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Niekamp P, Kim RH, Jayaraman A, Klement N, Kostlan R, Kim CH. The Nuclear Receptor NR1B1/RARα Arrests the Differentiation of Anti-Tumor Effector Cytotoxic T Cells. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2410241. [PMID: 40068101 PMCID: PMC12061256 DOI: 10.1002/advs.202410241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 02/26/2025] [Indexed: 05/10/2025]
Abstract
NR1B1/RARα expression is dynamically regulated in cytotoxic lymphocytes (CTLs) in tumors, but the importance of its expression in anti-tumor CTLs remains unknown. RARα gene expression is upregulated in CTLs in tumor microenvironments (TME), but its protein expression is downregulated by retinoic acid. The role of RARα expression in regulating anti-tumor effector CTL (Teff) differentiation is reported. Mice that over-express RARα in T cells are defective in early Teff differentiation and fail to populate tumors. In contrast, RARα-deficient CTLs are hyper-active in making tumor-populating Teff cells, suggesting that RARα represses Teff differentiation. Moreover, RARα negatively controls the trafficking receptor switch from the lymphoid to an effector type. Generation of chimeric antigen receptor (CAR) T cells with reduced RARα expression produces highly effective CAR T cells with enhanced anti-tumor cytotoxicity. Mechanistically, upregulated RARα expression decreases the nuclear histone acetylase (HAT) activity, required for TCF1 to BATF transcription factor and trafficking switches during Teff differentiation. Additionally, RARα and BATF closely associate with each other on Teff-associated genes on the chromatin for possible cross-regulation. In sum, T cell-expressed RARα is identified as a novel negative regulator and potential target of intervention in promoting anti-cancer T cell immunity.
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Affiliation(s)
- Patrick Niekamp
- Department of PathologyUniversity of Michigan School of MedicineAnn ArborMI48109USA
- Mary H. Weiser Food Allergy CenterUniversity of Michigan School of MedicineAnn ArborMI48109USA
| | - Ryun Hee Kim
- Department of PathologyUniversity of Michigan School of MedicineAnn ArborMI48109USA
- Mary H. Weiser Food Allergy CenterUniversity of Michigan School of MedicineAnn ArborMI48109USA
| | - Adithyan Jayaraman
- Department of PathologyUniversity of Michigan School of MedicineAnn ArborMI48109USA
- Mary H. Weiser Food Allergy CenterUniversity of Michigan School of MedicineAnn ArborMI48109USA
| | - Nils Klement
- University of BielefeldFaculty of Physics33615BielefeldGermany
| | - Raymond Kostlan
- Department of PathologyUniversity of Michigan School of MedicineAnn ArborMI48109USA
| | - Chang H. Kim
- Department of PathologyUniversity of Michigan School of MedicineAnn ArborMI48109USA
- Mary H. Weiser Food Allergy CenterUniversity of Michigan School of MedicineAnn ArborMI48109USA
- Immunology Graduate ProgramUniversity of MichiganAnn ArborMI48109USA
- Rogel Cancer CenterUniversity of Michigan School of MedicineAnn ArborMI48109USA
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Manna PR, Yang S, Manna C, Waters H, Islam MA, Reddy AP, Rawat P, Reddy PH. Steroidogenic acute regulatory protein mediated variations of gender-specific sex neurosteroids in Alzheimer's disease: Relevance to hormonal and neuronal imbalance. Neurosci Biobehav Rev 2025; 169:105969. [PMID: 39631487 DOI: 10.1016/j.neubiorev.2024.105969] [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: 05/13/2024] [Revised: 07/24/2024] [Accepted: 12/01/2024] [Indexed: 12/07/2024]
Abstract
The steroidogenic acute regulatory (StAR) protein mediates the rate-liming step in neuro/steroid biosynthesis. Multifaceted and delicate changes during aging, disrupting hormonal and neuronal homeostasis, constitute human senescence, an inevitable phenomenon that attributes to increased morbidity and mortality. Aging, along with progressive decreases in bioactive neurosteroids, is the primary risk factor for Alzheimer's disease (AD), which preferentially impacts two-thirds of women and one-third of men. AD is neuropathologically characterized by the accumulation of extracellular amyloid-β and intracellular phosphorylated Tau containing neurofibrillary tangles, resulting in dementia. Postmortem brains pertaining to gender-specific AD patients exhibit varied suppression of StAR and sex neurosteroid levels compared with age-matched cognitively healthy subjects, in which the attenuation of StAR is inversely correlated with the AD pathological markers. Interestingly, retinoid signaling upregulates StAR-motivated neurosteroid biosynthesis and reinstates various neurodegenerative vulnerabilities that promote AD pathogenesis. This review summarizes current understanding of StAR-driven alterations of sex neurosteroids in gender-specific AD risks and provides biochemical and molecular insights into therapeutic interventions for preventing and/or alleviating dementia for healthy aging.
