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Developmental Cell Oct 2023Neuroblastoma is the most common extracranial solid tumor in infants, arising from developmentally stalled neural crest-derived cells. Driving tumor differentiation is a...
Neuroblastoma is the most common extracranial solid tumor in infants, arising from developmentally stalled neural crest-derived cells. Driving tumor differentiation is a promising therapeutic approach for this devastating disease. Here, we show that the CDK4/6 inhibitor palbociclib not only inhibits proliferation but induces extensive neuronal differentiation of adrenergic neuroblastoma cells. Palbociclib-mediated differentiation is manifested by extensive phenotypic and transcriptional changes accompanied by the establishment of an epigenetic program driving expression of mature neuronal features. In vivo palbociclib significantly inhibits tumor growth in mouse neuroblastoma models. Furthermore, dual treatment with retinoic acid resets the oncogenic adrenergic core regulatory circuit of neuroblastoma cells, further suppresses proliferation, and can enhance differentiation, altering gene expression in ways that significantly correlate with improved patient survival. We therefore identify palbociclib as a therapeutic approach to dramatically enhance neuroblastoma differentiation efficacy that could be used in combination with retinoic acid to improve patient outcomes.
Topics: Animals; Mice; Humans; Cell Line, Tumor; Cell Differentiation; Tretinoin; Neuroblastoma; Adrenergic Agents; Piperazines; Pyridines
PubMed: 37734383
DOI: 10.1016/j.devcel.2023.08.028 -
Clinical Nutrition (Edinburgh, Scotland) Dec 2023Optimal maternal vitamin status during pregnancy and lactation is essential to support maternal and infant health. For instance, vitamin D is involved in infant bone... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND & AIMS
Optimal maternal vitamin status during pregnancy and lactation is essential to support maternal and infant health. For instance, vitamin D is involved in infant bone development, and B-vitamins are involved in various metabolic processes, including energy production. Through a double-blind randomised controlled trial, we investigated the effects of maternal supplementation from preconception throughout pregnancy until birth on human milk (HM) concentrations of vitamin D and B-vitamins. In addition, we aimed to characterise longitudinal changes in milk concentrations of these vitamins.
METHODS
Both control and intervention supplements contained calcium, iodine, iron, β-carotene, and folic acid, while the intervention also contained zinc, vitamins B, B, B, and D, probiotics, and myo-inositol. HM samples were collected across 4 time points from 1 week to 3 months post-delivery from 158 mothers in Singapore, and 7 time points from 1 week to 12 months from 180 mothers in New Zealand. HM vitamin D was quantified using supercritical fluid chromatography and B-vitamins with mass spectrometry. Potential intervention effects on HM vitamins D, B, B, and B, as well as other B-vitamin (B and B) concentrations were assessed using linear mixed models with a repeated measures design.
RESULTS
Over the first 3 months of lactation, HM 25-hydroxyvitamin D concentrations were 20% (95% CI 8%, 33%, P = 0.001) higher in the intervention group, with more marked effects in New Zealand. There were no observed intervention effects on HM concentrations of vitamins B, B, B, B, and B. In New Zealand mothers, longitudinally, vitamin D concentrations gradually increased from early lactation up to 12 months, while vitamins B and B peaked at 6 weeks, B at 3 weeks, and B and B at 3 months.
CONCLUSIONS
Maternal supplementation during preconception and pregnancy increased HM vitamin D, but not B-vitamin concentrations in lactation. Further studies are required to examine the discrete benefits of vitamin D supplementation starting preconception vs during pregnancy, and to further characterise the effects of supplementation on later offspring health outcomes.
CLINICAL TRIAL REGISTRATION
Registered at ClinicalTrials.gov on the 16 July 2015 (identifier NCT02509988); Universal Trial Number U1111-1171-8056. This study was academic-led by the EpiGen Global Research Consortium.
Topics: Pregnancy; Infant; Female; Humans; Vitamins; Vitamin D; Milk, Human; Dietary Supplements; Cholecalciferol; Lactation; Vitamin A; Double-Blind Method
PubMed: 38411017
DOI: 10.1016/j.clnu.2023.09.009 -
EMBO Molecular Medicine Nov 2023One of the defining features of acute myeloid leukemia (AML) is an arrest of myeloid differentiation whose molecular determinants are still poorly defined....
