Metabolic syndrome (MetS) is defined with well-determined metabolic alterations ^[1][2][34,35], which serve as a favorable breeding ground and characteristic indicators for many diseases, e.g., obesity, type 2 diabetes (T2DM), CVD, hypertension, cancers, and mental disorders ^{[3][4][5][6][7][8]}[138,139,140,141,142,143]. It has been shown that vitamin D deficiency is associated with T2DM development ^[9][10][144,145], and its level is negatively correlated with the disease state and positively with insulin sensitivity ^[11][146]. ThWe researchers detailed above that vitamin D and SIRT1 have a significant role in a healthy lipid metabolism, as well as in the healthy relationship between metabolic/energy homeostasis and the immune system, where both are linked to regulatory molecules. Indeed, decreased vitamin D is associated with MetS as a whole, and with some components, such as obesity, increased BMI, dyslipidemia, increased blood pressure, and altered insulin and glucose metabolism ^[12][13][25,147]. Thus, vitamin D and SIRT1 may play a beneficial role in the prevention and complementary treatment of metabolic syndrome, since both are key molecules in metabolic/energy sensing and in immune regulation ^[1][2][34,35].

Vitamin D has important roles in cardiovascular health, as was mentioned above, and, in addition to other risk factors, such as smoking, high cholesterol, hypertension, obesity, and diabetes, vitamin D deficiency is connected to the occurrence of cardiovascular diseases (CVD) ^[14][15][16][148,149,150]. Although observational studies, preclinical studies, and randomized control trials all showed the beneficial effect of vitamin D on vascular and cardiac functions, linear Mendelian randomization and large clinical trials failed to demonstrate significant benefits on CKD and high-risk CVD populations ^[17][151]. However, the vast majority of these trials of vitamin D supplementation did not restrict the study populations to individuals with vitamin D deficiency and did not follow-up the changes of vitamin D level during the trial, correlating the end points with these changes ^[18][152]. Additionally, nonlinear Mendelian randomization found significant benefits of vitamin D supplementation on CVD risks ^[19][153]. However, the significant positive effect of vitamin D is widely accepted only on the reduction of CVD-related mortality ^[20][21][22][19,20,23] and all-cause mortality ^[23][24][25][18,21,22]. The micro-RNA mir34a promotes calcification in vascular smooth muscle cells by downregulation of SIRT1 and Axl ^[26][64]. An appropriate level of SIRT1 decelerates vascular calcification by affecting several osteogenic processes, including the reversal of osteogenic phenotypic transdifferentiation in vascular smooth muscle cells, upregulation of eNOS and FoxOs, activation of antioxidant properties, and enhancement of adiponectin release from perivascular adipose tissue ^[27][16]. Resveratrol and SIRT1 activators improve cardiovascular health by improving systolic blood pressure and mean arterial pressure, decreasing triglyceride, leptin, inflammation level (Il-6, IL-8, TNFα and CRP) ^[28][154], and by maintaining endothelial function and by ameliorating events related to endothelial dysfunction, e.g., impaired vasorelaxation, eNOS uncoupling, leukocyte adhesion, endothelial senescence, and endothelial mesenchymal transition ^[29][155].

Kidney function is indispensable for the synthesis of calcitriol, which allows intestinal calcium absorption in order to maintain extracellular calcium as well as phosphate levels. Therefore, the loss of kidney function leads to elevation of parathyroid hormone (PTH) and, eventually, induces hyperplastic parathyroid growth to re-establish calcium and phosphate balance ^[30][156]. The expression, activity, and regulation of 1α-hydroxylase, which is induced by PTH, hypocalcemia, and hypophosphatemia and repressed by FGF23, hyperphosphatemia, hypercalcemia, and calcitriol, is impaired in CKD ^[31][157]. The complex of calcidiol and vitamin D-binding protein (25(OH)D₃/DBP) is filtered through the glomerulus from the circulation and is actively endocytosed into the proximal tubular cells by megalin, a member of the LDL receptor superfamily in the apical membrane ^[32][158]. Although PTH is upregulated in CKD, it is insufficient to restore calcitriol synthesis, as the elevated calcium and phosphate levels induce FGF23, metabolic acidosis, and PTH fragments directly inhibiting even non-renal 1α-hydroxylase expression and activity ^[33][159]. Additionally, normal kidney function is essential in the maintenance of the serum level of 25(OH)D₃ for local activation by non-renal 1α-hydroxylase and the autocrine/paracrine actions of the VDR ^[30][156]. Since, in CKD, both the glomerular filtration rate (GFR) and megalin content are lower, the amount of ultrafiltrated 25(OH)D₃/DBP is also lower. However, a sufficient amount of ultrafiltrated 25(OH)D₃/DBP is required both for its recycling into the circulation to act as a substrate of non-renal conversion and for conversion to calcitriol in the kidney. Therefore, a vicious cycle develops ^[34][35][36][160,161,162]. Consequently, the correction of the 25(OH)D₃ deficiency is necessary and sufficient in hemodialysed, and more so in anephric patients, to prevent calcitriol deficiency at an early stage of kidney disease. Moreover, epidemiological studies suggest that vitamin D deficiency is associated more strongly than calcitriol deficiency with a higher risk of disease progression and death in CKD ^[30][156]. Of note, the age-dependent decline of renal function observed over the age of 60 resulted in impaired postprandial calcium excretion. Therefore, the daily intake of vitamin D should be considered in light of this physiological decline, in order to prevent vitamin D toxicity in relation to abnormal serum and vascular calcium and phosphate homeostasis ^[37][63].

