Effect of Crocin and Crocetin Compared to Cyclophosphamide on the Expression Level of miRNA-16-1 in a B Cell Transformed with EBV Virus Cell Line.

INTRODUCTION: Crocin and Crocetin are compounds that have shown promising therapeutic potentials in various medical contexts. To date, the effect of crocin and crocetin on the expression level of miRNA-16-1 in Epstein Barr Virus (EBV)-induced lymphoma has not been investigated. This research delved into a comparative analysis of the cytotoxic effects of crocin and crocetin compared to cyclophosphamide, the main drug used in the treatment of lymphoma and PTLD, on B-cell lymphoma infected with EBV (cell line CO 88BV59-1). Additionally, the study examines the changes in miRNA-16-1 expression following these treatments in this cell line. MATERIALS AND METHODS: CO 88BV59-1 LCL cells were treated with crocin, crocetin (0.2 to 200 µM), and cyclophosphamide (0.05 to 50 µM) for 72 hours. Cell viability and apoptosis were assessed using resazurin and Annexin V/PI techniques, respectively. Additionally, the expression of miRNA-16-1-3p and miRNA-16-1-5p was determined using the Real-Time PCR method. The data were analyzed using one-way analysis of variance (ANOVA) with Tukey's multiple comparisons post-hoc test. RESULTS: Crocin and crocetin inhibited the proliferation and apoptosis caused by EBV-infected cells in a dose- and time-dependent manner (P<0.05). The expression levels of miRNA-16-1-3p and miRNA-16-1-5p remained unchanged in cells treated with crocin and crocetin. CONCLUSION: The study found that the cytotoxic effect of Crocin, Crocetin, and Cyclophosphamide on CO 88BV59-1 LCL is independent of the expression level of miRNA-16-1. The results showed a reduction in cell survival and an increase in cell death.

Solid Lipid Nanoparticles Incorporated with Retinol and Pentapeptide-18-Optimization, Characterization, and Cosmetic Application.

Solid lipid nanoparticles (SLNs) incorporated with retinol and oligopeptide can have a full spectrum of effects on the skin as a compatible combination of ingredients with broad anti-aging properties. The research's main objective was to ensure the stability of lipid nanocarriers containing retinol and peptide due to the planned use of this dispersion as a cosmetic raw material. To confirm the effectiveness of method optimization (high shear homogenization, HSH) and proper selection of substrates, SLN dispersions were obtained in three combinations: 1-non-incorporated SLNs; 2-SLNs containing only retinol; 3-SLNs containing retinol and pentapeptide-18; these were then stored at different temperatures (4, 25, 45 °C) for 4 weeks. The desired values of the physicochemical parameters of the optimized dispersion of lipid nanoparticles incorporated with retinol and oligopeptide over the required storage period were confirmed: mean particle size (Z-Ave) = 134.7 ± 0.3 nm; polydispersity index (PDI) = 0.269 ± 0.017 [-]; zeta potential (ZP) = 42.7 ± 1.2 mV (after 4 weeks at 25 °C). The results confirmed the proper selection of the SLN production method and the effectiveness of the optimization performed. The possibility of using the obtained raw material as an ingredient in cosmetic products with anti-aging properties was indicated.

Association between fat-soluble vitamins and metabolic syndromes in US adults: a cross-section study from NHANES database.

