Targeting the Hallmarks of Aging with Vitamin D: Starting to Decode the Myth.

Aging is the result of several complex and multifactorial processes, where several agents contribute to an increased intrinsic vulnerability and susceptibility to age-related diseases. The hallmarks of aging are a set of biological mechanisms that are finely regulated and strictly interconnected, initiating or contributing to biological changes and anticipating several age-related diseases. The complex network of cellular and intercellular connections between the hallmarks might represent a possible target for the research of agents with pleiotropic effects. Vitamin D (VitD) is known to have a positive impact not only on muscle and bone health but also on several extra-skeletal districts, due to the widespread presence of Vitamin D Receptors (VDRs). VitD and VDR could be molecules potentially targeting the hallmarks of the aging network. To date, evidence about the potential effects of VitD on the hallmarks of aging is scarce in humans and mainly based on preclinical models. Although underpowered and heterogeneous, in-human studies seem to confirm the modulatory effect of VitD on some hallmarks of aging and diseases. However, more investigations are needed to clarify the pleiotropic effects of VitD and its impact on the hallmark of aging, hopefully highlighting the courses for translational applications and potential clinical conclusions.

The effect of vitamin D2 supplementation on vitamin D levels in humans: A time and dose-response meta-analysis of randomized controlled trials.

BACKGROUND: Inconsistencies exist regarding the influence of vitamin D2 (ergocalciferol) supplementation on serum vitamin D levels. These inconsistencies could be attributed to numerous factors, such as dosage, baseline vitamin D levels, and duration of intervention. Hence, this dose-response meta-analysis of randomized controlled trials was conducted to assess the efficacy of vitamin D2 supplementation on vitamin D levels. METHODS: Relevant studies were searched in PubMed/Medline, Web of Science, Embase, and Scopus, from their inception to 3 January 2023. Variable alterations were considered to calculate the pooled weighted mean difference (WMD) with 95% confidence interval (CI) using the random effects model. RESULTS: Pooled results from 33 study arms demonstrated that Vitamin D2 treatment significantly increases total vitamin D concentrations (WMD: 11.47 ng/mL, 95 %CI: 9.29 to 13.64, p < 0.001), 25(OH)D2 concentrations (WMD: 11.40 ng/mL, 95 %CI: 4.72 to 18.09, p = 0.001), and 1,25(OH)D concentrations (WMD: 5.61 ng/mL, 95 %CI: 0.74 to 10.48, p = 0.024), but decreases 25(OH)D3 concentrations (WMD: -4.63 ng/mL, 95 %CI: -6.46 to -2.81, p < 0.001). In subgroup analyses, increase in total vitamin D concentrations was more significant in vitamin D2 doses >2000 IU/day (WMD: 13.82 ng/mL), studies with duration ≤12 weeks (WMD: 12.53 ng/mL), participants aged ≥60 years (WMD: 14.40 ng/mL), and trials with basal 25(OH)D concentrations <20 ng/mL (WMD: 11.47 ng/mL). CONCLUSIONS: This meta-analysis indicates that the supplementation of vitamin D2 significantly increases the serum concentrations of total vitamin D, 25(OH)D2, and 1,25(OH)D, but decreases 25(OH)D3 concentrations. Careful consideration of patient characteristics, dosage, and treatment duration is recommended for vitamin D2 supplementation.

Effects of antioxidant vitamins (A, D, E) and trace elements (Cu, Mn, Se, Zn) administration on gene expression, metabolic, antioxidants and immunological profiles during transition period in dromedary camels.

