|
1
|
Grundy MML, Deglaire A, Le Feunteun S, Reboul E, Moughan PJ, Wilde PJ, McClements DJ, Marze S. Bioaccessibility and associated concepts: Terminology in the context of in vitro food digestion studies. Food Chem 2025; 485:144424. [PMID: 40288343 DOI: 10.1016/j.foodchem.2025.144424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 04/15/2025] [Accepted: 04/18/2025] [Indexed: 04/29/2025]
Abstract
In vitro gastrointestinal models are widely used to study food digestion, in combination with analytical methods to determine the physicochemical and biochemical fate of food compounds. The in vitro bioaccessibility determined with these models is often used as an indicator of the in vivo bioavailability. However, the bioaccessibility concept is not used consistently within the scientific literature, leading to confusion and making it difficult to compare the results from different studies. The aim of this article is to provide standardized definitions of in vitro digestibility and bioaccessibility, detailing the main processes involved, including physical release, solubilization, and biochemical/metabolic reactions. The terminology of complementary cellular, ex vivo, and animal/human in vivo experiments is also given. Application of the in vitro terminology to different nutrients is discussed, including lipids, proteins, carbohydrates, vitamins, and other bioactive compounds. The proposed definitions unify most concepts related to the gastrointestinal fate of ingested food compounds.
Collapse
Affiliation(s)
- Myriam M-L Grundy
- INRAE, French National Research Institute for Agriculture, Food and Environment, UMR PEGASE, Institut Agro, 35590, Saint Gilles, France
| | | | | | | | - Paul J Moughan
- Riddet Institute, Massey University, Palmerston North 4474, New Zealand
| | - Pete J Wilde
- Quadram Institute Bioscience, Norwich Research Park, Norfolk, Norwich, NR4 7UQ, United Kingdom
| | | | | |
Collapse
|
|
2
|
Wang Z, Liu Y. Dual-modulation of nutrient-transporter axis and functionalized carriers: A paradigm shift for precision oral vitamin D delivery. Colloids Surf B Biointerfaces 2025; 253:114769. [PMID: 40344743 DOI: 10.1016/j.colsurfb.2025.114769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2025] [Revised: 04/25/2025] [Accepted: 05/05/2025] [Indexed: 05/11/2025]
Abstract
The transintestinal epithelial absorption of vitamin D is intricately regulated by specific transport protein networks. Emerging evidence from molecular nutrition research reveals that certain dietary nutrients can enhance intestinal vitamin D absorption through targeted modulation of lipid transport pathways. Despite significant advancements in vitamin D delivery systems demonstrating excellent intestinal mucoadhesion and in vitro bioaccessibility, their clinical translation remains limited by suboptimal in vivo bioavailability. To address this critical challenge, we propose an innovative synergistic nutrient absorption strategy that establishes precise coordination among three key elements: dietary nutrient composition, transport protein regulation, and intestinal absorption optimization. This comprehensive review systematically examines: (1) The molecular mechanisms governing transintestinal vitamin D transport and physiological modulation of protein-mediated absorption pathways; (2) The regulatory effects of dietary components on vitamin D absorption efficiency through protein pathway modulation, proposing a novel "nutrient-transporter-vitamin D axis" strategy integrating cutting-edge carrier technologies; (3) Future perspectives for developing functionalized vitamin D delivery systems. The proposed paradigm shift, combining nutrient-mediated transport enhancement with advanced carrier engineering, represents a transformative approach to overcome current limitations in oral vitamin D delivery. This dual-modulation strategy synergistically improves intestinal absorption and systemic bioavailability through simultaneous optimization of biological transport mechanisms and pharmaceutical delivery parameters, offering new possibilities for precision nutrition interventions.
Collapse
Affiliation(s)
- Zixiao Wang
- College of Ocean Food and Biological Engineering, Jimei University, Xiamen, Fujian 361021, PR China
| | - Yixiang Liu
- College of Ocean Food and Biological Engineering, Jimei University, Xiamen, Fujian 361021, PR China.
| |
Collapse
|
|
3
|
Steinbauer S, Wallner M, Karl LM, Gramatte T, Essl K, Iken M, Weghuber J, Blank-Landeshammer B, Röhrl C. Differential Enhancement of Fat-Soluble Vitamin Absorption and Bioefficacy via Micellization in Combination with Selected Plant Extracts In Vitro. Nutrients 2025; 17:359. [PMID: 39861489 PMCID: PMC11769215 DOI: 10.3390/nu17020359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 01/13/2025] [Accepted: 01/14/2025] [Indexed: 01/27/2025] Open
Abstract
Background/Objectives: Individuals with special metabolic demands are at risk of deficiencies in fat-soluble vitamins, which can be counteracted via supplementation. Here, we tested the ability of micellization alone or in combination with selected natural plant extracts to increase the intestinal absorption and bioefficacy of fat-soluble vitamins. Methods: Micellated and nonmicellated vitamins D3 (cholecalciferol), D2 (ergocalciferol), E (alpha tocopheryl acetate), and K2 (menaquionone-7) were tested in intestinal Caco-2 or buccal TR146 cells in combination with curcuma (Curcuma longa), black pepper (Piper nigrum), or ginger (Zingiber officinale Roscoe) plant extracts. The vitamin uptake was quantified via HPLC-MS, and bioefficacy was assessed via gene expression analyses or the Griess assay for nitric oxide generation. Results: Micellization increased the uptake of vitamin D into buccal and intestinal cells, with vitamin D3 being more efficient than vitamin D2 in increasing the expression of genes involved in calcium transport. The micellization of vitamin E acetate increased its uptake and conversion into biologically active free vitamin E in intestinal cells only. The vitamin K2 uptake into buccal and intestinal cells was increased via micellization. Plant extracts increased the uptake of select micellated vitamins, with no plant extract being effective in combination with all vitamins. The curcuma extract increased the uptake of vitamins D2/D3 but not their bioefficacy. Black pepper and ginger extracts increased the uptake of vitamin E acetate into intestinal cells but failed to increase its conversion into free vitamin E. The ginger extract augmented the uptake of vitamin K2 and increased NO generation additively. Conclusions: Our data substantiate the positive effects of micellization on fat-soluble vitamin absorption and bioefficacy in vitro. While the application of plant extracts in addition to micellization to further increase bioefficacy is an interesting approach, further studies are warranted to understand vitamin-specific interactions and translation into increased bioefficacy.
Collapse
Affiliation(s)
- Stefanie Steinbauer
- FFoQSI GmbH—Austrian Competence Centre for Feed and Food Quality, Safety and Innovation, Technopark 1D, 3430 Tulln, Austria; (S.S.); (M.W.); (T.G.); (J.W.); (B.B.-L.)
| | - Melanie Wallner
- FFoQSI GmbH—Austrian Competence Centre for Feed and Food Quality, Safety and Innovation, Technopark 1D, 3430 Tulln, Austria; (S.S.); (M.W.); (T.G.); (J.W.); (B.B.-L.)
| | - Lisa-Marie Karl
- Center of Excellence Food Technology and Nutrition, University of Applied Sciences Upper Austria, Stelzhamerstraße 23, 4600 Wels, Austria; (L.-M.K.); (K.E.)
| | - Theresa Gramatte
- FFoQSI GmbH—Austrian Competence Centre for Feed and Food Quality, Safety and Innovation, Technopark 1D, 3430 Tulln, Austria; (S.S.); (M.W.); (T.G.); (J.W.); (B.B.-L.)
| | - Katja Essl
- Center of Excellence Food Technology and Nutrition, University of Applied Sciences Upper Austria, Stelzhamerstraße 23, 4600 Wels, Austria; (L.-M.K.); (K.E.)
| | - Marcus Iken
- PM International AG, 15 Waistrooss, 5445 Schengen, Luxembourg;
| | - Julian Weghuber
- FFoQSI GmbH—Austrian Competence Centre for Feed and Food Quality, Safety and Innovation, Technopark 1D, 3430 Tulln, Austria; (S.S.); (M.W.); (T.G.); (J.W.); (B.B.-L.)