BACKGROUND: Previous studies have shown significant associations between individual fat-soluble vitamins (FSVs) and metabolic syndromes (MetS). However, evidence on the multiple FSVs co-exposure and MetS odds is limited. Given that individuals are typically exposed to different levels of FSVs simultaneously, and FSVs can interact with each other. It's necessary to explore the association between multiple FSVs co-exposure and MetS odds. This study aims to address this gap in general U.S. adults aged ≥ 20 years. METHODS: We conducted a cross-sectional study utilizing data from the National Health and Nutrition Examination Surveys (NHANESs) 2003-2006 and 2017-2018. Three FSV, including vitamin A (VA), vitamin E (VE), and vitamin D (VD), and MetS diagnosed according to the ATP III guidelines were selected as exposure and outcome, respectively. Multivariable-adjusted logistic model was used to explore the associations of individual FSV exposure with MetS odds and MetS components. Restricted cubic splines were performed to explore the dose-response relationships among them. The quantile g-computation method was adopted to explore the associations of multiple FSVs co-exposure with MetS odds and MetS components. RESULTS: The presented study included a total of 13,975 individuals, with 2400 (17.17%) were diagnosed with MetS. After adjusting for various confounders, a positive linear pattern was observed for serum VA and VE and MetS associations. Serum VD was found to be negatively associated with MetS in a linear dose-response way. For each component of MetS, higher serum VA and VE were associated with higher triglyceride and high-density lipoprotein; higher serum VD was negatively associated with triglyceride, blood pressure, and fasting plasma glucose. MetS odds increased by 15% and 13%, respectively, in response to one quartile increase in FSVs co-exposure index (qgcomp) in the conditional model (OR = 1.15, 95%CI: 1.06, 1.24) and the marginal structural model (OR = 1.13, 95%CI: 1.06, 1.20). Besides, co-exposure to VA, VE, and VD was positively associated with triglyceride, high-density lipoprotein, and blood pressure levels. CONCLUSION: Findings in the present study revealed that high serum VA and VE levels were associated with elevated MetS odds, while serum VD was inversely associated with MetS odds. FSVs co-exposure was positively associated with MetS odds.

Association of variant vitamin statuses and tuberculosis development: a systematic review and meta-analysis.

BACKGROUND: Several studies have suggested an association between vitamin deficiency and the development of tuberculosis; however, the precise impact remains unclear. This study aimed to elucidate the relationship between distinct vitamin statuses and the occurrence of tuberculosis. MATERIALS AND METHODS: Retrieval was conducted using several databases without language restrictions to capture the eligible studies on tuberculosis and vitamin status. Pooled odds ratios (ORs), relative risks (RRs), and hazard ratios (HRs) were used with 95% confidence intervals (CIs) to clarify the relationship between the different vitamin statuses (A, B, D, and E) and the occurrence of tuberculosis. Subgroup analysis, sensitivity analysis, meta-regression analysis, and Galbraith plot were performed to determine sources of heterogeneity. Potential publication biases were detected using Begg's test, Egger's test, and the trim-and-fill test. RESULTS: We identified 10,266 original records from our database searches, and 69 eligible studies were considered in this study. The random-effect model showed that people with tuberculosis may exhibit vitamin A deficiency (OR = 10.66, 95%CI: 2.61-43.63, p = .001), while limited cohort studies showed that vitamin A supplementation may reduce tuberculosis occurrence. Additionally, vitamin D deficiency was identified as a risk factor for tuberculosis development (RR = 1.69, 95%CI: 1.06-2.67, p = .026), and people with tuberculosis generally had lower vitamin D levels (OR = 2.19, 95%CI: 1.76-2.73, p < .001) compared to other groups. No publication bias was detected. CONCLUSIONS: This meta-analysis indicated that people with tuberculosis exhibited low levels of vitamins A and D, while vitamin D deficiency was identified as a risk factor for tuberculosis. More randomized controlled interventions at the community levels should be recommended to determine the association between specific vitamin supplementation and tuberculosis onset.

Evaluating a novel method for vitamin A analysis in an observational study of the UAE's obese population.

Vitamin A plays a critical role in various biological functions, including vision, cellular differentiation, and immune regulation. However, accurately assessing its status, particularly in obese individuals, presents challenges due to potential alterations in metabolism and distribution. This study utilized Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) methodology to precisely measure serum vitamin A concentrations in population of UAE. The methodology's reliability and precision, as demonstrated through validation procedures, underscore its potential utility in clinical settings. Employing the Multiple Reaction Monitoring mode of positive ion electrospray ionization, the LC-MS/MS system achieves a limit of detection (LOD) of 0.48 ng/mL in serum, while adhering to FDA-US regulations for accuracy and compliance. A key aspect of this study was the application of LC-MS/MS to assess vitamin A status in an obese population within UAE. By employing a diverse cohort of 452 Emirati participants, including 277 individuals from a randomized controlled trial who were assessed at baseline and at 6th month, and 175 healthy individuals aged 18-82 assessed at baseline, this study explores the relationship between obesity and vitamin A levels, shedding light on potential implications for health and well-being. It was an observational study based on a new vitamin A method and participants were asked to eat vitamin A rich foods. The robust performance of the LC-MS/MS methodology positions it as a valuable tool for clinical research. By accurately quantifying vitamin A levels in human serum, this methodology opens avenues for advancing our understanding of vitamin A physiology and its implications for health, particularly in obese populations. In summary, this LC-MS/MS methodology presents a potent tool for clinical studies, providing reliable, specific, and robust detection of vitamin A in human serum, thus, opening a new frontier for advancing our understanding of vitamin A related physiology and health in the obese population.

