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Biotechnology and Bioengineering Feb 2022Retinol is a fat-soluble vitamin A that is widely used in the food and pharmaceutical industries. Currently, retinol is commercially produced by chemical synthesis....
Retinol is a fat-soluble vitamin A that is widely used in the food and pharmaceutical industries. Currently, retinol is commercially produced by chemical synthesis. Microbial production of retinol has been alternatively explored but restricted to a mixture of retinoids including retinol, retinal, and retinoic acid. Thus, we introduced heterologous retinol dehydrogenase into retinoids mixture-producing Saccharomyces cerevisiae for the selective production of retinol using xylose. Expression of human RDH10 and Escherichia coli ybbO led to increase in retinol production, but retinal remained as a major product. In contrast, S. cerevisiae harboring human RDH12 produced retinol selectively with negligible production of retinal. The resulting strain (SR8A-RDH12) produced retinol only. However, more glycerol was accumulated due to intracellular redox imbalance. Therefore, Lactococcus lactis noxE coding for H O-forming NADH oxidase was additionally introduced to resolve the redox imbalance. The resulting strain produced 52% less glycerol and more retinol with a 30% higher yield than a parental strain. As the produced retinol was not stable, we examined culture and storage conditions including temperature, light, and antioxidants for the optimal production of retinol. In conclusion, we achieved selective production of retinol efficiently from xylose by introducing human RDH12 and NADH oxidase into S. cerevisiae.
Topics: Alcohol Oxidoreductases; Metabolic Engineering; Recombinant Proteins; Saccharomyces cerevisiae; Vitamin A; Xylose
PubMed: 34850377
DOI: 10.1002/bit.28004 -
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 -
Canadian Journal of Physiology and... May 2015A cluster of inter-related conditions such as central obesity, dyslipidemia, impaired glucose metabolism, and hypertension is referred to as Metabolic Syndrome, which is... (Review)
Review
A cluster of inter-related conditions such as central obesity, dyslipidemia, impaired glucose metabolism, and hypertension is referred to as Metabolic Syndrome, which is a risk factor for the development of type-2 diabetes. The micro- and macro-vascular complications of diabetes contribute to its morbidity and mortality. In addition to its calcitropic effect, vitamin D is a regulator of gene expression as well as cell proliferation and differentiation. Various cross-sectional and longitudinal cohort studies have indicated a beneficial effect from vitamin D supplementation on the development of type-2 diabetes. Binding of retinol-bound retinol-binding protein to a membrane-binding protein suppresses insulin signaling. All-trans retinoic acid, a derivative of vitamin A, reverses these effects, resulting in increased insulin sensitivity, suppression of the phosphoenolpyruvate carboxy kinase (PEPCK) gene, and the induction of the glucokinase gene. Glucokinase and PEPCK are also regulated in opposite directions by the vitamin biotin, acting at the transcriptional level. Biotin also regulates the synthesis of insulin by the islet of Langerhans cells of the pancreas. The increase in advanced glycation end products (AGEs) is implicated in the initiation and progression of diabetes-associated microvascular diseases. Benfotiamine, a derivative of thiamine, and pyridoxamine, a vitamer of vitamin B6, both have anti-AGE properties, making them valuable therapeutic adjuvants in the treatment of diabetic complications. Thus, various vitamins and their derivatives have profound therapeutic potential in the prevention and treatment of type-2 diabetes.
Topics: Animals; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Glycation End Products, Advanced; Humans; Insulin Resistance; Metabolic Syndrome; Treatment Outcome; Vitamin A; Vitamin D; Vitamins
PubMed: 25929424
DOI: 10.1139/cjpp-2014-0479 -
Nutrition Reviews Jan 2021Vitamin A (VA) and its pro-vitamin carotenoids are naturally occurring lipophilic compounds involved in several cellular processes and metabolic pathways. Despite... (Review)
Review
Vitamin A (VA) and its pro-vitamin carotenoids are naturally occurring lipophilic compounds involved in several cellular processes and metabolic pathways. Despite their broad spectrum of activities in the general population, dietary deficiencies of these compounds can potentially affect pregnancy outcomes. Since maternal nutritional status and diet composition during pregnancy and lactation can have long-lasting effects in offspring until adulthood, this study presents an overview of VA and the role of pro-VA carotenoids during pregnancy and lactation - the nutrition, metabolism, and biological effects in the offspring. The review aimed to discuss the pro-VA carotenoids and VA-associated pathways and summarize the results with reference to gestational disorders, and VA and pro-VA carotenoids as preventive agents. Also, considering that obesity, overweight, and metabolic diseases are major public health concerns worldwide, fetal and neonatal development is discussed, highlighting the physiological role of these molecules in obesity prevention. This review comprehensively summarizes the current data and shows the potential impact of these compounds on nutritional status in pregnancy and lactation.
