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 anti‐âge 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 N‐terminal, 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 structure‐activité, 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 anti‐âge pour des applications cosmétiques.

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.

Antioxidants play a pivotal role in maintaining skin health and integrity, combating the deleterious effects of oxidative stress induced by environmental aggressors such as UV ra-diation, pollution, and lifestyle factors. This paper reviews the contributions of key antioxidants, including Vitamin C, Vitamin E, Vitamin A, green tea extract, Coenzyme Q10, Resveratrol, Selenium, and Polyphenols, in skin health care. Vitamin C, known for its collagen synthesis promotion and photoprotection properties, alongside Vitamin E, a lipid-soluble antioxidant, syn-ergistically works to neutralize free radicals and repair damaged skin cells. Vitamin A, in the form of retinol, plays a critical role in skin cell regeneration and the maintenance of skin integ-rity. Green tea extract, rich in Polyphenols, offers anti-inflammatory and anticarcinogenic prop-erties, making it a potent ingredient for skin protection. Coenzyme Q10, a naturally occurring antioxidant in the body, aids in energy production for cell repair and regeneration, while Resveratrol, found in grapes and berries, provides anti-ageing benefits by enhancing skin\'s re-sistance to oxidative stress. Selenium, an essential mineral, contributes to the protection of skin cells from oxidative damage. The incorporation of these antioxidants in skincare products and dietary sources is discussed, highlighting the importance of a holistic approach in skincare re-gimes. The paper emphasizes the synergy between topical applications and dietary intake of antioxidants, advocating for a comprehensive strategy for promoting skin health and preventing age-related skin alterations. Method: For the review article, a variety of search engines and databases were used to identify relevant articles. Furthermore, for biomedical literature focusing on antioxidants and their ef-fects on skin health, PubMed was used. Moreover, to access a wide range of scholarly articles, including those related to dermatology and skincare, Google Scholar was used. Scopus provides comprehensive coverage of peer-reviewed literature across various scientific disciplines. Web of Science identifies high-impact articles and research on antioxidants in skincare. In addition, for accessing full-text articles on antioxidants and their applications in dermatology, Science Direct was used. The inclusion criteria for the review paper were as follows: only studies pub-lished in peer-reviewed journals were included to ensure the credibility and reliability of the information. Articles published in English were considered, to avoid language-related biases and ensure comprehension. Studies published within the last 10 years were included to provide the most current insights into antioxidant research in skincare. Articles must specifically focus on the role of antioxidants (Vitamin C, Vitamin E, Vitamin A, green tea extract, Coenzyme Q10, Resveratrol, Selenium, Polyphenols) in skin health care. Both experimental studies (in vivo and in vitro) and clinical trials were included to provide a comprehensive overview of the antioxidant effects. Full-text articles were included to allow for thorough data extraction and analysis. The exclusion criteria for the review paper were as follows: Publications that were not peer-re-viewed, such as editorials, opinion pieces, and non-scholarly articles, were excluded. Articles published in languages other than English were excluded due to potential translation challenges and to maintain consistency. Studies that did not focus on the specified antioxidants or their impact on skin health were excluded. Duplicate publications were excluded to avoid redundancy in the review. Articles with insufficient or incomplete data were excluded to ensure the quality and reliability of the review findings.

Skin aging results from complex interactions of intrinsic and extrinsic factors, leading to structural and biochemical changes such as wrinkles and dryness. Ultraviolet (UV) irradiation leads to the degradation of hyaluronic acid (HA) in the skin, and the with fragmented HA contributes to inflammation. This study revealed that the synergistic combination of carnosine and retinol (ROL) increases HA production in normal human epidermal keratinocytes (NHEKs) by upregulating hyaluronan synthase 2 (HAS2) gene transcription. Simultaneously, the combined treatment of carnosine and ROL significantly attenuates UVB-induced prostaglandin E2 (PGE2) synthesis in NHEKs. A significant correlation exists between the increase of HA synthesis and the inhibition of PGE2 production. This study suggested that combined treatment of carnosine and ROL can improve skin aging phenotypes associated with UVB irradiation.