Reduced retinol (vitamin A) and α-tocopherol (vitamin E) blood levels and increased myeloperoxidase (MPO) activity in children with high myopia.

The study assessed selected parameters of redox status in the plasma of patients suffering from high myopia (HM). Thirty-five children with mean age 13.7 ± 2.7 years with HM and 40 healthy children were included. Plasma redox status parameters were determined using colorimetric kits. The levels of retinol, α-tocopherol and coenzyme Q10 were determined with a high-performance liquid chromatograph. Negative correlations were observed between the concentrations of retinol and the axial length of the eye (r = - 0.514 p < 0.001). Increased myeloperoxidase (MPO) activity (p < 0.018), and decreased concentrations of retinol (p < 0.001) and α-tocopherol (p < 0.023) in patients with HM and the axial length of the eye > 26 mm compared to controls were established. Significantly lower retinol and α-tocopherol concentrations were found in patients with the axial length of the eye > 26 mm compared to those with the axial length of the eye ≤ 26 mm (p < 0.001, p < 0.021, respectively). Increased MPO activity in advanced stages of HM may confirm an inflammatory process in HM patients. Reduced retinol and α-tocopherol concentrations and their link to disease progression indicate a need for monitoring their levels and supplementation in children with HM.

The Influence of Retinol Ointment on Rabbit Skin (Oryctolagus cuniculus) Ion Transport-An In Vitro Study.

Retinoids are known to improve the condition of the skin. Transepithelial transport of sodium and chloride ions is important for proper skin function. So far, the effect of applying vitamin A preparations to the skin on ion transport has not been evaluated. In the study, electrophysiological parameters, including transepithelial electric potential (PD) and transepithelial resistance (R), of rabbit skin specimens after 24 h exposure to retinol ointment (800 mass units/g) were measured in a modified Ussing chamber. The R of the fragments incubated with retinol was significantly different than that of the control skin samples incubated in iso-osmotic Ringer solution. For the controls, the PD values were negative, whereas the retinol-treated specimens revealed positive PD values. Mechanical-chemical stimulation with the use of inhibitors of the transport of sodium (amiloride) or chloride (bumetanide) ions revealed specific changes in the maximal and minimal PD values measured for the retinol-treated samples. Retinol was shown to slightly modify the transport pathways of sodium and chloride ions. In particular, an intensification of the chloride ion secretion from keratinocytes was observed. The proposed action may contribute to deep hydration and increase skin tightness, limiting the action of other substances on its surface.

Food craving, vitamin A, and menstrual disorders: A comprehensive study on university female students.