As the liver and the kidney play crucial roles in the maintenance of the active vitamin D level, liver and kidney transplant recipients more frequently develop vitamin D deficiency ^[38][39][163,164]. Additionally, these patients have a higher ratio of vitamin D deficiency-associated comorbidities, such as fractures, diabetes, and infections ^[40][41][165,166]. Since vitamin D regulates the immune system, alteration in its level affects the outcome of allografts, e.g., acute cellular rejection (ACR) and infection ^[42][39]. Similarly, several other studies reported that transplanted patients have a higher risk of infections ^{[43][44][45][46][47]}[36,37,167,168,169] and rejections ^[48][49][38,170]. Thus, vitamin D supplementation and tight follow-up of its level is important in transplant recipient patients ^[42][39].

1,25(OH)₂D₃/VDR signaling is implicated in human innate and adaptive immune response ^[50][51][82,171], but it appears to be species-specific and cell-specific ^[52][42]. Based on mouse models, the beneficial effects of vitamin D are suggested in allergies, autoimmune and inflammatory diseases such as inflammatory bowel disease (IBD) ^[53][54][55][172,173,174], multiple sclerosis (MS) ^[56][57][175,176], autoimmune encephalomyelitis ^[58][177], diabetes ^[59][60][61][178,179,180], systemic lupus erythematosus (SLE) ^[62][181], rheumatoid arthritis (RA) ^[50][82], and asthma ^[63][182]. Prospective observational studies have found that higher vitamin D level is associated with lower rates of T2DM ^[64][183], and animal studies suggest that vitamin D promotes β-cell biosynthetic capacity and conversion of proinsulin to insulin ^[65][184]. Additionally, vitamin D increases insulin sensitivity, possibly through increased Ca²⁺ influx, stimulated insulin receptor expression, activation of GLUT-4 glucose transporter, and activation of peroxisome proliferator-activated receptor delta (PPAR-δ) ^[64][66][183,185]. However, RCTs failed to prove the positive effect of vitamin D supplementation in risk reduction of T2DM, although patients were not stratified by vitamin D deficiency and the levels of vitamin D were not continuously monitored during the follow-up, similarly to other RCTs in relation to other diseases ^[67][68][186,187]. A meta-analysis of observational studies found significantly decreased vitamin D levels in SLE patients compared to healthy subjects; therefore, vitamin D supplementation with regular monitoring is suggested as part of the health management of SLE patients ^[62][181]. Vitamin D induces BCAA catabolism in macrophages and leads to mTOR inhibition; however, parallel to this, it induces the expression of amino acid transporter SLC7A5 in macrophages but not in epithelial cells ^[52][42]. SLC7A5 expression level in macrophages positively correlated with clinical parameters and inflammatory conditions in RA patients, and its pharmacological blockade significantly reduced IL-1β level, a downstream target of leucin-mediated mTORC1, the signaling contributor of proinflammatory cytokine production ^[69][88]. These findings seem contradictory; however, it is possible that appropriate vitamin D levels simultaneously increase the uptake of amino acids and inhibit mTOR while SLC7A5 then fuels normal anabolic pathways. In contrast, vitamin D in a low level is likely not able to properly coordinate this metabolic network. Additionally, as synovial T cells are relatively insensitive to 1,25(OH₂)D₃ compared to circulating blood immune cells, treatment with vitamin D is more potent for enhancing a localized reaction in combination with other RA therapies ^[70][71][188,189]. Moreover, these seemingly contradictory results may have originated in the heterogeneity of this disease; of note, few studies have addressed the analysis of RA subgroups and stages ^[50][82]. Although the specific benefits of vitamin D supplementation for treatment and prevention of RA are less accepted because of inconsistent results in randomized clinical trials, conceivable benefits for the improvement of disease of RA, SLE, and osteoarthritis have been reported in meta-analyses ^[72][190]. Thus, it is advisable for patients with RA to maintain a serum 25(OH)D₃ level of at least 30 ng/mL (75 nmol/mL) to prevent osteomalacia, secondary osteoporosis, and fractures ^[72][190]. In asthmatic patients, a significant reduction of exacerbation was associated with vitamin D supplementation; this was more pronounced in a subgroup of patients, where vitamin D insufficiency (<30 ng/mL) was diagnosed ^[63][182].