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Affiliation(s)
- Pulak R Manna
- Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
| | - Shengping Yang
- Department of Biostatistics, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA 70808, USA
| | - Chayan Manna
- Baylor College of Medicine, Ben Taub Research Center, 1 Baylor Plaza, Houston, TX 77030, USA
| | - Hope Waters
- Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Md Ariful Islam
- Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Arubala P Reddy
- Nutritional Sciences Department, College of Human Sciences, Texas Tech University, Lubbock, TX 79409, USA
| | - Priyanka Rawat
- Nutritional Sciences Department, College of Human Sciences, Texas Tech University, Lubbock, TX 79409, USA
| | - P Hemachandra Reddy
- Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Nutritional Sciences Department, College of Human Sciences, Texas Tech University, Lubbock, TX 79409, USA; Neurology, Departments of School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Public Health Department of Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Speech, Language and Hearing Sciences, School Health Professions, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
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Ge H, Di G, Song P, Han W, Chen P, Wang Y. Role of vitamin A on the ocular surface. Exp Eye Res 2025; 250:110179. [PMID: 39581361 DOI: 10.1016/j.exer.2024.110179] [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: 07/24/2024] [Revised: 11/14/2024] [Accepted: 11/21/2024] [Indexed: 11/26/2024]
Abstract
Vitamin A is an essential fat-soluble vitamin that cannot be endogenously synthesized by the human body. Retinoic acid (RA) is the biologically active form of vitamin A. Utilizing both nuclear and non-nuclear receptor-mediated pathways, RA plays a crucial role in regulating various biological processes, including apoptosis, differentiation, and anti-inflammatory properties within the cornea and conjunctiva. In addition, RA has been demonstrated to exert a significant influence on anti-tumor mechanisms. Disruption of RA signaling can result in corneal defects, anophthalmia, and microphthalmia. However, the beneficial effects of RA are only observed when it is administered at appropriate dosages, and higher doses have an adverse impact. Ocular abnormalities are often early indicators of a vitamin A deficiency. The lacrimal gland secretes vitamin A onto the ocular surface, where it is metabolized into RA via two sequential steps. This article provides a comprehensive overview of how vitamin A is transformed and transported from the intestine to the ocular surface, ultimately contributing to the maintenance of the normal physiological function of the ocular surface.
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Affiliation(s)
- Huanhuan Ge
- School of Basic Medicine, Qingdao University, Qingdao, 266071, Shandong Province, China
| | - Guohu Di
- School of Basic Medicine, Qingdao University, Qingdao, 266071, Shandong Province, China; Institute of Stem Cell Regeneration Medicine, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Peirong Song
- School of Basic Medicine, Qingdao University, Qingdao, 266071, Shandong Province, China
| | - Wenshuo Han
- School of Basic Medicine, Qingdao University, Qingdao, 266071, Shandong Province, China
| | - Peng Chen
- School of Basic Medicine, Qingdao University, Qingdao, 266071, Shandong Province, China; Department of Ophthalmology, Qingdao Eighth People's Hospital, Qingdao, Shandong, 266121, China; Institute of Stem Cell Regeneration Medicine, School of Basic Medicine, Qingdao University, Qingdao, 266071, China.
| | - Ye Wang
- Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao, Shandong, 266042, China.
