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International Journal of Molecular... Jul 2023Cancer stem cells are the root cause of cancer, which, in essence, is a developmental disorder. All- retinoic acid (ATRA) signaling via ligand-activation of the retinoic... (Review)
Review
Cancer stem cells are the root cause of cancer, which, in essence, is a developmental disorder. All- retinoic acid (ATRA) signaling via ligand-activation of the retinoic acid receptors (RARs) plays a crucial role in tissue patterning and development during mammalian embryogenesis. In adults, active RARγ maintains the pool of hematopoietic stem cells, whereas active RARα drives myeloid cell differentiation. Various findings have revealed that ATRA signaling is deregulated in many cancers. The enzymes for ATRA synthesis are downregulated in colorectal, gastric, lung, and oropharyngeal cancers. ATRA levels within breast, ovarian, pancreatic, prostate, and renal cancer cells were lower than within their normal counterpart cells. The importance is that 0.24 nM ATRA activates RARγ (for stem cell stemness), whereas 100 times more is required to activate RARα (for differentiation). Moreover, RARγ is an oncogene regarding overexpression within colorectal, cholangiocarcinoma, hepatocellular, ovarian, pancreatic, and renal cancer cells. The microRNA (miR) 30a-5p downregulates expression of RARγ, and miR-30a/miR-30a-5p is a tumor suppressor for breast, colorectal, gastric, hepatocellular, lung, oropharyngeal, ovarian, pancreatic, prostate, and renal cancer. These complementary findings support the view that perturbations to ATRA signaling play a role in driving the abnormal behavior of cancer stem cells. Targeting ATRA synthesis and RARγ has provided promising approaches to eliminating cancer stem cells because such agents have been shown to drive cell death.
Topics: Male; Animals; Humans; Tretinoin; Retinoic Acid Receptor alpha; Kidney Neoplasms; Colorectal Neoplasms; MicroRNAs; Mammals
PubMed: 37569466
DOI: 10.3390/ijms241512089 -
Clinical Ophthalmology (Auckland, N.Z.) 2023Vitamin deficiencies can have adverse effects on health, including on the visual system. The ocular manifestations of a vitamin deficiency are related to the underlying... (Review)
Review
Vitamin deficiencies can have adverse effects on health, including on the visual system. The ocular manifestations of a vitamin deficiency are related to the underlying biochemical function of the particular nutrient. While vitamin deficiencies are not common in developed counties, they are still prevalent in parts of the developing world and in specific, vulnerable populations. Vitamin deficiencies can cause or contribute to many ophthalmological conditions and eye diseases may even be the first presenting finding of a vitamin deficiency. As such, it is important for ophthalmologists to be aware of the ocular manifestations of vitamin deficiencies, especially given that the complications can be severe and effectively treated if identified early. This review summarizes the literature on the main vitamins known to have characteristic ocular manifestations: vitamins A, B1, B2, B9, B12, C, D, E and K. The function, epidemiology, manifestations, workup, and management of each vitamin is discussed in detail.
PubMed: 37489231
DOI: 10.2147/OPTH.S401262 -
Nutrients Jul 2023Recent research supports previous contentions that encapsulating vitamins and minerals with liposomes help improve overall bioavailability. This study examined whether... (Randomized Controlled Trial)
Randomized Controlled Trial
Recent research supports previous contentions that encapsulating vitamins and minerals with liposomes help improve overall bioavailability. This study examined whether ingesting a liposomal multivitamin and mineral supplement (MVM) differentially affects the appearance and/or clearance of vitamins and minerals in the blood compared to a non-liposomal MVM supplement. In a double-blind, randomized, and counterbalanced manner, 34 healthy men and women fasted for 12 h. Then, they ingested a non-liposomal (NL) or liposomal (L) MVM supplement and a standardized snack. Venous blood samples were obtained at 0, 2, 4, and 6 h after MVM ingestion and analyzed for a panel of vitamins and minerals. Plasma levels of vitamins and minerals and mean changes from baseline with 95% confidence intervals (CIs) were analyzed using general linear model statistics with repeated measures. The observed values were also entered into pharmacokinetic analysis software and analyzed through univariate analysis of variance with repeated measure contrasts. The results revealed an overall treatment x time interaction effect among the vitamins and minerals evaluated ( = 0.051, ηp2 = 0.054, moderate effect). Differences between treatments were also observed in volume distribution area (vitamin E, iron), median residence time (vitamin E, iron), volume distribution area (iron), volume of distribution steady state (vitamin A, E, iron), clearance rates (vitamin A, E), elimination phase half-life (vitamin E, iron), distribution/absorption phase intercept (vitamin A), and distribution/absorption phase slope and rate (vitamin C, calcium). Vitamin volume distribution was lower with liposomal MVM ingestion than non-liposomal MVM sources, suggesting greater clearance and absorption since similar amounts of vitamins and minerals were ingested. These findings indicate that coating a MVM with liposomes affects individual nutrient pharmacokinetic profiles. Additional research should evaluate how long-term supplementation of liposomal MVM supplements may affect vitamin and mineral status, nutrient function, and/or health outcomes.