- Center of Excellence Food Technology and Nutrition, University of Applied Sciences Upper Austria, Stelzhamerstraße 23, 4600 Wels, Austria; (L.-M.K.); (K.E.)
| | - Bernhard Blank-Landeshammer
- FFoQSI GmbH—Austrian Competence Centre for Feed and Food Quality, Safety and Innovation, Technopark 1D, 3430 Tulln, Austria; (S.S.); (M.W.); (T.G.); (J.W.); (B.B.-L.)
- Center of Excellence Food Technology and Nutrition, University of Applied Sciences Upper Austria, Stelzhamerstraße 23, 4600 Wels, Austria; (L.-M.K.); (K.E.)
| | - Clemens Röhrl
- Center of Excellence Food Technology and Nutrition, University of Applied Sciences Upper Austria, Stelzhamerstraße 23, 4600 Wels, Austria; (L.-M.K.); (K.E.)
| |
Collapse
|
|
4
|
Alvarado-Ramos K, Bravo-Núñez Á, Vairo D, Sabran C, Landrier JF, Reboul E. Overweight Leads to an Increase in Vitamin E Absorption and Status in Mice. Mol Nutr Food Res 2024; 68:e2400509. [PMID: 39548902 DOI: 10.1002/mnfr.202400509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 09/16/2024] [Indexed: 11/18/2024]
Abstract
SCOPE This study investigates whether vitamin E (VE) deficiency in subjects with obesity could, at least partly, be due to a defect in VE intestinal absorption. METHODS AND RESULTS Mice follow either a high-fat (HF) or a control (CTL) diet for 12 weeks. The study evaluates their VE status, the expression of genes encoding proteins involved in lipid and fat-soluble vitamin intestinal absorption, and VE absorption using a γ-tocopherol-rich emulsion. HF mice have a weight (+23.0%) and an adiposity index (AI, +157.0) superior to CTL mice (p < 0.05). α-Tocopherol concentrations are higher in both plasma (+45.0%) and liver (+116.9%) of HF mice compared to CTL mice (p < 0.05). α-Tocopherol concentration in the adipose tissue of HF mice is higher than that of CTL mice after correction by the AI (+72.4%, p < 0.05). No difference is found in the expression of genes coding for proteins involved in intestinal lipid metabolism in fasting mice. After force-feeding, γ-tocopherol plasma concentration is higher in HF mice compared to CTL mice (+181.5% at 1.5 h after force-feeding, p < 0.05). CONCLUSION HF mice display higher status and more efficient absorption of VE than CTL mice. VE absorption is thus likely not impaired in the early stages of obesity.
Collapse
Affiliation(s)
| | - Ángela Bravo-Núñez
- Aix-Marseille Université, INRAE, INSERM, C2VN, Marseille, France
- Universidad de Valladolid, Palencia, 34004, Spain
| | - Donato Vairo
- Aix-Marseille Université, INRAE, INSERM, C2VN, Marseille, France
| | - Charlotte Sabran
- Aix-Marseille Université, INRAE, INSERM, C2VN, Marseille, France
| | | | | |
Collapse
|
|
5
|
Tęcza K, Kalinowska-Herok M, Rusinek D, Zajkowicz A, Pfeifer A, Oczko-Wojciechowska M, Pamuła-Piłat J. Are the Common Genetic 3'UTR Variants in ADME Genes Playing a Role in Tolerance of Breast Cancer Chemotherapy? Int J Mol Sci 2024; 25:12283. [PMID: 39596349 PMCID: PMC11594993 DOI: 10.3390/ijms252212283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 11/08/2024] [Accepted: 11/13/2024] [Indexed: 11/28/2024] Open
Abstract
We studied the associations between 3'UTR genetic variants in ADME genes, clinical factors, and the risk of breast cancer chemotherapy toxicity. Those variants and factors were tested in relation to seven symptoms belonging to myelotoxicity (anemia, leukopenia, neutropenia), gastrointestinal side effects (vomiting, nausea), nephrotoxicity, and hepatotoxicity, occurring in overall, early, or recurrent settings. The cumulative risk of overall symptoms of anemia was connected with AKR1C3 rs3209896 AG, ERCC1 rs3212986 GT, and >6 cycles of chemotherapy; leukopenia was determined by ABCC1 rs129081 allele G and DPYD rs291593 allele T; neutropenia risk was correlated with accumulation of genetic variants of DPYD rs291583 allele G, ABCB1 rs17064 AT, and positive HER2 status. Risk of nephrotoxicity was determined by homozygote DPYD rs291593, homozygote AKR1C3 rs3209896, postmenopausal age, and negative ER status. Increased risk of hepatotoxicity was connected with NR1/2 rs3732359 allele G, postmenopausal age, and with present metastases. The risk of nausea and vomiting was linked to several genetic factors and premenopausal age. We concluded that chemotherapy tolerance emerges from the simultaneous interaction of many genetic and clinical factors.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Jolanta Pamuła-Piłat
- Department of Clinical and Molecular Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-102 Gliwice, Poland; (K.T.); (M.K.-H.); (D.R.); (A.Z.); (A.P.); (M.O.-W.)
| |
Collapse
|
|
6
|
Röpcke M, Lu S, Plate C, Meinzer F, Lisiecki A, Dobler S. Substrate Specificity of ABCB Transporters Predicted by Docking Simulations Can Be Confirmed by Experimental Tests. Molecules 2024; 29:5272. [PMID: 39598661 PMCID: PMC11596062 DOI: 10.3390/molecules29225272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 10/24/2024] [Accepted: 10/31/2024] [Indexed: 11/29/2024] Open
Abstract
ATP-binding cassette (ABC) transporters, particularly those of subfamily B, are involved in cell detoxification, multidrug resistance, drug treatment pharmacodynamics, and also ecological adaptation. In this regard, ABCB transporters may play a decisive role in the co-evolution between plants and herbivores. Cardenolides, toxic steroid glycosides, are secondary plant metabolites that defend plants against herbivores by targeting their sodium-potassium ATPase. Despite their toxicity, several herbivorous insects such as the large milkweed bug (Oncopeltus fasciatus) have evolved adaptations to tolerate cardenolides and sequester them for their own defense. We investigate the role of two ABCB transporters of O. fasciatus for the paracellular transport of cardenolides by docking simulations and ATPase assays. Cardenolide binding of OfABCB1 and OfABCB2 is predicted by docking simulations and calculated binding energies are compared with substrate specificities determined in ATPase assays. Both tested ABCB transporters showed activity upon exposure to cardenolides and Km values that agreed well with the predictions of our docking simulations. We conclude that docking simulations can help identify transporter binding regions and predict substrate specificity, as well as provide deeper insights into the structural basis of ABC transporter function.