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Gray R, Lovely CB. Redefining retinoic acid receptor expression in zebrafish embryos using Hybridization Chain Reaction. Differentiation 2024; 140:100822. [PMID: 39627912 DOI: 10.1016/j.diff.2024.100822] [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: 07/12/2024] [Revised: 11/25/2024] [Accepted: 11/27/2024] [Indexed: 12/14/2024]
Abstract
Retinoic Acid (RA) is the key signaling molecule during embryonic development with the RA pathway playing multiple roles in throughout development. Previous work has shown RA signaling to be key in development of the craniofacial skeleton. RA signaling is driven by RA binding to the nuclear transcription factors, retinoic acid receptor (RAR) and retinoic X receptor (RXR). RARs and RXR heterodimerize to bind specific DNA sequences known as retinoic acid response elements or RAREs. Though the genes that code for these receptors are known to be involved during craniofacial development, in which tissues they are expressed remains uncharacterized, varying temporally and spatially. To address this, we used Hybridization Chain Reaction (HCR) to fluorescently visualize rar and rxr mRNA expression in tissue-specific transgenic zebrafish embryos. Here, we show the overall and tissue-specific expression of each receptor in the pharyngeal endoderm and Cranial Neural Crest Cells (CNCC), two cell types that have been shown to be sensitive to RA perturbations. Here we show that the expression of many of the rar/rxr genes overlap with the endoderm-specific sox17:eGFP and/or the CNCC-specific sox10:eGFP transgenic lines between 12 and 32 h post fertilization; time points that capture CNCC and endoderm migration and morphogenesis.
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Affiliation(s)
- Raèden Gray
- University of Louisville, School of Medicine, Department of Biochemistry and Molecular Genetics, 580 S Preston St, Louisville, KY, 40202, USA
| | - C Ben Lovely
- University of Louisville, School of Medicine, Department of Biochemistry and Molecular Genetics, 580 S Preston St, Louisville, KY, 40202, USA.
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Perrotta G, Condrea D, Ghyselinck NB. Meiosis and retinoic acid in the mouse fetal gonads: An unforeseen twist. Curr Top Dev Biol 2024; 161:59-88. [PMID: 39870439 DOI: 10.1016/bs.ctdb.2024.10.006] [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] [Indexed: 01/29/2025]
Abstract
In mammals, differentiation of germ cells is crucial for sexual reproduction, involving complex signaling pathways and environmental cues defined by the somatic cells of the gonads. This review examines the long-standing model positing that all-trans retinoic acid (ATRA) acts as a meiosis-inducing substance (MIS) in the fetal ovary by inducing expression of STRA8 in female germ cells, while CYP26B1 serves as a meiosis-preventing substance (MPS) in the fetal testis by degrading ATRA and preventing STRA8 expression in the male germ cells until postnatal development. Recent genetic studies in the mouse challenge this paradigm, revealing that meiosis initiation in female germ cells can occur independently of ATRA signaling, with key roles played by other intrinsic factors like DAZL and DMRT1, and extrinsic signals such as BMPs and vitamin C. Thus, ATRA can no longer be considered as 'the' long-searched MIS. Furthermore, evidence indicates that CYP26B1 does not prevent meiosis by degrading ATRA in the fetal testis, but acts by degrading an unidentified MIS or synthesizing an equally unknown MPS. By emphasizing the necessity of genetic loss-of-function approaches to accurately delineate the roles of signaling molecules such ATRA in vivo, this chapter calls for a reevaluation of the mechanisms instructing and preventing meiosis initiation in the fetal ovary and testis, respectively. It highlights the need for further research into the molecular identities of the signals involved in these processes.
