Chronic alcohol drinking causes hepatic vitamin A (retinoids and derivatives) decreases, which correlate with the progression and severity of alcohol-associated liver disease (ALD). However, the effects of short-term ethanol (EtOH) intake on liver retinoids and ALD are still undefined.

Using high-performance liquid chromatography and high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC, HPLC-MS/MS), and molecular biology techniques in mice and cultured human hepatocytes, we investigated the temporal EtOH effects on retinoids and ALD.

In female and male mice, acute EtOH intake caused hepatic retinol (ROL) and retinyl palmitate (RP) decreases within hours, whereas it did not significantly change the retinoic acid (RA) levels, and those of the RA catabolism metabolite, 4-oxo-RA. After EtOH withdrawal, the liver recovered the ROL and RP levels within 48 h, whereas RA and 4-oxo-RA levels remained almost undetectable by this time point. Compared with control diet-fed mice, hepatic ROL and RP levels remained decreased in the 10-day and 3-week-long EtOH treatments, while retinyl oleate and linoleate increased. Interestingly, some of the RA signaling receptors, Rarβ, along with Cyp26a1, revealed dramatic transcript increases during the 10-day-long experiments that attenuated over time (up to 8 weeks), reflecting impaired RA signaling. Our work also showed that primary human hepatocytes serve as a model to better define the role of EtOH in retinoid biology.

This work reveals that acute and short-term exposures to EtOH disrupt retinoid homeostasis, identifying key events in the early pathogenesis of ALD.

Currently, HE staining and microscopic imaging are the main approaches for the diagnosis of cancerous tissues, which are inefficient, and the results are heavily dependent on doctors' experience. Therefore, establishing a rapid and accurate method for identifying cancerous tissues is of great value for the preoperative and intraoperative assessments. Raman spectroscopy is a non-destructive, label-free and highly specific method, and it has been widely reported in cancer tissue research. However, the low accuracy of Raman spectral results due to the complex compositions of the tissues limits the clinical applications of Raman spectroscopy. In this study, two-dimensional features of the biochemical composition and morphological structure were combined to classify colorectal cancer tissue by innovatively fusing the elastic scattering spectrum and Raman spectrum. In this study, the elastic scattering spectrum and Raman spectrum of 20 clinical colorectal tissues were acquired using a Raman spectrometer and a homemade elastic scattering light device. After multi-modal spectrum data processing and fusion, a composite AI model called spec-transformer was trained and tested. The results showed that the new model classified colorectal tissues with an accuracy of ≥97%. Moreover, Grad-CAM technology was applied to analyse the compositional variation between normal and colorectal cancer tissues, and it demonstrated a high expression of tryptophan and unsaturated fatty acids in cancer tissues with a reduction in tyrosine and beta-carotene expression. Our approach has potential for colorectal cancer diagnosis and could be extended for diagnosis and research on other cancers.

Maternal tobacco smoking in the perinatal period increases the risk for adverse outcomes in offspring.

To better understand the biological pathways through which maternal tobacco use may have long-term impacts on child metabolism, we performed a high-resolution metabolomics (HRM) analysis in newborns, following an untargeted metabolome-wide association study workflow.

The study population included 899 children without cancer diagnosis before age 6 and born between 1983 and 2011 in California. Newborn dried blood spots were collected by the California Genetic Disease Screening Program between 12 and 48 h after birth and stored for later research use. Based on HRM, we considered mothers to be active smokers if they were self- or provider-reported smokers on birth certificates or if we detected any cotinine or high hydroxycotinine intensities in newborn blood. We used partial least squares discriminant analysis and Mummichog pathway analysis to identify metabolites and metabolic pathways associated with maternal tobacco smoking.

A total of 26,183 features were detected with HRM, including 1003 that were found to be associated with maternal smoking late in pregnancy and early postpartum (Variable Importance in Projection (VIP) scores > = 2). Smoking affected metabolites and metabolic pathways in neonatal blood including vitamin A (retinol) metabolism, the kynurenine pathway, and tryptophan and arachidonic acid metabolism.

The smoking-associated metabolites and pathway perturbations that we identified suggested inflammatory responses and have also been implicated in chronic diseases of the central nervous system and the lung. Our results suggest that infant metabolism in the early postnatal period reflects smoking specific physiologic responses to maternal smoking with strong biologic plausibility.

Liver is the major organ involved in apoA-I synthesis and HDL-C turnover, but the impact of apoA-I/HDL on hepatic transcriptome has never been investigated before. In the present study, a transcriptomic analysis by high-throughput RNA-seq was conducted in the liver of atherosclerosis-prone mice, with the aim of identifying new genes/pathways modulated by apoA-I/HDL with a potential effect on atherosclerosis development.

Eight-week-old apoE knockout (apoEKO) mice lacking apoA-I/HDL (DKO) and with physiological levels of apoA-I/HDL (DKO/hA-I) were fed either a standard rodent diet (SRD) or a Western diet (WD) for 22 weeks. After both dietary treatments, DKO mice were characterized by lower cholesterol levels, but increased atherosclerosis development, compared to DKO/hA-I mice. The liver transcriptome of DKO and DKO/hA-I mice fed SRD diverged in a relatively small number of genes, suggestive of a greater activation of the PPAR signaling pathway and the retinoid metabolism pathway in DKO/hA-I mice. Following WD, transcriptomic analysis highlighted in both genotypes an upregulated expression of immune/inflammatory genes and a reduced activation of the retinoid metabolism. The evaluation of the hepatic response of the two genotypes to the dietary switch from SRD to WD revealed strong divergences in genes involved in metabolic pathways only in the presence of apoA-I/HDL, with reduced endogenous sterol biosynthesis and glutathione metabolism, together with increased glucose metabolism.

The presence or absence of apoA-I expression differently alters hepatic pathways involved not only in cholesterol metabolism, but also in those of glutathione and glucose metabolism.

Studies on transcription regulation in platyhelminth development are scarce, especially for parasitic flatworms. Here, we employed single-cell transcriptomics to identify genes involved in reproductive development in the trematode model Schistosoma mansoni. This parasite causes schistosomiasis, a major neglected infectious disease affecting >240 million people worldwide. The pathology of schistosomiasis is closely associated with schistosome eggs deposited in host organs including the liver. Unlike other trematodes, schistosomes exhibit distinct sexes, with egg production reliant on the pairing-dependent maturation of female reproductive organs. Despite this significance, the molecular mechanisms underlying ovary development and oocyte differentiation remain largely unexplored. Utilizing an organ isolation approach for S. mansoni, we extracted ovaries of paired females followed by single-cell RNA sequencing (RNA-seq) with disassociated oocytes. A total of 1967 oocytes expressing 7872 genes passed quality control (QC) filtering. Unsupervised clustering revealed four distinct cell clusters: somatic, germ cells and progeny, intermediate and late germ cells. Among distinct marker genes for each cluster, we identified a hitherto uncharacterized transcription factor of the retinoic acid receptor family, SmRAR. Functional analyses of SmRAR and associated genes like Smmeiob (meiosis-specific, oligonucleotide/oligosaccharide binding motif (OB) domain-containing) demonstrated their pairing-dependent and ovary-preferential expression and their decisive roles in oocyte differentiation of S. mansoni.

