|
1
|
Zhang Y, Wang X, Ji Y, Hong H, Geng X, Zhang K, Fu Z, Cai G, Chen X, Li P, Hong Q. All-trans retinoic acid pretreatment of mesenchymal stem cells enhances the therapeutic effect on acute kidney injury. Cell Commun Signal 2024; 22:291. [PMID: 38802835 PMCID: PMC11129434 DOI: 10.1186/s12964-024-01671-1] [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: 02/21/2024] [Accepted: 05/20/2024] [Indexed: 05/29/2024] Open
Abstract
A promising new therapy option for acute kidney injury (AKI) is mesenchymal stem cells (MSCs). However, there are several limitations to the use of MSCs, such as low rates of survival, limited homing capacity, and unclear differentiation. In search of better therapeutic strategies, we explored all-trans retinoic acid (ATRA) pretreatment of MSCs to observe whether it could improve the therapeutic efficacy of AKI. We established a renal ischemia/reperfusion injury model and treated mice with ATRA-pretreated MSCs via tail vein injection. We found that AKI mice treated with ATRA-MSCs significantly improved renal function compared with DMSO-MSCs treatment. RNA sequencing screened that hyaluronic acid (HA) production from MSCs promoted by ATRA. Further validation by chromatin immunoprecipitation experiments verified that retinoic acid receptor RARα/RXRγ was a potential transcription factor for hyaluronic acid synthase 2. Additionally, an in vitro hypoxia/reoxygenation model was established using human proximal tubular epithelial cells (HK-2). After co-culturing HK-2 cells with ATRA-pretreated MSCs, we observed that HA binds to cluster determinant 44 (CD44) and activates the PI3K/AKT pathway, which enhances the anti-inflammatory, anti-apoptotic, and proliferative repair effects of MSCs in AKI. Inhibition of the HA/CD44 axis effectively reverses the renal repair effect of ATRA-pretreated MSCs. Taken together, our study suggests that ATRA pretreatment promotes HA production by MSCs and activates the PI3K/AKT pathway in renal tubular epithelial cells, thereby enhancing the efficacy of MSCs against AKI.
Collapse
Affiliation(s)
- Yifan Zhang
- Medical School of Chinese PLA, Beijing, 100853, China
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, National Clinical Research Center for Kidney Diseases, No.28 Fuxing Road, Beijing, 100853, China
| | - Xiaochen Wang
- Medical School of Chinese PLA, Beijing, 100853, China
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, National Clinical Research Center for Kidney Diseases, No.28 Fuxing Road, Beijing, 100853, China
| | - Yuwei Ji
- Medical School of Chinese PLA, Beijing, 100853, China
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, National Clinical Research Center for Kidney Diseases, No.28 Fuxing Road, Beijing, 100853, China
| | - Haijuan Hong
- Songjiang District Central Hospital, Shanghai, China
| | - Xiaodong Geng
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, National Clinical Research Center for Kidney Diseases, No.28 Fuxing Road, Beijing, 100853, China
- Health Care Office of the Service Bureau of Agency for Offices Administration of the Central Military Commission, Beijing, China
| | - Keying Zhang
- Medical School of Chinese PLA, Beijing, 100853, China
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, National Clinical Research Center for Kidney Diseases, No.28 Fuxing Road, Beijing, 100853, China
| | - Zhangning Fu
- Medical School of Chinese PLA, Beijing, 100853, China
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, National Clinical Research Center for Kidney Diseases, No.28 Fuxing Road, Beijing, 100853, China
| | - Guangyan Cai
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, National Clinical Research Center for Kidney Diseases, No.28 Fuxing Road, Beijing, 100853, China
| | - Xiangmei Chen
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, National Clinical Research Center for Kidney Diseases, No.28 Fuxing Road, Beijing, 100853, China
| | - Ping Li
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, National Clinical Research Center for Kidney Diseases, No.28 Fuxing Road, Beijing, 100853, China.
| | - Quan Hong
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, National Clinical Research Center for Kidney Diseases, No.28 Fuxing Road, Beijing, 100853, China.
| |
Collapse
|
|
2
|
Japanese soup stocks (katsuo-dashi and kombu-dashi) modulate food factor sensing-related gene expression in mice. Int J Gastron Food Sci 2022. [DOI: 10.1016/j.ijgfs.2022.100573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
|
|
3
|
Role of Nuclear Receptors in Controlling Erythropoiesis. Int J Mol Sci 2022; 23:ijms23052800. [PMID: 35269942 PMCID: PMC8911257 DOI: 10.3390/ijms23052800] [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: 02/04/2022] [Revised: 02/25/2022] [Accepted: 02/27/2022] [Indexed: 02/04/2023] Open
Abstract
Nuclear receptors (NRs), are a wide family of ligand-regulated transcription factors sharing a common modular structure composed by an N-terminal domain and a ligand-binding domain connected by a short hinge linker to a DNA-binding domain. NRs are involved in many physiological processes, including metabolism, reproduction and development. Most of them respond to small lipophilic ligands, such as steroids, retinoids, and phospholipids, which act as conformational switches. Some NRs are still "orphan" and the search for their ligands is still ongoing. Upon DNA binding, NRs can act both as transcriptional activators or repressors of their target genes. Theoretically, the possibility to modulate NRs activity with small molecules makes them ideal therapeutic targets, although the complexity of their signaling makes drug design challenging. In this review, we discuss the role of NRs in erythropoiesis, in both homeostatic and stress conditions. This knowledge is important in view of modulating red blood cells production in disease conditions, such as anemias, and for the expansion of erythroid cells in culture for research purposes and for reaching the long-term goal of cultured blood for transfusion.