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Affiliation(s)
- Giulia Perrotta
- Université de Strasbourg, IGBMC UMR 7104, Illkirch, France; CNRS, UMR 7104, Illkirch, France; Inserm, UMR-S 1258, Illkirch, France; IGBMC, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
| | - Diana Condrea
- Université de Strasbourg, IGBMC UMR 7104, Illkirch, France; CNRS, UMR 7104, Illkirch, France; Inserm, UMR-S 1258, Illkirch, France; IGBMC, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
| | - Norbert B Ghyselinck
- Université de Strasbourg, IGBMC UMR 7104, Illkirch, France; CNRS, UMR 7104, Illkirch, France; Inserm, UMR-S 1258, Illkirch, France; IGBMC, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
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Havel SL, Griswold MD. The action of retinoic acid on spermatogonia in the testis. Curr Top Dev Biol 2024; 161:143-166. [PMID: 39870432 DOI: 10.1016/bs.ctdb.2024.10.005] [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] [Indexed: 01/29/2025]
Abstract
For mammalian spermatogenesis to proceed normally, it is essential that the population of testicular progenitor cells, A undifferentiated spermatogonia (Aundiff), undergoes differentiation during the A to A1 transition that occurs at the onset of spermatogenesis. The commitment of the Aundiff population to differentiation and leaving a quiescent, stem-like state gives rise to all the spermatozoa produced across the lifespan of an individual, and ultimately determines male fertility. The action of all-trans retinoic acid (atRA) on the Aundiff population is the determining factor that induces this change. Sertoli cells, omnipresent, nurse cells within the mammalian testis are responsible for synthesizing the atRA that prompts this change in the neonatal testicular environment. The mechanism of atRA synthesis and signaling has been robustly explored and, in this review, we have summarized what is currently known about the action of testicular atRA at the onset of spermatogenesis. We have combined this with evidence gained from prominent genetic studies that have further elucidated the function of genes critical to atRA synthesis. We have additionally described the effects of the first pulse of atRA delivered to the germ cells of the testis, which has been investigated using WIN 18,446 treatment which prevents atRA synthesis and induces spermatogenic synchrony. This method provides unparalleled resolution into cell and stage specific testicular changes, and combined with transgenic animal models, has allowed researchers to elucidate much regarding the onset of spermatogenesis.
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Affiliation(s)
- Shelby L Havel
- School of Molecular Biosciences, Washington State University, Pullman, Washington, United States
| | - Michael D Griswold
- School of Molecular Biosciences, Washington State University, Pullman, Washington, United States.
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Engfer ZJ, Palczewski K. The multifaceted roles of retinoids in eye development, vision, and retinal degenerative diseases. Curr Top Dev Biol 2024; 161:235-296. [PMID: 39870435 DOI: 10.1016/bs.ctdb.2024.10.003] [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] [Indexed: 01/29/2025]
Abstract
Vitamin A (all-trans-retinol; at-Rol) and its derivatives, known as retinoids, have been adopted by vertebrates to serve as visual chromophores and signaling molecules, particularly in the eye/retina. Few tissues rely on retinoids as heavily as the retina, and the study of genetically modified mouse models with deficiencies in specific retinoid-metabolizing proteins has allowed us to gain insight into the unique or redundant roles of these proteins in at-Rol uptake and storage, or their downstream roles in retinal development and function. These processes occur during embryogenesis and continue throughout life. This review delves into the role of these genes in supporting retinal function and maps the impact that genetically modified mouse models have had in studying retinoid-related genes. These models display distinct perturbations in retinoid biochemistry, physiology, and metabolic flux, mirroring human ocular diseases.
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Affiliation(s)
- Zachary J Engfer
- Center for Translational Vision Research, Department of Ophthalmology, Gavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United States; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, United States.
| | - Krzysztof Palczewski
- Center for Translational Vision Research, Department of Ophthalmology, Gavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United States; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, United States; Department of Chemistry, University of California Irvine, Irvine, CA, United States; Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, United States.
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8
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Chen Y, Anderson MT, Payne N, Santori FR, Ivanova NB. Nuclear Receptors and the Hidden Language of the Metabolome. Cells 2024; 13:1284. [PMID: 39120315 PMCID: PMC11311682 DOI: 10.3390/cells13151284] [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: 06/12/2024] [Revised: 07/16/2024] [Accepted: 07/22/2024] [Indexed: 08/10/2024] Open
Abstract
Nuclear hormone receptors (NHRs) are a family of ligand-regulated transcription factors that control key aspects of development and physiology. The regulation of NHRs by ligands derived from metabolism or diet makes them excellent pharmacological targets, and the mechanistic understanding of how NHRs interact with their ligands to regulate downstream gene networks, along with the identification of ligands for orphan NHRs, could enable innovative approaches for cellular engineering, disease modeling and regenerative medicine. We review recent discoveries in the identification of physiologic ligands for NHRs. We propose new models of ligand-receptor co-evolution, the emergence of hormonal function and models of regulation of NHR specificity and activity via one-ligand and two-ligand models as well as feedback loops. Lastly, we discuss limitations on the processes for the identification of physiologic NHR ligands and emerging new methodologies that could be used to identify the natural ligands for the remaining 17 orphan NHRs in the human genome.