One of the defining features of acute myeloid leukemia (AML) is an arrest of myeloid differentiation whose molecular determinants are still poorly defined. Pharmacological removal of the differentiation block contributes to the cure of acute promyelocytic leukemia (APL) in the absence of cytotoxic chemotherapy, but this approach has not yet been translated to non-APL AMLs. Here, by investigating the function of hypoxia-inducible transcription factors HIF1α and HIF2α, we found that both genes exert oncogenic functions in AML and that HIF2α is a novel regulator of the AML differentiation block. Mechanistically, we found that HIF2α promotes the expression of transcriptional repressors that have been implicated in suppressing AML myeloid differentiation programs. Importantly, we positioned HIF2α under direct transcriptional control by the prodifferentiation agent all-trans retinoic acid (ATRA) and demonstrated that HIF2α blockade cooperates with ATRA to trigger AML cell differentiation. In conclusion, we propose that HIF2α inhibition may open new therapeutic avenues for AML treatment by licensing blasts maturation and leukemia debulking.
Topics: Humans; Transcription Factors; Leukemia, Myeloid, Acute; Tretinoin; Gene Expression Regulation; Cell Differentiation; Leukemia, Promyelocytic, Acute
PubMed: 37807875
DOI: 10.15252/emmm.202317810 -
BMC Pediatrics Jan 2024Dietary intakes of vitamins are associated with asthma. However, previous studies mainly explored the association between a single vitamin intake and asthma, which did...
BACKGROUND
Dietary intakes of vitamins are associated with asthma. However, previous studies mainly explored the association between a single vitamin intake and asthma, which did not take the multivitamins into consideration. Herein, this study aims to explore the overall effect of dietary multivitamins consumption on childhood asthma.
METHODS
Data of children and adolescents (aged 2-17 years old) were extracted from the National Health and Nutrition Examination Survey (NHANES) database in 2015-2018 in this cross-sectional study. Weighted univariate logistic regression analysis was used to screen covariates. The association between multivitamins (including vitamin A, C, D, E, B1, B2, B6, B12, K, niacin, folic acid, and choline) and childhood asthma was explored using univariate and multivariate logistic regression analyses. The evaluation indexes were odds ratio (OR) and 95% confidence interval (CI). We further introduced the Bayesian kernel machine regression (BKMR) to assess the joint effect of the twelve vitamins on childhood asthma, the impact of an individual vitamin as part of a vitamin mixture, and the potential interactions among different vitamins.
RESULTS
Among 4,715 eligible children and adolescents, 487 (10.3%) had asthma. After adjusting for covariates including race, family history of asthma, pregnant smoking, BMI Z-score, energy intake, breast feeding, and low birth weight, we found that for each 1-unit increase in vitamin K consumption, the odds of childhood asthma decreased 0.99 (P=0.028). The overall effect analysis reported a trend of negative relationship between the multivitamins and childhood asthma, especially at the 75th percentile and over. According to the BKMR models, when other vitamins are fixed at the median level, the odds of childhood asthma increased along with the elevated vitamin D (VD) and vitamin B2 (VB2), whereas along with the depressed vitamin C (VC). In addition, no potential interaction has been found between every two vitamins of multivitamins on childhood asthma.
CONCLUSION
Among children and adolescents who have high-risk of asthma, it may be beneficial to increase dietary consumption of multivitamins. Our findings recommended that children and adolescents should increase the intake of VC-rich foods, whereas control the dietary consumption of VD and VB2 in daily life.
Topics: Pregnancy; Child; Female; Adolescent; Humans; Child, Preschool; Cross-Sectional Studies; Nutrition Surveys; Bayes Theorem; Vitamins; Vitamin A; Ascorbic Acid; Asthma
PubMed: 38297283
DOI: 10.1186/s12887-024-04540-5 -
International Journal For Vitamin and... Dec 2023
Topics: Antioxidants; Vitamin A; Ascorbic Acid; Vitamin E
PubMed: 35291873
DOI: 10.1024/0300-9831/a000752 -
Medicine Dec 2023Sarcopenia increases disability, hospital stays, readmissions, and mortality in older adults. Antioxidative nutrients and fatty acids consumption may help maintain...