BACKGROUND: Nutrition has a primary role for optimum expression of genetic potential, and most of the farmers have limited resources of green fodder. Hence, a fat-soluble vitamin, especially vitamin A and E and trace elements remained most critical in the animal's ration and affects their productive and reproductive performance adversely. Animals cannot be able to produce these vitamins in their bodies; hence, an exogenous regular supply is needed to fulfil the physiological needs and to maintain high production performance. This study elucidated effects of antioxidant vitamins (A, D, E) and trace elements (Cu, Mn, Se, Zn) administration on gene expression, metabolic, antioxidants and immunological parameters in dromedary camels during transition period. RESULTS: At 0 day, there were no appreciable differences in the expression patterns of the metabolic (IGF-I, ACACA, SCD, FASN, LPL, and BTN1A1) genes between the control and treatment groups, despite lower levels. A substantial variation in the mRNA levels of SOD1, SOD3, PRDX2, PRDX3, PRDX4, PRDX6, and AhpC/TSA was observed between the control and treatment groups, according to the antioxidant markers. In comparison to the control group, the treatment group displayed a significant up-regulation at 0 and 21 days. The treatment and control groups exhibited substantial differences in the mRNA values of IL-1α, IL-1ß, IL-6, and TNFα, as indicated by immunological markers. In comparison to the control group, there was a noticeable down-regulation in the treatment group at 0 and + 21 days. But IL10 produced the opposite pattern. No significant difference was observed in glucose, cholesterol, triglyceride, HDL, total protein, NEFA, BHBA, cortisol and IGF-1 levels between control and treatment group. The activity of serum GPx, SOD and TAC was significantly affected by time and treatment x time in supplemented groups as compared with control group. IL-1, IL-1, IL-6, and TNF were noticeably greater in the control group and lower in the treatment group. Additionally, in all groups, the concentration of all pro-inflammatory cytokines peaked on the day of delivery and its lowest levels showed on day 21 following calving. The IL-10 level was at its peak 21 days prior to calving and was lowest on calving day. CONCLUSION: The results demonstrated a beneficial effect of antioxidant vitamins and trace elements on the metabolic, antioxidant and immunological markers in dromedary camels throughout their transition period.

Fibroblast Growth Factor Receptor Inhibitors Decrease Proliferation of Melanoma Cell Lines and Their Activity Is Modulated by Vitamin D.

Regardless of the unprecedented progress in malignant melanoma treatment strategies and clinical outcomes of patients during the last twelve years, this skin cancer remains the most lethal one. We have previously documented that vitamin D and its low-calcaemic analogues enhance the anticancer activity of drugs including a classic chemotherapeutic-dacarbazine-and an antiangiogenic VEGFRs inhibitor-cediranib. In this study, we explored the response of A375 and RPMI7951 melanoma lines to CPL304110 (CPL110), a novel selective inhibitor of fibroblast growth factor receptors (FGFRs), and compared its efficacy with that of AZD4547, the first-generation FGFRs selective inhibitor. We also tested whether 1,25(OH)2D3, the active form of vitamin D, modulates the response of the cells to these drugs. CPL304110 efficiently decreased the viability of melanoma cells in both A375 and RPMI7951 cell lines, with the IC50 value below 1 µM. However, the metastatic RPMI7951 melanoma cells were less sensitive to the tested drug than A375 cells, isolated from primary tumour site. Both tested FGFR inhibitors triggered G0/G1 cell cycle arrest in A375 melanoma cells and increased apoptotic/necrotic SubG1 fraction in RPMI7951 melanoma cells. 1,25(OH)2D3 modulated the efficacy of CPL304110, by decreasing the IC50 value by more than 4-fold in A375 cell line, but not in RPMI7951 cells. Further analysis revealed that both inhibitors impact vitamin D signalling to some extent, and this effect is cell line-specific. On the other hand, 1,25(OH)2D3, have an impact on the expression of FGFR receptors and phosphorylation (FGFR-Tyr653/654). Interestingly, 1,25(OH)2D3 and CPL304110 co-treatment resulted in activation of the ERK1/2 pathway in A375 cells. Our results strongly suggested possible crosstalk between vitamin D-activated pathways and activity of FGFR inhibitors, which should be considered in further clinical studies.

The Vitamin C Enantiomers Possess a Comparable Potency in the Induction of Oxidative Stress in Cancer Cells but Differ in Their Toxicity.

The use of vitamin C (VC) in high doses demonstrates a potent tumor suppressive effect by mediating a glucose-dependent oxidative stress in Kirsten rat sarcoma (KRAS) mutant cancer cells. VC with arsenic trioxide (ATO) is a promising drug combination that might lead to the development of effective cancer therapeutics. Considering that a tumor suppressive effect of VC requires its high-dose administration, it is of interest to examine the toxicity of two enantiomers of VC (enantiomer d-optical isomer D-VC and natural l-optical isomer L-VC) in vitro and in vivo. We show that the combinations of L-VC with ATO and D-VC with ATO induced a similar cytotoxic oxidative stress in KrasG12D-expressing mutant cancer cells as indicated by a substantial increase in reactive oxidative species (ROS) production and depolarization of mitochondria. To examine the L-VC and D-VC toxicity effects, we administered high doses of D-VC and L-VC to CD1 mice and carried out an evaluation of their toxic effects. The daily injections of L-VC at a dose of 9.2 g/kg for 18 days were lethal to mice, while 80% of mice remained alive following the similar high-dose administration of D-VC. Following the drug injection courses and histopathological studies, we determined that a natural form of VC (L-VC) is more harmful and toxic to mice when compared to the effects caused by the similar doses of D-VC. Thus, our study indicates that the two enantiomers of VC have a similar potency in the induction of oxidative stress in cancer cells, but D-VC has a distinctive lower toxicity in mice compared to L-VC. While the mechanism of a distinctive toxicity between D-VC and L-VC is yet to be defined, our finding marks D-VC as a more preferable option compared to its natural enantiomer L-VC in clinical settings.