The inevitable attrition of skin due to ultraviolet radiation, termed photoaging, can be partially restored by treatment with retinoid compounds. Photoaged skin in lightly pigmented individuals, clinically presents with the appearance of wrinkles, increased laxity, and hyper- and hypopigmentation. Underlying these visible signs of ageing are histological features such as epidermal thinning, dermal-epidermal junction flattening, solar elastosis and loss of the dermal fibrillin microfibrillar network, fibrillar collagen and glycosaminoglycans. Retinoid compounds are comprised of three main generations with the first generation (all-trans retinoic acid, retinol, retinaldehyde and retinyl esters) primarily used for the clinical and cosmetic treatment of photoaging, with varying degrees of efficacy, tolerance and stability. All-trans retinoic acid is considered the 'gold standard' for skin rejuvenation; however, it is a prescription-only product largely confined to clinical use. Therefore, retinoid derivatives are readily incorporated into cosmeceutical formulations. The literature reported in this review suggests that retinol, retinyl esters and retinaldehyde that are used in many cosmeceutical products, are efficacious, safe and well-tolerated. Once in the skin, retinoids utilize a complex signalling pathway that promotes remodelling of photoaged epidermis and dermis and leads to the improvement of the cutaneous signs of photoaging.

Vitamin A is an essential fat-soluble vitamin that cannot be endogenously synthesized by the human body. Retinoic acid (RA) is the biologically active form of vitamin A. Utilizing both nuclear and non-nuclear receptor-mediated pathways, RA plays a crucial role in regulating various biological processes, including apoptosis, differentiation, and anti-inflammatory properties within the cornea and conjunctiva. In addition, RA has been demonstrated to exert a significant influence on anti-tumor mechanisms. Disruption of RA signaling can result in corneal defects, anophthalmia, and microphthalmia. However, the beneficial effects of RA are only observed when it is administered at appropriate dosages, and higher doses have an adverse impact. Ocular abnormalities are often early indicators of a vitamin A deficiency. The lacrimal gland secretes vitamin A onto the ocular surface, where it is metabolized into RA via two sequential steps. This article provides a comprehensive overview of how vitamin A is transformed and transported from the intestine to the ocular surface, ultimately contributing to the maintenance of the normal physiological function of the ocular surface.

The degree of yellowness of the skin is an important factor affecting the market popularity and sales price of yellow-feathered broilers. Despite its commercial importance, the specific pigments and genetic mechanisms involved remain unclear. This study identified lutein as the primary carotenoid in the skin and established serum lutein concentration as a molecular marker for predicting skin yellowness in carcasses. Through RNA sequencing of broilers with varying yellowness, we identified key genes like CYP26A1, CYP1B1, CYP2C18, CYP2W1, HSD17B2, AOX1, KMO, PLIN1, and RET, which may regulate carotenoid absorption and deposition. Additionally, a single nucleotide polymorphism in the CYP1A1 gene was significantly associated with skin yellowness in Ma-Huang chickens. Overall, this study examined the primary pigment types that influence the skin yellowness of yellow-feathered broilers, emphasizing that lutein can serve as a molecular marker for skin yellowness and providing insights into the regulatory factors that regulate skin yellowness. These findings provide essential theoretical support for the breeding of skin color traits in yellow-feathered broilers.

Lipid droplets are fat storage organelles composed of a protein envelope and lipid-rich core. Regulation of this protein envelope underlies differential lipid droplet formation and function. In melanoma, lipid droplet formation has been linked to tumor progression and metastasis, but it is unknown whether lipid droplet proteins play a role. To address this, we performed proteomic analysis of the lipid droplet envelope in melanoma. We found that lipid droplet proteins were differentially enriched in distinct melanoma states; from melanocytic to undifferentiated. DHRS3, which converts all-trans-retinal to all-trans-retinol, is upregulated in the MITFLO/undifferentiated/neural crest-like melanoma cell state and reduced in the MITFHI/melanocytic state. Increased DHRS3 expression is sufficient to drive MITFHI/melanocytic cells to a more undifferentiated/invasive state. These changes are due to retinoic acid-mediated regulation of melanocytic genes. Our data demonstrate that melanoma cell state can be regulated by expression of lipid droplet proteins which affect downstream retinoid signaling.

Retinol has a long history of treating skin conditions, including photoaging. However, skin irritation with repeated use of retinol is well documented. The present study assessed the effectiveness of a novel topical formulation, referred to as retinol topical formulation (RTF), to improve the quality of skin health. The RTF was composed of a low dose retinol, a synthetic retinoid ester, a pea peptide, and an antioxidant blend.

In vitro assessment of RTF on human skin co-cultures (human keratinocytes, melanocytes, and dermal fibroblasts) identified gene expression levels and skin biomarkers after 24 h exposure. An 8-week clinical study was conducted to evaluate once-nightly application of the RTF for short-term and long-term benefits in 30 adult subjects between 35 and 70 years of age (21 female, 9 male). Skin evaluations were conducted via bioinstrumentation (for hydration, transepidermal water loss and elasticity) and at 0, 1-, 2-, 4-, and 8-week self-assessment questionnaires and photo-imaging analysis were performed.

RTF treatment of skin in vitro co-cultures upregulated aquaporin-3, PER1, collagen, and elastin, and downregulated expression of MMP1 and the pigmentation genes TYRP1 and MITF. The clinical assessment significantly improved hydration, transepidermal water loss, and elasticity along with incremental but significant increases in nine skin parameters (hydration, clarity, radiance/glow, smoothness, brightness, texture, appearance of pores, dark spots/hyperpigmentation, and skin tone evenness from baseline) with continuous use over 8 weeks compared to baseline values.

The RTF in vitro analysis showed significant positive changes for several skin biomarkers, and the clinical assessment showed RTF significantly improved the visible signs of dermal aging, without irritation.

Pasteurella multocida is an opportunistic bacterium that causes pneumonic pasteurellosis (PP). The common treatment against PP is using antibiotics in conjunction with nonsteroidal anti-inflammatory drugs (NSAIDs). This combination presents various complications, i.e., immune-depression. Hence, the alternative therapy to replace the effects of NSAIDs needs to be clarified. One of them is using fermented calabash [Crescentia cujete (L.)] (FCC).

This study aimed to elucidate the efficacy of FCC in combination with enrofloxacin against artificially induced PP in rat models.