Collapse
|
|
4
|
Schönberger K, Obier N, Romero-Mulero MC, Cauchy P, Mess J, Pavlovich PV, Zhang YW, Mitterer M, Rettkowski J, Lalioti ME, Jäcklein K, Curtis JD, Féret B, Sommerkamp P, Morganti C, Ito K, Ghyselinck NB, Trompouki E, Buescher JM, Pearce EL, Cabezas-Wallscheid N. Multilayer omics analysis reveals a non-classical retinoic acid signaling axis that regulates hematopoietic stem cell identity. Cell Stem Cell 2022; 29:131-148.e10. [PMID: 34706256 PMCID: PMC9093043 DOI: 10.1016/j.stem.2021.10.002] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 08/05/2021] [Accepted: 10/06/2021] [Indexed: 02/08/2023]
Abstract
Hematopoietic stem cells (HSCs) rely on complex regulatory networks to preserve stemness. Due to the scarcity of HSCs, technical challenges have limited our insights into the interplay between metabolites, transcription, and the epigenome. In this study, we generated low-input metabolomics, transcriptomics, chromatin accessibility, and chromatin immunoprecipitation data, revealing distinct metabolic hubs that are enriched in HSCs and their downstream multipotent progenitors. Mechanistically, we uncover a non-classical retinoic acid (RA) signaling axis that regulates HSC function. We show that HSCs rely on Cyp26b1, an enzyme conventionally considered to limit RA effects in the cell. In contrast to the traditional view, we demonstrate that Cyp26b1 is indispensable for production of the active metabolite 4-oxo-RA. Further, RA receptor beta (Rarb) is required for complete transmission of 4-oxo-RA-mediated signaling to maintain stem cells. Our findings emphasize that a single metabolite controls stem cell fate by instructing epigenetic and transcriptional attributes.
Collapse
Affiliation(s)
- Katharina Schönberger
- Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany; International Max Planck Research School for Molecular and Cellular Biology (IMPRS-MCB), Freiburg, Germany
| | - Nadine Obier
- Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany
| | | | - Pierre Cauchy
- Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany
| | - Julian Mess
- Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), Freiburg, Germany; Centre for Integrative Biological Signalling Studies (CIBSS), Freiburg, Germany
| | - Polina V Pavlovich
- Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany; International Max Planck Research School for Molecular and Cellular Biology (IMPRS-MCB), Freiburg, Germany
| | - Yu Wei Zhang
- Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany; International Max Planck Research School for Molecular and Cellular Biology (IMPRS-MCB), Freiburg, Germany
| | - Michael Mitterer
- Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany
| | - Jasmin Rettkowski
- Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), Freiburg, Germany
| | - Maria-Eleni Lalioti
- Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany
| | - Karin Jäcklein
- Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany
| | - Jonathan D Curtis
- Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany
| | - Betty Féret
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), UMR 7104 Centre National de la Recherche Scientifique (CNRS) et Université de Strasbourg (UNISTRA), U1258 Institut National de la Santé et de la Recherche Médicale (INSERM), Illkirch, France
| | - Pia Sommerkamp
- German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Claudia Morganti
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Departments of Cell Biology and Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Keisuke Ito
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Departments of Cell Biology and Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Norbert B Ghyselinck
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), UMR 7104 Centre National de la Recherche Scientifique (CNRS) et Université de Strasbourg (UNISTRA), U1258 Institut National de la Santé et de la Recherche Médicale (INSERM), Illkirch, France
| | - Eirini Trompouki
- Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany
| | - Joerg M Buescher
- Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany
| | - Erika L Pearce
- Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Johns Hopkins University, Baltimore, MD, USA
| | - Nina Cabezas-Wallscheid
- Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; Centre for Integrative Biological Signalling Studies (CIBSS), Freiburg, Germany.
| |
Collapse
|
|
5
|
Abstract
PURPOSE OF REVIEW This review aims to bring together recent advances in basic, translational and clinical research on the pathogenesis and treatment of orbital inflammatory conditions. RECENT FINDINGS Basic science studies provide mechanistic insights into why the orbit is targeted for inflammation by autoimmune inflammatory disorders. Using Graves' disease as a test case reveals that endocrine pathways, such as the TSH and IGF1 receptor pathways play important roles in stimulating orbital inflammation. Furthermore, orbital tissues contain high concentrations of retinoids - byproducts of the visual pathway that diffuse across the sclera and can activate de novo transcription of inflammatory cytokines. Such cytokine expression places the orbit in a hyper-inflammatory 'resting' state, prone to respond to any additional systemic or local pro-inflammatory signals. The HIF2A--LOX pathway appears important for orbital tissue fibrosis. Lastly, bench-to-bedside studies of the IGF1R pathway have led to an FDA-approved drug, teprotumumab that represents a novel treatment approach for Graves' orbitopathy. Unfortunately, high drug costs and misplaced insurance company 'step-therapy' policies may block patients from receiving therapy that can protect vision and improve quality of life. SUMMARY Improved understanding of orbital inflammatory conditions has led to a new drug and promises additional breakthroughs. Translational research is successful, but requires time, resources, and patience.