Topics: Female; Humans; Male; Dietary Supplements; Iron; Liposomes; Minerals; Vitamin A; Vitamin E; Vitamin K; Vitamins; Double-Blind Method
PubMed: 37447400
DOI: 10.3390/nu15133073 -
Archives of Dermatological Research Dec 2023Microencapsulation has received extensive attention because of its various applications. Since its inception in the 1940s, this technology has been used across several... (Review)
Review
Microencapsulation has received extensive attention because of its various applications. Since its inception in the 1940s, this technology has been used across several areas, including the chemical, food, and pharmaceutical industries. Over-the-counter skin products often contain ingredients that readily and unevenly degrade upon contact with the skin. Enclosing these substances within a silica shell can enhance their stability and better regulate their delivery onto and into the skin. Silica microencapsulation uses silica as the matrix material into which ingredients can be embedded to form microcapsules. The FDA recognizes amorphous silica as a safe inorganic excipient and recently approved two new topical therapies for the treatment of rosacea and acne. The first approved formulation uses a novel silica-based controlled vehicle delivery technology to improve the stability of two active ingredients that are normally not able to be used in the same formulation due to potential instability and drug degradation. The formulation contains 3.0% benzoyl peroxide (BPO) and 0.1% tretinoin topical cream to treat acne vulgaris in adults and pediatric patients. The second formulation contains silica microencapsulated 5.0% BPO topical cream to treat inflammatory rosacea lesions in adults. Both formulations use the same amorphous silica sol-gel microencapsulation technology to improve formulation stability and skin compatibility parameters.
Topics: Adult; Humans; Child; Dermatologic Agents; Benzoyl Peroxide; Acne Vulgaris; Tretinoin; Pharmaceutical Vehicles; Rosacea; Nonprescription Drugs; Gels; Treatment Outcome; Drug Combinations
PubMed: 37792034
DOI: 10.1007/s00403-023-02725-z -
Notch and retinoic acid signals regulate macrophage formation from endocardium downstream of Nkx2-5.Nature Communications Sep 2023Hematopoietic progenitors are enriched in the endocardial cushion and contribute, in a Nkx2-5-dependent manner, to tissue macrophages required for the remodeling of...
Hematopoietic progenitors are enriched in the endocardial cushion and contribute, in a Nkx2-5-dependent manner, to tissue macrophages required for the remodeling of cardiac valves and septa. However, little is known about the molecular mechanism of endocardial-hematopoietic transition. In the current study, we identified the regulatory network of endocardial hematopoiesis. Signal network analysis from scRNA-seq datasets revealed that genes in Notch and retinoic acid (RA) signaling are significantly downregulated in Nkx2-5-null endocardial cells. In vivo and ex vivo analyses validate that the Nkx2-5-Notch axis is essential for the generation of both hemogenic and cushion endocardial cells, and the suppression of RA signaling via Dhrs3 expression plays important roles in further differentiation into macrophages. Genetic ablation study revealed that these macrophages are essential in cardiac valve remodeling. In summary, the study demonstrates that the Nkx2-5/Notch/RA signaling plays a pivotal role in macrophage differentiation from hematopoietic progenitors.
Topics: Endocardium; Macrophages; Histiocytes; Cell Differentiation; Tretinoin
PubMed: 37669937
DOI: 10.1038/s41467-023-41039-6 -
The Journal of Nutrition Aug 2023Niacin-derived nicotinamide adenine dinucleotide is an essential cofactor for many dehydrogenase enzymes involved in vitamin A (VA) metabolism. Several countries with...