The calabash was collected and fermented. Moreover, the product of FCC was standardized regarding its biochemical compounds using Liquid chromatography-tandem mass spectrometry and high-performance liquid chromatography. This study used 30 male Sprague Dawley rats, weighing 251.52 ± 2.65 grams, 6 months old. The rats were divided into six groups as follows: G1 (control); G2 (infected with Pasteurella multocida + untreated); G3 (infected + 20 mg/kg enrofloxacin); G4 (infected + 20 mg/kg enrofloxacin + 30 mg/kg ibuprofen); G5 (infected + 20 mg/kg enrofloxacin + 2.96 mg/kg FCC); and G6 (infected + 20 mg/kg enrofloxacin + 5.92 mg/kg FCC). The treatment was given once daily for 7 days. On day eight, the rats were radiographed. The serum was collected and tested against C-reactive protein (CRP) and procalcitonin. The rats were euthanized and lung tissue was collected for histopathology and immunohistochemistry against CD4+, CD8+, and COX-2. The data were analyzed using SPSS.

This study indicated that FCC contains choline, phytonadione, alpha-tocopherol, and retinol. Moreover, using FCC as a combination therapy with enrofloxacin against PP in group G6 promotes a repair of radiology image compared to other treatments (p < 0.05). Group G5 and G6 showed increased activity of bronchial-associated lymphoid tissue, immune expression of CD4+ and COX-2, and the level of CRP and procalcitonin within the lung tissue (p < 0.05). Group G6 indicated better effects in various parameters in this study. However, the FCC has not influenced the immune expression of CD8+ during PP (p > 0.05).

This study proved that FCC could be used in rat models as an alternative anti-inflammatory treatment in combination with enrofloxacin against PP. Further research is needed to explore other effects of FCC to support the current findings.

Vitamins play an intrinsic role in human health and are targets for clinical intervention through dietary or pharmacological approaches. Biomarkers of vitamin status are complex traits, measurable phenotypes that arise from an interplay between dietary and other environmental factors with a genetic component that is polygenic, meaning many genes are plausibly involved. Studying these genetic influences will improve our knowledge of fundamental vitamin biochemistry, refine estimates of the effects of vitamins on human health, and may in future prove clinically actionable. Here, we evaluate genetic studies of circulating and excreted biomarkers of vitamin status in the era of hypothesis-free genome-wide association studies (GWAS) that have provided unprecedented insights into the genetic architecture of these traits. We found that the most comprehensive and well-powered GWAS currently available were for circulating status biomarkers of vitamin A, C, D, and a subset of the B vitamins (B9 and B12). The biology implicated by GWAS of measured biomarkers of each vitamin is then discussed, both in terms of key genes and higher-order processes. Across all major vitamins, there were genetic signals revealed by GWAS that could be directly linked with known vitamin biochemistry. We also outline how genetic variants associated with vitamin status biomarkers have been already extensively used to estimate causal effects of vitamins on human health outcomes, which is particularly important given the large number of randomized control trials of vitamin related interventions with null findings. Finally, we discuss the current evidence for the clinical applicability of findings from vitamin GWAS, along with future directions for the field to maximize the utility of these data.

Disruption of gut microbiota is closely related to the progression of alcoholic liver disease (ALD). This study aimed to explore the therapeutic effect of fecal microbiota transplantation (FMT) in ALD rats using a combination of microbiological and metabolomic techniques.

Three liver injury rat models were constructed using alcohol, CCL4, and alcohol combined with CCL4, and administered an FMT treatment comprising the fecal microbiota of healthy rats via the gastric route for 12 consecutive weeks. We measured the therapeutic effect of FMT treatment on liver inflammation, intestinal mucosal barrier, and bacterial translocation in ALD rats using 16S rRNA and UPLC-Q/TOF-MS technology to detect the effects of FMT on the intestinal microbiota and metabolic patterns of ALD rats.

FMT treatment effectively improved liver function, prolonged survival time, improved the intestinal mucosal barrier, reduced bacterial translocation, alleviated liver inflammation, and delayed the progression of liver fibrosis in three types of liver injury models. The microbiome and metabolomic results showed that FMT can effectively improve gut microbiota disorder in ALD rats and improve metabolic patterns by regulating metabolic pathways such as the arachidonic acid and retinol pathways.

FMT treatment could reverse alcohol induced liver injury by improving gut microbiota and metabolic patterns in ALD rats, and oral FMT could be an effective therapeutic approach for ALD.

For mammalian spermatogenesis to proceed normally, it is essential that the population of testicular progenitor cells, A undifferentiated spermatogonia (Aundiff), undergoes differentiation during the A to A1 transition that occurs at the onset of spermatogenesis. The commitment of the Aundiff population to differentiation and leaving a quiescent, stem-like state gives rise to all the spermatozoa produced across the lifespan of an individual, and ultimately determines male fertility. The action of all-trans retinoic acid (atRA) on the Aundiff population is the determining factor that induces this change. Sertoli cells, omnipresent, nurse cells within the mammalian testis are responsible for synthesizing the atRA that prompts this change in the neonatal testicular environment. The mechanism of atRA synthesis and signaling has been robustly explored and, in this review, we have summarized what is currently known about the action of testicular atRA at the onset of spermatogenesis. We have combined this with evidence gained from prominent genetic studies that have further elucidated the function of genes critical to atRA synthesis. We have additionally described the effects of the first pulse of atRA delivered to the germ cells of the testis, which has been investigated using WIN 18,446 treatment which prevents atRA synthesis and induces spermatogenic synchrony. This method provides unparalleled resolution into cell and stage specific testicular changes, and combined with transgenic animal models, has allowed researchers to elucidate much regarding the onset of spermatogenesis.

Glucose is the primary source of energy for most of the cells and essential for basic functionalities of life's biochemical processes. Transportation of glucose via biological membranes is essential for life mediated by glucose transporters (GLUT) through facilitated diffusion. Glucose transporters perform a crucial role in maintaining normal health as they transfer the most essential molecules of life, glucose. There are 14 various types of glucose transporters that transport primarily glucose and fructose. GUTTs are trans-membrane proteins expressed in the plasma membrane that facilitate the entry of carbohydrate molecules inside the cells. These transporters provide the passage for the carbohydrate molecules, which undergo oxidation inside the cells and provide essential energy in the form of ATPs. Lipid-soluble vitamins, namely A, D, E, and K have been reported to play a key role in stimulating several glucose transporters. Supplementation of lipid-soluble vitamins stimulates the expression of glucose transporters, most importantly GLUT4, GLUT2, GLUT1, and GLUT3, which play a critical role in regulating glucose metabolism in muscle, liver, brain, and RBCs. For their ability to increase the expression of GLUTs, the lipid-soluble vitamins can be the potential micronutrient for combating various non-communicable diseases. The present article discusses the essential role of lipid-soluble vitamins in the regulation of glucose transporters.