Collapse
|
|
6
|
de Freitas REM, Medeiros PHQS, Rodrigues FADP, Clementino MADF, Fernandes C, da Silva AVA, Prata MDMG, Cavalcante PA, Lima AÂM, Havt A. Retinoids delay cell cycle progression and promote differentiation of intestinal epithelial cells exposed to nutrient deprivation. Nutrition 2020; 85:111087. [PMID: 33545543 DOI: 10.1016/j.nut.2020.111087] [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: 07/13/2020] [Revised: 10/10/2020] [Accepted: 11/12/2020] [Indexed: 11/28/2022]
Abstract
OBJECTIVE Vitamin A is commonly recommended as a treatment for diarrhea and undernutrition; however, little is known about the underlying cellular mechanisms. The aim of this study was to investigate the modulation of cell cycle by vitamin A derivatives (retinyl palmitate or retinol) in undernourished intestinal epithelial crypts (IEC-6). METHODS IEC-6 cells were exposed to nutrient deprivation (no serum and no glutamine) and supplemented with retinyl palmitate or retinol at a range of 2 to 20 μM. Proliferation, apoptosis/necrosis, cell cycle process, and gene transcription were assessed. RESULTS Nutrient deprivation for 6, 12, 24, or 48 h decreased cell proliferation, and retinyl palmitate further decreased it after 24 and 48 h. Apoptosis rates were reduced by undernourishment and further reduced by retinyl palmitate after 48 h; whereas necrosis rates were unaltered. Undernourishment induced overall cell quiescence, increased percentage of cells in G0/G1 phase and decreased percentage of cells in S phase after 12 h and in G2/M phases at 6, 12, and 24 h after treatment. Both retinoids also showed cell quiescence induction with less cells in G2/M phases after 48 h, whereas only retinol showed significant modulation of G0/G1 and S phases. Both retinoids also increased markers of cell differentiation Fabp and Iap gene transcriptions in about fivefold rates after 42 h. Furthermore, specific gene transcriptions related to MAP kinase signaling pathway regulation of cell differentiation and cell cycle regulation were triggered by retinoids in undernourished IEC-6, with higher levels of expression for Atf2 and C-jun genes. CONCLUSIONS These findings indicated that both vitamin A derivatives induce further survival mechanisms in undernourished intestinal epithelial crypt cells. These mechanisms include increased cell quiescence, decreased apoptosis, increased cell differentiation, and transcription of genes related to MAP kinase signaling pathway.
Collapse
Affiliation(s)
- Rosa Elayne Marques de Freitas
- Institute of Biomedicine and Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | | | | | | | - Camila Fernandes
- Institute of Biomedicine and Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Antonio Vinicios Alves da Silva
- Institute of Biomedicine and Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Mara de Moura Gondim Prata
- Institute of Biomedicine and Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | | | | | - Alexandre Havt
- Institute of Biomedicine and Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil.
| |
Collapse
|
|
7
|
Xiao N, Hu Y, Juan L. Comprehensive Analysis of Differentially Expressed lncRNAs in Gastric Cancer. Front Cell Dev Biol 2020; 8:557. [PMID: 32695786 PMCID: PMC7338654 DOI: 10.3389/fcell.2020.00557] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 06/11/2020] [Indexed: 01/26/2023] Open
Abstract
Gastric cancer (GC) is the fourth most common malignant tumor. The mechanism underlying GC occurrence and development remains unclear. Previous studies have indicated that long non-coding RNAs (lncRNAs) are significantly associated with gastric cancer, but a systematic understanding of the role of lncRNAs in gastric cancer is lacking. In recent years, with the development of next-generation sequencing technology, tens of thousands of lncRNAs have been discovered. However, a large number of unannotated lncRNAs remain unidentified in different tissues, including potential gastric cancer-related lncRNAs. In this study, RNA sequencing (RNA-seq) data from 16 samples of eight gastric cancer patients were obtained and analyzed. A total of 1,854 previously unannotated lncRNAs were identified by ab initio assembly, and 520 differentially expressed lncRNAs were validated in the TCGA expression dataset. Methylation and copy number variation (CNV) array data from the same sample were integrated in the analysis. Changes in DNA methylation levels and CNVs may be responsible for the differential expression of 91 lncRNAs. Differentially expressed lncRNAs were enriched in coexpressed clusters of genes related to functions such as cell signaling, cell cycle, immune response, metabolic processes, angiogenesis, and regulation of retinoic acid (RA) receptors. Finally, a differentially expressed lncRNA, AC004510.3, was identified as a potential biomarker for the prediction of the overall survival of gastric cancer patients.
Collapse
Affiliation(s)
- Nan Xiao
- School of Life Sciences and Technology, Harbin Institute of Technology, Harbin, China.,School of Pharmaceutical Sciences, Tsinghua University, Beijing, China
| | - Yang Hu
- School of Life Sciences and Technology, Harbin Institute of Technology, Harbin, China
| | - Liran Juan
- School of Life Sciences and Technology, Harbin Institute of Technology, Harbin, China
| |
Collapse
|
|
8
|
The potential of retinoids for combination therapy of lung cancer: Updates and future directions. Pharmacol Res 2019; 147:104331. [PMID: 31254665 DOI: 10.1016/j.phrs.2019.104331] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 06/23/2019] [Accepted: 06/25/2019] [Indexed: 12/20/2022]
Abstract
Lung cancer is the most common cancer-related death worldwide. Natural compounds have shown high biological and pharmaceutical relevance as anticancer agents. Retinoids are natural derivatives of vitamin A having many regulatory functions in the human body, including vision, cellular proliferation and differentiation, and activation of tumour suppressor genes. Retinoic acid (RA) is a highly active retinoid isoform with promising anti-lung cancer activity. The abnormal expression of retinoid receptors is associated with loss of anticancer activities and acquired resistance to RA in lung cancer. The preclinical promise has not translated to the general clinical utility of retinoids for lung cancer patients, especially those with a history of smoking. Newer retinoid nano-formulations and the combinatorial use of retinoids has been associated with lower toxicity and more favorably efficacy in both the preclinical and clinical settings. Here, we highlight epidemiological and clinical therapeutic studies involving retinoids and lung cancer. We also discuss the biological actions of retinoids in lung cancer, which include effects on cancer stem cell differentiation, angiogenesis, metastasis, and proliferative. We suggest that the use of retinoids in combination with conventional and targeted anticancer agents will broaden the utility of these potent anticancer compounds in the lung cancer clinic.