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Affiliation(s)
- Yujie Chen
- Center for Molecular Medicine, University of Georgia, Athens, GA 30602, USA; (Y.C.); (M.T.A.); (N.P.)
- Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA
| | - Matthew Tom Anderson
- Center for Molecular Medicine, University of Georgia, Athens, GA 30602, USA; (Y.C.); (M.T.A.); (N.P.)
| | - Nathaniel Payne
- Center for Molecular Medicine, University of Georgia, Athens, GA 30602, USA; (Y.C.); (M.T.A.); (N.P.)
| | - Fabio R. Santori
- Center for Molecular Medicine, University of Georgia, Athens, GA 30602, USA; (Y.C.); (M.T.A.); (N.P.)
| | - Natalia B. Ivanova
- Center for Molecular Medicine, University of Georgia, Athens, GA 30602, USA; (Y.C.); (M.T.A.); (N.P.)
- Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA
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Zhao H, Cao J, Mu H, Bi Y, Shi Y, Wang Y. WITHDRAWN: ATRA regulates myoblast differentiation and fusion through the RARα/Pitx2 signaling pathway, causing abnormal development of PFMs in ARM fetal rats. Dev Biol 2024:8883. [PMID: 38878992 DOI: 10.1016/j.ydbio.2024.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 06/12/2024] [Indexed: 12/19/2024]
Abstract
This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/policies/article-withdrawal.
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Affiliation(s)
- Hanbin Zhao
- Department of General Surgery &Neonatal Surgery Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Engineering Research Center of Stem Cell Therapy
| | - Jian Cao
- Department of General Surgery &Neonatal Surgery Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Engineering Research Center of Stem Cell Therapy
| | - Huaqi Mu
- Department of General Surgery &Neonatal Surgery Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Engineering Research Center of Stem Cell Therapy
| | - Yang Bi
- Department of General Surgery &Neonatal Surgery Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Engineering Research Center of Stem Cell Therapy
| | - Yuan Shi
- Department of Neonatology Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders
| | - Yi Wang
- Department of General Surgery &Neonatal Surgery Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Engineering Research Center of Stem Cell Therapy
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BharathwajChetty B, Sajeev A, Vishwa R, Aswani BS, Alqahtani MS, Abbas M, Kunnumakkara AB. Dynamic interplay of nuclear receptors in tumor cell plasticity and drug resistance: Shifting gears in malignant transformations and applications in cancer therapeutics. Cancer Metastasis Rev 2024; 43:321-362. [PMID: 38517618 DOI: 10.1007/s10555-024-10171-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 01/19/2024] [Indexed: 03/24/2024]
Abstract
Recent advances have brought forth the complex interplay between tumor cell plasticity and its consequential impact on drug resistance and tumor recurrence, both of which are critical determinants of neoplastic progression and therapeutic efficacy. Various forms of tumor cell plasticity, instrumental in facilitating neoplastic cells to develop drug resistance, include epithelial-mesenchymal transition (EMT) alternatively termed epithelial-mesenchymal plasticity, the acquisition of cancer stem cell (CSC) attributes, and transdifferentiation into diverse cell lineages. Nuclear receptors (NRs) are a superfamily of transcription factors (TFs) that play an essential role in regulating a multitude of cellular processes, including cell proliferation, differentiation, and apoptosis. NRs have been implicated to play a critical role in modulating gene expression associated with tumor cell plasticity and drug resistance. This review aims to provide a comprehensive overview of the current understanding of how NRs regulate these key aspects of cancer biology. We discuss the diverse mechanisms through which NRs influence tumor cell plasticity, including EMT, stemness, and metastasis. Further, we explore the intricate relationship between NRs and drug resistance, highlighting the impact of NR signaling on chemotherapy, radiotherapy and targeted therapies. We also discuss the emerging therapeutic strategies targeting NRs to overcome tumor cell plasticity and drug resistance. This review also provides valuable insights into the current clinical trials that involve agonists or antagonists of NRs modulating various aspects of tumor cell plasticity, thereby delineating the potential of NRs as therapeutic targets for improved cancer treatment outcomes.
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Affiliation(s)
- Bandari BharathwajChetty
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Anjana Sajeev
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Ravichandran Vishwa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Babu Santha Aswani
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha, 61421, Saudi Arabia
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha, 61421, Saudi Arabia
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India.