The active metabolite of vitamin A, all-trans-retinoic acid (atRA), is critical for maintenance of many cellular processes. Although the enzymes that can synthesize and clear atRA in mammals have been identified, their tissue and cell-type specific roles are still not fully established. Based on the plasma protein binding, tissue distribution and lipophilicity of atRA, atRA partitions extensively to lipid membranes and other neutral lipids in cells. As a consequence, free atRA concentrations in cells are expected to be exceedingly low. As such mechanisms must exist that allow sufficiently high atRA concentrations to occur for binding to retinoic acid receptor (RARs) and for RAR mediated signaling. Kinetic simulations suggest that cellular retinoic acid binding proteins (CRABPs) provide a cytosolic reservoir for atRA to allow high enough cytosolic concentrations that enable RAR signaling. Yet, the different CRABP family members CRABP1 and CRABP2 may serve different functions in this context. CRABP1 may reside in the cytosol as a member of a cytosolic signalosome and CRABP2 may bind atRA in the cytosol and localize to the nucleus. Both CRABPs appear to interact with the atRA-degrading cytochrome P450 (CYP) family 26 enzymes in the endoplasmic reticulum. These interactions, together with the expression levels of the CRABPs and CYP26s, likely modulate cellular atRA concentration gradients and tissue atRA concentrations in a tightly coordinated manner. This review provides a summary of the current knowledge of atRA distribution, metabolism and protein binding and how these characteristics may alter tissue atRA concentrations.

Background: Our study presented a novel LC-MS/MS method for the simultaneous quantification of α-tocopherol (α-TOH) and its phase II metabolites, α-13'-COOH and α-13'-OH, in human serum using deuterium-labeled internal standards (d6-α-TOH, d6-α-13'-COOH, d6-α-13'-OH). Methods: The method addresses the analytical challenge posed by the significantly different concentration ranges of α-TOH (µmol/L) and its metabolites (nmol/L). Previous methods quantified these analytes separately, which caused an increase in workflow complexity. Results: Key features include the synthesis of stable isotope-labeled standards and the use of a pentafluorophenyl-based core-shell chromatography column for baseline separation of both α-TOH and its metabolites. Additionally, solid phase extraction (SPE) with a HybridSPE® material provides a streamlined sample preparation, enhancing analyte recovery and improving sensitivity. By utilizing deuterium-labeled standards, the method compensates for matrix effects and ion suppression. This new approach achieves precise and accurate measurements with limits of detection (LOD) and quantification (LOQ), similar to previous studies. Calibration, accuracy, and precision parameters align well with the existing literature. Conclusions: Our method offers significant advantages in the simultaneous analysis of tocopherol and its metabolites despite concentration differences spanning up to three orders of magnitude. In contrast to earlier studies, which required separate sample preparations and analytical techniques for tocopherol and its metabolites, our approach streamlines this process. The use of a solid-phase extraction procedure allows for parallel sample preparation. This not only enhances efficiency but also significantly accelerates pre-analytical workflows, making the method highly suitable for large-scale studies.

The COVID-19 pandemic caused by the SARS-CoV-2 virus infected more than 775,686,716 humans and was responsible for the death of more than 7,054,093 individuals. COVID-19 has taught us that the development of vaccines, repurposing of drugs, and understanding the mechanism of a disease can be done within a short time. The COVID-19 proteomics and metabolomics has contributed to its diagnosis, understanding of its progression, host-virus interaction, disease mechanism, and also in the search of suitable anti-COVID therapeutics. Mass spectrometry based proteomics was used to find the potential biomarkers of different stages of COVID-19 including severe and nonsevere cases in the blood serum. Notably, protein-protein interaction techniques to understand host-virus interactions were also significantly useful. The single-cell proteomics studies were carried out to ascertain the changes in immune cell composition and its activation in mild COVID-19 patients versus severe COVID-19 patients using whole-blood and peripheral-blood mononuclear cells. Modern technologies were helpful to deal with the pandemic; however, there is still scope for further development. Further, attempts were made to understand the protein-protein, metabolite-metabolite, and protein-metabolite interactomes, derived from proteins and metabolite fingerprints of COVID-19 patients by reanalysis of COVID-19 public mass spectrometry based proteomics and metabolomics studies. Further, some of these interactions were supported by the literature as validations in the COVID-19 studies.

The deficiency of vitamins, a condition known as "hidden hunger", causes comprehensive pathological states. Research over the years has identified a relationship between liver diseases and hypovitaminosis or defects in vitamin metabolism. The exact mechanisms remain elusive; however, the crucial involvement of specific vitamins in metabolic functions, alongside the reclassification of liver disease as metabolic dysfunction-associated steatotic liver disease (MASLD), has prompted researchers to investigate the potential cause-effect dynamics between vitamin deficiency and liver disease. Moreover, scientists are increasingly investigating how the deficiency of vitamins might disrupt specific organ crosstalk, potentially contributing to liver disease. Although the concept of a dysmetabolic circuit linking adipose tissue and the liver, leading to liver disease, has been discussed, the possible involvement of vitamin deficiency in this axis is a relatively recent area of study, with numerous critical aspects yet to be fully understood. In this review, we examine research from 2019 to July 2024 focusing on the possible link between liver-adipose tissue crosstalk and vitamin deficiency involved in the onset and progression of non-alcoholic fatty liver disease (NAFLD). Studies report that vitamin deficiency can affect the liver-adipose tissue axis, mainly affecting the regulation of systemic energy balance and inflammation.

Retinol binding protein 4 (RBP4) is an adipokine that has been explored as a key biomarker of type 2 diabetes mellitus (T2DM) in recent years. Researchers have conducted a series of experiments to understand the interplay between RBP4 and T2DM, including its role in insulin resistance and pancreatic β-cell function. The results of these studies indicate that RBP4 has a significant influence on T2DM and is considered a potential biomarker of T2DM. However, there have also been some controversies about the relationship between RBP4 levels and T2DM. In this review, we update and summarize recent studies focused on the relationship between RBP4 and T2DM and its role in insulin resistance and pancreatic β-cell function to clarify the existing controversy and provide evidence for future studies. We also assessed the potential therapeutic applications of RBP4 in treating T2DM.

A narrative review.

Overall, there were significant associations between RBP4 levels, insulin resistance, pancreatic β-cell function, and T2DM.

More mechanistic studies are needed to determine the role of RBP4 in the onset of T2DM, especially in terms of pancreatic β-cell function. In addition, further studies are required to evaluate the effects of drug intervention, lifestyle intervention, and bariatric surgery on RBP4 levels to control T2DM and the role of reducing RBP4 levels in improving insulin sensitivity and pancreatic β-cell function.