Collapse
|
|
9
|
Jones T, Zhang B, Major S, Webb A. All-trans retinoic acid eluting poly(diol citrate) wafers for treatment of glioblastoma. J Biomed Mater Res B Appl Biomater 2019; 108:619-628. [PMID: 31087625 DOI: 10.1002/jbm.b.34416] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 04/15/2019] [Accepted: 04/25/2019] [Indexed: 12/23/2022]
Abstract
Current treatments for glioblastoma have failed to significantly increase patient survival, are extremely cytotoxic, can cause severe side effects, and are ineffective. Given these limitations, drugs other than cytotoxic chemotherapeutic agents are being explored. Recent studies show that all-trans retinoic acid (ATRA) could be effective on cancer cells as they have been shown to suppress carcinogenesis in a variety of tumor types and can reverse premalignant lesions and inhibit the development of secondary tumors in the head and neck of cancer patients. However, the therapeutic effects of retinoids such as ATRA are undermined by its rapid in vivo metabolism by cytochrome P450 enzymes, difficulty in crossing the blood-brain barrier, and sensitivity to isomerization/degradation. To overcome these limitations, we have developed a porous poly(1,8-octanediol-co-citrate; POC) wafer that stabilizes all-trans retinoic acid, while slowly releasing ATRA over 3 months. Release of ATRA from POC wafers inhibited proliferation of U87MG (glioblastoma) cells and caused upregulation in genes associated with differentiation into normal phenotype and apoptosis. Therefore, ATRA eluting poly(diol citrate) wafers are a promising treatment option compared to traditional cytotoxic chemotherapeutic agents.
Collapse
Affiliation(s)
- Tarielle Jones
- Department of Materials Science and Engineering, University of Florida, Gainesville, Florida
| | - Bisheng Zhang
- Department of Materials Science and Engineering, University of Florida, Gainesville, Florida
| | - Stephano Major
- Department of Materials Science and Engineering, University of Florida, Gainesville, Florida
| | - Antonio Webb
- Department of Materials Science and Engineering, University of Florida, Gainesville, Florida
| |
Collapse
|
|
10
|
Karabulutoglu M, Finnon R, Imaoka T, Friedl AA, Badie C. Influence of diet and metabolism on hematopoietic stem cells and leukemia development following ionizing radiation exposure. Int J Radiat Biol 2018; 95:452-479. [PMID: 29932783 DOI: 10.1080/09553002.2018.1490042] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE The review aims to discuss the prominence of dietary and metabolic regulators in maintaining hematopoietic stem cell (HSC) function, long-term self-renewal, and differentiation. RESULTS Most adult stem cells are preserved in a quiescent, nonmotile state in vivo which acts as a "protective state" for stem cells to reduce endogenous stress provoked by DNA replication and cellular respiration as well as exogenous environmental stress. The dynamic balance between quiescence, self-renewal and differentiation is critical for supporting a functional blood system throughout life of an organism. Stress-conditions, for example ionizing radiation exposure can trigger the blood forming HSCs to proliferate and migrate through extramedullary tissues to expand the number of HSCs and increase hematopoiesis. In addition, a wealth of investigation validated that deregulation of this balance plays a critical pathogenic role in various different hematopoietic diseases including the leukemia development. CONCLUSION The review summarizes the current knowledge on how alterations in dietary and metabolic factors could alter the risk of leukemia development following ionizing radiation exposure by inhibiting or even reversing the leukemic progression. Understanding the influence of diet, metabolism, and epigenetics on radiation-induced leukemogenesis may lead to the development of practical interventions to reduce the risk in exposed populations.
Collapse
Affiliation(s)
- Melis Karabulutoglu
- a Cancer Mechanisms and Biomarkers group, Biological Effects Department, Centre for Radiation, Chemical and Environmental Hazards , Public Health England , Didcot , UK.,b CRUK & MRC Oxford Institute for Radiation Oncology, Department of Oncology , University of Oxford , Oxford , UK
| | - Rosemary Finnon
- a Cancer Mechanisms and Biomarkers group, Biological Effects Department, Centre for Radiation, Chemical and Environmental Hazards , Public Health England , Didcot , UK
| | - Tatsuhiko Imaoka
- c Department of Radiation Effects Research, National Institute of Radiological Sciences , National Institutes for Quantum and Radiological Science and Technology , Chiba , Japan
| | - Anna A Friedl
- d Department of Radiation Oncology , University Hospital, LMU Munich , Munich , Germany
| | - Christophe Badie
- a Cancer Mechanisms and Biomarkers group, Biological Effects Department, Centre for Radiation, Chemical and Environmental Hazards , Public Health England , Didcot , UK
| |
Collapse
|
|
11
|
Malivindi R, Rago V, De Rose D, Gervasi MC, Cione E, Russo G, Santoro M, Aquila S. Influence of all‐
trans
retinoic acid on sperm metabolism and oxidative stress: Its involvement in the physiopathology of varicocele‐associated male infertility. J Cell Physiol 2018; 233:9526-9537. [DOI: 10.1002/jcp.26872] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Accepted: 05/18/2018] [Indexed: 12/15/2022]
Affiliation(s)
- Rocco Malivindi
- Department of Pharmacy and Sciences of Health and Nutrition University of Calabria Cosenza Italy
| | - Vittoria Rago
- Department of Pharmacy and Sciences of Health and Nutrition University of Calabria Cosenza Italy