Collapse
Affiliation(s)
- Mario Röpcke
- Institute of Cell and System Biology of Animals, Universität Hamburg, 20146 Hamburg, Germany; (S.L.); (C.P.); (F.M.); (A.L.)
| | | | | | | | | | - Susanne Dobler
- Institute of Cell and System Biology of Animals, Universität Hamburg, 20146 Hamburg, Germany; (S.L.); (C.P.); (F.M.); (A.L.)
| |
Collapse
|
|
7
|
Shadid ILC, Guchelaar HJ, Weiss ST, Mirzakhani H. Vitamin D beyond the blood: Tissue distribution of vitamin D metabolites after supplementation. Life Sci 2024; 355:122942. [PMID: 39134205 PMCID: PMC11371480 DOI: 10.1016/j.lfs.2024.122942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 07/24/2024] [Accepted: 08/04/2024] [Indexed: 08/25/2024]
Abstract
Vitamin D3's role in mineral homeostasis through its endocrine function, associated with the main circulating metabolite 25-hydroxyvitamin D3, is well characterized. However, the increasing recognition of vitamin D3's paracrine and autocrine functions-such as cell growth, immune function, and hormone regulation-necessitates examining vitamin D3 levels across different tissues post-supplementation. Hence, this review explores the biodistribution of vitamin D3 in blood and key tissues following oral supplementation in humans and animal models, highlighting the biologically active metabolite, 1,25-dihydroxyvitamin D3, and the primary clearance metabolite, 24,25-dihydroxyvitamin D3. While our findings indicate significant progress in understanding how circulating metabolite levels respond to supplementation, comprehensive insight into their tissue concentrations remains limited. The gap is particularly significant during pregnancy, a period of drastically increased vitamin D3 needs and metabolic alterations, where data remains sparse. Within the examined dosage ranges, both human and animal studies indicate that vitamin D3 and its metabolites are retained in tissues selectively. Notably, vitamin D3 concentrations in tissues show greater variability in response to administered doses. In contrast, its metabolites maintain a more consistent concentration range, albeit different among tissues, reflecting their tighter regulatory mechanisms following supplementation. These observations suggest that serum 25-hydroxyvitamin D3 levels may not adequately reflect vitamin D3 and its metabolite concentrations in different tissues. Therefore, future research should aim to generate robust human data on the tissue distribution of vitamin D3 and its principal metabolites post-supplementation. Relating this data to clinically appropriate exposure metrics will enhance our understanding of vitamin D3's cellular effects and guide refinement of clinical trial methodologies.
Collapse
Affiliation(s)
- Iskander L C Shadid
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, the Netherlands
| | - Henk-Jan Guchelaar
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, the Netherlands
| | - Scott T Weiss
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Hooman Mirzakhani
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
|
8
|
Renaud D, Höller A, Michel M. Potential Drug-Nutrient Interactions of 45 Vitamins, Minerals, Trace Elements, and Associated Dietary Compounds with Acetylsalicylic Acid and Warfarin-A Review of the Literature. Nutrients 2024; 16:950. [PMID: 38612984 PMCID: PMC11013948 DOI: 10.3390/nu16070950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 03/19/2024] [Accepted: 03/22/2024] [Indexed: 04/14/2024] Open
Abstract
In cardiology, acetylsalicylic acid (ASA) and warfarin are among the most commonly used prophylactic therapies against thromboembolic events. Drug-drug interactions are generally well-known. Less known are the drug-nutrient interactions (DNIs), impeding drug absorption and altering micronutritional status. ASA and warfarin might influence the micronutritional status of patients through different mechanisms such as binding or modification of binding properties of ligands, absorption, transport, cellular use or concentration, or excretion. Our article reviews the drug-nutrient interactions that alter micronutritional status. Some of these mechanisms could be investigated with the aim to potentiate the drug effects. DNIs are seen occasionally in ASA and warfarin and could be managed through simple strategies such as risk stratification of DNIs on an individual patient basis; micronutritional status assessment as part of the medical history; extensive use of the drug-interaction probability scale to reference little-known interactions, and application of a personal, predictive, and preventive medical model using omics.
Collapse
Affiliation(s)
- David Renaud
- DIU MAPS, Fundamental and Biomedical Sciences, Paris-Cité University, 75006 Paris, France
- DIU MAPS, Health Sciences Faculty, Universidad Europea Miguel de Cervantes, 47012 Valladolid, Spain
- Fundacja Recover, 05-124 Skrzeszew, Poland
| | - Alexander Höller
- Department of Nutrition and Dietetics, University Hospital Innsbruck, 6020 Innsbruck, Austria
| | - Miriam Michel
- Department of Child and Adolescent Health, Division of Pediatrics III—Cardiology, Pulmonology, Allergology and Cystic Fibrosis, Medical University of Innsbruck, 6020 Innsbruck, Austria
| |
Collapse
|
|
9
|
Peng J, Song X, Zhu F, Zhang C, Xia J, Zou D, Liu J, Yin F, Yin L, Guo H, Liu J. ABCG2 plays a central role in the dysregulation of 25-hydrovitamin D in Crohn's disease. J Nutr Biochem 2023; 118:109360. [PMID: 37087072 DOI: 10.1016/j.jnutbio.2023.109360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 04/15/2023] [Accepted: 04/17/2023] [Indexed: 04/24/2023]
Abstract
Vitamin D (VD) deficiency, as indicated by the main circulating form of VD metabolite 25-hydrovitamin D3 (25(OH)D3), in patients with Crohn's disease (CD) has been well documented, but the reasons for this remain unclear. In this study, 367 patients with CD and 57 healthy individuals who were enrolled, and the association between 25(OH)D3 level and clinical biochemical characteristics including hepatic and renal functions, inflammatory response was analyzed with binary logistic regression models. VD metabolic enzymes and transporters were screened with bioinformatical analysis and identified with qRT-PCR and western blot. Compared to the healthy controls, serum 25(OH)D3 was significantly reduced in patients with CD, but the protein level of adenosine triphosphate (ATP)-binding cassette efflux transporter G2 (ABCG2) was evidently increased in the ileum and colon. Meanwhile, in lipopolysaccharide (LPS)-treated CaCO2 cells, the mRNA and protein levels of ABCG2 were significantly increased, and the overexpression of ABCG2 obviously promoted 25(OH)D3 efflux, but, Ko143, an ABCG2 inhibitors, substantially prevented the efflux of 25(OH)D3. In addition, in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced CD model mice, the ABCG2 protein levels were significantly increased in the ileum, colon, kidney and liver, and administration of Ko143 significantly inhibited the efflux of 25 (OH) D3in vivo. All of these findings suggest that VD deficiency in patients with CD may be associated with an abnormal increase in ABCG2 expression, but not directly implicated in hepatic and renal function, and inflammatory response in patients with CD.
Collapse
Affiliation(s)
- Jiaxue Peng
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, People's Republic of China
| | - Xiaomei Song
- Department of Gastroenterology, Chongqing General Hospital, University of the Chinese Academy of Sciences, Chongqing 401147, People's Republic of China
| | - Fuyun Zhu
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, People's Republic of China
| | - Chuan Zhang
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, People's Republic of China; Clinical Laboratory, Chongqing Seventh General Hospital, Chongqing 400054, People's Republic of China
| | - Jiying Xia
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, People's Republic of China
| | - Dezheng Zou
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, People's Republic of China
| | - Jinfan Liu
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, People's Republic of China
| | - Fei Yin
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, People's Republic of China
| | - Li Yin
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, People's Republic of China
| | - Hong Guo
- Department of Gastroenterology, Chongqing General Hospital, University of the Chinese Academy of Sciences, Chongqing 401147, People's Republic of China.
| | - Jianhui Liu
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, People's Republic of China.
| |
Collapse
|
|
10
|
Borel P, Dangles O, Kopec RE. Fat-soluble vitamin and phytochemical metabolites: Production, gastrointestinal absorption, and health effects. Prog Lipid Res 2023; 90:101220. [PMID: 36657621 DOI: 10.1016/j.plipres.2023.101220] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 12/12/2022] [Accepted: 01/12/2023] [Indexed: 01/18/2023]
Abstract
Consumption of diets rich in fruits and vegetables, which provide some fat-soluble vitamins and many phytochemicals, is associated with a lower risk of developing certain degenerative diseases. It is well accepted that not only the parent compounds, but also their derivatives formed upon enzymatic or nonenzymatic transformations, can produce protective biological effects. These derivatives can be formed during food storage, processing, or cooking. They can also be formed in the lumen of the upper digestive tract during digestion, or via metabolism by microbiota in the colon. This review compiles the known metabolites of fat-soluble vitamins and fat-soluble phytochemicals (FSV and FSP) that have been identified in food and in the human digestive tract, or could potentially be present based on the known reactivity of the parent compounds in normal or pathological conditions, or following surgical interventions of the digestive tract or consumption of xenobiotics known to impair lipid absorption. It also covers the very limited data available on the bioavailability (absorption, intestinal mucosa metabolism) and summarizes their effects on health. Notably, despite great interest in identifying bioactive derivatives of FSV and FSP, studying their absorption, and probing their putative health effects, much research remains to be conducted to understand and capitalize on the potential of these molecules to preserve health.