Antioxidant Metabolism Pathways in Vitamins, Polyphenols, and Selenium: Parallels and Divergences.

Free radicals (FRs) are unstable molecules that cause reactive stress (RS), an imbalance between reactive oxygen and nitrogen species in the body and its ability to neutralize them. These species are generated by both internal and external factors and can damage cellular lipids, proteins, and DNA. Antioxidants prevent or slow down the oxidation process by interrupting the transfer of electrons between substances and reactive agents. This is particularly important at the cellular level because oxidation reactions lead to the formation of FR and contribute to various diseases. As we age, RS accumulates and leads to organ dysfunction and age-related disorders. Polyphenols; vitamins A, C, and E; and selenoproteins possess antioxidant properties and may have a role in preventing and treating certain human diseases associated with RS. In this review, we explore the current evidence on the potential benefits of dietary supplementation and investigate the intricate connection between SIRT1, a crucial regulator of aging and longevity; the transcription factor NRF2; and polyphenols, vitamins, and selenium. Finally, we discuss the positive effects of antioxidant molecules, such as reducing RS, and their potential in slowing down several diseases.

A Blended Vitamin Supplement Improves Spatial Cognitive and Short-Term Memory in Aged Mice.

Although many types of antioxidant supplements are available, the effect is greater if multiple types are taken simultaneously rather than one type. However, it is difficult to know which type and how much to take, as it is possible to take too many of some vitamins. As it is difficult for general consumers to make this choice, it is important to provide information based on scientific evidence. This study investigated the various effects of continuous administration of a blended supplement to aging mice. In 18-month-old C57BL/6 mice given a blended supplement ad libitum for 1 month, spatial cognition and short-term memory in the Morris water maze and Y-maze improved compared with the normal aged mice (spontaneous alternative ratio, normal aged mice, 49.5%, supplement-treated mice, 68.67%, p < 0.01). No significant differences in brain levels of secreted neurotrophic factors, such as nerve growth factor and brain-derived neurotrophic factor, were observed between these two groups. In treadmill durability tests before and after administration, the rate of increase in running distance after administration was significantly higher than that of the untreated group (increase rate, normal aged mice, 91.17%, supplement-treated aged mice, 111.4%, p < 0.04). However, training had no reinforcing effect, and post-mortem serum tests showed a significant decrease in aspartate aminotransferase, alanine aminotransferase, and total cholesterol values. These results suggest continuous intake of a blended supplement may improve cognitive function and suppress age-related muscle decline.

The role of fat-soluble vitamins in efferocytosis.

Cell death and the efficient removal of dead cells are two basic mechanisms that maintain homeostasis in multicellular organisms. efferocytosis, which includes four steps recruitment, recognition, binding and signaling, and engulfment. Effectively and quickly removes apoptotic cells from the body. Any alteration in efferocytosis can lead to several diseases, including autoimmune and inflammatory conditions, atherosclerosis, and cancer. A wide range of dietary components affects apoptosis and, subsequently, efferocytosis. Some vitamins, including fat-soluble vitamins, affect different stages of efferocytosis. Among other things, by affecting macrophages, they are effective in the apoptotic cleansing of cells. Also, polyphenols indirectly intervene in efferocytosis through their effect on apoptosis. Considering that there are limited articles on the effect of nutrition on efferocytosis, in this article we will examine the effect of some dietary components on efferocytosis.

Effect of vitamin D3 supplementation on blood parameters and liver gene expression in female rats.