| | - Daniela De Rose
- Department of Pharmacy and Sciences of Health and Nutrition University of Calabria Cosenza Italy
- Centro Sanitario, University of Calabria Cosenza Italy
| | | | - Erika Cione
- Department of Pharmacy and Sciences of Health and Nutrition University of Calabria Cosenza Italy
| | - Giampiero Russo
- Consultorio Familiare UNICAL, ASP—National Health Service, Centro Sanitario, University of Calabria Rende Italy
| | - Marta Santoro
- Department of Pharmacy and Sciences of Health and Nutrition University of Calabria Cosenza Italy
- Centro Sanitario, University of Calabria Cosenza Italy
| | - Saveria Aquila
- Department of Pharmacy and Sciences of Health and Nutrition University of Calabria Cosenza Italy
- Centro Sanitario, University of Calabria Cosenza Italy
| |
Collapse
|
|
12
|
Cañete A, Cano E, Muñoz-Chápuli R, Carmona R. Role of Vitamin A/Retinoic Acid in Regulation of Embryonic and Adult Hematopoiesis. Nutrients 2017; 9:E159. [PMID: 28230720 PMCID: PMC5331590 DOI: 10.3390/nu9020159] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2016] [Revised: 02/05/2017] [Accepted: 02/16/2017] [Indexed: 12/11/2022] Open
Abstract
Vitamin A is an essential micronutrient throughout life. Its physiologically active metabolite retinoic acid (RA), acting through nuclear retinoic acid receptors (RARs), is a potent regulator of patterning during embryonic development, as well as being necessary for adult tissue homeostasis. Vitamin A deficiency during pregnancy increases risk of maternal night blindness and anemia and may be a cause of congenital malformations. Childhood Vitamin A deficiency can cause xerophthalmia, lower resistance to infection and increased risk of mortality. RA signaling appears to be essential for expression of genes involved in developmental hematopoiesis, regulating the endothelial/blood cells balance in the yolk sac, promoting the hemogenic program in the aorta-gonad-mesonephros area and stimulating eryrthropoiesis in fetal liver by activating the expression of erythropoietin. In adults, RA signaling regulates differentiation of granulocytes and enhances erythropoiesis. Vitamin A may facilitate iron absorption and metabolism to prevent anemia and plays a key role in mucosal immune responses, modulating the function of regulatory T cells. Furthermore, defective RA/RARα signaling is involved in the pathogenesis of acute promyelocytic leukemia due to a failure in differentiation of promyelocytes. This review focuses on the different roles played by vitamin A/RA signaling in physiological and pathological mouse hematopoiesis duddurring both, embryonic and adult life, and the consequences of vitamin A deficiency for the blood system.
Collapse
Affiliation(s)
- Ana Cañete
- Department of Animal Biology, Faculty of Science, University of Malaga, Campus de Teatinos s/n Malaga 29071, Spain and Andalusian Center for Nanomedicine and Biotechnology (BIONAND), Severo Ochoa 25, Campanillas 29590, Spain.
| | - Elena Cano
- Max-Delbruck Center for Molecular Medicine, Robert Roessle-Strasse 10, 13125 Berlin, Germany.
| | - Ramón Muñoz-Chápuli
- Department of Animal Biology, Faculty of Science, University of Malaga, Campus de Teatinos s/n Malaga 29071, Spain and Andalusian Center for Nanomedicine and Biotechnology (BIONAND), Severo Ochoa 25, Campanillas 29590, Spain.
| | - Rita Carmona
- Department of Animal Biology, Faculty of Science, University of Malaga, Campus de Teatinos s/n Malaga 29071, Spain and Andalusian Center for Nanomedicine and Biotechnology (BIONAND), Severo Ochoa 25, Campanillas 29590, Spain.
| |
Collapse
|
|
13
|
Suwa H, Kishi H, Imai F, Nakao K, Hirakawa T, Minegishi T. Retinoic acid enhances progesterone production via the cAMP/PKA signaling pathway in immature rat granulosa cells. Biochem Biophys Rep 2016. [PMID: 29541688 PMCID: PMC5616100 DOI: 10.1016/j.bbrep.2016.08.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Retinoic acid (RA) is a metabolite of vitamin A and has important roles in development, differentiation, and reproduction. Activin has been shown to regulate the RA pathway and affect granulosa cell (GC) proliferation, suggesting that RA is important for early follicle development. However, little is known about the effects of RA on GC functions, particularly steroidogenesis, during the early follicle stage. The aim of this study was to investigate the effects of all-trans-RA (atRA) on progesterone production in immature rat GCs cultured without gonadotropin. Our results demonstrated that atRA enhanced progesterone production by upregulating the levels of steroidogenic acute regulatory protein (StAR) and cytochrome P450scc (Cyp11a1) mRNAs, but not 3β-hydroxysteroid dehydrogenase mRNA in immature rat GCs. Additionally, analysis of the mechanisms through which atRA upregulated StAR and Cyp11a1 mRNAs revealed that atRA enhanced intracellular cAMP accumulation and phosphorylation of cAMP response-element binding protein (CREB). In addition, H-89, an inhibitor of protein kinase A (PKA), abolished the stimulatory effects of atRA, indicating that atRA enhanced progesterone synthesis through cAMP/PKA signaling. In conclusion, our data demonstrated that atRA has a crucial role in progesterone synthesis in rat GCs during the early follicle stage.
atRA upregulated StAR and Cyp11a1 and enhanced progesterone production. atRA enhanced intracellular cAMP accumulation and phosphorylation of CREB. Inhibition of PKA abolished the stimulatory effects of atRA. atRA mediated progesterone synthesis in rat GCs during the early follicle stage.
