Vitamin A and Retinoic Acid in Cognition and Cognitive Disease

Wołoszynowska-Fraser, Marta Urszula; Kouchmeshky, Azita; McCaffery, Peter

doi:10.1146/annurev-nutr-122319-034227

Cited by 92 publications

(49 citation statements)

References 160 publications

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“…RA is an important physiological ligand of the nuclear receptors RAR and RXR that when activated exert growth inhibitory effects on various tumors [ 15 ]. However, whether sulfarotene that exerts high therapeutic selectivity and efficacy on the TRCs of HCC as described above utilizes a similar RAR- or RXR-dependent mechanism remains unclear.…”

Section: Resultsmentioning

confidence: 99%

Sulfarotene, a synthetic retinoid, overcomes stemness and sorafenib resistance of hepatocellular carcinoma via suppressing SOS2-RAS pathway

Feng

Qin²,

Zhang

et al. 2021

J Exp Clin Cancer Res

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Background Recurrent hepatocellular carcinoma (HCC) shows strong resistance to sorafenib, and the tumor-repopulating cells (TRCs) with cancer stem cell-like properties are considered a driver for its high recurrent rate and drug resistance. Methods Suppression of TRCs may thus be an effective therapeutic strategy for treating this fatal disease. We evaluated the pharmacology and mechanism of sulfarotene, a new type of synthetic retinoid, on the cancer stem cell-like properties of HCC TRCs, and assessed its preclinical efficacy in models of HCC patient-derived xenografts (PDXs). Results Sulfarotene selectively inhibited the growth of HCC TRCs in vitro and significantly deterred TRC-mediated tumor formation and lung metastasis in vivo without apparent toxicity, with an IC50 superior to that of acyclic retinoid and sorafenib, to which the recurrent HCC exhibits significant resistance at advanced stage. Sulfarotene promoted the expression and activation of RARα, which down-regulated SOS2, a key signal mediator associated with RAS activation and signal transduction involved in multiple downstream pathways. Moreover, sulfarotene selectively inhibited tumorigenesis of HCC PDXs with high expression for SOS2. Conclusions Our study identified sulfarotene as a selective inhibitor for the TRCs of HCC, which targets a novel RARα-SOS2-RAS signal nexus, shedding light on a new, promising strategy of target therapy for advanced liver cancer.

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Section: Resultsmentioning

confidence: 99%

Sulfarotene, a synthetic retinoid, overcomes stemness and sorafenib resistance of hepatocellular carcinoma via suppressing SOS2-RAS pathway

Feng

Qin²,

Zhang

et al. 2021

J Exp Clin Cancer Res

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“…Genes involved in growth factors and Vitamin A regulation have been found to affect lung function. Both growth patterns and Vitamin A levels may have a role in cognitive function [23,32]. It may be that genetic pleiotropy can determine both lung function and cognitive trajectories.…”

Section: Discussionmentioning

confidence: 99%

Lung function, COPD and cognitive function: a multivariable and two sample Mendelian randomization study

et al. 2021

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Background Observational studies show an association between reduced lung function and impaired cognition. Cognitive dysfunction influences important health outcomes and is a precursor to dementia, but treatments options are currently very limited. Attention has therefore focused on identifying modifiable risk factors to prevent cognitive decline and preserve cognition. Our objective was to determine if lung function or risk of COPD causes reduced cognitive function using Mendelian randomization (MR). Methods Single nucleotide polymorphisms from genome wide association studies of lung function and COPD were used as exposures. We examined their effect on general cognitive function in a sample of 132,452 individuals. We then performed multivariable MR (MVMR), examining the effect of lung function before and after conditioning for covariates. Results We found only weak evidence that reduced lung function (Beta − 0.002 (SE 0.02), p-value 0.86) or increased liability to COPD (− 0.008 (0.008), p-value 0.35) causes lower cognitive function. MVMR found both reduced FEV1 and FVC do cause lower cognitive function, but that after conditioning for height (− 0.03 (0.03), p-value 0.29 and − 0.01 (0.03) p-value 0.62, for FEV1 and FVC respectively) and educational attainment (− 0.03 (0.03) p-value 0.33 and − 0.01 (0.02), p-value 0.35) the evidence became weak. Conclusion We did not find evidence that reduced lung function or COPD causes reduced cognitive function. Previous observational studies are probably affected by residual confounding. Research efforts should focus on shared risk factors for reduced lung function and cognition, rather than lung function alone as a modifiable risk factor.

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“…These changes appear unrelated to metabolic aging, and instead most are specifically related to individual differences in the cognitive outcome of aging rather than chronological age. The importance of neuronal excitation/inhibition balance in relation to cognitive outcome has been highlighted in many studies and is the core of numerous neurologic diseases where altered RA signaling is implicated ( Wołoszynowska-Fraser et al, 2020 ). Together, the current results lean in favor of increased RA signaling, potentially contributing to the excitation/inhibition imbalance that is prominently featured in age-related cognitive impairment.…”

Section: Discussionmentioning

confidence: 99%

Differential Retinoic Acid Signaling in the Hippocampus of Aged Rats with and without Memory Impairment

Wołoszynowska-Fraser

Rossi

Long

et al. 2021

eNeuro

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Retinoic acid (RA), a metabolite of vitamin A, has many physiological functions, and mounting evidence points to important roles in cognition. In vitro experiments indicate that RA is involved in homeostatic synaptic scaling in the hippocampus, which supports overall network stability during learning. It has been previously determined that disrupted RA signaling in the hippocampus causes deterioration of memory, that RA signaling declines with age in brain, and that application of RA reverses this decline. Here, we explore whether RA signaling is altered in an animal model of neurocognitive aging. We used a Morris water maze protocol to study cognitive decline in aged rats, which assesses hippocampus-dependent spatial memory and reveals substantial interindividual differences in aged animals. Aged unimpaired (AU) rats perform on par with young (Y), while aged impaired (AI) animals exhibit spatial memory deficits. We show that the major substrate for RA, retinol binding protein 4 (RBP4), is decreased in AU rats, and retinol cell surface receptor declines with chronological age. Other affected components of RA signaling include selective increases in AI animals in hippocampal synthesis (RALDH1) and catabolism of RA (CYP26B1), RA receptor α, the RA regulated ionotropic glutamate receptor (GluR1), as well as fragile X mental retardation protein (FMRP). The results support the conclusion that, surprisingly, increased RA signaling in the aged hippocampus is associated with poor cognitive outcome.

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Vitamin A and Retinoic Acid in Cognition and Cognitive Disease

Cited by 92 publications

References 160 publications

Sulfarotene, a synthetic retinoid, overcomes stemness and sorafenib resistance of hepatocellular carcinoma via suppressing SOS2-RAS pathway

Sulfarotene, a synthetic retinoid, overcomes stemness and sorafenib resistance of hepatocellular carcinoma via suppressing SOS2-RAS pathway

Lung function, COPD and cognitive function: a multivariable and two sample Mendelian randomization study

Differential Retinoic Acid Signaling in the Hippocampus of Aged Rats with and without Memory Impairment

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