BACKGROUND: To better understand the molecular mechanism responsible for the therapeutic potential of vitamin D, we conducted an analysis of the liver transcriptomes of adult female rats. METHODS: Adult female rats (n = 18) were divided into three groups, receiving different doses of vitamin D: group I, 0; group II, 1000 U/kg; and group III, 5000 U/kg. Growth, body weight, the weight of main organs, blood haematological and biochemical parameters were evaluated. Gene expression in the liver were analyzed using RNA-seq and qPCR techniques. RESULTS: We observed a lower platelet count (p < 0,008) and a significantly greater (p < 0.02) number of WBCs in rats supplemented with 1000 U/kg than in rats from group III (5000 U/kg). Moreover, we noted a trend (p < 0.06) in total cholesterol concentration, suggesting a linear decrease with increasing doses of vitamin D. RNA-seq analysis did not reveal any differentially expressed genes with FDR < 0.05. However, GSEA revealed significant activation of a number of processes and pathways, including: "metallothionein, and TspO/MBR family", and "negative regulation of tumor necrosis factor production". qPCR analysis revealed significant upregulation of the Mt1, Mt2 and Orm1 genes in animals receiving high doses of vitamin D (p < 0.025, p < 0.025, and p < 0009, respectively). Moreover, Srebp2 and Insig2 were significantly lower in both experimental groups than in the control group (p < 0.003 and p < 0.036, respectively). CONCLUSIONS: Our results support the anti-inflammatory, anitioxidant and anticholesterologenic potential of vitamin D but suggest that high doses of vitamin D are needed to obtain significant results in this regard.

Opposing Effects of Nutritional Supply on Bone Health at Different Ages: Based on the National Health and Nutrition Examination Survey Database.

(1) Background: Nutrients play an essential role in bone health, whether in achieving peak bone mineral density (BMD) or maintaining bone health. This study explores the relationship between nutrient supply and femoral bone health at different ages. (2) Methods: A total of 5603 participants meeting the inclusion and exclusion criteria were included in this study using the National Health and Nutrition Examination Survey (NHANES) database from 2005 to 2010, 2013 to 2014, and 2017 to 2018. Femoral bone mineral density and bone status were dependent variables, and dietary nutrient intake and nutrient intake status were independent variables. The relationship between dietary nutrient intake and bone mineral density was explored, and the importance of nutrients affecting bone status was analyzed through a neural network model. At the same time, we investigated the relationship between nutrient intake and bone status. (3) Results: The peak of age and femoral bone mineral density appeared at 20 years old in our study. After grouping by age, logistic regression analysis showed that before 20 years old, without adjusting other variables, high-fat diet was more likely to have normal bone mass than appropriate fat diet (OR: 4.173, 95%CI: 1.007-17.289). After adjusting for all demographic factors, niacin intake (OR: 1.062, 95%CI: 1.019-1.108) was beneficial for normal bone mass, while vitamin B6 intake (OR: 0.627, 95%CI: 0.408-0.965) was not. After 20 years old, after adjusting for carbohydrate, protein, vitamin B6, niacin, dietary fat, vitamin B2, and vitamin B12, vitamin B2 intake (OR: 1.153, 95%CI: 1.04-1.278) was beneficial for normal bone mass, while vitamin B6 intake (OR: 0.842, 95%CI: 0.726-0.976) was not. After adjusting for all confounding factors, vitamin B2 intake (OR: 1.288, 95%CI: 1.102-1.506) was beneficial for normal bone mass. In addition, we found that even if there was no statistical significance, the effects of high-fat diet on bone mass were different at different ages. (4) Conclusions: By conducting an in-depth analysis of the NHANES database, this study reveals that dietary factors exert divergent effects on bone health across different age groups, implying the necessity of implementing tailored dietary strategies to maintain optimal bone health at distinct life stages.

Vitamin C Inhibited Pulmonary Metastasis through Activating Nrf2/HO-1 Pathway.

As an important nutritional component, vitamin C (Vc) shows good antitumor activity in a variety of cancer, but there are few studies in pulmonary metastasis. In order to verify its anticancer and antimetastatic effect, the study sets up H22 pulmonary metastasis mouse model. The results show that intraperitoneal injection of Vc inhibits pulmonary metastasis through up-regulating the expression of Nrf2, HO-1, cleaved caspases 3 and 9, and causing DNA damage and apoptosis which is similar to the pro-oxidant effect of Vc in p53 null cells (H1299 cells). Meanwhile, oral administration of Vc up-regulates the expression of p53, directly activates Nrf2/HO-1 pathway, increases expression of cleaved caspases 3 and 9, and ultimately inhibits pulmonary metastasis, which is the same as the antioxidant result of Vc in p53 wild-type cells. In addition, Vc inhibits the proliferation and migration of lung cancer cells in a concentration-dependent manner and has little cytotoxic effects on normal cells. Notably, the experiment further illustrates that besides intravenous Vc, oral Vc significantly inhibits the pulmonary metastasis in mice. All in all, these findings provide new clues for Vc-treated pulmonary metastasis in clinical research.