BACKGROUND: Menstrual disorders, influenced by dietary habits like high fat intake and low fruit and vegetable consumption, are a global public health issue. This study assessed the prevalence of dysmenorrhea, premenstrual syndrome (PMS), and irregular menstrual cycle (IMC) among female university students in Bangladesh, focusing on food cravings and low vitamin A intake as risk factors. METHODS: In this comprehensive study, data from randomly selected female university students were collected using a structured questionnaire. The associations were analyzed through chi-square tests and multivariable logistic regression, reported as adjusted odds ratios (AOR). RESULTS: The most prevalent menstrual disorder was dysmenorrhea (68.3%) followed by PMS (33.8%), and IMC (24.3%). Food cravers for high-fat and sweet foods were likely to experience dysmenorrhea (AOR: 2.4, 95% CI: 1.5-3.9, P<0.001), suffer from PMS (AOR: 3.9, 95% CI: 2.3-6.6, P<0.001), and have IMC (AOR: 3.0, 95% CI: 1.6-5.3, P<0.001) vs. subjects who didn't. Subjects consuming vitamin A-rich plant foods had 40% (AOR: 0.6, 95% CI: 0.4-0.9, P < 0.01) and 60% (AOR: 0.4, 95% CI: 0.2-0.6, P<0.001) less likely suffering from dysmenorrhea and IMC vs. who didn't. Both underweight and overweight/obese subjects experienced more than 2-fold dysmenorrhea vs. normal-weight peers. The chance of IMC was nearly 3-fold among overweight/obese subjects. However, lower physical activity was associated with PMS and IMC whereas family history was associated with dysmenorrhea and PMS. Among the socio-demographic factors, maternal education, place of residence, and earlier menarche (≤12 years) were associated with dysmenorrhea while marital status was associated with IMC. CONCLUSION: This study indicates that increasing the intake of vitamin A-rich plant foods and reducing high-fat, sweet foods can lower the risk of dysmenorrhea and IMC. Additionally, it highlights the need for regular exercise to mitigate the increased risk of PMS and IMC.

Impact of nutritional and multiple micronutrients supplementation to lactating mothers 6 months postpartum on the maternal and infant micronutrient status: a randomised controlled trial in Delhi, India.

OBJECTIVES: To assess the impact of nutritional and multiple-micronutrient supplementation to lactating mothers on the micronutrient status of mother-infant dyad at 6 months of age postnatally. DESIGN: This study was a trial that aimed to investigate the impact of maternal nutritional supplementation on infant growth. A secondary objective was to assess the effect on the micronutrient status of mother-infant pairs. The intervention group mothers received snacks with 600 kcal energy, 20 g protein and daily micronutrient tablets. SETTING: Blood samples were collected from both mothers and infants at 6 months. PARTICIPANTS: The participants in this study were mother-infant pairs. The micronutrient status of these pairs was assessed through blood samples, focusing on vitamins A, D, B12, ferritin, Zn and folate. RESULTS: Micronutrient analysis of serum samples from 600 mother-infant pairs showed that mothers in the intervention group had higher levels of serum ferritin (mean difference (MD) 14·7 ng/ml), retinol (MD 0·6 µmol/l), folate (MD 3·3 ng/ml) and vitamin D (1·03 ng/ml) at 6 months postpartum. Additionally, the supplementation was associated with a higher mean ± sd of serum ferritin (MD 8·9 ng/ml) and vitamin A (MD 0·2 µmol/l) levels in infants at 6 months. CONCLUSIONS: The study found that supplementing maternal nutrition with additional dietary and micronutrient intakes during lactation improved maternal micronutrient status and slightly increased ferritin and vitamin A levels in infants at 6 months. The findings highlight the importance of nutritional interventions for improving the micronutrient health of mother-infant pairs, with significant public health implications.Trial registered at www.clinicaltrials.gov (CTRI/2018/04/013095).

[Construction of Saccharomyces cerevisiae cell factories for fermentation production of retinol].

Retinol is one of the main active forms of vitamin A, crucial for the organism's growth, development, and maintenance of eye and skin functions. It is widely used in cosmetics, pharmaceuticals, and feed additives. Although animals lack a complete pathway for synthesizing vitamin A internally, they can obtain vitamin A directly through diet or convert ß-carotene acquired from the diet. To boost the research on the biosynthesis of retinol, three different sources of alcohol dehydrogenase were firstly screened based on the ß-carotene synthesis platform CAR*1. It was determined that ybbO from Escherichia coli exhibited the highest catalytic activity,with a conversion rate of 95. 6%. To further enhance the reaction rate and yield of retinol, protein fusion technology was employed to merge two adjacent enzymes, blh and ybbO, within the retinol synthesis module. The evaluation was conducted using the high-yield engineered strain CAR*3 of ß-carotene. The optimal combination, blh-GGGS-ybbO, was obtained, with a 44. 9% increase in yield after fusion, reaching(111. 1± 3. 5) mg·L~(-1). Furthermore, through the introduction of human-derived retinol-binding protein(RBP4) and transthyretin(TTR), the process of hepatic cell secreting retinol was simulated in Saccharomyces cerevisiae, leading to an increased retinol yield of(158. 0±13. 1)mg·L~(-1). Finally, optimization strategies including overexpressing INO2 to enhance the reaction area for ß-carotene synthesis, enhancing hemoglobin VHb expression to improve oxygen supply, and strengthening PDR3m expression to facilitate retinol transport were implemented. A two-stage fermentation process resulted in the successful elevation of retinol production to(2 320. 0±26. 0)mg·L~(-1) in the fermentation tank of 5 L, which provided a significant foundation for the industrial development of retinol.