Collapse
Affiliation(s)
- Patrick Borel
- C2VN, INRAE, INSERM, Aix-Marseille Univ, Marseille, France.
| | | | - Rachel E Kopec
- Human Nutrition Program, Department of Human Sciences, Foods for Health Discovery Theme, The Ohio State University, Columbus, OH 43210, USA.
| |
Collapse
|
|
11
|
Reboul E. Proteins involved in fat-soluble vitamin and carotenoid transport across the intestinal cells: New insights from the past decade. Prog Lipid Res 2023; 89:101208. [PMID: 36493998 DOI: 10.1016/j.plipres.2022.101208] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 11/28/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022]
Abstract
It is now well established that vitamins D, E, and K and carotenoids are not absorbed solely through passive diffusion. Broad-specificity membrane transporters such as SR-BI (scavenger receptor class B type I), CD36 (CD36 molecule), NPC1L1 (Niemann Pick C1-like 1) or ABCA1 (ATP-binding cassette A1) are involved in the uptake of these micronutrients from the lumen to the enterocyte cytosol and in their secretion into the bloodstream. Recently, the existence of efflux pathways from the enterocyte back to the lumen or from the bloodstream to the lumen, involving ABCB1 (P-glycoprotein/MDR1) or the ABCG5/ABCG8 complex, has also been evidenced for vitamins D and K. Surprisingly, no membrane proteins have been involved in dietary vitamin A uptake so far. After an overview of the metabolism of fat-soluble vitamins and carotenoids along the gastrointestinal tract (from the mouth to the colon where interactions with microbiota may occur), a focus is placed on the identified and candidate proteins participating in the apical uptake, intracellular transport, basolateral secretion and efflux back to the lumen of fat-soluble vitamins and carotenoids in enterocytes. This review also highlights the mechanisms that remain to be identified to fully unravel the pathways involved in fat-soluble vitamin and carotenoid intestinal absorption.
Collapse
|
|
12
|
Janoušek J, Pilařová V, Macáková K, Nomura A, Veiga-Matos J, Silva DDD, Remião F, Saso L, Malá-Ládová K, Malý J, Nováková L, Mladěnka P. Vitamin D: sources, physiological role, biokinetics, deficiency, therapeutic use, toxicity, and overview of analytical methods for detection of vitamin D and its metabolites. Crit Rev Clin Lab Sci 2022; 59:517-554. [PMID: 35575431 DOI: 10.1080/10408363.2022.2070595] [Citation(s) in RCA: 79] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Vitamin D has a well-known role in the calcium homeostasis associated with the maintenance of healthy bones. It increases the efficiency of the intestinal absorption of dietary calcium, reduces calcium losses in urine, and mobilizes calcium stored in the skeleton. However, vitamin D receptors are present ubiquitously in the human body and indeed, vitamin D has a plethora of non-calcemic functions. In contrast to most vitamins, sufficient vitamin D can be synthesized in human skin. However, its production can be markedly decreased due to factors such as clothing, sunscreens, intentional avoidance of the direct sunlight, or the high latitude of the residence. Indeed, more than one billion people worldwide are vitamin D deficient, and the deficiency is frequently undiagnosed. The chronic deficiency is not only associated with rickets/osteomalacia/osteoporosis but it is also linked to a higher risk of hypertension, type 1 diabetes, multiple sclerosis, or cancer. Supplementation of vitamin D may be hence beneficial, but the intake of vitamin D should be under the supervision of health professionals because overdosing leads to intoxication with severe health consequences. For monitoring vitamin D, several analytical methods are employed, and their advantages and disadvantages are discussed in detail in this review.
Collapse
Affiliation(s)
- Jiří Janoušek
- Department of Pharmacognosy, Faculty of Pharmacy, Charles University, Hradec Králové, Czech Republic
| | - Veronika Pilařová
- Department of Analytical Chemistry, Faculty of Pharmacy, Charles University, Hradec Králové, Czech Republic
| | - Kateřina Macáková
- Department of Pharmacognosy, Faculty of Pharmacy, Charles University, Hradec Králové, Czech Republic
| | - Anderson Nomura
- UCIBIO - Applied Molecular Biosciences Unit, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal.,Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, Porto, Portugal
| | - Jéssica Veiga-Matos
- UCIBIO - Applied Molecular Biosciences Unit, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal.,Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, Porto, Portugal
| | - Diana Dias da Silva
- UCIBIO - Applied Molecular Biosciences Unit, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal.,Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, Porto, Portugal.,TOXRUN - Toxicology Research Unit, University Institute of Health Sciences, CESPU CRL, Gandra, Portugal
| | - Fernando Remião
- UCIBIO - Applied Molecular Biosciences Unit, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal.,Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, Porto, Portugal
| | - Luciano Saso
- Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Rome, Italy
| | - Kateřina Malá-Ládová
- Department of Social and Clinical Pharmacy, Faculty of Pharmacy, Charles University, Hradec Králové, Czech Republic
| | - Josef Malý
- Department of Social and Clinical Pharmacy, Faculty of Pharmacy, Charles University, Hradec Králové, Czech Republic
| | - Lucie Nováková
- Department of Analytical Chemistry, Faculty of Pharmacy, Charles University, Hradec Králové, Czech Republic
| | - Přemysl Mladěnka
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Hradec Králové, Czech Republic
| |
Collapse
|
|
13
|
Fliri AF, Kajiji S. Functional characterization of nutraceuticals using spectral clustering: Centrality of caveolae-mediated endocytosis for management of nitric oxide and vitamin D deficiencies and atherosclerosis. Front Nutr 2022; 9:885364. [PMID: 36046126 PMCID: PMC9421303 DOI: 10.3389/fnut.2022.885364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 07/14/2022] [Indexed: 11/13/2022] Open
Abstract
It is well recognized that redox imbalance, nitric oxide (NO), and vitamin D deficiencies increase risk of cardiovascular, metabolic, and infectious diseases. However, clinical studies assessing efficacy of NO and vitamin D supplementation have failed to produce unambiguous efficacy outcomes suggesting that the understanding of the pharmacologies involved is incomplete. This raises the need for using systems pharmacology tools to better understand cause-effect relationships at biological systems levels. We describe the use of spectral clustering methodology to analyze protein network interactions affected by a complex nutraceutical, Cardio Miracle (CM), that contains arginine, citrulline, vitamin D, and antioxidants. This examination revealed that interactions between protein networks affected by these substances modulate functions of a network of protein complexes regulating caveolae-mediated endocytosis (CME), TGF beta activity, vitamin D efficacy and host defense systems. Identification of this regulatory scheme and the working of embedded reciprocal feedback loops has significant implications for treatment of vitamin D deficiencies, atherosclerosis, metabolic and infectious diseases such as COVID-19.