In relation to cancer cells, vitamin D promoted epithelial differentiation ^[73][191] and, consequently, decreased cell proliferation and differentiation in many cancer types, both by direct and indirect pathways ^[74][75][76][32,192,193]. Vitamin D induced apoptosis ^[77][194] and markedly modulated methylation, which leaded to gene repression by histone modification of the DNA ^[78][195]. Vitamin D upregulated p21^WAF/CIP and p27^KIP inhibitors of cell cycle arrest in colorectal cancer cells, and since the promoter region of p21 contains vitamin D response elements, calcitriol can directly regulate p21 transcription ^[79][196]. The promotion of VDR/β-catenin binding reduced the amount of β-catenin binding to T cell factor (TCF), which induces expression of E-cadherin as well as extracellular Wnt inhibitor DKK-1 ^[80][81][82][197,198,199]. CYP24A1 mitochondrial protein expression, which determines the half-life of 1,25(OH₂)D₃, is regulated both by its methylation status and by vitamin D. Its inhibition facilitates the antiproliferative effect of vitamin D on the downregulation of the WNT/β-catenin pathway and on the inhibition of targeted genes, e.g., c-Myc, TCF1, and LEF1 ^[83][200]. Vitamin D suppressed antiapoptotic protein expression while inducing proapoptotic protein expression on colorectal cancer cells, but not in normal colon epithelia, where it inhibited proapoptotic signaling by the downregulation of PUMA ^[82][199]. Vitamin D diminished the expression of HIF-1, VEGF, as well as IL-8, which are all important angiogenic factors ^[84][201]. Vitamin D-induced Nrf2, at a low level, can protect cells from carcinogenic ROS and inflammation, but its constitutive activation caused by mutations or pro-oncogenic signaling can protect cancer cells from cytotoxic effects of chemotherapy, creating chemoresistance ^[82][85][87,199]. Since there are several vitamin D target genes regulating proliferation, migration, invasiveness, differentiation, angiogenesis, extracellular matrix, or immunomodulation of cancer cell, this highlights the possible impact of an appropriate level of vitamin D on its anticancer role ^[74][32]. In a meta-analysis of cohort studies, a highly significant linear dose–response relationship was found between the overall survival of breast cancer patient and circulating 25(OH)D₃ level ^[24][21]. Similarly, other prospective and retrospective epidemiological studies reported an association between a 25(OH)D₃ level below 20 ng/mL and a 30–50% increased risk of colon, prostate, and breast cancer and higher mortality ^[86][85]. A systematic review found that vitamin D supplementation induced a shift in colon microbiome composition and increased its diversity ^[73][191]. In renal cancer, VDR expression is a prognostic marker and its higher expression predicted a better survival rate ^[87][202]. Resveratrol, a natural antioxidant polyphenol and dietary component which upregulates SIRT1, induced apoptosis through activation of p53 by the PI3K pathway, parallel with the inhibition of S6 ribosomal protein in breast cancer cells ^[88][203]. This dietary component inhibits estrogen-induced breast carcinogenesis as well through induction of the Nrf2-mediated pathway ^[89][90][204,205]. Moreover, it reverses doxorubicin-chemoresistance by the upregulation of the SIRT1/β-catenin signaling pathway ^[91][206]. Studies investigating SIRT1/vitamin D/FOXO interaction suggest a link between VDR, SIRT1, and FOXO3 function, and provide a molecular basis for the cancer chemoprevention actions of 1,25(OH₂)D₃ ^[92][93][94][207,208,209]. Resveratrol suppressed ovarian cancer growth and liver metastasis by inhibiting glycolysis and targeting the AMPK/mTOR pathway ^[95][210]. In addition to the beneficial effects of resveratrol on cancer cells, by inducing apoptosis under hypoxia while not affecting normal cells, it also attenuated their migratory properties through downregulation of hypoxia-induced LPA and subsequent activation of HIF-1α and VEGF signaling ^[96][92]. Resveratrol, in a cell and organ specific manner, can induce or inhibit hypoxia and ROS production, but both ultimately resulted in cell death in the cancer cells ^[96][92]. Additionally, resveratrol suppressed the production of extracellular matrix degrading and remodelling of MMP-2 and MMP-9 ^[97][211]. Resveratrol reduces the level of TNF-α, IL-1β, and IL-6 proinflammatory cytokines and suppresses STAT3 and NFκB signaling ^[98][99][212,213]. Moreover, it modulates non-cancer cells in the tumor microenvironment (e.g., CAFs, macrophages, T cells, and endothelial cells), facilitating their tumor-suppressive effects ^[96][92]. Resveratrol was suggested as potential alternative to NSAID and selective COX inhibitor in CRC chemoprevention, demonstrating no obvious side effects even after daily oral administration of 5 g/day for 14 days, as reported in a clinical trial ^[100][214]. Finally, a dosage ranging from 0–200 µM in combination with FOLFOX (10 µM) was sufficient to enhance antitelomeric and apoptotic potential through resensitization to chemotherapy ^[85][101][87,215].