From ß-Carotene to Retinoids: A Review of Microbial Production of Vitamin A.

Vitamin A (retinoids) is crucial for human health, with significant demand across the food, pharmaceutical, and animal feed industries. Currently, the market primarily relies on chemical synthesis and natural extraction methods, which face challenges such as low synthesis efficiency and complex extraction processes. Advances in synthetic biology have enabled vitamin A biosynthesis using microbial cell factories, offering a promising and sustainable solution to meet the increasing market demands. This review introduces the key enzymes involved in the biosynthesis of vitamin A from ß-carotene, evaluates achievements in vitamin A production using various microbial hosts, and summarizes strategies for optimizing vitamin A biosynthesis. Additionally, we outline the remaining challenges and propose future directions for the biotechnological production of vitamin A.

Suppression of ferroptosis by vitamin A or radical-trapping antioxidants is essential for neuronal development.

The development of functional neurons is a complex orchestration of multiple signaling pathways controlling cell proliferation and differentiation. Because the balance of antioxidants is important for neuronal survival and development, we hypothesized that ferroptosis must be suppressed to gain neurons. We find that removal of antioxidants diminishes neuronal development and laminar organization of cortical organoids, which is fully restored when ferroptosis is inhibited by ferrostatin-1 or when neuronal differentiation occurs in the presence of vitamin A. Furthermore, iron-overload-induced developmental growth defects in C. elegans are ameliorated by vitamin E and A. We determine that all-trans retinoic acid activates the Retinoic Acid Receptor, which orchestrates the expression of anti-ferroptotic genes. In contrast, retinal and retinol show radical-trapping antioxidant activity. Together, our study reveals an unexpected function of vitamin A in coordinating the expression of essential cellular gatekeepers of ferroptosis, and demonstrates that suppression of ferroptosis by radical-trapping antioxidants or by vitamin A is required to obtain mature neurons and proper laminar organization in cortical organoids.

Strategies to combat heat stress in Isa Brown layer hens: Unveiling the roles of vitamin A, vitamin E, vitamin K, vitamin C, selenium, folic acid, and in combination.

Background: Due to their efficient insulation, lack of sweat glands, relatively quick metabolic rate, and heightened sensitivity to heat, the poultry industry faces a serious problem with heat stress. Combining vitamins has been demonstrated to be more effective than implementing a single vitamin in reducing the effects of heat stress. Aim: This study aimed to investigate the efficacy of the multivitamin combination in feed on the growth performance, egg quality, and antioxidant enzymes in laying hens exposed to heat stress. Methods: A total of 28 Isa Brown strains aged 18 weeks were randomly designated into seven groups with four replications, i.e., (C-) normal temperature group, (C+) heat stress group, and the others with the administration of vitamin A and E (AE), vitamin K and C (KC), vitamin C and E (CE), vitamin E and selenium (ESE), and vitamin C and folic acid (CAF). Feed intake, feed efficiency, eggshell thickness, shape index, haugh unit (HU), yolk, and albumen index were evaluated at 22, 23, 24, and 25 weeks. Meanwhile, antioxidant enzymes were quantified at 22 and 25 weeks. Results: As a result, feed intake was reported a significant improvement in the AE and CE groups compared to the C+ group. Meanwhile, the feed efficiency was reported to be efficient in the CE and ESE groups. Based on egg quality evaluation, we reported significant shell thickness in the CE, ESE, and CAF groups compared to the C+; yolk index was reported slightly significant results in the AE and CAF groups; albumen index and HU were reported to increase significantly in the CAF group. Meanwhile, superoxide dismutase (SOD), malondialdehyde (MDA), and GPx activity were ameliorated significantly in the ESE and CAF groups. Conclusion: Combinations of multivitamins can thereby enhance feed intake, feed efficiency, egg quality, and antioxidant activity. The CE, ESE, and CAF groups were found to have made equivalent improvements in the eggshell thickness, shape index, HU, yolk, and albumen index.