Collapse
|
|
14
|
Zhong C, Pu LY, Fang MM, Gu Z, Rao JH, Wang XH. Retinoic acid receptor α promotes autophagy to alleviate liver ischemia and reperfusion injury. World J Gastroenterol 2015; 21:12381-12391. [PMID: 26604645 PMCID: PMC4649121 DOI: 10.3748/wjg.v21.i43.12381] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Revised: 06/19/2015] [Accepted: 08/25/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the role of autophagy and the relationship between retinoic acid receptor α (RARα) and autophagy in liver ischemia and reperfusion (IR) injury.
METHODS: All-trans retinoic acid (ATRA) was administered to mice for two weeks before operation. Reverse transcription-polymerase chain reaction and Western blot were used to detect the expression levels of related factors. To demonstrate the role of RARα, LE540, a RARα inhibitor, was used to treat hepatocytes injured by H2O2in vitro.
RESULTS: ATRA pretreatment noticeably diminished levels of serum alanine aminotransferase and aspartate aminotransferase as well as the degree of histopathological changes. Apoptosis was also inhibited, whereas autophagy was promoted. In vitro, RARα was inhibited by LE540, which resulted in decreased autophagy and increased apoptosis. Similarly, the expression of Foxo3a and p-Akt was downregulated, but Foxo1 expression was upregulated.
CONCLUSION: This research provides evidence that ATRA can protect the liver from IR injury by promoting autophagy, which is dependent on Foxo3/p-Akt/Foxo1 signaling.
Collapse
|
|
15
|
Arts RJW, Blok BA, van Crevel R, Joosten LAB, Aaby P, Benn CS, Netea MG. Vitamin A induces inhibitory histone methylation modifications and down-regulates trained immunity in human monocytes. J Leukoc Biol 2015; 98:129-36. [PMID: 25934925 DOI: 10.1189/jlb.6ab0914-416r] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Accepted: 04/01/2015] [Indexed: 11/24/2022] Open
Abstract
Epidemiologic studies suggest that VAS has long-lasting immunomodulatory effects. We hypothesized that ATRA inhibits inflammatory cytokines in a model of trained immunity in monocytes by inducing epigenetic reprogramming through histone modifications. We used an previously described in vitro model of trained immunity, in which adherent monocytes of healthy volunteers were incubated for 24 h with BCG in the presence or absence of ATRA. After washing the cells, they were incubated for an additional 6 d in culture medium and restimulated with microbial ligands, and cytokine production was assessed. ATRA inhibited cytokine responses upon restimulation of monocytes, and this effect was exerted through increased expression of SUV39H2, a histone methyltransferase that induces the inhibitory mark H3K9me3. H3K9me3 at promoter sites of several cytokines was up-regulated by ATRA, and inhibition of SUV39H2 restored cytokine production. In addition to H3K9me3, the stimulatory histone mark H3K4me3 was down-regulated by ATRA at several promoter locations of cytokine genes. Therefore, we can conclude that ATRA inhibits cytokine production in models of direct stimulation or BCG-induced trained immunity and that these effects are mediated by histone modifications.
Collapse
Affiliation(s)
- Rob J W Arts
- *Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark; and OPEN, University of Southern Denmark/Odense University Hospital, Copenhagen, Denmark
| | - Bastiaan A Blok
- *Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark; and OPEN, University of Southern Denmark/Odense University Hospital, Copenhagen, Denmark
| | - Reinout van Crevel
- *Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark; and OPEN, University of Southern Denmark/Odense University Hospital, Copenhagen, Denmark
| | - Leo A B Joosten
- *Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark; and OPEN, University of Southern Denmark/Odense University Hospital, Copenhagen, Denmark
| | - Peter Aaby
- *Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark; and OPEN, University of Southern Denmark/Odense University Hospital, Copenhagen, Denmark
| | - Christine Stabell Benn
- *Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark; and OPEN, University of Southern Denmark/Odense University Hospital, Copenhagen, Denmark
| | - Mihai G Netea
- *Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark; and OPEN, University of Southern Denmark/Odense University Hospital, Copenhagen, Denmark
| |
Collapse
|
|
16
|
di Masi A, Leboffe L, De Marinis E, Pagano F, Cicconi L, Rochette-Egly C, Lo-Coco F, Ascenzi P, Nervi C. Retinoic acid receptors: from molecular mechanisms to cancer therapy. Mol Aspects Med 2015; 41:1-115. [PMID: 25543955 DOI: 10.1016/j.mam.2014.12.003] [Citation(s) in RCA: 256] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Accepted: 12/15/2014] [Indexed: 02/07/2023]
Abstract
Retinoic acid (RA), the major bioactive metabolite of retinol or vitamin A, induces a spectrum of pleiotropic effects in cell growth and differentiation that are relevant for embryonic development and adult physiology. The RA activity is mediated primarily by members of the retinoic acid receptor (RAR) subfamily, namely RARα, RARβ and RARγ, which belong to the nuclear receptor (NR) superfamily of transcription factors. RARs form heterodimers with members of the retinoid X receptor (RXR) subfamily and act as ligand-regulated transcription factors through binding specific RA response elements (RAREs) located in target genes promoters. RARs also have non-genomic effects and activate kinase signaling pathways, which fine-tune the transcription of the RA target genes. The disruption of RA signaling pathways is thought to underlie the etiology of a number of hematological and non-hematological malignancies, including leukemias, skin cancer, head/neck cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, renal cell carcinoma, pancreatic cancer, liver cancer, glioblastoma and neuroblastoma. Of note, RA and its derivatives (retinoids) are employed as potential chemotherapeutic or chemopreventive agents because of their differentiation, anti-proliferative, pro-apoptotic, and anti-oxidant effects. In humans, retinoids reverse premalignant epithelial lesions, induce the differentiation of myeloid normal and leukemic cells, and prevent lung, liver, and breast cancer. Here, we provide an overview of the biochemical and molecular mechanisms that regulate the RA and retinoid signaling pathways. Moreover, mechanisms through which deregulation of RA signaling pathways ultimately impact on cancer are examined. Finally, the therapeutic effects of retinoids are reported.