Topics: Animals; Breast Feeding; Carotenoids; Diet; Female; Fetus; Humans; Infant; Infant Nutritional Physiological Phenomena; Infant, Newborn; Lactation; Maternal Nutritional Physiological Phenomena; Metabolic Networks and Pathways; Nutritional Status; Obesity; Pregnancy; Vitamin A; Vitamin A Deficiency
PubMed: 33301001
DOI: 10.1093/nutrit/nuaa075 -
The Biochemical Journal Oct 2021The hetero-oligomeric retinoid oxidoreductase complex (ROC) catalyzes the interconversion of all-trans-retinol and all-trans-retinaldehyde to maintain the steady-state...
The hetero-oligomeric retinoid oxidoreductase complex (ROC) catalyzes the interconversion of all-trans-retinol and all-trans-retinaldehyde to maintain the steady-state output of retinaldehyde, the precursor of all-trans-retinoic acid that regulates the transcription of numerous genes. The interconversion is catalyzed by two distinct components of the ROC: the NAD(H)-dependent retinol dehydrogenase 10 (RDH10) and the NADP(H)-dependent dehydrogenase reductase 3 (DHRS3). The binding between RDH10 and DHRS3 subunits in the ROC results in mutual activation of the subunits. The molecular basis for their activation is currently unknown. Here, we applied site-directed mutagenesis to investigate the roles of amino acid residues previously implied in subunit interactions in other SDRs to obtain the first insight into the subunit interactions in the ROC. The results of these studies suggest that the cofactor binding to RDH10 subunit is critical for the activation of DHRS3 subunit and vice versa. The C-terminal residues 317-331 of RDH10 are critical for the activity of RDH10 homo-oligomers but not for the binding to DHRS3. The C-terminal residues 291-295 are required for DHRS3 subunit activity of the ROC. The highly conserved C-terminal cysteines appear to be involved in inter-subunit communications, affecting the affinity of the cofactor binding site in RDH10 homo-oligomers as well as in the ROC. Modeling of the ROC quaternary structure based on other known structures of SDRs suggests that its integral membrane-associated subunits may be inserted in adjacent membranes of the endoplasmic reticulum (ER), making the formation and function of the ROC dependent on the dynamic nature of the tubular ER network.
Topics: Alcohol Oxidoreductases; Amino Acid Sequence; Animals; Biocatalysis; Carbonyl Reductase (NADPH); Catalytic Domain; Endoplasmic Reticulum; HEK293 Cells; Humans; Membrane Proteins; Mutagenesis, Site-Directed; Protein Structure, Quaternary; Retinaldehyde; Spodoptera; Structure-Activity Relationship; Tretinoin
PubMed: 34542554
DOI: 10.1042/BCJ20210589 -
International Journal of Molecular... Jan 2021Corneal and conjunctival inflammation and dry eye develop in systemic vitamin A deficiency (VAD). The objective of this study was to investigate the lacrimal ocular...
Corneal and conjunctival inflammation and dry eye develop in systemic vitamin A deficiency (VAD). The objective of this study was to investigate the lacrimal ocular surface retinoid axis, particularly immunomodulatory effects of retinoic acid (RA) and change in conjunctival myeloid cell number and phenotype in VAD. We discovered that ocular surface epithelial and myeloid cells express retinoid receptors. Both all - and 9--RA suppressed production of dry eye relevant inflammatory mediators [interleukin(IL)-1β, IL-12, regulated upon activation, normal T cell expressed and secreted (RANTES)] by myeloid cells. Systemic VAD was associated with significant goblet cell loss and an increased number of CD45+ immune cells in the conjunctiva. MHCIICD11b classical monocytes were significantly increased in the conjunctiva of VAD C57BL/6 and RXR-α mutated Pinkie strains. RNA seq revealed significantly increased expression of innate immune/inflammatory genes in the Pinkie conjunctiva. These findings indicate that retinoids are essential for maintaining a healthy, well-lubricated ocular surface and have immunomodulatory effects in the conjunctiva that are mediated in part via RXR-α signaling. Perturbation of the homeostatic retinoid axis could potentiate inflammation on the ocular surface.
Topics: Animals; Chemokine CCL5; Conjunctiva; Cornea; Dry Eye Syndromes; Eye; Female; Goblet Cells; Homeostasis; Immunity, Innate; Inflammation; Interleukin-12 Subunit p35; Interleukin-1beta; Lacrimal Apparatus; Mice; Mice, Inbred C57BL; Myeloid Cells; Receptors, Retinoic Acid; Retinoids; Signal Transduction; Tretinoin; Vitamin A; Vitamin A Deficiency
PubMed: 33499199
DOI: 10.3390/ijms22031092 -
Pharmacology & Therapeutics Feb 2022Vitamin A is an important micro-essential nutrient, whose primary dietary source is retinyl esters. In addition, β-carotene (pro-vitamin A) is a precursor of vitamin A... (Review)
Review
Vitamin A is an important micro-essential nutrient, whose primary dietary source is retinyl esters. In addition, β-carotene (pro-vitamin A) is a precursor of vitamin A contained in green and yellow vegetables that is converted to retinol in the body after ingestion. Retinol is oxidized to produce visual retinal, which is further oxidized to retinoic acid (RA), which is used as a therapeutic agent for patients with promyelocytic leukemia. Thus, the effects of retinal and RA are well known. In this paper, we will introduce (1) vitamin A circulation in the body, (2) the actions and mechanisms of retinal and RA, (3) retinoylation: another RA mechanism not depending on RA receptors, (4) the relationship between cancer and actions of retinol or β-carotene, whose roles in vivo are still unknown, and (5) anti-cancer actions of vitamin A derivatives derived from fenretinide (4-HPR). We propose that vitamin A nutritional management is effective in the prevention of cancer.
