediated suppression of FoxO1 translocation
J Nutr Biochem.
(2020 Jun)
J.J. Hill et al.
The myostatin propeptide and the follistatin-related gene are inhibitory binding proteins of myostatin in normal serum
Journal of Biological Chemistry.
(2002)
T. Inoue et al.
1,25-Dihydroxyvitamin D3 stimulates 45Ca2+-uptake by cultured vascular smooth muscle cells derived from rat aorta
Biochem Biophys Res Commun.
(1988)
Y. Itoh
Metalloproteinases in Rheumatoid Arthritis: Potential Therapeutic Targets to Improve Current Therapies
Prog Mol Biol Transl Sci
(2017)
S.P. Jackson et al.
Thromboinflammation: Challenges of therapeutically targeting coagulation and other host defense mechanisms
Blood
(2019)
H. Kawashima
1,25-Dihydroxyvitamin D3 stimulates Ca-ATPase in a vascular smooth muscle cell line
Biochem Biophys Res Commun.
(1988)
E. Kuhn et al.
Ovarian Brenner tumour: a morphologic and immunohistochemical analysis suggesting an origin from fallopian tube epithelium
Eur J Cancer.
(2013 Dec)
F. Labrie et al.
Structure and tissue-specific expression of 3 beta-hydroxysteroid dehydrogenase/5-ene-4-ene isomerase genes in human and rat classical and peripheral steroidogenic tissues
J Steroid Biochem Mol Biol.
(1992 Mar)
V. Landel et al.
Differential expression of vitamin D-associated enzymes and receptors in brain cell subtypes
J Steroid Biochem Mol Biol.
(2018 Mar)
A. Lampron et al.
Innate immunity in the CNS: redefining the relationship between the CNS and Its environment
Neuron.
(2013 Apr 24)
S.B. Larsen et al.
epithelial cells: liaisons of immunity
Curr Opin Immunol.
(2020 Feb)
S.A. Liddelow et al.
Reactive astrocytes: Production, Function, and Therapeutic Potential
Immunity.
(2017 Jun 20)
T.E. Lipkie et al.
Quantification of vitamin D and 25-hydroxyvitamin D in soft tissues by liquid chromatography-tandem mass spectrometry
J Chromatogr B Analyt Technol Biomed Life Sci.
(2013 Aug)
J.J. McMurray et al.
The rise and fall of myotrophin in heart failure
J Am Coll Cardiol.
(2003 Aug 20)
S. Alarifi et al.
Oxidative stress contributes to cobalt oxide nanoparticles-induced cytotoxicity and DNA damage in human hepatocarcinoma cells
Int J Nanomedicine.
(2013)
J. Albarrán-Juárez et al.
Piezo1 and g(q)/g(11) promote endothelial inflammation depending on flow pattern and integrin activation
J. Exp. Med.
(2018)
J.N. Artaza et al.
Vitamin D reduces the expression of collagen and key profibrotic factors by inducing an antifibrotic phenotype in mesenchymal multipotent cells
J Endocrinol.
(2009)
T. Asahara et al.
endothelial progenitor cells for vascular regeneration
J Hematother Stem Cell Res.
(2002)
G.C. Blobe et al.
Role of transforming growth factor beta in human disease
N Engl J Med
(2000)
C. Burucoa et al.
Epidemiology of Helicobacter pylori infection
Helicobacter.
(2017 Sep)
S. Cataldi et al.
Effect of Vitamin D in HN9.10e Embryonic Hippocampal Cells and in Hippocampus from MPTP-Induced Parkinson's Disease Mouse Model
Front Cell Neurosci.
(2018 Feb)
S. Cataldi et al.
The Effect of Vitamin D3 and Silver Nanoparticles on HaCaT Cell Viability
Int J Mol Sci.
(2022 Jan 26)
G. Cimmino et al.
Vitamin D Inhibits IL-6 Pro-Atherothrombotic Effects in Human endothelial Cells: A Potential Mechanism for Protection against COVID-19 Infection?
J Cardiovasc Dev Dis.
(2022 Jan 13)
Z. Chen et al.
Brain Energy Metabolism: astrocytes in Neurodegenerative Diseases
CNS Neurosci Ther.
(2023 Jan)
A. Clerico et al.
cardiac endocrine function is an essential component of the homeostatic regulation network: physiological and clinical implications
Am J Physiol Heart Circ Physiol.
(2006 Jan)
P.L.F. Costa et al.
Transcriptomic Response to 1,25-Dihydroxyvitamin D in Human fibroblasts with or without a Functional Vitamin D Receptor (VDR): Novel Target Genes and Insights into VDR Basal Transcriptional Activity
Cells.
(2019 Apr 5)
P. Cui et al.
Vitamin D Attenuates Hypoxia-Induced Injury in Rat Primary Neuron Cells through Downregulation of the Dual Oxidase 1 (DUOX1) Gene
Med Sci Monit.
(2020 Jul)
A. Daiou et al.
Developmental and regenerative biology of cardiomyocytes
Int J Dev Biol.
(2022;66(1–2-3):59–75.)
L.C. Davies et al.
Tissue-resident macrophages: then and now
Immunology.
(2015 Apr)
J. Deguine et al.
MyD88: a central player in innate immune signaling
F1000Prime Rep.
(2014 Nov)
B. Diffey Climate change, ozone depletion and the impact on ultraviolet exposure of human skin Phys Med Biol (2004)
J. Dong et al. Calcitriol protects renovascular function in hypertension by down-regulating angiotensin II type 1 receptors and reducing oxidative stress Eur Heart J. (2012 Dec)
Y.A. Dulla et al. Regulatory Mechanisms of Vitamin D3 on Production of Nitric Oxide and Pro-inflammatory Cytokines in microglial BV-2 Cells Neurochem Res. (2016 Nov)
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Note: There are 5,300 types of cells in the mouse brain as of Dec 2023
- indentified individual cells based on which genes they are expressing.
- more than 3,300 different types of neurons
- "Until just a few years ago, based on analyses of our tissues under microscopes, most researchers believed that the approximately 36 trillion cells in an adult human body could be categorized into only a few hundred distinct types: three types of muscle cells, epithelial and fibroblast cells in the skin, various kinds of neurons in the nervous system, endothelial cells lining the blood vessels, and so on. But the successes of the Human Genome Project invited researchers to look at our cellular makeup more deeply, at a genetic level."