BACKGROUND
Niacin-derived nicotinamide adenine dinucleotide is an essential cofactor for many dehydrogenase enzymes involved in vitamin A (VA) metabolism. Several countries with high prevalence of VA deficiency rely on maize, a poor source of available niacin, as a dietary staple.
OBJECTIVES
This study evaluated the interaction of dietary niacin on VA homeostasis using male Sprague-Dawley rats, aged 21 d (baseline body weight 88.3 ± 6.6 g).
METHODS
After 1 wk of acclimation, baseline samples were collected (n = 4). Remaining rats (n = 54) were split into 9 groups to receive low tryptophan, VA-deficient feed with 3 different amounts of niacin (0, 15, or 30 mg/kg) and 3 different oral VA doses (50, 350, or 3500 nmol/d) in a 3 × 3 design. After 4 wk, the study was terminated. Serum, livers, and small intestine were analyzed for retinoids using high-performance liquid chromatography. Niacin and metabolites were evaluated with nuclear magnetic resonance. Plasma pyridoxal-P (PLP) was measured with high-performance liquid chromatography.
RESULTS
Niacin intake correlated with serum retinol concentrations (r = 0.853, P < 0.001). For rats receiving the highest VA dose, liver retinol concentrations were lower in the 30-mg/kg niacin group (5.39 ± 0.27 μmol/g) than those in the 0-mg/kg and 15-mg/kg groups (9.18 ± 0.62 and 8.75 ± 0.07 μmol/g, respectively; P ≤ 0.05 for both). This phenomenon also occurred in the lower VA doses (P ≤ 0.05 for all). Growth and tissue weight at endline were associated with niacin intake (P ≤ 0.001 for all). Plasma PLP correlated with estimated niacin intake (r = 0.814, P < 0.001).
CONCLUSIONS
Optimal niacin intake is associated with lower liver VA and higher serum retinol and plasma PLP concentrations. The extent to which vitamin B intake affects VA homeostasis requires further investigation to determine if the effects are maintained in humans.
Topics: Humans; Male; Rats; Animals; Vitamin A; Niacin; Rats, Sprague-Dawley; Vitamin A Deficiency; Liver
PubMed: 37354977
DOI: 10.1016/j.tjnut.2023.06.026 -
Nature Communications Feb 2024Retinol is a fat-soluble vitamin that plays an essential role in many biological processes throughout the human lifespan. Here, we perform the largest genome-wide...
Retinol is a fat-soluble vitamin that plays an essential role in many biological processes throughout the human lifespan. Here, we perform the largest genome-wide association study (GWAS) of retinol to date in up to 22,274 participants. We identify eight common variant loci associated with retinol, as well as a rare-variant signal. An integrative gene prioritisation pipeline supports novel retinol-associated genes outside of the main retinol transport complex (RBP4:TTR) related to lipid biology, energy homoeostasis, and endocrine signalling. Genetic proxies of circulating retinol were then used to estimate causal relationships with almost 20,000 clinical phenotypes via a phenome-wide Mendelian randomisation study (MR-pheWAS). The MR-pheWAS suggests that retinol may exert causal effects on inflammation, adiposity, ocular measures, the microbiome, and MRI-derived brain phenotypes, amongst several others. Conversely, circulating retinol may be causally influenced by factors including lipids and serum creatinine. Finally, we demonstrate how a retinol polygenic score could identify individuals more likely to fall outside of the normative range of circulating retinol for a given age. In summary, this study provides a comprehensive evaluation of the genetics of circulating retinol, as well as revealing traits which should be prioritised for further investigation with respect to retinol related therapies or nutritional intervention.
Topics: Humans; Vitamin A; Genome-Wide Association Study; Phenotype; Obesity; Adiposity; Mendelian Randomization Analysis; Retinol-Binding Proteins, Plasma
PubMed: 38374065
DOI: 10.1038/s41467-024-45779-x -
Nature Cancer Nov 2023Cachexia is a major cause of morbidity and mortality in individuals with cancer and is characterized by weight loss due to adipose and muscle tissue wasting. Hallmarks...