Identification of Genes Responding to Iron or Choline Treatment for Early-Life Iron Deficiency in the Male Rat Hippocampal Transcriptomes.

BACKGROUND: Developmental iron deficiency (ID) is associated with long-term cognitive and affective behavioral impairments in humans. Preclinical studies have shown that developmental ID has short- and long-term effects on gene regulation. Prenatal choline supplementation partially rescues early-life ID-induced cognitive deficits in adult male rats. OBJECTIVES: To identify acute and long-term changes in biological processes regulated by developmental ID and modifiable by choline. METHODS: This study compares the hippocampal transcriptomes of postnatal day (P) 15 iron-deficient (acute) and P65 formerly ID (persistent) rats with or without prenatal choline treatment. Pregnant rats were fed an ID (4 mg/kg Fe) or iron-sufficient (IS) (200 mg/kg Fe) diet from gestational day (G) 2 to P7 with or without choline supplementation (5 g/kg choline) from G11 to G18. Hippocampi were collected from P15 or P65 offspring and analyzed for gene expression by RNA sequencing. RESULTS: Developmental ID-induced changes suggested modified activity of oxidative phosphorylation and fatty acid metabolism. Prenatal choline supplementation induced robust changes in gene expression, particularly in iron-deficient animals, where it partially mitigated the early-life ID-dysregulated genes. Choline supplementation also altered the hippocampal transcriptome in the IS rats, with indications for both beneficial and adverse effects. CONCLUSIONS: This study provided global assessments of gene expression regulated by iron and choline. Our new findings highlight genes responding to iron or choline treatments, including a potentially novel choline-regulated transporter (IPO7), with shared effects on neuroinflammation in the male rat hippocampus.

Oral post-treatment supplementation with a combination of glutamine, citrulline, and antioxidant vitamins additively mitigates jejunal damage, oxidative stress, and inflammation in rats with intestinal ischemia and reperfusion.

INTRODUCTION: Intestinal ischemia and reperfusion (IIR) injury is closely associated with oxidative stress. Evidence shows that oral supplementation with glutamine and citrulline alleviates IIR-induced jejunal damage. We investigated the effects of a combination of glutamine, citrulline, and antioxidant vitamins on IIR-induced jejunal damage, oxidative stress, and inflammation. METHOD: Male Wistar rats that underwent 60 min of superior mesenteric artery occlusion were orally administered glutamine plus citrulline (GC), vitamin C plus E (CE), or a combination of GC and CE 15 min before and 3, 9, and 21 h after reperfusion. Healthy rats without IIR were used as controls. RESULTS: After reperfusion for 24 h, rats with IIR showed lower levels of red blood cells, hemoglobin, serum glucose, and jejunal DNA and increased white blood cell counts compared to controls (1-way ANOVA with the least significant difference, P < 0.05). The IIR-induced decrease in serum albumin and increase in plasma interleukin-6 and jejunal thiobarbituric acid-reactive substances (TBARS) were significantly reversed by GC and/or CE. The results of the 2-way ANOVA indicated that GC was the main factor that increased jejunal villus height and muscularis DNA, and CE was the main factor that increased jejunal muscularis protein and decreased jejunal proinflammatory cytokine levels and myeloperoxidase activity. In addition, GC and CE are the main factors that decrease plasma proinflammatory cytokine levels and the jejunal apoptotic index. CONCLUSION: Oral post-treatment supplementation with glutamine and citrulline, combined with vitamins C and E, may alleviate IIR-induced oxidative stress, inflammation, and jejunal damage.

Effects of vitamin D levels during pregnancy on prematurity: a systematic review protocol.