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11
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Oluwamodupe C, Adeleye AO. Targeting Retinol-Binding Protein 4 (RBP4) in the Management of Cardiometabolic Diseases. Cardiovasc Toxicol 2023; 23:285-294. [PMID: 37587250 DOI: 10.1007/s12012-023-09803-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Accepted: 08/05/2023] [Indexed: 08/18/2023]
Abstract
The ancient use of herbs for the treatment of various human diseases have been documented, with several scientific literatures supporting the use of medicinal plants. There is however a major concern about the phyto-constituents in the plants that performs the healing function and the mechanism by which it works for different ailments are still a research prospect. Cardiometabolic disease (CMD) is no doubt becoming more frequent globally and this is due to poor approach in therapy, contrary effects linked with intensive control, inept strategies with old drugs, inadequate control of some risk factors and lack of knowledge of the pathophysiological mechanisms that lead to this malaise. Retinol-binding protein 4 (RBP4) are predominantly secreted in the liver and adipose tissues and several researches have observed that elevation in serum levels of RBP4 often observed in obese experimental animals and human subjects causes CMD (obesity, insulin resistance, hyperlipidemia, etc.). RBP4 has gained special attention in the last 20 years in the field of metabolism research. This review aims to show research interaction of some medicinal plants targeting RBP4 in treating CMD and to encourage researchers, who are interested in CMD drug design, to focus on medicinal plants that inhibit the secretion of serum RBP4 in the adipose tissue for therapeutic approach to CMD. It also aims to identify the major bioactive compounds of plants that serves as a better and cheaper drug candidate for CMD and also study the signaling pathway which the plant material uses to regulate the metabolic consequences.
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Affiliation(s)
- Cecilia Oluwamodupe
- Department of Chemical Sciences (Biochemistry Program), Olusegun Agagu University of Science and Technology, P. M. B. 353, Okitipupa, Nigeria.
| | - Adesola Oluwaseun Adeleye
- Department of Chemical Sciences (Biochemistry Program), Olusegun Agagu University of Science and Technology, P. M. B. 353, Okitipupa, Nigeria
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Ghorayshian A, Danesh M, Mostashari-Rad T, fassihi A. Discovery of novel RARα agonists using pharmacophore-based virtual screening, molecular docking, and molecular dynamics simulation studies. PLoS One 2023; 18:e0289046. [PMID: 37616260 PMCID: PMC10449137 DOI: 10.1371/journal.pone.0289046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 07/10/2023] [Indexed: 08/26/2023] Open
Abstract
Nuclear retinoic acid receptors (RARs) are ligand-dependent transcription factors involved in various biological processes, such as embryogenesis, cell proliferation, differentiation, reproduction, and apoptosis. These receptors are regulated by retinoids, i.e., retinoic acid (RA) and its analogs, as receptor agonists. RAR agonists are promising therapeutic agents for the treatment of serious dermatological disorders, including some malignant conditions. By inducing apoptosis, they are able to inhibit the proliferation of diverse cancer cell lines. Also, RAR agonists have recently been identified as therapeutic options for some neurodegenerative diseases. These features make retinoids very attractive molecules for medical purposes. Synthetic selective RAR agonists have several advantages over endogenous ones, but they suffer poor pharmacokinetic properties. These compounds are normally lipophilic acids with unfavorable drug-like features such as poor oral bioavailability. Recently, highly selective, potent, and less toxic RAR agonists with proper lipophilicity, thus, good oral bioavailability have been developed for some therapeutic applications. In the present study, ligand and structure-based virtual screening technique was exploited to introduce some novel RARα agonists. Pharmacokinetic assessment was also performed in silico to suggest those compounds which have optimized drug-like features. Finally, two compounds with the best in silico pharmacological features are proposed as lead molecules for future development of RARα agonists.