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.
OBJECTIVE: 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.
METHODS: 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.
CONCLUSIONS: 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.

Lecithin:retinol acyltransferase (LRAT) is the main enzyme producing retinyl esters (REs) in quiescent hepatic stellate cells (HSCs). When cultured on stiff plastic culture plates, quiescent HSCs activate and lose their RE stores in a process similar to that in the liver following tissue damage, leading to fibrosis. Here we validated HSC cultures in soft gels to study RE metabolism in stable quiescent HSCs and investigated RE synthesis and breakdown in activating HSCs. HSCs cultured in a soft gel maintained characteristics of quiescent HSCs, including the size, amount and composition of their characteristic large lipid droplets. Quiescent gel-cultured HSCs maintained high expression levels of Lrat and a RE storing phenotype with low levels of RE breakdown. Newly formed REs are highly enriched in retinyl palmitate (RP), similar to freshly isolated quiescent HSCs, which is associated with high LRAT activity. Comparison of these quiescent gel-cultured HSCs with activated plastic-cultured HSCs showed that although during early activation the total RE levels and RP-enrichment are reduced, levels of RE formation are maintained and mediated by LRAT. Loss of REs was caused by enhanced RE breakdown in activating HSCs. Upon prolonged culturing, activated HSCs have lost their LRAT activity and produce small amounts of REs by DGAT1. This study reveals unexpected dynamics in RE metabolism during early HSC activation, which might be important in liver disease as early stages are reversible. Soft gel cultures provide a promising model to study RE metabolism in quiescent HSCs, allowing detailed molecular investigations on the mechanisms for storage and release.

BACKGROUND: Hepatic stellate cells (HSC) have numerous critical roles in liver function and homeostasis, while they are also known for their importance during liver injury and fibrosis. There is therefore a need for relevant in vitro human HSC models to fill current knowledge gaps. In particular, the roles of vitamin A (VA), lipid droplets (LDs), and energy metabolism in human HSC activation are poorly understood.
METHODS: In this study, human pluripotent stem cell-derived HSCs (scHSCs), benchmarked to human primary HSC, were exposed to 48-hour starvation of retinol (ROL) and palmitic acid (PA) in the presence or absence of the potent HSC activator TGF-β. The interventions were studied by an extensive set of phenotypic and functional analyses, including transcriptomic analysis, measurement of activation-related proteins and cytokines, VA- and LD storage, and cell energy metabolism.
RESULTS: The results show that though the starvation of ROL and PA alone did not induce scHSC activation, the starvation amplified the TGF-β-induced activation-related transcriptome. However, TGF-β-induced activation alone did not lead to a reduction in VA or LD stores. Additionally, reduced glycolysis and increased mitochondrial fission were observed in response to TGF-β.
CONCLUSIONS: scHSCs are robust models for activation studies. The loss of VA and LDs is not sufficient for scHSC activation in vitro, but may amplify the TGF-β-induced activation response. Collectively, our work provides an extensive framework for studying human HSCs in healthy and diseased conditions.

The association between vitamin A and single cardiometabolic diseases has been extensively studied, but the relationship between dietary vitamin A intake and the risk of cardiometabolic multimorbidity (CMM) has not been studied. Therefore, the present study was conducted to explore the association with CMM risk by analyzing different sources of vitamin A. This study utilized 13,603 subjects aged ≥ 18 years from 1997 to 2015 from the China Health and Nutrition Survey (CHNS). Dietary intake was calculated from 3 consecutive 24-h dietary recalls combined with a house hold food inventory. CMM is defined as the development of at least two cardiometabolic diseases. After a median follow-up of 9.0 years, there were 1050 new cases of CMM. The risk of CMM was significantly lower in those with higher vitamin A intake (Q1 vs Q5 HR 0.66, 95% CI 0.54-0.81). β-carotene (Q1 vs Q5 HR 0.82, 95% CI 0.66-1.02) and retinol (Q1 vs Q5 HR 0.59, 95% CI 0.48-0.73) intake had a similarly negative correlation. Using restricted cubic spline found an L-shaped relationship between retinol intake and CMM (p non-linear < 0.001). Negative associations were also found in specific CMD groups (hypertension, cardiovascular disease, stroke and diabetes). Dietary intake of vitamin A was negatively associated with CMM risk, and this protective effect was more pronounced in patients with cardiovascular disease. There was an L-shaped association between retinol intake and CMM risk.