INTRODUCTION: Prematurity is an urgent public health problem worldwide. Recent studies associate maternal hypovitaminosis D during pregnancy with an increased risk of prematurity. However, the evidence on this association remains inconclusive, and there is lack of consensus in the literature. The exact mechanism by which low vitamin D levels may increase the risk of preterm birth is not yet fully understood. Nevertheless, it is known that vitamin D may play a role in maintaining a healthy pregnancy by regulating inflammation and immunomodulation by acting on the maternal and fetal immune systems. Inflammation and immune dysregulation are both associated with preterm birth, and low vitamin D levels may exacerbate these processes. The results of this review may have important implications for clinical practice and public health policy, particularly regarding vitamin D supplementation during pregnancy. METHODS AND ANALYSIS: A systematic review of the literature will be conducted. The search will be performed in electronic databases: CINAHL; MEDLINE; Cochrane Central Register of Controlled Trials; Cochrane Library; Academic Search Complete; Information Science and Technology Abstracts; MedicLatina; SCOPUS; PubMed; and Google Scholar, with the chronological range of January 2018 to November 2022. The search strategy will include the following Medical Subject Headings or similar terms: 'Vitamin D'; '25-hydroxyvitamin D'; 'Hypovitaminosis D'; 'Pregnancy'; 'Pregnant women'; 'Expectant mother'; 'Prematurity'; 'Premature birth'; 'Premature delivery'; 'Preterm birth'; and 'Preterm labour'. This review will include quantitative primary studies, both experimental (clinical trials) and observational (cohort, cross-sectional, and case-control). The quality of each selected study and the results obtained will be assessed by two reviewers separately, using the Cochrane risk of bias tool for evaluating randomised clinical trials or the Newcastle Ottawa Scale for non-randomised studies, following the respective checklist. In case of disagreement, a third reviewer will be consulted. ETHICS AND DISSEMINATION: This study does not involve human subjects and therefore does not require ethics approval. The results will be disseminated through publication in a peer-reviewed scientific journal and through conference presentations. All changes made to the protocol will be registered in PROSPERO, with information on the nature and justification for the changes made. PROSPERO REGISTRATION NUMBER: CRD42022303901.

Maternal Diet Associates with Offspring Bone Mineralization, Fracture Risk and Enamel Defects in Childhood and Influences the Prenatal Effect of High-Dose Vitamin D Supplementation.

We previously demonstrated a beneficial effect of high-dose vitamin D in pregnancy on offspring bone and dental health. Here, we investigated the effect of maternal dietary patterns during pregnancy on the risk of bone fractures, bone mineralization and enamel defects until age 6 years in the offspring. Further, the influence of diet on the effect of high-dose vitamin D was analyzed in the COPSAC2010 mother-child cohort including 623 mother-child pairs. A weighted network analysis on FFQs revealed three specific maternal dietary patterns that associated (Bonferroni p < 0.05) with both offspring bone and dental health. The effect of prenatal high-dose (2800 IU/day) vs. standard-dose (400 IU/day) vitamin D on offspring bone mineral content (adjusted mean difference (aMD): 33.29 g, 95% CI: 14.48-52.09, p < 0.001), bone mineral density (aMD: 0.02 g/cm2 (0.01-0.04), p < 0.001), fracture risk (adjusted incidence rate ratio: 0.36 (0.16-0.84), p = 0.02), and enamel defects in primary (adjusted odds ratio (aOR): 0.13 (0.03-0.58), p < 0.01) and permanent molars (aOR: 0.25; (0.10-0.63), p < 0.01) was most pronounced when mothers had lower intake of fruit, vegetables, meat, eggs, sweets, whole grain, offal and fish. This study suggests that prenatal dietary patterns influence offspring bone and dental development, and should be considered in order to obtain the full benefits of vitamin D to enhance personalized supplementation strategy.

Roles of Glutathione and AP-1 in the Enhancement of Vitamin D-Induced Differentiation by Activators of the Nrf2 Signaling Pathway in Acute Myeloid Leukemia Cells.