Collapse
|
|
14
|
Cheng J, Zhai J, Zhong W, Zhao J, Zhou L, Wang B. Lactobacillus rhamnosus GG Promotes Intestinal Vitamin D Absorption by Upregulating Vitamin D Transporters in Senile Osteoporosis. Calcif Tissue Int 2022; 111:162-170. [PMID: 35616697 DOI: 10.1007/s00223-022-00975-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 03/25/2022] [Indexed: 11/26/2022]
Abstract
Intestinal absorption of vitamin D is an important way to improve the vitamin D level in senile osteoporosis (SOP). There is a link between oral probiotics and vitamin D, but the mechanism is still unclear. We aimed to evaluate whether Lactobacillus rhamnosus GG culture supernatant (LCS) can affect cholecalciferol absorption, transport, and hydroxylation in SOP, and explore underlying mechanisms. In the study, specific-pathogen-free SAMP6 mice were randomly divided into an experimental group administered undiluted LCS and a control group administered normal drinking water. Furthermore, levels of cholecalciferol absorption were compared between Caco-2 cells cultured with varying concentrations of cholecalciferol and stimulated with LCS or de Man, Rogosa, and Sharpe (MRS) broth (control). Similarly, LCS-stimulated HepG2 cells were compared with MRS-stimulated HepG2 cells. Finally, protein levels of VD transporters in small intestine tissues and Caco-2 cells, as well as vitamin D-binding protein and 25-hydroxylase in liver tissues and HepG2 cells, were detected by western blot. The results showed that plasma concentrations of cholecalciferol and 25OHD3 were higher in mice of the LCS group compared with the control group, and these values were positively correlated. With the addition of LCS, cholecalciferol uptake was increased with 0.5 μM or 10 μM cholecalciferol in the medium. Protein levels of CD36 and NPC1L1 were higher in the LCS group compared with the control group, while SR-BI protein was decreased, both in vitro and in vivo. In conclusion, LCS can promotes intestinal absorption cholecalciferol by affecting protein levels of VD transporters and improves 25OHD3 levels in SOP.
Collapse
Affiliation(s)
- Jing Cheng
- Gastroenterology Department, Tianjin Medical University General Hospital, Tianjin, China
- Department of Orthointernal, Tianjin Hospital, Tianjin, China
| | - Jianhua Zhai
- Gastroenterology Department, Tianjin Medical University General Hospital, Tianjin, China
| | - Weilong Zhong
- Gastroenterology Department, Tianjin Medical University General Hospital, Tianjin, China
| | - Jingwen Zhao
- Gastroenterology Department, Tianjin Medical University General Hospital, Tianjin, China
| | - Lu Zhou
- Gastroenterology Department, Tianjin Medical University General Hospital, Tianjin, China.
| | - Bangmao Wang
- Gastroenterology Department, Tianjin Medical University General Hospital, Tianjin, China.
| |
Collapse
|
|
15
|
Antoine T, El Aoud A, Alvarado-Ramos K, Halimi C, Vairo D, Georgé S, Reboul E. Impact of pulses, starches and meat on vitamin D and K postprandial responses in mice. Food Chem 2022; 402:133922. [DOI: 10.1016/j.foodchem.2022.133922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 07/12/2022] [Accepted: 08/08/2022] [Indexed: 11/17/2022]
|
|
16
|
Bennour I, Haroun N, Sicard F, Mounien L, Landrier JF. Vitamin D and Obesity/Adiposity—A Brief Overview of Recent Studies. Nutrients 2022; 14:nu14102049. [PMID: 35631190 PMCID: PMC9143180 DOI: 10.3390/nu14102049] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 05/10/2022] [Accepted: 05/11/2022] [Indexed: 12/12/2022] Open
Abstract
Observational studies classically find an inverse relationship between human plasma 25-hydroxyvitamin D concentration and obesity. However, interventional and genetic studies have failed to provide clear conclusions on the causal effect of vitamin D on obesity/adiposity. Likewise, vitamin D supplementation in obese rodents has mostly failed to improve obesity parameters, whereas several lines of evidence in rodents and prospective studies in humans point to a preventive effect of vitamin D supplementation on the onset of obesity. Recent studies investigating the impact of maternal vitamin D deficiency in women and in rodent models on adipose tissue biology programming in offspring further support a preventive metabolically driven effect of vitamin D sufficiency. The aim of this review is to summarize the state of the knowledge on the relationship between vitamin D and obesity/adiposity in humans and in rodents and the impact of maternal vitamin D deficiency on the metabolic trajectory of the offspring.
Collapse
Affiliation(s)
- Imene Bennour
- Aix-Marseille Université, C2VN, INRAE, INSERM, 13000 Marseille, France; (I.B.); (N.H.); (F.S.); (L.M.)
| | - Nicole Haroun
- Aix-Marseille Université, C2VN, INRAE, INSERM, 13000 Marseille, France; (I.B.); (N.H.); (F.S.); (L.M.)
| | - Flavie Sicard
- Aix-Marseille Université, C2VN, INRAE, INSERM, 13000 Marseille, France; (I.B.); (N.H.); (F.S.); (L.M.)
- PhenoMARS Aix-Marseille Technology Platform, CriBiom, 13000 Marseille, France
| | - Lourdes Mounien
- Aix-Marseille Université, C2VN, INRAE, INSERM, 13000 Marseille, France; (I.B.); (N.H.); (F.S.); (L.M.)
- PhenoMARS Aix-Marseille Technology Platform, CriBiom, 13000 Marseille, France
| | - Jean-François Landrier
- Aix-Marseille Université, C2VN, INRAE, INSERM, 13000 Marseille, France; (I.B.); (N.H.); (F.S.); (L.M.)
- PhenoMARS Aix-Marseille Technology Platform, CriBiom, 13000 Marseille, France
- Correspondence: ; Tel.: +33-4-9129-4275
| |
Collapse
|
|
17
|
Eder K, Grundmann SM. Vitamin D in dairy cows: metabolism, status and functions in the immune system. Arch Anim Nutr 2022; 76:1-33. [PMID: 35249422 DOI: 10.1080/1745039x.2021.2017747] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The function of vitamin D in calcium homoeostasis in dairy cows, such as in other vertebrates, is known for many years. In recent years, new and interesting, non-classical functions of vitamin D have been elucidated, including effects on the immune system. The major aim of this review is to provide an overview of effects of vitamin D or its metabolites on the immune system in dairy cows. The first part of the review provides an overview of vitamin D metabolism, with particular reference to the role of various proteins (25- and 1-hydroxylases, vitamin D binding protein, vitamin D receptor) in vitamin D signalling. The second part deals with the role of the concentration of 25-hydroxyvitamin D [25(OH)D] in plasma as an indicator of the vitamin D status in dairy cows, and its dependence on sunlight exposure and dietary vitamin D supplementation. In this part also the "free hormone hypothesis" is discussed, indicating that the concentration of free 25(OH)D might be a more valid indicator of the vitamin D status than the concentration of total 25(OH)D. The third part deals with classical and the non-classical functions of vitamin D. Among the non-classical functions which are based on an autocrine vitamin D signalling, particular reference is given to the effects of vitamin D and vitamin D metabolites on the immune system in bovine immune cells and in dairy cows. Recent findings provide some indication that vitamin D or its metabolite 25(OH)D could enhance the immune function in dairy cows and be useful for the prevention and therapy of mastitis. However, the number of studies reported so far in this respect is very limited. Thus, much more research is required to yield clear concepts for an optimised usage of vitamin D to improve the immune system and prevent infectious diseases in dairy cows.