Carotenoids, yellow and red pigments found abundantly in nature, play essential roles in various aspects of human physiology. They serve as critical molecules in vision by functioning as antioxidants and as filters for blue light within the retina. Furthermore, carotenoids are the natural precursors of vitamin A, which is indispensable for the synthesis of retinaldehyde, the visual chromophore, and retinoic acid, a small molecule that regulates gene expression. Insufficient levels of carotenoids and retinoids have been linked to age-related macular degeneration and xerophthalmia, respectively. Nevertheless, the mechanisms by which the eye maintains carotenoid and retinoid homeostasis have remained a mystery. Recent breakthroughs identified the molecular players involved in this process and provided valuable biochemical insights into their functioning. Mutations in the corresponding genes disrupt the homeostasis of carotenoids and retinoids, leading to visual system pathologies. This review aims to consolidate our current understanding of these pathways, including their regulatory principles.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant that disrupts hepatic function leading to steatotic liver disease (SLD)-like pathologies, such as steatosis, steatohepatitis, and fibrosis. These effects are mediated by the aryl hydrocarbon receptor following changes in gene expression. Although diverse cell types are involved, initial cell-specific changes in gene expression have not been reported. In this study, differential gene expression in hepatic cell types was examined in male C57BL/6 mice gavaged with 30 µg/kg of TCDD using single-nuclei RNA-sequencing. Ten liver cell types were identified with the proportions of most cell types remaining unchanged, except for neutrophils which increased at 72 h. Gene expression suggests TCDD induced genes related to oxidative stress in hepatocytes as early as 2 h. Lipid homeostasis was disrupted in hepatocytes, macrophages, B cells, and T cells, characterized by the induction of genes associated with lipid transport, steroid hormone biosynthesis, and the suppression of β-oxidation, while linoleic acid metabolism was altered in hepatic stellate cells (HSCs), B cells, portal fibroblasts, and plasmacytoid dendritic cells. Pro-fibrogenic processes were also enriched, including the induction retinol metabolism genes in HSCs and the early induction of anti-fibrolysis genes in hepatocytes, endothelial cells, HSCs, and macrophages. Hepatocytes also had gene expression changes consistent with hepatocellular carcinoma. Collectively, these findings underscore the effects of TCDD in initiating SLD-like phenotypes and identified cell-specific gene expression changes related to oxidative stress, steatosis, fibrosis, cell proliferation and the development of HCC.

Up to half of the senior dogs suffer from canine cognitive dysfunction syndrome (CCDS), the diagnosis method relies on subjective questionnaires such as canine cognitive dysfunction rating (CCDR) scores. Therefore, the necessity of objective diagnosis is emerging. Here, we developed blood-based biomarkers for CCDS early detection. Blood samples from dogs with CCDR scores above 25 were analyzed, and the biomarkers retinol-binding protein 4 (RBP4), C-X-C-motif chemokine ligand 10 (CXCL10), and NADPH oxidase 4 (NOX4) were validated against neurodegenerative models. Lower biomarker levels were correlated with higher CCDR scores, indicating cognitive decline. Machine-learning analysis revealed the highest predictive accuracy when analyzing the combination of RBP4 and NOX4 using the support vector machine algorithm and confirmed potential diagnostic biomarkers. These results suggest that blood-based biomarkers can notably improve CCDS early detection and treatment, with implications for neurodegenerative disease management in both animals and humans.

This study aimed to investigate the impact of Vitamin A (VA) on intestinal glucose metabolic phenotypes.

Male C57BL/6 mice were randomized assigned to a VA-normal diet (VAN) or a VA-deficient diet (VAD) for 12 weeks. After12 weeks, the VAD mice were given 30 IU/g/d retinol for 10 days and VAN diet (VADN) for 10 weeks. By using glucose tolerance tests, immunofluorescence staining, quantitative polymerase chain reaction, siRNA transduction, and enzyme-linked immunosorbent assay, the glucose metabolic phenotypes as well as secretory function and intracellular hormone changes of STC-1 were assessed.

VAD mice showed a decrease of glucose-stimulated insulin secretion and a loss of intestinal glucagon-like peptide-1 (GLP-1) expression. Through reintroducing dietary VA to VAD mice, the intestinal VA levels, GLP-1 expression and normal glucose can be restored. The incubation with retinol increased VA signaling factors expression within STC-1 cells, especially retinoic acid receptor β (RARβ). The activation of RARβ restored intracellular incretin hormone synthesis and secretory function.

VA deficiency leads to an imbalance of intestinal glucose metabolic phenotypes through a mechanism involving RARβ signaling pathway, suggesting a new method to achieve the treatment for VAD induced glucose metabolism impairment.

In the developing world, the twin challenges of depleted health and growing issue of food waste management loom large, demanding simultaneous attention and innovative solutions. This review explores how these issues can be effectively mitigated while shedding light on the transformative impact of food waste valorization on health management. A spotlight is cast on vitamin A deficiency (VAD), an acute public health concern, especially prevalent in South Asia, driven by economic constraints, sociocultural factors, inadequate diets, and poor nutrient absorption. VAD's devastating effects are exacerbated by limited education, lack of sanitation, ineffective food regulations, and fragile monitoring systems, disproportionately affecting children and women of childbearing age. Recent studies in South Asian countries have revealed rising rates of illness and death, notably among children and women of childbearing age, due to VAD. To address inadequate dietary intake in children utilizing vegetable waste, particularly from carrots and beetroot, which are rich in β-carotene, and betalains, respectively, offers a sustainable solution. Extracting these compounds from vegetable waste for supplementation, fortification, and dietary diversification could significantly improve public health, addressing both food waste and health disparities economically. This approach presents a compelling avenue for exploration and implementation. In summary, this review presents an integrated approach to tackle health and food waste challenges in the developing world. By tapping into the nutritional treasure troves within vegetable waste, we can enhance health outcomes while addressing food waste, forging a brighter and healthier future for communities in need.

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.

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.

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.

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.

Vitamin A is an important nutrient for multiple physiological functions. To elucidate the role of vitamin A in vivo, vitamin A-deficient diets have been often used in mice to establish a vitamin A-deficiency model. However, the information on the appropriate feeding periods and time course of changes in vitamin A content in organs after the start of vitamin A-deficient diet feeding is lacking. This study aimed to assess the retinoids levels in liver and white adipose tissue in mice fed a vitamin A-deficient diet for ≤8 weeks. High-performance liquid chromatography was used to measure the retinoids levels in liver and white adipose tissue every 2 weeks for ≤8 weeks. Vitamin A-deficient diet feeding significantly decreased retinol in the liver over 6 weeks, but retinyl palmitate, a main storage form of vitamin A, was not changed over 8 weeks. The plasma retinol level remained constant throughout the experiment. In white adipose tissue, retinyl palmitate gradually decreased over 8 weeks. These results indicate that vitamin A-deficient diet feeding longer than 6 weeks reduced retinol in liver and retinyl palmitate in white adipose tissue over 8 weeks, although it is not enough for the induction of a whole-body vitamin A deficiency.