Collapse
Affiliation(s)
- Alessandra di Masi
- Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, Roma I-00146, Italy
| | - Loris Leboffe
- Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, Roma I-00146, Italy
| | - Elisabetta De Marinis
- Department of Medical and Surgical Sciences and Biotechnologies, University of Roma "La Sapienza", Corso della Repubblica 79, Latina I-04100
| | - Francesca Pagano
- Department of Medical and Surgical Sciences and Biotechnologies, University of Roma "La Sapienza", Corso della Repubblica 79, Latina I-04100
| | - Laura Cicconi
- Department of Biomedicine and Prevention, University of Roma "Tor Vergata", Via Montpellier 1, Roma I-00133, Italy; Laboratory of Neuro-Oncohematology, Santa Lucia Foundation, Via Ardeatina, 306, Roma I-00142, Italy
| | - Cécile Rochette-Egly
- Department of Functional Genomics and Cancer, IGBMC, CNRS UMR 7104 - Inserm U 964, University of Strasbourg, 1 rue Laurent Fries, BP10142, Illkirch Cedex F-67404, France.
| | - Francesco Lo-Coco
- Department of Biomedicine and Prevention, University of Roma "Tor Vergata", Via Montpellier 1, Roma I-00133, Italy; Laboratory of Neuro-Oncohematology, Santa Lucia Foundation, Via Ardeatina, 306, Roma I-00142, Italy.
| | - Paolo Ascenzi
- Interdepartmental Laboratory for Electron Microscopy, Roma Tre University, Via della Vasca Navale 79, Roma I-00146, Italy.
| | - Clara Nervi
- Department of Medical and Surgical Sciences and Biotechnologies, University of Roma "La Sapienza", Corso della Repubblica 79, Latina I-04100.
| |
Collapse
|
|
17
|
Lee SA, Jiang H, Trent CM, Yuen JJ, Narayanasamy S, Curley RW, Harrison EH, Goldberg IJ, Maurer MS, Blaner WS. Cardiac dysfunction in β-carotene-15,15'-dioxygenase-deficient mice is associated with altered retinoid and lipid metabolism. Am J Physiol Heart Circ Physiol 2014; 307:H1675-84. [PMID: 25260612 DOI: 10.1152/ajpheart.00548.2014] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Dietary carotenoids like β-carotene are converted within the body either to retinoid, via β-carotene-15,15'-dioxygenase (BCO1), or to β-apo-carotenoids, via β-carotene-9',10'-oxygenase 2. Some β-apo-carotenoids are potent antagonists of retinoic acid receptor (RAR)-mediated transcriptional regulation, which is required to ensure normal heart development and functions. We established liquid chromatography tandem mass spectrometery methods for measuring concentrations of 10 β-apo-carotenoids in mouse plasma, liver, and heart and assessed how these are influenced by Bco1 deficiency and β-carotene intake. Surprisingly, Bco1(-/-) mice had an increase in heart levels of retinol, nonesterified fatty acids, and ceramides and a decrease in heart triglycerides. These lipid changes were accompanied by elevations in levels of genes important to retinoid metabolism, specifically retinol dehydrogenase 10 and retinol-binding protein 4, as well as genes involved in lipid metabolism, including peroxisome proliferator-activated receptor-γ, lipoprotein lipase, Cd36, stearoyl-CoA desaturase 1, and fatty acid synthase. We also obtained evidence of compromised heart function, as assessed by two-dimensional echocardiography, in Bco1(-/-) mice. However, the total absence of Bco1 did not substantially affect β-apo-carotenoid concentrations in the heart. β-Carotene administration to matched Bco1(-/-) and wild-type mice elevated total β-apo-carotenal levels in the heart, liver, and plasma and total β-apo-carotenoic acid levels in the liver. Thus, BCO1 modulates heart metabolism and function, possibly by altering levels of cofactors required for the actions of nuclear hormone receptors.