Collapse
Affiliation(s)
- Klaus Eder
- Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-Universität Giessen, Giessen, Germany
| | - Sarah M Grundmann
- Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-Universität Giessen, Giessen, Germany
| |
Collapse
|
|
18
|
Lee HW, Kang WY, Jung W, Gwon MR, Cho K, Lee B, Seong SJ, Yoon YR. Pharmacokinetic Drug Interaction Between Raloxifene and Cholecalciferol in Healthy Volunteers. Clin Pharmacol Drug Dev 2022; 11:623-631. [PMID: 34984851 PMCID: PMC9305550 DOI: 10.1002/cpdd.1062] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 12/07/2021] [Indexed: 12/24/2022]
Abstract
Osteoporosis is a common skeletal disorder, often leading to fragility fracture. Combination therapy with raloxifene, a selective estrogen receptor modulator, and cholecalciferol (vitamin D3) has been proposed to improve the overall efficacy and increase compliance of raloxifene therapy for postmenopausal osteoporosis. To our knowledge, there has been no report of any study on the pharmacokinetic interaction between raloxifene and cholecalciferol. This study aimed to evaluate the possible pharmacokinetic interactions between raloxifene and cholecalciferol in healthy adult male Korean volunteers. Twenty subjects completed this open‐label, randomized, single‐dose, 3‐period, 6‐sequence, crossover phase 1 study with a 14‐day washout period. Serial blood samples were collected from 20 hours before dosing to 96 hours after dosing. The plasma concentrations of raloxifene and cholecalciferol were determined using a validated method for high‐performance liquid chromatography with tandem mass spectrometry. The geometric mean ratios (90%CIs) for area under the plasma concentration–time curve from time 0 to the last quantifiable time point and maximum plasma concentration of raloxifene with or without cholecalciferol were 1.02 (0.87‐1.20) and 0.87 (0.70‐1.08), respectively. For baseline‐corrected cholecalciferol, geometric mean ratios (90%CIs) of area under the plasma concentration–time curve from time 0 to the last quantifiable time point and maximum plasma concentration with or without raloxifene were 1.01 (0.93‐1.09) and 0.99 (0.92‐1.06), respectively. Concurrent treatment with raloxifene and cholecalciferol was generally well tolerated. These results suggest that raloxifene and cholecalciferol have no clinically relevant pharmacokinetic drug‐drug interactions when administered concurrently. All treatments were well tolerated, with no serious adverse events.
Collapse
Affiliation(s)
- Hae Won Lee
- Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.,Department of Clinical Pharmacology, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Woo Youl Kang
- Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.,Department of Clinical Pharmacology, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Wookjae Jung
- Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.,Department of Clinical Pharmacology, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Mi-Ri Gwon
- Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.,Department of Clinical Pharmacology, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Kyunghee Cho
- Analytical Research Division, Biocore Co. Ltd., Seoul, Republic of Korea
| | - Backhwan Lee
- Department of Clinical Development, Alvogen Korea Co. Ltd., Seoul, Republic of Korea
| | - Sook Jin Seong
- Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.,Department of Clinical Pharmacology, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Young-Ran Yoon
- Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.,Department of Clinical Pharmacology, Kyungpook National University Hospital, Daegu, Republic of Korea
| |
Collapse
|
|
19
|
Bagchee-Clark AJ, Mucaki EJ, Whitehead T, Rogan PK. Pathway-extended gene expression signatures integrate novel biomarkers that improve predictions of patient responses to kinase inhibitors. MedComm (Beijing) 2021; 1:311-327. [PMID: 34766125 PMCID: PMC8491218 DOI: 10.1002/mco2.46] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 11/11/2020] [Accepted: 11/15/2020] [Indexed: 12/11/2022] Open
Abstract
Cancer chemotherapy responses have been related to multiple pharmacogenetic biomarkers, often for the same drug. This study utilizes machine learning to derive multi‐gene expression signatures that predict individual patient responses to specific tyrosine kinase inhibitors, including erlotinib, gefitinib, sorafenib, sunitinib, lapatinib and imatinib. Support vector machine (SVM) learning was used to train mathematical models that distinguished sensitivity from resistance to these drugs using a novel systems biology‐based approach. This began with expression of genes previously implicated in specific drug responses, then expanded to evaluate genes whose products were related through biochemical pathways and interactions. Optimal pathway‐extended SVMs predicted responses in patients at accuracies of 70% (imatinib), 71% (lapatinib), 83% (sunitinib), 83% (erlotinib), 88% (sorafenib) and 91% (gefitinib). These best performing pathway‐extended models demonstrated improved balance predicting both sensitive and resistant patient categories, with many of these genes having a known role in cancer aetiology. Ensemble machine learning‐based averaging of multiple pathway‐extended models derived for an individual drug increased accuracy to >70% for erlotinib, gefitinib, lapatinib and sorafenib. Through incorporation of novel cancer biomarkers, machine learning‐based pathway‐extended signatures display strong efficacy predicting both sensitive and resistant patient responses to chemotherapy.
Collapse
Affiliation(s)
- Ashis J Bagchee-Clark
- Department of Biochemistry, Schulich School of Medicine and Dentistry University of Western Ontario, London, Canada N6A 2C8 Canada
| | - Eliseos J Mucaki
- Department of Biochemistry, Schulich School of Medicine and Dentistry University of Western Ontario, London, Canada N6A 2C8 Canada
| | - Tyson Whitehead
- SHARCNET University of Western Ontario London Ontario N6A 5B7 Canada
| | - Peter K Rogan
- Department of Biochemistry, Schulich School of Medicine and Dentistry University of Western Ontario, London, Canada N6A 2C8 Canada.,Cytognomix Inc., 60 North Centre Road, Box 27052, London, Canada N5X 3X5 Canada
| |
Collapse
|
|
20
|
Antoine T, Le May C, Margier M, Halimi C, Nowicki M, Defoort C, Svilar L, Reboul E. The Complex ABCG5/ABCG8 Regulates Vitamin D Absorption Rate and Contributes to its Efflux from the Intestine. Mol Nutr Food Res 2021; 65:e2100617. [PMID: 34510707 DOI: 10.1002/mnfr.202100617] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 08/31/2021] [Indexed: 12/20/2022]
Abstract
SCOPE Most people are vitamin D insufficient around the world. Vitamin D intestinal absorption should thus be optimized. The role of the ATP-binging cassette G5/G8 (ABCG5/G8) heterodimer in vitamin D intestinal efflux is investigated. METHODS AND RESULTS Both cholecalciferol and 25-hydroxycholecalciferol apical effluxes are increased by ABCG5/G8 overexpression in human Griptite cells. Mice deficient in ABCG5/G8 at the intestinal level (I-Abcg5/g8-/- mice) display an accumulation of cholecalciferol in plasma in females and in liver in males compared to control animals. I-Abcg5/g8- / - mice display a delay in cholecalciferol postprandial response after gavage compared with controls. 25-Hydroxycholecalciferol transfer from plasma to lumen is observed in vivo in intestine-perfused mice, and the lack of intestinal ABCG5/G8 complex induces a decrease in this efflux, while vitamin D bile excretion remains unchanged. CONCLUSION Overall, it is showed for the first time that the ABCG5/G8 heterodimer regulates the kinetics of absorption of dietary vitamin D by contributing to its efflux back to the lumen, and that it also participates in vitamin D transintestinal efflux.