Dietary recommendations on vitamin intake for human food fortification concerning vitamin A in various countries, larger economic zones and international organizations are mainly based on the Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO) "Codex Alimentarius standards". The general vitamin A terminology is based on regulations of the International Union of Pure and Applied Chemistry (IUPAC) that are used to describe the involved derivatives. These regulations and terminology were set up in the middle of the last century. Starting with the decade of the 80ies in the 20th century a large improvement of molecular biological methodologies, background physiological mechanisms as well as analytical techniques contributed to a large diversification of this simply claimed vitamin A terminology. Unfortunately, the following terminology and governmental regulations for food fortification are imprecise and non-harmonized. In this article we tried to unravel this terminology for updating terminology, nutritional suggestions and governmental regulations for vitamin A, which are currently based on various uncertainties. According to the current regulations, the newly found vitamin A5/X can be included in the current vitamin A terminology as "vitamin A5" or alternatively or even in parallel as a new vitamin A-independent terminology as "vitamin X". Based on the detailed knowledge of research from the early beginning of general vitamin A pathway identification towards detailed research of the last decades the commonly used and simplified term vitamin A with relevance for governmental recommendations on vitamin intake and food fortification advice was now more correctly sub-categorized to further vitamin A1, and A5 sub-categories with vitamin A1-alcohol as retinol, vitamin A2-alcohol as 3,4-didehydroretinol and vitamin A5-alcohol as 9-cis-13,14-dihydroretinol as their mainly relevant vitamin forms present in the human organism. Here we suggest and advise how the vitamin A terminology and further governmental regulations should be organized depending on a successful unraveling of the organization of the current vitamin A terminology.

Following two requests from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the revision of the tolerable upper intake level (UL) for preformed vitamin A and β-carotene. Systematic reviews of the literature were conducted for priority adverse health effects of excess vitamin A intake, namely teratogenicity, hepatotoxicity and endpoints related to bone health. Available data did not allow to address whether β-carotene could potentiate preformed vitamin A toxicity. Teratogenicity was selected as the critical effect on which to base the UL for preformed vitamin A. The Panel proposes to retain the UL for preformed vitamin A of 3000 μg RE/day for adults. This UL applies to men and women, including women of child-bearing age, pregnant and lactating women and post-menopausal women. This value was scaled down to other population groups using allometric scaling (body weight0.75), leading to ULs between 600 μg RE/day (infants 4-11 months) and 2600 μg RE/day (adolescents 15-17 years). Based on available intake data, European populations are unlikely to exceed the UL for preformed vitamin A if consumption of liver, offal and products thereof is limited to once per month or less. Women who are planning to become pregnant or who are pregnant are advised not to consume liver products. Lung cancer risk was selected as the critical effect of excess supplemental β-carotene. The available data were not sufficient and suitable to characterise a dose-response relationship and identify a reference point; therefore, no UL could be established. There is no indication that β-carotene intake from the background diet is associated with adverse health effects. Smokers should avoid consuming food supplements containing β-carotene. The use of supplemental β-carotene by the general population should be limited to the purpose of meeting vitamin A requirements.

A deleterious effect of elevated levels of vitamin A on bone health has been reported in clinical studies. Mechanistic studies in rodents have shown that numbers of periosteal osteoclasts are increased, while endocortical osteoclasts are simultaneously decreased by vitamin A treatment. The present study investigated the in vitro and in vivo effect of all-trans retinoic acid (ATRA), the active metabolite of vitamin A, on periosteal osteoclast progenitors. Mouse calvarial bone cells were cultured in media containing ATRA, with or without the osteoclastogenic cytokine receptor activator of nuclear factor kappa B-ligand (RANKL), on plastic dishes or bone discs. Whereas ATRA did not stimulate osteoclast formation alone, the compound robustly potentiated the formation of RANKL-induced bone resorbing osteoclasts. This effect was due to stimulation by ATRA (half-maximal stimulation ∼3 nM) on the numbers of macrophages/osteoclast progenitors in the bone cell cultures, as assessed by mRNA and protein expression of several macrophage and osteoclast progenitor cell markers, such as macrophage colony-stimulating factor receptor, receptor activator of nuclear factor kappa B, F4/80, and CD11b, as well as by flow cytometry (FACS) analysis of CD11b+/F480+/Gr1- cells. The stimulation of macrophage numbers in the periosteal cell cultures was not mediated by increased macrophage colony-stimulating factor or interleukin-34. In contrast, ATRA did not enhance macrophages in bone marrow cell cultures. Importantly, ATRA treatment upregulated the mRNA expression of several macrophage-related genes in the periosteum of tibia in adult mice. These observations demonstrate a novel mechanism by which vitamin A enhances osteoclast formation specifically on periosteal surfaces.

Chronic alcohol consumption is a major public health issue. The primary organ damaged by alcohol abuse is the liver, leading to alcohol-associated liver disease (ALD). ALD begins with hepatic steatosis and can progress to fibrosis and cirrhosis; however, we have an incomplete understanding of ALD pathogenesis. Interestingly, the liver is also the major organ for vitamin A metabolism and storage, and ALD has previously been linked with altered hepatic vitamin A homeostasis. We hypothesize that alcohol-induced vitamin A depletion disrupts its normal function in the liver, contributing to the pathogenesis of ALD. To test this hypothesis, we postulated that adding copious vitamin A to the diet might alleviate ALD, and conversely, that a vitamin A deficient diet would worsen ALD.

We conducted two dietary intervention studies in mice comparing deficient (0 IU/g diet) and copious (25 IU/g diet) dietary vitamin A intake versus control (4 IU/g diet), using the NIAAA chronic-binge model of ALD. Hepatic steatosis was assessed using histopathological and biochemical approaches. Tissue Vitamin A levels were measured using high-performance liquid chromatography. Markers of ALD, hepatic inflammation and lipid metabolism were analyzed by the quantitative polymerase chain reaction and western blotting.

As expected, a 0 IU/g Vitamin A diet decreased, and a 25 IU/g Vitamin A diet increased hepatic Vitamin A stores. However, alcohol induced changes in hepatic triglyceride levels, markers of hepatic lipid metabolism, inflammation and fibrosis were not significantly different in mice consuming a copious or deficient vitamin A diet compared to control.

Altered vitamin A intake and hepatic vitamin A storage have a minor effect on the pathogenesis of ALD. Thus, given the known link between altered retinoic acid signaling and ALD, future studies that further explore this linkage are warranted.

Vitamin A, an essential micronutrient, is integral to various biological processes crucial for organismal development and maintenance. Dietary sources of vitamin A encompass preformed retinol, retinyl esters, and provitamin A carotenoids. Retinoic acid (RA), a key component, plays pivotal roles in vision, cell proliferation, apoptosis, immune function, and gene regulation. Drug repurposing, an effective strategy for identifying new therapeutic applications for existing drugs, has gained prominence in recent years. This review seeks to provide a comprehensive overview of the current research landscape surrounding retinoids and drug repurposing. The scope of this review encompasses a comprehensive examination of retinoids and their potential for repurposing in various therapeutic contexts. Despite their efficacy in treating dermatological conditions, concerns about toxicity persist, driving the search for safer and more potent retinoids. The molecular mechanisms underlying retinoid activity involve binding to retinoic acid receptors (RARs) and retinoid X receptors (RXRs), leading to transcriptional regulation of target genes. This review seeks to shed light on the possibilities for repurposing retinoids to cover a wider spectrum of therapeutic uses by exploring recent scientific progress. It also aims to offer a more comprehensive understanding of the therapeutic prospects of retinoids and the broader impact of drug repositioning in contemporary medicine.