Associations of Serum Vitamin A and E Concentrations with Pulmonary Function Parameters and Chronic Obstructive Pulmonary Disease.

BACKGROUND/OBJECTIVES: Oxidative stress, an imbalance between oxidants and antioxidants, is known to affect pulmonary function (PF), thereby leading to the development of chronic obstructive pulmonary disease (COPD). However, data on the associations of serum vitamin A and E concentrations with PF parameters and COPD are inconsistent. The present cross-sectional study aimed to investigate these associations, considering inflammatory status. PARTICIPANTS/METHODS: This study included 2005 male and female adults aged ≥40 years who had participated in a population-based national survey. Spirometry without a bronchodilator was conducted to yield PF parameters, such as forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and the FEV1/FVC ratio, which were used to define COPD. Serum vitamin A (retinol) and E (α-tocopherol) concentrations were assayed. Multivariable regression analysis was performed after adjusting for potential confounding variables. RESULTS: Serum vitamin A concentration was positively associated with FEV1 (p for trend < 0.01) among all participants. In addition, the odds ratio (95% confidence interval) of the highest serum vitamin A concentration tertile for the prevalence of COPD, which was defined by the FEV1/FVC ratio < 0.7, was 0.53 (0.31, 0.90) compared with that of the lowest tertile (p for trend < 0.05). Analysis stratified by a cutoff point of 1 mg/L serum high-sensitivity C-reactive protein (hs-CRP) revealed that such associations with FEV1 and COPD prevalence were stronger in participants with lower hs-CRP levels (p for trend < 0.05). In contrast, serum vitamin E concentration was associated with neither PF parameters nor COPD prevalence. CONCLUSIONS: These findings suggest that serum vitamin A concentration may be important in preventing the progressive decline in PF parameters that results in COPD. Further epidemiological investigations are warranted to evaluate the causal associations of antioxidant vitamin status with PF parameters and COPD.

Glutamine is the only amino acid that can adequately support the generation of NADPH in rod photoreceptors.

NADPH, the primary source of reducing equivalents in the cytosol, is used in vertebrate rod photoreceptor outer segments to reduce the all-trans retinal released from photoactivated visual pigment to all-trans retinol. Light activation of the visual pigment isomerizes the 11-cis retinal chromophore to all-trans, thereby destroying it and necessitating its regeneration. Release and reduction of all-trans retinal are the first steps in the series of reactions that regenerate the visual pigment. Glucose and glutamine can both support the reduction of all-trans retinal to retinol, indicating that the NADPH used in rod photoreceptor outer segments can be generated by the pentose phosphate pathway as well as by mitochondria-linked pathways. We have used the conversion of all-trans retinal to all-trans retinol to examine whether amino acids other than glutamine can also support the generation of NADPH in rod photoreceptors. We have measured this conversion in single isolated mouse rod photoreceptors by imaging the fluorescence of the all-trans retinal and retinol generated after exposure of the cells to light. In agreement with previous work, we find that 5 mM glucose or 0.5 mM glutamine support the conversion of ∼70-80% of all-trans retinal to retinol, corresponding to a reduced NADP fraction of ∼10%. All other amino acids at 0.5 mM concentration support the conversion to a much lesser extent, indicating reduced NADP fractions of 1-2% at most. Taurine was also ineffective at supporting NADPH generation, while formic acid, the toxic metabolite of methanol, suppressed the generation of NADPH by either glucose or glutamine.

Retinoids: Molecular Aspects and Treatment in Premalignant Lesions and Cervical Cancer.