UNASSIGNED: Maternal nutritional and vitamin status during pregnancy may have long-term effects on offspring health and disease. The aim of this study was to examine the associations between maternal vitamin A and D status in pregnancy and offspring bone mineral content (BMC) at nine years of age.
UNASSIGNED: This is a post-hoc study of a randomized control trial including 855 pregnant women from two Norwegian cities; Trondheim and Stavanger. The women were randomized into an exercise intervention or standard antenatal care. Mother and child pairs for the present study were recruited from those still living in Trondheim after 8-10 years. Serum vitamin A (retinol) and vitamin D (25(OH)D) were measured in the 2nd and 3rd trimesters of pregnancy, and active vitamin D (1,25(OH)2D) in serum was measured in a subgroup. Spine BMC and trabecular bone score were measured in the children at nine years of age. Associations were analyzed with linear regression models.
UNASSIGNED: A total of 119 mother and child pairs were included in the analyses. Vitamin A insufficiency (retinol< 1.05 µmol/L) and vitamin D deficiency (25(OH)D< 50 mmol/L) increased from ~7% to ~43% and from ~28% to ~33%, respectively, from the 2nd to the 3rd trimester. An increase in serum 1,25(OH)2D from the 2nd to the 3rd trimester was observed in the subgroup. There was a negative association between serum retinol in the 2nd trimester and spine BMC in the boys, but not in the girls, when adjusted for maternal and child confounders. No other associations between maternal serum vitamin A or D and BMC in the children were found.
UNASSIGNED: We observed a high prevalence of vitamin A insufficiency and vitamin D deficiency during pregnancy. A negative association between mid-pregnancy vitamin A status and spine BMC was observed in boys, but not girls, while no associations were found between maternal vitamin D status and child BMC. The implications of optimal vitamin A and D status in pregnancy for offspring bone health, remains a subject for further investigations.

Excessive vitamin A (VA) negatively impacts bone. Interactions between VA and vitamin D (VD) in bone health are not well-understood. This study used a traditional two-by-two factorial design. Pigs were weaned and randomized to four treatments (n = 13/group): -A-D, -A+D, +A-D, and +A+D for 3 and 5 wk. Serum, liver, kidney, adrenal glands, spleen, and lung were analyzed by ultra-performance LC. Growth was evaluated by weight measured weekly and BMD by DXA. Weights were higher in -A+D (18.1 ± 1.0 kg) and +A+D (18.2 ± 2.3 kg) at 5 wk than in -A-D (15.5 ± 2.1 kg) and +A-D (15.8 ± 1.5 kg). Serum retinol concentrations were 0.25 ± 0.023, 0.22 ± 0.10, 0.77 ± 0.12, and 0.84 ± 0.28 µmol/L; and liver VA concentrations were 0.016 ± 0.015, 0.0065 ± 0.0035, 2.97 ± 0.43, 3.05 ± 0.68 µmol/g in -A-D, -A+D, +A-D, and +A+D, respectively. Serum 25(OH)D3 concentrations were 1.5 ± 1.11, 1.8 ± 0.43, 27.7 ± 8.91, and 23.9 ± 6.67 ng/mL in -A-D, +A-D, -A+D, +A+D, respectively, indicating a deficiency in -D and adequacy in +D. BMD was highest in +D (p < 0.001). VA and the interaction had no effect on BMD. Dietary VD influenced weight gain, BMD, and health despite VA status.