The first evidence of the existence of vitamin A was the observation 1881 that a substance present in small amounts in milk was necessary for normal development and life. It was not until more than 100 years later that it was understood that vitamin A acts as a hormone through nuclear receptors. Unlike classical hormones, vitamin A cannot be synthesized by the body but needs to be supplied by the food as retinyl esters in animal products and ß-carotene in vegetables and fruits. Globally, vitamin A deficiency is a huge health problem, but in the industrialized world excess of vitamin A has been suggested to be a risk factor for secondary osteoporosis and enhanced susceptibility to fractures. Preclinical studies unequivocally have shown that increased amounts of vitamin A cause decreased cortical bone mass and weaker bones due to enhanced periosteal bone resorption. Initial clinical studies demonstrated a negative association between intake of vitamin A, as well as serum levels of vitamin A, and bone mass and fracture susceptibility. In some studies, these observations have been confirmed, but in other studies no such associations have been observed. One meta-analysis found that both low and high serum levels of vitamin A were associated with increased relative risk of hip fractures. Another meta-analysis also found that low levels of serum vitamin A increased the risk for hip fracture but could not find any association with high serum levels of vitamin A and hip fracture. It is apparent that more clinical studies, including large numbers of incident fractures, are needed to determine which levels of vitamin A that are harmful or beneficial for bone mass and fracture. It is the aim of the present review to describe how vitamin A was discovered and how vitamin A is absorbed, metabolized and is acting as a ligand for nuclear receptors. The effects by vitamin A in preclinical studies are summarized and the clinical investigations studying the effect by vitamin A on bone mass and fracture susceptibility are discussed in detail.

Currently, 30% of the global population is overweight or obese, with projections from the World Obesity Federation suggesting that this figure will surpass 50% by 2035. Adipose tissue dysfunction, a primary characteristic of obesity, is closely associated with an increased risk of metabolic abnormalities, such as hypertension, hyperglycemia, and dyslipidemia, collectively termed metabolic syndrome. In particular, visceral fat accretion is considered as a hallmark of aging and is strongly linked to higher mortality rates in humans. Adipokines, bioactive peptides secreted by adipose tissue, play crucial roles in regulating appetite, satiety, adiposity, and metabolic balance, thereby rendering them key players in alleviating metabolic diseases and potentially extending health span. In this review, we elucidated the role of adipokines in the development of obesity and related metabolic disorders while also exploring the potential of certain adipokines as candidates for longevity interventions.

In this review, we outline our current understanding of the mechanisms involved in the absorption, storage, and transport of dietary vitamin A to the eye, and the trafficking of rhodopsin protein to the photoreceptor outer segments, which encompasses the logistical backbone required for photoreceptor cell function. Two key mechanisms of this process are emphasized in this manuscript: ocular and systemic vitamin A membrane transporters, and rhodopsin transporters. Understanding the complementary mechanisms responsible for the generation and proper transport of the retinylidene protein to the photoreceptor outer segment will eventually shed light on the importance of genes encoded by these proteins, and their relationship on normal visual function and in the pathophysiology of retinal degenerative diseases.

There is growing interest in the potential health benefits of probiotics for both humans and animals. The study aimed to investigate the effects of feeding the canine-derived probiotic Pediococcus acidilactici GLP06 to adult beagles by analysing the microbiome and metabolome. Twenty-four healthy adult beagles were randomly assigned to four groups. The CK group received a standard diet, while the three probiotic groups, the LG group (2 × 108 CFU/day/dog), MG group (2 × 109 CFU/day/dog), and HG group (2 × 1010 CFU/day/dog), received the standard diet supplemented with varying amounts of probiotics. The results show that, compared to the CK group, total antioxidant capacity was significantly increased in the MG and HG groups (p < 0.05), and superoxide dismutase and catalase were significantly increased in the HG group (p < 0.05). Compared to the CK group, malondialdehyde and blood urea nitrogen content were significantly decreased in the MG and HG groups (p < 0.05). Additionally, secretory immunoglobulin A activity was significantly increased in the HG group compared to the CK and LG groups (p < 0.05), and immunoglobulin G activity was significantly increased in the HG group compared to the CK, LG, and MG groups (p < 0.05). In addition, compared with the CK group, the abundance of Faecalitalea and Collinsella increased in the LG group, and the relative abundance of Tyzzerella and Parasutterella increased in the MG group. The α diversity and the relative abundances of beneficial bacteria (Faecalibacterium, Lachnospiraceae_NK4A1316, and Ruminococcaceae_UCG-005) were higher in the HG group than in the CK group. Furthermore, acetic acid content was significantly increased in the HG group compared to the CK, LG, and MG groups (p < 0.05). Butyric acid, isobutyric acid, and the total SCFA content were significantly increased in the HG group compared to the CK group (p < 0.05). Moreover, metabolome analysis revealed 111 upregulated and 171 downregulated metabolites in the HG group. In conclusion, this study presents evidence that supplementing with P. acidilactici GLP06 can have a positive impact on antioxidant activity, immunoproteins, SCFAs, and gut microbiota in adult beagles. These findings highlight the potential of probiotics as a dietary intervention to enhance gut health and overall wellbeing in companion animals.

Liver fibrosis is the excessive accumulation of extracellular matrix proteins, primarily collagen, in response to liver injury caused by chronic liver diseases. HIV infection accelerates the progression of liver fibrosis in patients co-infected with HCV or HBV compared to those who are only mono-infected. The early event in the progression of liver fibrosis involves the activation of hepatic stellate cells (HSCs), which entails the loss of lipid droplets (LD) to fuel the production of extracellular matrix components crucial for liver tissue healing. Thus, we are examining the mechanism by which HIV stimulates the progression of liver fibrosis. HIV-R5 tropic infection was unable to induce the expression of TGF-β, collagen deposition, α-smooth muscle actin (α-SMA), and cellular proliferation. However, this infection induced the secretion of the profibrogenic cytokine IL-6 and the loss of LD. This process involved the participation of peroxisome proliferator-activated receptor (PPAR)-α and an increase in lysosomal acid lipase (LAL), along with the involvement of Microtubule-associated protein 1 A/1B-light chain 3 (LC3), strongly suggesting that LD loss could occur through acid lipolysis. These phenomena were mimicked by the gp120 protein from the R5 tropic strain of HIV. Preincubation of HSCs with the CCR5 receptor antagonist, TAK-779, blocked gp120 activity. Additionally, experiments performed with pseudotyped-HIV revealed that HIV replication could also contribute to LD loss. These results demonstrate that the cross-talk between HSCs and HIV involves a series of interactions that help explain some of the mechanisms involved in the exacerbation of liver damage observed in co-infected individuals.