Persistent infection with high-risk human papillomavirus remains the primary factor associated with the progression of cervical squamous intraepithelial lesions and the development of cervical cancer. Nevertheless, a combination of factors, including genetic predisposition, immune response, hormonal influences, and nutritional status, contribute synergistically to the development of cervical cancer. Among the various factors involved in the pathogenesis and therapy of cervical cancer, retinoids have gained considerable attention due to their multifaceted roles in different cellular processes. This review investigates defects within the vitamin A metabolism pathway and their correlation with cervical cancer. Additionally, it integrates epidemiological and experimental findings to discuss the potential utility of retinoid-based therapies, either alone or combined with other therapies, as agents against premalignant lesions and cervical cancer.

New findings in the metabolism of the saffron apocarotenoids, crocins and crocetin, by the human gut microbiota.

The main constituents of saffron are the apocarotenoids crocins and crocetin, present in the stigmas. Numerous healthy properties, especially those related to the effects on the central nervous system, have been attributed to these compounds but the metabolites responsible for these effects are still unknown. Previous evidences in animal models suggest a role for the gut microbiota in the pharmacokinetics and the neuroprotective effects of these compounds. However, the interaction between these apocarotenoids and the gut microbiota has been poorly studied. In this article, we have thoroughly investigated the batch fermentation of crocin-1 and crocetin (10 µM) with human fecal samples of two donors at different incubation times (0-240 h) using a metabolomic approach. We corroborated a rapid transformation of crocin-1 which looses the glucose molecules through de-glycosylation reactions until its complete transformation into crocetin in 6 hours. A group of intermediate crocins with different degrees of glycosylation were detected in a very short time. Crocetin was further metabolized and new microbial metabolites produced by double-bond reduction and demethylation reactions were identified for the first time: dihydro and tetrahydro crocetins and di-demethyl crocetin. In addition, we detected changes in the levels of the short chain fatty acids valeric acid and hexanoic acid suggesting further structural modifications of crocetin or changes in the catabolic production of these compounds. This research is a pioneering study of the action of the human gut microbiota on the saffron apocarotenoids and goes one step further towards the discovery of metabolites potentially involved in the benefits of saffron.

Dysregulated serum concentrations of fat-soluble vitamins in dogs with chronic enteropathy.

BACKGROUND: In inflammatory bowel disease (IBD) of humans, nutrient malabsorption can result in fat-soluble vitamin deficiency, especially of vitamin D. In veterinary species, decreased concentrations of vitamin D are relatively common in dogs with chronic enteropathy (CE), but data on the status of other fat-soluble vitamins (FSVs) is lacking. OBJECTIVES: Determine the serum concentrations of retinol, vitamin D, and α-tocopherol in dogs with CE compared with healthy dogs and compare clinical, clinicopathologic variables between CE and healthy dogs to detect associations with decreased FSVs concentrations. ANIMALS: Eighteen client-owned dogs with CE and 33 healthy dogs. METHODS: Serum 25-hydroxyvitamin D (25[OH]D), serum retinol and α-tocopherol concentrations were compared between groups. Correlations and multiple regression modeling were used to examine the relationship between serum 25(OH)D, retinol, and α-tocopherol concentrations and clinical and clinicopathological variables. RESULTS: Dogs with low serum albumin concentrations were more likely to have lower 25(OH)D concentrations than dogs with normal serum albumin concentration. Dogs with CE had higher serum concentrations of retinol, and variable α-tocopherol concentrations. The cause of these dysregulated vitamin concentrations is unclear and requires further study. CONCLUSION AND CLINICAL IMPORTANCE: Dogs with severe forms of CE should be monitored for decreased concentrations of 25(OH)D. Additional studies are needed to evaluate the clinical relevance and the possible benefit of vitamin D supplementation in these patients.

Boosting of retinol activity using novel lecithin: Retinol acyltransferase inhibitors.