Collapse
Affiliation(s)
- Tiffany Antoine
- Aix-Marseille Univerité, INSERM, INRA, C2VN, Marseille, France
| | - Cédric Le May
- Université de Nantes, CNRS, INSERM, Institut du thorax, F-44000 Nantes, France
| | | | | | - Marion Nowicki
- Aix-Marseille Univerité, INSERM, INRA, C2VN, Marseille, France
| | - Catherine Defoort
- Aix-Marseille Univerité, INSERM, INRA, C2VN, Marseille, France.,CRIBIOM, Criblage Biologique Marseille, Faculté de Médecine de la Timone, Marseille, France
| | - Ljubica Svilar
- CRIBIOM, Criblage Biologique Marseille, Faculté de Médecine de la Timone, Marseille, France
| | | |
Collapse
|
|
21
|
McQuerry JA, Chen J, Chang JT, Bild AH. Tepoxalin increases chemotherapy efficacy in drug-resistant breast cancer cells overexpressing the multidrug transporter gene ABCB1. Transl Oncol 2021; 14:101181. [PMID: 34298440 PMCID: PMC8322466 DOI: 10.1016/j.tranon.2021.101181] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/10/2021] [Accepted: 07/12/2021] [Indexed: 12/13/2022] Open
Abstract
The COX-2 encoding gene PTGS2 is up-regulated upon ABCB1 overexpression in mammary epithelial cells. The 5-LOX, COX-1/2 inhibitor tepoxalin plus chemotherapy improves treatment efficacy in ABCB1-expressing cells. Tepoxalin reduces chemotherapy-induced selection for drug-resistant ABCB1-expressing cells. Effective cancer chemotherapy treatment requires both therapy delivery and retention by malignant cells. Cancer cell overexpression of the multidrug transmembrane transporter gene ABCB1 (MDR1, multi-drug resistance protein 1) thwarts therapy retention, leading to a drug-resistant phenotype. We explored the phenotypic impact of ABCB1 overexpression in normal human mammary epithelial cells (HMECs) via acute adenoviral delivery and in breast cancer cell lines with stable integration of inducible ABCB1 expression. One hundred sixty-two genes were differentially expressed between ABCB1-expressing and GFP-expressing HMECs, including the gene encoding the cyclooxygenase-2 protein, PTGS2. Several breast cancer cell lines with inducible ABCB1 expression demonstrated sensitivity to the 5-lipoxygenase, cyclooxygenase-1/2 inhibitor tepoxalin in two-dimensional drug response assays, and combination treatment of tepoxalin either with chemotherapies or with histone deacetylase (HDAC) inhibitors improved therapeutic efficacy in these lines. Moreover, selection for the ABCB1-expressing cell population was reduced in three-dimensional co-cultures of ABCB1-expressing and GFP-expressing cells when chemotherapy was given in combination with tepoxalin. Further study is warranted to ascertain the clinical potential of tepoxalin, an FDA-approved therapeutic for use in domesticated mammals, to restore chemosensitivity and improve drug response in patients with ABCB1-overexpressing drug-resistant breast cancers.
Collapse
Affiliation(s)
- Jasmine A McQuerry
- Department of Oncological Sciences, School of Medicine, University of Utah, 2000 Circle of Hope Drive, Salt Lake City, UT 84112, USA; Department of Medical Oncology and Therapeutics Research, City of Hope, 1218 S Fifth Avenue, Monrovia, CA 91016, USA
| | - Jinfeng Chen
- Department of Medical Oncology and Therapeutics Research, City of Hope, 1218 S Fifth Avenue, Monrovia, CA 91016, USA
| | - Jeffrey T Chang
- Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Andrea H Bild
- Department of Medical Oncology and Therapeutics Research, City of Hope, 1218 S Fifth Avenue, Monrovia, CA 91016, USA.
| |
Collapse
|
|
22
|
Influences of dietary oils and fats, and the accompanied minor content of components on the gut microbiota and gut inflammation: A review. Trends Food Sci Technol 2021. [DOI: 10.1016/j.tifs.2021.05.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
|
|
23
|
Margier M, Le May C, Antoine T, Halimi C, Nowicki M, Lespine A, Reboul E. P-glycoprotein (ABCB1) is involved in vitamin K efflux. Food Chem 2021; 343:128510. [PMID: 33172753 DOI: 10.1016/j.foodchem.2020.128510] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 10/26/2020] [Accepted: 10/26/2020] [Indexed: 11/20/2022]
Abstract
ABCB1 (P-glycoprotein/MDR1) is a multidrug efflux transporter that has previously been involved in cholesterol and vitamin D metabolism. Our aim was to explore whether ABCB1 is also involved in vitamin K efflux. Vitamin K apical efflux was significantly decreased in presence of ABCB1 inhibitor in Caco-2 cells (-20.4%; p < 0.05) and increased in Griptite cells overexpressing ABCB1 (+40.7%; p < 0.05). In vivo, the vitamin K postprandial response was higher in male Abcb1-/- mice after gavage compared to control animals (+115%; p < 0.05), but was unchanged in female mice. Finally, a vitamin K transintestinal efflux and a biliary vitamin K efflux were observed, but the specific involvement of ABCB1 could not be confirmed in these pathways. Overall, we showed for the first time that ABCB1 is involved in enterocyte vitamin K efflux in both cell and mouse models and regulates vitamin K absorption in mice.
Collapse
Affiliation(s)
| | - Cédric Le May
- Université de Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes, France.
| | | | | | - Marion Nowicki
- INRAE, INSERM, Aix Marseille Univ, C2VN, Marseille, France.
| | - Anne Lespine
- INTHERES, Université de Toulouse, INRAE, ENVT, Toulouse, France.
| | | |
Collapse
|
|
24
|
Hsu S, Zelnick LR, Lin YS, Best CM, Kestenbaum B, Thummel KE, Rose LM, Hoofnagle AN, de Boer IH. Differences in 25-Hydroxyvitamin D Clearance by eGFR and Race: A Pharmacokinetic Study. J Am Soc Nephrol 2021; 32:188-198. [PMID: 33115916 PMCID: PMC7894669 DOI: 10.1681/asn.2020050625] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 09/08/2020] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Conversion of 25-hydroxyvitamin D (25[OH]D) to the active form of vitamin D occurs primarily in the kidney. Observational studies suggest 25(OH)D clearance from the circulation differs by kidney function and race. However, these potential variations have not been tested using gold-standard methods. METHODS We administered intravenous, deuterated 25(OH)D3 (d-25[OH]D3) in a pharmacokinetic study of 87 adults, including 43 with normal eGFR (≥60 ml/min per 1.73 m2), 24 with nondialysis CKD (eGFR <60 ml/min per 1.73 m2), and 20 with ESKD treated with hemodialysis. We measured concentrations of d-25(OH)D3 and deuterated 24,25-dihydroxyvitamin D3 at 5 minutes and 4 hours after administration, and at 1, 4, 7, 14, 21, 28, 42, and 56 days postadministration. We calculated 25(OH)D clearance using noncompartmental analysis of d-25(OH)D3 concentrations over time. We remeasured 25(OH)D clearance in a subset of 18 participants after extended oral vitamin-D3 supplementation. RESULTS The mean age of the study cohort was 64 years; 41% were female, and 30% were Black. Mean 25(OH)D clearances were 360 ml/d, 313 ml/d, and 263 ml/d in participants with normal eGFR, CKD, and kidney failure, respectively (P=0.02). After adjustment for age, sex, race, and estimated blood volume, lower eGFR was associated with reduced 25(OH)D clearance (β=-17 ml/d per 10 ml/min per 1.73 m2 lower eGFR; 95% CI, -21 to -12). Black race was associated with higher 25(OH)D clearance in participants with normal eGFR, but not in those with CKD or kidney failure (P for interaction=0.05). Clearance of 25(OH)D before versus after vitamin-D3 supplementation did not differ. CONCLUSIONS Using direct pharmacokinetic measurements, we show that 25(OH)D clearance is reduced in CKD and may differ by race. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER Clearance of 25-hydroxyvitamin D in Chronic Kidney Disease (CLEAR), NCT02937350; Clearance of 25-hydroxyvitamin D3 During Vitamin D3 Supplementation (CLEAR-PLUS), NCT03576716.