The health of companion animals, particularly dogs and cats, is significantly influenced by nutrition, with vitamins playing a crucial role. Vitamin A, in particular, is indispensable, with diverse roles ranging from vision to immune modulation and reproduction. Despite its importance, the metabolism and dietary requirements of vitamin A in companion animals remain complex and not fully understood. This review provides a comprehensive overview of the historical perspective, the digestion, the metabolism, the physiological roles, the deficiency, the excess, and the interactions with other micronutrients of vitamin A in companion animals. Additionally, it highlights future research directions and gaps in our understanding. Insights into the metabolism of vitamin A in companion animals, personalized nutrition strategies based on genetic variability, longitudinal studies tracking the status of vitamin A, and investigations into its immunomodulatory effects are crucial for optimizing pet health and wellness. Furthermore, understanding the stability and bioavailability of vitamin A in pet food formulations is essential for ensuring the provision of adequate micronutrients. Overall, this review underscores the importance of vitamin A in companion animal nutrition and the need for further research to enhance our understanding and to optimize dietary recommendations for pet health and well-being.

The purpose of this investigation was to evaluate the impacts of vitamin A (VA) supplementation in feed at levels of 0 (control), 2,000, 4,000, 6,000, and 8,000 IU VA/kg diet on the reproductive efficiency and antioxidative properties of aged Sinai laying hens at 52 wk of age (n = 300 females and 30 males) in 6 replicates (10 females + 1 male/replicate). As well as blood biochemical indicators, carcass characteristics, growth performance, immunity, and the antioxidative status of their chicks. Results showed that diets supplemented with 2,000 or 6,000 IU/kg of VA increased fertility rate and decreased early embryonic mortality (P < 0.05). Increasing VA from 4,000 to 6,000 IU/kg significantly boosted hatchability rates. All VA levels significantly enhanced glutathione peroxidase (GPx) and reduced malondialdehyde (MDA) and late embryonic mortality. In the shell gland, dietary supplementation of 6,000 or 8,000 IU/kg of VA enhanced actions of GPx actions, catalase (CAT), and superoxide dismutase (SOD). In hatched chicks, all VA levels boosted (P < 0.05) hemoglobin, red blood cell count, and serum concentration of total proteins and IgA while decreasing eosinophils percentage and aspartate aminotransferase activity (AST) concentration. Dietary VA supplementations from 4,000 to 8,000 IU/kg improved lymphocytes, serum total antioxidant capacity (TAC), SOD, and IgM, while decreasing heterophils, heterophils/lymphocytes ratio, and creatinine in hatched chicks. Serum triglyceride concentration was reduced by adding 6,000 or 8,000 IU/kg of VA, while globulin and high-density lipoprotein concentrations were heightened only by 8,000 IU/kg of VA. It could be concluded that the dietary supplementation of VA (6,000 IU/kg) improved reproductive efficiency and antioxidative status in the liver and the shell gland of aged laying hens and improved hemato-biochemicals parameters, antioxidative status, and immunity of their offspring.

Retinoic acid plays diverse physiological and pathophysiological roles in reproduction, immune function, energy metabolism and carcinogenesis. Because of the potential benefits of inhibiting retinoic acid biosynthesis in certain disease states, efforts are underway to develop inhibitors of retinoic acid biosynthesis via inhibition of the aldehyde dehydrogenase-1 A (ALDH1A) family of enzymes. However, many potential ALDH1A inhibitors also inhibit the related ALDH2 enzyme that plays a role in the metabolism of ethanol. Accurate in vitro assessment of ALDH2 inhibition is problematic, and to date, there are no published in vivo assays to determine inhibition of ALDH2 by candidate ALDH1A inhibitors.

To address this, we developed a novel gas-chromatography-mass-spectrometry ethanol clearance assay in mice using orally administered ethanol and serial measurement of ethanol over time. We then used this assay to determine pharmacological inhibition of ALDH2 by candidate ALDH1A inhibitors.

Ethanol clearance in untreated male mice occurs within sixty minutes. Male mice treated with WIN 18,446, a known ALDH1A inhibitor that also inhibits ALDH2, demonstrated significant inhibition of ethanol clearance compared to untreated controls. Novel pyrazole and piperazine ALDH1A inhibitors were then tested with the piperazine inhibitor demonstrating ALDH2 inhibition via impaired ethanol clearance while the pyrazole inhibitor did not interfere with ethanol metabolism, suggesting a lack of ALDH2 inhibition.

Inhibition of ethanol clearance is a useful in vivo method of inferring pharmacologic inhibition of hepatic ALDH2. This assay may be useful in the development of novel ALDH1A specific inhibitors for a variety of therapeutic indications.

Lactoferrin (LF) is a glycoprotein that binds to iron ions (Fe2+) and other metallic ions, such as Mg2+, Zn2+, and Cu2+, and has antibacterial and immunomodulatory properties. The antibacterial properties of LF are due to its ability to sequester iron. The immunomodulatory capability of LF promotes homeostasis in the enteric environment, acting directly on the beneficial microbiota. LF can modulate antigen-presenting cell (APC) biology, including migration and cell activation. Nonetheless, some gut microbiota strains produce toxic metabolites, and APCs are responsible for initiating the process that inhibits the inflammatory response against them. Thus, eliminating harmful strains lowers the risk of inducing chronic inflammation, and consequently, metabolic disease, which can progress to type 2 diabetes mellitus (T2DM). LF and retinoic acid (RA) exhibit immunomodulatory properties such as decreasing cytokine production, thus modifying the inflammatory response. Their activities have been observed both in vitro and in vivo. The combined, simultaneous effect of these molecules has not been studied; however, the synergistic effect of LF and RA may be employed for enhancing the secretion of humoral factors, such as IgA. We speculate that the combination of LF and RA could be a potential prophylactic alternative for the treatment of metabolic dysregulations such as T2DM. The present review focuses on the importance of a healthy diet for a balanced gut and describes how probiotics and prebiotics with immunomodulatory activity as well as inductors of differentiation and cell proliferation could be acquired directly from the diet or indirectly through the oral administration of formulations aimed to maintain gut health or restore a eubiotic state in an intestinal environment that has been dysregulated by external factors such as stress and a high-fat diet.

Vitamin A, supplied by the diet, is critical for brain health, but little is known about its delivery across the blood-brain barrier (BBB). Brain microvascular endothelial-like cells (BMECs) differentiated from human-derived induced pluripotent stem cells (iPSCs) form a tight barrier that recapitulates many of the properties of the human BBB. We paired iPSC-derived BMECs with recombinant vitamin A serum transport proteins, retinol-binding protein (RBP), and transthyretin (TTR), to create an in vitro model for the study of vitamin A (retinol) delivery across the human BBB. iPSC-derived BMECs display a strong barrier phenotype, express key vitamin A metabolism markers, and can be used for quantitative modeling of retinol accumulation and permeation. Manipulation of retinol, RBP, and TTR concentrations, and the use of mutant RBP and TTR, yielded novel insights into the patterns of retinol accumulation in, and permeation across, the BBB. The results described herein provide a platform for deeper exploration of the regulatory mechanisms of retinol trafficking to the human brain.