Sarcopenia increases disability, hospital stays, readmissions, and mortality in older adults. Antioxidative nutrients and fatty acids consumption may help maintain muscle mass by reducing oxidative stress. This study aims to assess the association between antioxidant and fatty acid intake and low muscle mass in community-dwelling older people. This retrospective analysis used data from the National Health and Nutrition Examination Survey from 1999 to 2004. Participants ≥ 60 years with information on muscle mass measured by Dual energy X-ray absorptiometry (DXA) were included. Appendicular skeletal muscle mass was assessed. Associations between antioxidants and fatty acids intake, and low muscle mass were evaluated using logistic regressions. 3648 (1748 men and 1900 women) were included. The prevalence of low muscle mass was 41% and 26% among men and women ≥ 75 years, and 45.2% and 28.4% among obese men and women. In obese males, a natural-log-unit increase of vitamin A (aOR = 0.806, 95% CI: 0.652-0.996), vitamin C (aOR = 0.878, 95% CI: 0.779-0.990), selenium intake (aOR = 0.716, 95% CI: 0.517-0.993), and higher saturated fatty acids (aOR = 0.956, 95% CI: 0.915-0.998) and monounsaturated fatty acids (aOR = 0.959, 95% CI: 0.925-0.994) intake were associated with decreased odds for low muscle mass. Among obese females, a natural-log-unit increase of vitamin E (P = .036), vitamin B12 (P = .014), total folate (P = .015), zinc (P = .005), and selenium intake (P = .018) were associated with increased odds of low muscle mass, whereas higher saturated fatty acids (P < .001), monounsaturated fatty acids (P = .001), and polyunsaturated fatty acids intake (P = .006) were associated with decreased odds for low muscle mass. Antioxidants (vitamin A, C, E, B6, B12, total folate, zinc, magnesium, selenium) intake does not consistently relate to low muscle mass across age and sex. Higher intake of saturated, monounsaturated, and polyunsaturated fatty acids are independently associated with reduced likelihood of low muscle mass in both obese older men and women.
Topics: Male; Humans; Female; Aged; Antioxidants; Nutrition Surveys; Fatty Acids; Vitamin A; Selenium; Independent Living; Retrospective Studies; Energy Intake; Obesity; Fatty Acids, Unsaturated; Zinc; Fatty Acids, Monounsaturated; Folic Acid; Muscles
PubMed: 38115288
DOI: 10.1097/MD.0000000000036517 -
Cureus Nov 2023Vitamin A, also known as retinol, is a non-water-soluble vitamin. Vitamin A is very important for the proper functioning of the human body. Retinol, especially in the... (Review)
Review
Vitamin A, also known as retinol, is a non-water-soluble vitamin. Vitamin A is very important for the proper functioning of the human body. Retinol, especially in the form of retinyl ester, can be found in many animal-based products and is essential for the efficient operation of many physiological processes. Fruits and vegetables are also excellent sources of vitamin A; the majority of them include carotenoids, which are precursors to vitamin A. The human body has the ability to convert natural retinols like retinyl ester, retinoic acid, and provitamin A into biologically active forms that interact with a variety of molecular targets like nuclear receptors and retinal opsins. This review article provides knowledge regarding retinol deficiency in humans. It provides brief information about the sources, etiology, epidemiology, pathophysiology, and treatment of vitamin A deficiency.
PubMed: 38111435
DOI: 10.7759/cureus.49011 -
Nutrients Jul 2023Cardiovascular diseases (CVDs) are the leading cause of death worldwide, far ahead of cancer. Epidemiological data emphasize the participation of many risk factors that... (Review)
Review
Cardiovascular diseases (CVDs) are the leading cause of death worldwide, far ahead of cancer. Epidemiological data emphasize the participation of many risk factors that increase the incidence of CVDs, including genetic factors, age, and sex, but also lifestyle, mainly nutritional irregularities and, connected with them, overweight and obesity, as well as metabolic diseases. Despite the importance of cardiovascular problems in the whole society, the principles of prevention of CVDs are not widely disseminated, especially among the youngest. As a result, nutritional neglect, growing from childhood and adolescence, translates into the occurrence of numerous disease entities, including CVDs, in adult life. This review aimed to draw attention to the role of selected minerals and vitamins in health and the development and progression of CVDs in adults and children. Particular attention was paid to the effects of deficiency and toxicity of the analyzed compounds in the context of the cardiovascular system and to the role of intestinal microorganisms, which by interacting with nutrients, may contribute to the development of cardiovascular disorders. We hope this article will draw the attention of society and the medical community to emphasize promoting healthy eating and proper eating habits in children and adults, translating into increased awareness and a reduced risk of CVD.
Topics: Adolescent; Humans; Adult; Child; Vitamins; Gastrointestinal Microbiome; Minerals; Vitamin A; Vitamin K; Heart Diseases; Cardiovascular Diseases
PubMed: 37513682
DOI: 10.3390/nu15143264 -
Frontiers in Immunology 2024Previous studies have shown conflicting results regarding the impact of circulating antioxidants on the risk of inflammatory bowel disease (IBD). In this study, our... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Previous studies have shown conflicting results regarding the impact of circulating antioxidants on the risk of inflammatory bowel disease (IBD). In this study, our intent was to investigate the causal relationship between circulating antioxidants and IBD using Mendelian randomization (MR).