Cachexia is a major cause of morbidity and mortality in individuals with cancer and is characterized by weight loss due to adipose and muscle tissue wasting. Hallmarks of white adipose tissue (WAT) remodeling, which often precedes weight loss, are impaired lipid storage, inflammation and eventually fibrosis. Tissue wasting occurs in response to tumor-secreted factors. Considering that the continuous endothelium in WAT is the first line of contact with circulating factors, we postulated whether the endothelium itself may orchestrate tissue remodeling. Here, we show using human and mouse cancer models that during precachexia, tumors overactivate Notch1 signaling in distant WAT endothelium. Sustained endothelial Notch1 signaling induces a WAT wasting phenotype in male mice through excessive retinoic acid production. Pharmacological blockade of retinoic acid signaling was sufficient to inhibit WAT wasting in a mouse cancer cachexia model. This demonstrates that cancer manipulates the endothelium at distant sites to mediate WAT wasting by altering angiocrine signals.
Topics: Animals; Humans; Male; Mice; Adipose Tissue, White; Cachexia; Neoplasms; Signal Transduction; Tretinoin; Receptor, Notch1
PubMed: 37749321
DOI: 10.1038/s43018-023-00622-y -
Cell Communication and Signaling : CCS Aug 2023Sorafenib resistance greatly reduces the efficacy of treatments in advanced hepatocellular carcinoma (HCC) patients, but the underlying mechanisms are not thoroughly...
BACKGROUND
Sorafenib resistance greatly reduces the efficacy of treatments in advanced hepatocellular carcinoma (HCC) patients, but the underlying mechanisms are not thoroughly understood. All-trans retinoic acid (ATRA), an anti-leukaemia agent, has attracted considerable attention due to its role in sensitizing cells to other anticancer treatments. We aimed to investigate the combined effect of ATRA and Sorafenib on HCC and the underlying mechanisms.
METHODS
CCK-8, cell sphere formation, trans-well migration, and wound-healing assays were used to analyse the biological behaviours of HCC cells in vitro. Western blotting and qRT-PCR analysis were conducted to measure the expression of p21 activated kinase 1 (PAK1) and phospho-p21 activated kinase 1 (pPAK1). Xenograft models were established to confirm the synergistic effects of ATRA and Sorafenib in vivo. TUNEL assays and immunohistochemistry were utilized to determine apoptosis, proliferation, PAK1 and pPAK1 levels in tumour tissues.
RESULTS
We observed that PAK1 was overexpressed in HCC, and its expression was negatively correlated with the survival of patients. PAK1 promoted the proliferation, self-renewal and epithelial-mesenchymal transition of HCC cells. Correlation analysis indicated that the IC of Sorafenib was positively correlated with the level of pPAK1 in HCC cell lines. ATRA inhibited the progression of HCC and sensitized HCC response to Sorafenib by downregulation of PAK1, as shown by the calculated coefficient of drug interaction and the data obtained from xenograft models.
CONCLUSIONS
Our findings indicated that instead of treatment with Sorafenib alone, the combination of ATRA and Sorafenib provides a more effective treatment for HCC patients. Video Abstract.
Topics: Humans; Sorafenib; Carcinoma, Hepatocellular; p21-Activated Kinases; Down-Regulation; Liver Neoplasms; Cell Line, Tumor; Tretinoin; Apoptosis; Cell Proliferation; Antineoplastic Agents; Drug Resistance, Neoplasm
PubMed: 37537668
DOI: 10.1186/s12964-023-01194-1 -
Frontiers in Immunology 2023Vitamin A has long been associated with bladder cancer, and many exogenous vitamin A supplements, vitamin A derivatives, and synthetic drugs have been investigated over... (Review)
Review
Vitamin A has long been associated with bladder cancer, and many exogenous vitamin A supplements, vitamin A derivatives, and synthetic drugs have been investigated over the years. However, the effectiveness of these strategies in clinical practice has not met expectations, and they have not been widely adopted. Recent medical research on intestinal flora has revealed that bladder cancer patients exhibit reduced serum vitamin A levels and an imbalance of gut microbiota. In light of the close relationship between gut microbiota and vitamin A, one can speculate that a complex regulatory mechanism exists between the two in the development and occurrence of bladder cancer. As such, further exploration of their interaction in bladder cancer may help guide the use of vitamin A for preventive purposes. During the course of this review, attention is paid to the influence of intestinal microbiota on the vitamin A metabolism and the RA signaling pathway, as well as the mutual promotion relationships between them in the prevention of bladder cancer, In addition, it emphasizes the importance of intestinal microbiota for bladder cancer prevention and treatment.
Topics: Humans; Gastrointestinal Microbiome; Vitamin A; Urinary Bladder Neoplasms; Biomedical Research; Dietary Supplements
PubMed: 37711628
DOI: 10.3389/fimmu.2023.1252616