Active vitamin D derivatives (VDDs)-1α,25-dihydroxyvitamin D3/D2 and their synthetic analogs-are well-known inducers of cell maturation with the potential for differentiation therapy of acute myeloid leukemia (AML). However, their dose-limiting calcemic activity is a significant obstacle to using VDDs as an anticancer treatment. We have shown that different activators of the NF-E2-related factor-2/Antioxidant Response Element (Nrf2/ARE) signaling pathway, such as the phenolic antioxidant carnosic acid (CA) or the multiple sclerosis drug monomethyl fumarate (MMF), synergistically enhance the antileukemic effects of various VDDs applied at low concentrations in vitro and in vivo. This study aimed to investigate whether glutathione, the major cellular antioxidant and the product of the Nrf2/ARE pathway, can mediate the Nrf2-dependent differentiation-enhancing activity of CA and MMF in HL60 human AML cells. We report that glutathione depletion using L-buthionine sulfoximine attenuated the enhancing effects of both Nrf2 activators concomitant with downregulating vitamin D receptor (VDR) target genes and the activator protein-1 (AP-1) family protein c-Jun levels and phosphorylation. On the other hand, adding reduced glutathione ethyl ester to dominant negative Nrf2-expressing cells restored both the suppressed differentiation responses and the downregulated expression of VDR protein, VDR target genes, as well as c-Jun and P-c-Jun levels. Finally, using the transcription factor decoy strategy, we demonstrated that AP-1 is necessary for the enhancement by CA and MMF of 1α,25-dihydroxyvitamin D3-induced VDR and RXRα protein expression, transactivation of the vitamin D response element, and cell differentiation. Collectively, our findings suggest that glutathione mediates, at least in part, the potentiating effect of Nrf2 activators on VDDs-induced differentiation of AML cells, likely through the positive regulation of AP-1.

Vitamin D Reduces GABA-Positive Astrocytes in the 5xFAD Mouse Model of Alzheimer's Disease.

Background: Vitamin D has neuroprotective and immunomodulating functions that may impact glial cell function in the brain. Previously, we reported molecular and behavioral changes caused by deficiency and supplementation of vitamin D in an Alzheimer's disease (AD) mouse model. Recent studies have highlighted reactive astrocytes as a new therapeutic target for AD treatment. However, the mechanisms underlying the therapeutic effects of vitamin D on the glial cells of AD remain unclear. Objective: To investigate the potential association between vitamin D deficiency/supplementation and the pathological progression of AD, including amyloid-ß (Aß) pathology and reactive astrogliosis. Methods: Transgenic hemizygous 5XFAD male mice were subjected to different dietary interventions and intraperitoneal vitamin D injections to examine the effects of vitamin D deficiency and supplementation on AD. Brain tissue was then analyzed using immunohistochemistry for Aß plaques, microglia, and astrocytes, with quantifications performed via ImageJ software. Results: Our results demonstrated that vitamin D deficiency exacerbated Aß plaque formation and increased GABA-positive reactive astrocytes in AD model mice, while vitamin D supplementation ameliorated these effects, leading to a reduction in Aß plaques and GABA-positive astrocytes. Conclusions: Our findings highlight the significant impact of vitamin D status on Aß pathology and reactive astrogliosis, underscoring its potential role in the prevention and treatment of AD. This study provides the first in vivo evidence of the association between vitamin D and reactive astrogliosis in AD model mice, indicating the potential for targeting vitamin D levels as a novel therapeutic approach for AD.

Novel dietary strategies to manage sarcopenia.

PURPOSE OF REVIEW: Sarcopenia is a wasting disease, mostly age-related in which muscle strength and mass decline, such as physical performance. With aging, both lower dietary protein intake and anabolic resistance lead to sarcopenia. Moreover, aging and sarcopenia display low-grade inflammation, which also worsen muscle condition. In this review, we focused on these two main targets to study dietary strategies. RECENT FINDINGS: The better understanding in mechanisms involved in sarcopenia helps building combined dietary approaches including physical activity that would slow the disease progression. New approaches include better understanding in the choice of quality proteins, their amount and schedule and the association with antioxidative nutrients. SUMMARY: First, anabolic resistance can be countered by increasing significantly protein intake. If increasing amount remains insufficient, the evenly delivery protein schedule provides interesting results on muscle strength. Quality of protein is also to consider for decreasing risk for sarcopenia, because varying sources of proteins appears relevant with increasing plant-based proteins ratio. Although new techniques have been developed, as plant-based proteins display a lower availability, we need to ensure an adapted overall amount of proteins. Finally, specific enrichment with leucine from whey protein remains the dietary combined approach most studied and studies on citrulline provide interesting results. As cofactor at the edge between anabolic and antioxidative properties, vitamin D supplementation is to recommend. Antioxidative dietary strategies include both fibers, vitamins, micronutrients and polyphenols from various sources for positive effects on physical performance. The ω 3 -polyunsaturated fatty acids also display positive modifications on body composition. Gut microbiota modifiers, such as prebiotics, are promising pathways to improve muscle mass and function and body composition in sarcopenic patients. Nutritional interventions could be enhanced by combination with physical activity on sarcopenia. In healthy older adults, promoting change in lifestyle to get near a Mediterranean diet could be one of the best options. In sarcopenia adults in which lifestyle changes appears unprobable, specific enrichement potentialized with physical activity will help in the struggle against sarcopenia. Longitudinal data are lacking, which makes it hard to draw strong conclusions. However, the effects of a physical activity combined with a set of nutrition interventions on sarcopenia seems promising.