Lecithin:retinol acyltransferase (LRAT) is the main enzyme catalysing the esterification of retinol to retinyl esters and, hence, is of central importance for retinol homeostasis. As retinol, by its metabolite retinoic acid, stimulates fibroblasts to synthesize collagen fibres and inhibits collagen-degrading enzymes, the inhibition of LRAT presents an intriguing strategy for anti-ageing ingredients by increasing the available retinol in the skin. Here, we synthesized several derivatives mimicking natural lecithin substrates as potential LRAT inhibitors. By exploring various chemical modifications of the core scaffold consisting of a central amino acid and an N-terminal acylsulfone, we explored 10 different compounds in a biochemical assay, resulting in two compounds with IC50 values of 21.1 and 32.7 µM (compounds 1 and 2), along with a simpler arginine derivative with comparative inhibitory potency. Supported by computational methods, we investigated their structure-activity relationship, resulting in the identification of several structural features associated with high inhibition of LRAT. Ultimately, we conducted an ex vivo study with human skin, demonstrating an increase of collagen III associated with a reduction of the skin ageing process. In conclusion, the reported compounds offer a promising approach to boost retinol abundance in human skin and might present a new generation of anti-ageing ingredients for cosmetic application.

La lécithine/rétinol acyltransférase (LRAT) est la principale enzyme qui catalyse l'estérification du rétinol en esters de rétinyle et, par conséquent, est d'une importance centrale pour l'homéostasie du rétinol. Étant donné que le rétinol, par son métabolite l'acide rétinoïque, stimule les fibroblastes pour synthétiser les fibres de collagène et inhibe les enzymes de dégradation du collagène, l'inhibition de la LRAT constitue une stratégie intéressante pour les ingrédients anti­âge en augmentant le rétinol disponible dans la peau. Ici, nous avons synthétisé plusieurs dérivés imitant les substrats naturels de la lécithine comme inhibiteurs de LRAT potentiels. En étudiant différentes modifications chimiques du noyau composé d'un acide aminé central et d'un acylsulfone N­terminal, nous avons étudié dix composés différents dans le cadre d'un essai biochimique; il en est résulté deux composés avec des valeurs de CI50 de 21.1 et 32.7 µm (composés 1 et 2), ainsi qu'un dérivé d'arginine plus simple avec une puissance inhibitrice comparative. Avec le soutien de méthodes computationnelles, nous avons étudié leur relation structure­activité, ce qui a permis d'identifier plusieurs caractéristiques structurelles associées à une inhibition élevée de la LRAT. Enfin, nous avons mené une étude ex vivo sur la peau humaine, démontrant une augmentation du collagène III associée à une réduction du processus de vieillissement de la peau. En conclusion, les composés rapportés offrent une approche prometteuse pour stimuler l'abondance du rétinol dans la peau humaine et pourraient aboutir à une nouvelle génération d'ingrédients anti­âge pour des applications cosmétiques.

Vitamin A carotenoids, but not retinoids, mediate the impact of a healthy diet on gut microbial diversity.

BACKGROUND: Vitamin A is essential for physiological processes like vision and immunity. Vitamin A's effect on gut microbiome composition, which affects absorption and metabolism of other vitamins, is still unknown. Here we examined the relationship between gut metagenome composition and six vitamin A-related metabolites (two retinoid: -retinol, 4 oxoretinoic acid (oxoRA) and four carotenoid metabolites, including beta-cryptoxanthin and three carotene diols). METHODS: We included 1053 individuals from the TwinsUK cohort with vitamin A-related metabolites measured in serum and faeces, diet history, and gut microbiome composition assessed by shotgun metagenome sequencing. Results were replicated in 327 women from the ZOE PREDICT-1 study. RESULTS: Five vitamin A-related serum metabolites were positively correlated with microbiome alpha diversity (r = 0.15 to r = 0.20, p < 4 × 10-6). Carotenoid compounds were positively correlated with the short-chain fatty-acid-producing bacteria Faecalibacterium prausnitzii and Coprococcus eutactus. Retinol was not associated with any microbial species. We found that gut microbiome composition could predict circulating levels of carotenoids and oxoretinoic acid with AUCs ranging from 0.66 to 0.74 using random forest models, but not retinol (AUC = 0.52). The healthy eating index (HEI) was strongly associated with gut microbiome diversity and with all carotenoid compounds, but not retinoids. We investigated the mediating role of carotenoid compounds on the effect of a healthy diet (HEI) on gut microbiome diversity, finding that carotenoids significantly mediated between 18 and 25% of the effect of HEI on gut microbiome alpha diversity. CONCLUSIONS: Our results show strong links between circulating carotene compounds and gut microbiome composition and potential links to a healthy diet pattern.