Collapse
Affiliation(s)
- Seung-Ah Lee
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York
| | - Hongfeng Jiang
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York
| | - Chad M Trent
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York
| | - Jason J Yuen
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York
| | - Sureshbabu Narayanasamy
- College of Pharmacy, The Ohio State University, Columbus, Ohio; and Department of Human Nutrition, The Ohio State University, Columbus, Ohio
| | - Robert W Curley
- College of Pharmacy, The Ohio State University, Columbus, Ohio; and
| | - Earl H Harrison
- Department of Human Nutrition, The Ohio State University, Columbus, Ohio
| | - Ira J Goldberg
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York
| | - Mathew S Maurer
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York
| | - William S Blaner
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York;
| |
Collapse
|
|
18
|
Occhi G, Regazzo D, Albiger NM, Ceccato F, Ferasin S, Scanarini M, Denaro L, Cosma C, Plebani M, Cassarino MF, Mantovani G, Stalla GK, Pecori Giraldi F, Paez-Pareda M, Scaroni C. Activation of the dopamine receptor type-2 (DRD2) promoter by 9-cis retinoic acid in a cellular model of Cushing's disease mediates the inhibition of cell proliferation and ACTH secretion without a complete corticotroph-to-melanotroph transdifferentiation. Endocrinology 2014; 155:3538-49. [PMID: 24926820 DOI: 10.1210/en.2013-1820] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Cushing's disease (CD) is a rare condition in which hypercortisolemia is secondary to excessive ACTH release from a pituitary corticotroph adenoma. CD is associated with significant morbidity and mortality, and a safe therapy that effectively targets the pituitary tumor is still lacking. Retinoic acid (RA) and dopamine agonists (DAs) have recently been considered as monotherapy in CD patients, and satisfactory results have been reported, albeit in a limited number of patients. Given the permissive role of RA on the dopamine receptor type-2 (DRD2), the aim of the present study was to see whether a combination of 9-cis RA and the DA bromocriptine (Br) might represent a possible treatment for CD. Here we show that 9-cis RA induces a functional DRD2 in the pituitary corticotroph cell line AtT20, and increases cell sensitivity to Br via a mechanism only partially related to corticotroph-to-melanotroph transdifferentiation. In addition, 9-cis RA and Br act synergistically to modulate cell viability, with favorable implications for clinical use. In nearly 45% of corticotropinoma-derived primary cultures, the combined administration of 9-cis RA and Br lowered the steady-state level of the ACTH precursor proopiomelanocortin (POMC) more efficiently than either of the drugs alone. In conclusion, the effects of a combination of 9-cis RA and Br on ACTH synthesis/secretion and cell viability in AtT20, and on POMC transcriptional activity in human corticotropinomas might represent a suitable starting point for assessing the potential of this treatment regimen for ACTH-secreting pituitary adenomas. This study thus has potentially important implications for novel therapeutic approaches to CD.
Collapse
Affiliation(s)
- Gianluca Occhi
- Endocrinology Division, Departments of Medicine (G.O., D.R., N.M.A., F.C., S.F., C.S.) and Laboratory Medicine (C.C., M.P.), Academic Neurosurgery Unit (L.D.), Neuroscience Department, Padova University Hospital, 35128 Padova Italy; Neurosurgery Division (M.S.), Padova University Hospital, 35128 Padova, Italy; Neuroendocrinology Research Laboratory (M.F.C., F.P.G.), Istituto Auxologico Italiano Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20149 Milan, Italy; Department of Clinical Sciences and Community Health (G.M., F.P.-G.), University of Milan; Endocrinology and Diabetology Unit (G.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; and Clinical Neuroendocrinology (G.K.S., M.P.-P.), Department of Clinical Research, Max Planck Institute of Psychiatry, 80804 Munich, Germany
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
19
|
Dewamitta SR, Joseph C, Purton LE, Walkley CR. Erythroid-extrinsic regulation of normal erythropoiesis by retinoic acid receptors. Br J Haematol 2014; 164:280-5. [PMID: 24383846 DOI: 10.1111/bjh.12578] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Accepted: 08/21/2013] [Indexed: 12/16/2023]
Abstract
Vitamin A and its derivatives (retinoids) are important regulators of haematopoiesis, acting via retinoic acid receptors (RARs). Epidemiological studies indicated an association of vitamin A deficiency with anaemia in humans. To define the requirements of RARs in erythropoiesis, we evaluated erythroid parameters in RAR germ-line deficient and conditional knock out mice with erythroid specific deletion of RARs. Adult RARγ(-/-) mice were anaemic, however, Epor-Cre Rara(fl/fl) , Epor-Cre Rarg(fl/fl) and Epor-Cre Rara(fl/fl) g(fl/fl) mice were normal, indicating a lack of an erythroid intrinsic RAR function. Therefore, erythroid-specific RAR function is dispensable for erythropoiesis and RARγ plays an erythroid extrinsic role in erythropoiesis.
Collapse
Affiliation(s)
- Sita R Dewamitta
- Department of Medicine at St. Vincent's Hospital, St. Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, Vic., Australia
| | | | | | | |
Collapse
|
|
20
|
HU KONGWANG, PAN XIAOHUA, CHEN FEIHU, QIN RONG, WU LIMING, ZHU HUAGANG, WU FANRONG, GE JINFANG, HAN WENXIU, YIN CHUNLIN, LI HONGJUN. A novel retinoic acid analog, 4-amino-2-trifluoromethyl-phenyl retinate, inhibits gastric cancer cell growth. Int J Mol Med 2013; 33:415-22. [DOI: 10.3892/ijmm.2013.1574] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Accepted: 10/31/2013] [Indexed: 11/05/2022] Open
|
|
21
|
Al Tanoury Z, Piskunov A, Rochette-Egly C. Vitamin A and retinoid signaling: genomic and nongenomic effects. J Lipid Res 2013; 54:1761-75. [PMID: 23440512 DOI: 10.1194/jlr.r030833] [Citation(s) in RCA: 281] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Vitamin A or retinol is arguably the most multifunctional vitamin in the human body, as it is essential from embryogenesis to adulthood. The pleiotropic effects of vitamin A are exerted mainly by one active metabolite, all-trans retinoic acid (atRA), which regulates the expression of a battery of target genes through several families of nuclear receptors (RARs, RXRs, and PPARβ/δ), polymorphic retinoic acid (RA) response elements, and multiple coregulators. It also involves extranuclear and nontranscriptional effects, such as the activation of kinase cascades, which are integrated in the nucleus via the phosphorylation of several actors of RA signaling. However, vitamin A itself proved recently to be active and RARs to be present in the cytosol to regulate translation and cell plasticity. These new concepts expand the scope of the biologic functions of vitamin A and RA.
Collapse
Affiliation(s)
- Ziad Al Tanoury
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM), U964, CNRS, UMR7104, Université de Strasbourg, 67404 Illkirch Cedex, France
| | | | | |
Collapse
|