METHODS
Instrumental variables for absolute circulating antioxidants (ascorbate, retinol, lycopene, and β-carotene) and circulating antioxidant metabolites (α-tocopherol, γ-tocopherol, ascorbate, and retinol) were screened from published studies. We obtained outcome data from two genome-wide association study (GWAS) databases, including the international inflammatory bowel disease genetics consortium (IIBDGC, 14,927 controls and 5,956 cases for Crohn's disease (CD), 20,464 controls and 6,968 cases for ulcerative colitis (UC), and 21,770 controls and 12,882 cases for IBD) and the FinnGen study (375,445 controls and 1,665 cases for CD, 371,530 controls and 5,034 cases for UC, and 369,652 controls and 7,625 cases for IBD). MR analysis was performed in each of the two databases and those results were pooled using meta-analysis to assess the overall effect of exposure on each phenotype. In order to confirm the strength of the findings, we additionally conducted a replication analysis using the UK Biobank.
RESULTS
In the meta-analysis of the IIBDGC and FinnGen, we found that each unit increase in absolute circulating level of retinol was associated with a 72% reduction in the risk of UC (OR: 0.28, 95% CI: 0.10 to 0.78, =0.015). The UC GWAS data from the UK Biobank also confirmed this causal relationship (OR: 0.99, 95% CI: 0.97 to 1.00, =0.016). In addition, there was suggestive evidence that absolute retinol level was negatively associated with IBD (OR: 0.41, 95% CI: 0.18 to 0.92, =0.031). No other causal relationship was found.
CONCLUSION
Our results provide strong evidence that the absolute circulating level of retinol is associated with a reduction in the risk of UC. Further MR studies with more instrumental variables on circulating antioxidants, especially absolute circulating antioxidants, are needed to confirm our results.
Topics: Humans; Antioxidants; Vitamin A; Genome-Wide Association Study; Mendelian Randomization Analysis; Diet; Inflammatory Bowel Diseases; Colitis, Ulcerative; Crohn Disease
PubMed: 38449867
DOI: 10.3389/fimmu.2024.1334395 -
Biomedical Papers of the Medical... Jun 2024Retinoids participate in multiple key processes in the human body e.g., vision, cell differentiation and embryonic development. There is growing evidence of the...
AIMS
Retinoids participate in multiple key processes in the human body e.g., vision, cell differentiation and embryonic development. There is growing evidence of the relationship between retinol, its active metabolite- all-trans retinoic acid (ATRA) - and several pancreatic disorders. Although low levels of ATRA in pancreatic ductal adenocarcinoma (PDAC) tissue have been reported, data on serum levels of ATRA in PDAC is still limited. The aim of our work was to determine serum concentrations of retinol and ATRA in patients with PDAC, type-2 diabetes mellitus (T2DM), chronic pancreatitis (CHP) and healthy controls.
METHODS
High performance liquid chromatography with UV detection (HPLC) was used to measure serum levels of retinol and ATRA in 246 patients with different stages of PDAC, T2DM, CHP and healthy controls.
RESULTS
We found a significant decrease in the retinol concentration in PDAC (0.44 mg/L) compared to T2DM (0.65 mg/L, P<0.001), CHP (0.60 mg/L, P< 0.001) and healthy controls (0.61 mg/L, P<0.001), significant decrease of ATRA levels in PDAC (1.14 ug/L) compared to T2DM (1.37 ug/L, P<0.001) and healthy controls(1.43 ug/L, P<0.001). Differences between early stages (I+II) of PDAC and non-carcinoma groups were not significant. We describe correlations between retinol, prealbumin and transferrin, and correlation of ATRA and IGFBP-2.
CONCLUSION
Significant decrease in retinol and ATRA levels in PDAC compared to T2DM, healthy individuals and/or CHP supports existing evidence of the role of retinoids in PDAC. However, neither ATRA nor retinol are suitable for detection of early PDAC. Correlation of ATRA levels and IGFBP-2 provides new information about a possible IGF and retinol relationship.
Topics: Humans; Pancreatitis, Chronic; Vitamin A; Tretinoin; Diabetes Mellitus, Type 2; Male; Female; Middle Aged; Pancreatic Neoplasms; Aged; Carcinoma, Pancreatic Ductal; Adult; Case-Control Studies; Chromatography, High Pressure Liquid
PubMed: 38058194
DOI: 10.5507/bp.2023.049