Effect of multivitamin-mineral supplementation versus placebo on cognitive function: results from the clinic subcohort of the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial and meta-analysis of 3 cognitive studies within COSMOS.

BACKGROUND: Longer effects of multivitamin-mineral (MVM) supplementation on late-life cognitive function remain untested using in-person, detailed neuropsychological assessments. Furthermore, insufficient evidence exists for healthcare providers to recommend daily MVM supplements to prevent cognitive decline. OBJECTIVES: This study aimed to test MVM effects on cognitive change using in-person, detailed neuropsychological assessments and conduct a meta-analysis within COSMOS (COcoa Supplement and Multivitamin Outcomes Study) cognitive substudies for a robust evaluation of MVM effects on cognition. METHODS: COSMOS is a 2 × 2 factorial trial of cocoa extract (500 mg flavanols/d) and/or a daily MVM supplement for cardiovascular disease and cancer prevention among 21,442 United States adults aged ≥60 y. There were 573 participants in the clinic subcohort of COSMOS (that is, COSMOS-Clinic) who completed all cognitive tests administered at baseline. For the meta-analysis, we included nonoverlapping participants across 3 COSMOS cognitive substudies: COSMOS-Clinic (n = 573); COSMOS-Mind (n = 2158); COSMOS-Web (n = 2472). RESULTS: In COSMOS-Clinic, we observed a modest benefit of MVM compared with placebo on global cognition over 2 y {mean difference [95% confidence interval (CI)] = 0.06 SD units (SU) (-0.003, 0.13)}, with a significantly more favorable change in episodic memory [mean difference (95% CI) = 0.12 SU (0.002, 0.23)] but not in executive function or attention [mean difference (95% CI) = 0.04 SU (-0.04, 0.11)]. The meta-analysis of COSMOS substudies showed clear evidence of MVM benefits on global cognition [mean difference (95% CI) = 0.07 SU (0.03, 0.11); P = 0.0009] and episodic memory [mean difference (95% CI) = 0.06 SU (0.03, 0.10); P = 0.0007]; the magnitude of effect on global cognition was equivalent to reducing cognitive aging by 2 y. CONCLUSIONS: In COSMOS-Clinic, daily MVM supplementation leads to a significantly more favorable 2-y change in episodic memory. The meta-analysis within COSMOS cognitive substudies indicates that daily MVM significantly benefits both global cognition and episodic memory. These findings within the COSMOS trial support the benefits of a daily MVM in preventing cognitive decline among older adults. This trial was registered at COSMOS-clinicaltrials.gov as NCT02422745, at COSMOS-Mind-clinicaltrials.gov as NCT03035201, and at COSMOS-Web-clinicaltrials.gov as NCT04582617.

Vitamin D inhibits tamoxifen-induced non-alcoholic fatty liver disease through a nonclassical estrogen receptor/liver X receptor pathway.

Non-alcoholic Fatty Liver Disease (NAFLD) is one of the common side effects of tamoxifen treatment for estrogen receptor-positive breast cancer, and is representative of disorders of energy metabolism. Fatty liver is induced after tamoxifen (TAM) inhibition of estrogen receptor activity, but the exact mechanism is not clear. This study investigated the effects and mechanisms of TAM-induced steatosis in the liver. The effects and mechanisms of TAM on hepatocyte lipid metabolism were assessed using C57BL/6 female mice and human hepatoma cells. TAM promoted fat accumulation in the liver by upregulation of Srebp-1c expression. Regarding the molecular mechanism, TAM promoted the recruitment of the auxiliary transcriptional activator, p300, and dissociated the auxiliary transcriptional repressor, nuclear receptor corepressor (NCOR), of the complexes, which led to enhancement of Srebp-1c transcription and an increase of triglyceride (TG) synthesis. Vitamin D (VD), a common fat-soluble vitamin, can decrease TAM-induced NAFLD by promoting p300 dissociation and NCOR recruitment. Tamoxifen promoted the recruitment and dissociation of co-transcription factors on the LXR/ER/RXR receptor complex, leading to a disorder of liver lipid metabolism. VD interfered with TAM-induced liver lipid metabolism disorders by reversing this process.