Topics: Cell Differentiation; Delivery of Health Care; Humans; Neoplasms; Receptors, Retinoic Acid; Tretinoin; Vitamin A
PubMed: 34175370
DOI: 10.1016/j.pharmthera.2021.107942 -
Wiley Interdisciplinary Reviews.... May 2017Vitamin A and its active metabolite retinoic acid are essential for embryonic development and adult homeostasis. Surprisingly, excess or deficiency of vitamin A and... (Review)
Review
Vitamin A and its active metabolite retinoic acid are essential for embryonic development and adult homeostasis. Surprisingly, excess or deficiency of vitamin A and retinoic acid can cause similar developmental defects. Therefore, strict feedback and other mechanisms exist to regulate the levels of retinoic acid within a narrow physiological range. The oxidation of vitamin A to retinal has recently been established as a critical nodal point in the synthesis of retinoic acid, and over the past decade, RDH10 and DHRS3 have emerged as the predominant enzymes that regulate this reversible reaction. Together they form a codependent complex that facilitates negative feedback maintenance of retinoic acid levels and thus guard against the effects of dysregulated vitamin A metabolism and retinoic acid synthesis. This review focuses on advances in our understanding of the roles of Rdh10 and Dhrs3 and their impact on development and disease. WIREs Dev Biol 2017, 6:e264. doi: 10.1002/wdev.264 For further resources related to this article, please visit the WIREs website.
Topics: Animals; Embryonic Development; Homeostasis; Humans; Signal Transduction; Vitamin A
PubMed: 28207193
DOI: 10.1002/wdev.264 -
Renal Failure Dec 2022Retinol concentrations in serum are significantly higher in patients on hemodialysis (HD) compared to healthy controls. Its lower concentrations have been reported to be...
BACKGROUND
Retinol concentrations in serum are significantly higher in patients on hemodialysis (HD) compared to healthy controls. Its lower concentrations have been reported to be an independent predictor of mortality. ATRA - all-trans retinoic acid - is an important compound related to retinol. The objective was to determine ATRA concentrations in serum and to find their association with the prognosis of patients on long-term HD.
METHODS
ATRA was determined by high-performance liquid chromatography in a group of 247 HD patients (follow-up five years) and 54 healthy controls.
RESULTS
Although serum retinol concentrations were higher in the studied cohort of HD patients, ATRA was lower - median 1.13 (interquartile range 0.90-1.60) ng/mL in HD patients versus 1.42 (1.08-1.63) ng/mL in healthy controls, = 0.02. Lower ATRA was significantly related to overall mortality of HD patients (HR (95%CI) 0.63 (0.47-0.85) per interquartile range, = 0.003). The best prognosis was observed in patients with concentrations of both ATRA and retinol above the median ( = 0.003).
CONCLUSIONS
We detected decreased retinoic acid levels in HD patients compared to healthy controls. Lower concentrations of ATRA represent a significant predictor of mortality and provide additional information to retinol.
Topics: Humans; Tretinoin; Vitamin A; Prognosis; Chromatography, High Pressure Liquid; Renal Dialysis
PubMed: 36330606
DOI: 10.1080/0886022X.2022.2126786 -
Photochemistry and Photobiology 2015Retinol degrades rapidly in light into a variety of photoproducts. It is remarkable that visual cycle retinoids can evade photodegradation as they are exchanged between...
Retinol degrades rapidly in light into a variety of photoproducts. It is remarkable that visual cycle retinoids can evade photodegradation as they are exchanged between the photoreceptors, retinal pigment epithelium and Müller glia. Within the interphotoreceptor matrix, all-trans retinol, 11-cis retinol and retinal are bound by interphotoreceptor retinoid-binding protein (IRBP). Apart from its role in retinoid trafficking and targeting, could IRBP have a photoprotective function? HPLC was used to evaluate the ability of IRBP to protect all-trans and 11-cis retinols from photodegradation when exposed to incandescent light (0 to 8842 μW cm(-2)); time periods of 0-60 min, and bIRBP: retinol molar ratios of 1:1 to 1:5. bIRBP afforded a significant prevention of both all-trans and 11-cis retinol to rapid photodegradation. The effect was significant over the entire light intensity range tested, and extended to the bIRBP: retinol ratio 1:5. In view of the continual exposure of the retina to light, and the high oxidative stress in the outer retina, our results suggest IRBP may have an important protective role in the visual cycle by reducing photodegradation of all-trans and 11-cis retinols. This role of IRBP is particularly relevant in the high flux conditions of the cone visual cycle.
Topics: Animals; Cattle; Dose-Response Relationship, Radiation; Eye Proteins; Light; Photolysis; Radiation-Protective Agents; Retina; Retinaldehyde; Retinol-Binding Proteins; Vitamin A
PubMed: 25565073
DOI: 10.1111/php.12416