Collapse
Affiliation(s)
- Simon Hsu
- Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington
- Kidney Research Institute, University of Washington, Seattle, Washington
| | - Leila R. Zelnick
- Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington
- Kidney Research Institute, University of Washington, Seattle, Washington
| | - Yvonne S. Lin
- Department of Pharmaceutics, University of Washington, Seattle, Washington
| | - Cora M. Best
- Kidney Research Institute, University of Washington, Seattle, Washington
- Department of Laboratory Medicine, University of Washington, Seattle, Washington
| | - Bryan Kestenbaum
- Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington
- Kidney Research Institute, University of Washington, Seattle, Washington
- Department of Epidemiology, University of Washington, Seattle, Washington
| | - Kenneth E. Thummel
- Department of Pharmaceutics, University of Washington, Seattle, Washington
| | - Lynn M. Rose
- Department of Pharmacy, University of Washington, Seattle, Washington
| | - Andrew N. Hoofnagle
- Kidney Research Institute, University of Washington, Seattle, Washington
- Department of Laboratory Medicine, University of Washington, Seattle, Washington
| | - Ian H. de Boer
- Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington
- Kidney Research Institute, University of Washington, Seattle, Washington
- Veterans Affairs Puget Sound Health Care System, Seattle, Washington
| |
Collapse
|
|
25
|
Reboul E. The gut: a regulatory hall governing fat-soluble micronutrient absorption. Am J Clin Nutr 2019; 110:1045-1046. [PMID: 31495899 DOI: 10.1093/ajcn/nqz199] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Affiliation(s)
- Emmanuelle Reboul
- Human Micronutrition, Faculty of Medicine, Center for Cardiovascular and Nutrition Research, Aix-Marseille University, INRA, INSERM, C2VN, Marseille, France
| |
Collapse
|
|
26
|
Administration of Vitamin D Metabolites Affects RNA Expression of Xenobiotic Metabolising Enzymes and Function of ABC Transporters in Rats. J CHEM-NY 2019. [DOI: 10.1155/2019/1279036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
From studies on different species and in cell culture systems, it has been suggested that vitamin D metabolites might affect the metabolism and elimination of xenobiotics. Although most studies performed on rodents and cell cultures report an upregulation of respective enzymes and transporters, data from the literature are inconsistent. Especially results obtained with sheep differ from these observations. As vitamin D metabolites are widely used as feed additives or therapeutics in livestock animals, we aimed to assess whether these differences indicate species-specific responses or occurred due to the very high dosages used in the rodent studies. Therefore, we applied treatment protocols to rats that had been used previously in sheep or cattle. Forty-eight female rats were divided into three treatment and corresponding placebo groups: (1) a single intraperitoneal injection of 1,25-(OH)2D3 or placebo 12 h before sacrifice; (2) daily supplementation with 25-OHD3 by oral gavage or placebo for 10 days; and (3) a single intramuscular injection of vitamin D3 10 days before sacrifice. In contrast to a previous study using sheep, treatment of rats with 1,25-dihydroxyvitamin D3 did not result in an upregulation of cytochrome P450 3A isoenzymes (CYP3A), but a decrease was found in hepatic and intestinal expressions. In addition, a downregulation of P-glycoprotein (P-gp) and breast cancer resistance protein was found in the brain. Taken together, the stimulating effects of vitamin D metabolites on the expression of genes involved in the metabolism and elimination of xenobiotics reported previously for rodents and sheep could not be reproduced. In contrast, we even observed a negative impact on the expression of CYP3A enzymes and their most important regulator, the pregnane X receptor. Most interestingly, we could demonstrate an effect of treatment with 25-hydroxyvitamin D3 and vitamin D3 on the functional activity of ileal P-glycoprotein (P-gp) using the Ussing chamber technique.
Collapse
|
|
27
|
Reboul E. Mechanisms of Carotenoid Intestinal Absorption: Where Do We Stand? Nutrients 2019; 11:nu11040838. [PMID: 31013870 PMCID: PMC6520933 DOI: 10.3390/nu11040838] [Citation(s) in RCA: 97] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 04/04/2019] [Accepted: 04/06/2019] [Indexed: 12/21/2022] Open
Abstract
A growing literature is dedicated to the understanding of carotenoid beneficial health effects. However, the absorption process of this broad family of molecules is still poorly understood. These highly lipophilic plant metabolites are usually weakly absorbed. It was long believed that β-carotene absorption (the principal provitamin A carotenoid in the human diet), and thus all other carotenoid absorption, was driven by passive diffusion through the brush border of the enterocytes. The identification of transporters able to facilitate carotenoid uptake by the enterocytes has challenged established statements. After a brief overview of carotenoid metabolism in the human upper gastrointestinal tract, a focus will be put on the identified proteins participating in the transport and the metabolism of carotenoids in intestinal cells and the regulation of these processes. Further progress in the understanding of the molecular mechanisms regulating carotenoid intestinal absorption is still required to optimize their bioavailability and, thus, their health effects.
Collapse
Affiliation(s)
- Emmanuelle Reboul
- Aix-Marseille University, INRA, INSERM, C2VN, 13005 Marseille, France.
| |
Collapse
|
|
28
|
Bouillon R, Schuit F, Antonio L, Rastinejad F. Vitamin D Binding Protein: A Historic Overview. Front Endocrinol (Lausanne) 2019; 10:910. [PMID: 31998239 PMCID: PMC6965021 DOI: 10.3389/fendo.2019.00910] [Citation(s) in RCA: 188] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 12/13/2019] [Indexed: 02/06/2023] Open
Abstract
Vitamin D and all its metabolites are bound to a specific vitamin D binding protein, DBP. This protein was originally first discovered by its worldwide polymorphism and called Group-specific Component (GC). We now know that DBP and GC are the same protein and appeared early in the evolution of vertebrates. DBP is genetically the oldest member of the albuminoid family (including albumin, α-fetoprotein and afamin, all involved in transport of fatty acids or hormones). DBP has a single binding site for all vitamin D metabolites and has a high affinity for 25OHD and 1,25(OH)2D, thereby creating a large pool of circulating 25OHD, which prevents rapid vitamin D deficiency. DBP of higher vertebrates (not amphibians or reptiles) binds with very high affinity actin, thereby preventing the formation of polymeric actin fibrils in the circulation after tissue damage. Megalin is a cargo receptor and is together with cubilin needed to reabsorb DBP or the DBP-25OHD complex, thereby preventing the urinary loss of these proteins and 25OHD. The total concentrations of 25OHD and 1,25(OH)2D in DBP null mice or humans are extremely low but calcium and bone homeostasis remain normal. This is the strongest argument for claiming that the "free hormone hypothesis" also applies to the vitamin D hormone, 1,25(OH)2D. DBP also transports fatty acids, and can play a role in the immune system. DBP is genetically very polymorphic with three frequent alleles (DBP/GC 1f, 1s, and 2) but in total more than 120 different variants but its health consequences, if any, are not understood. A standardization of DBP assays is essential to further explore the role of DBP in physiology and diseases.
Collapse
Affiliation(s)
- Roger Bouillon
- Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
- *Correspondence: Roger Bouillon
| | - Frans Schuit
- Gene Expression Unit, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Leen Antonio
- Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
- Department of Endocrinology, University Hospitals Leuven, Leuven, Belgium
| | - Fraydoon Rastinejad
- Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford, United Kingdom
| |
Collapse
|