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Affiliation(s)
- Atefeh Ghorayshian
- Department of Cell and Molecular Biology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Mahshid Danesh
- Functional Genomics & System Biology Group, Department of Bioinformatics, Biocenter, Am Hubland, University of Wuerzburg, Wuerzburg, Germany
| | - Tahereh Mostashari-Rad
- Department of Artificial Intelligence, Smart University of Medical Sciences, Tehran, Iran
| | - Afshin fassihi
- Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
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DiKun KM, Gudas LJ. Vitamin A and retinoid signaling in the kidneys. Pharmacol Ther 2023; 248:108481. [PMID: 37331524 PMCID: PMC10528136 DOI: 10.1016/j.pharmthera.2023.108481] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 05/18/2023] [Accepted: 06/14/2023] [Indexed: 06/20/2023]
Abstract
Vitamin A (VA, retinol) and its metabolites (commonly called retinoids) are required for the proper development of the kidney during embryogenesis, but retinoids also play key roles in the function and repair of the kidney in adults. Kidneys filter 180-200 liters of blood per day and each kidney contains approximately 1 million nephrons, which are often referred to as the 'functional units' of the kidney. Each nephron consists of a glomerulus and a series of tubules (proximal tubule, loop of Henle, distal tubule, and collecting duct) surrounded by a network of capillaries. VA is stored in the liver and converted to active metabolites, most notably retinoic acid (RA), which acts as an agonist for the retinoic acid receptors ((RARs α, β, and γ) to regulate gene transcription. In this review we discuss some of the actions of retinoids in the kidney after injury. For example, in an ischemia-reperfusion model in mice, injury-associated loss of proximal tubule (PT) differentiation markers occurs, followed by re-expression of these differentiation markers during PT repair. Notably, healthy proximal tubules express ALDH1a2, the enzyme that metabolizes retinaldehyde to RA, but transiently lose ALDH1a2 expression after injury, while nearby myofibroblasts transiently acquire RA-producing capabilities after injury. These results indicate that RA is important for renal tubular injury repair and that compensatory mechanisms exist for the generation of endogenous RA by other cell types upon proximal tubule injury. ALDH1a2 levels also increase in podocytes, epithelial cells of the glomeruli, after injury, and RA promotes podocyte differentiation. We also review the ability of exogenous, pharmacological doses of RA and receptor selective retinoids to treat numerous kidney diseases, including kidney cancer and diabetic kidney disease, and the emerging genetic evidence for the importance of retinoids and their receptors in maintaining or restoring kidney function after injury. In general, RA has a protective effect on the kidney after various types of injuries (eg. ischemia, cytotoxic actions of chemicals, hyperglycemia related to diabetes). As more research into the actions of each of the three RARs in the kidney is carried out, a greater understanding of the actions of vitamin A is likely to lead to new insights into the pathology of kidney disorders and the development of new therapies for kidney diseases.
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Affiliation(s)
- Krysta M DiKun
- Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY, USA; New York Presbyterian Hospital, New York, NY, USA; Weill Cornell Graduate School of Medical Sciences, New York, NY, USA
| | - Lorraine J Gudas
- Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY, USA; Department of Urology, Weill Cornell Medicine, New York, NY, USA; New York Presbyterian Hospital, New York, NY, USA; Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.
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14
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King AC, Zenker AK. Sex blind: bridging the gap between drug exposure and sex-related gene expression in Danio rerio using next-generation sequencing (NGS) data and a literature review to find the missing links in pharmaceutical and environmental toxicology studies. FRONTIERS IN TOXICOLOGY 2023; 5:1187302. [PMID: 37398910 PMCID: PMC10312089 DOI: 10.3389/ftox.2023.1187302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 06/01/2023] [Indexed: 07/04/2023] Open
Abstract
The sex of both humans and Danio rerio has previously been shown to affect the way individuals respond to drug exposure. Genes which allow identification of sex in juvenile zebrafish show potential to reveal these confounding variables between sex in toxicological and preclinical trials but the link between these is so far missing. These sex-specific, early expressed genes where expression is not altered by drug exposure must be carefully selected for this purpose. We aimed to discover genes which can be used in pharmaceutical trials and environmental toxicology studies to uncover sex-related variations in gene expression with drug application using the model organism Danio rerio. Previously published early sex determining genes from King et al. were evaluated as well as additional genes selected from our zebrafish Next-generation sequencing (NGS) data which are known from previously published works not to be susceptible to changes in expression with drug exposure. NGS revealed a further ten female-specific genes (vtg1, cyp17a1, cyp19a1a, igf3, ftz-f1, gdf9, foxl2a, Nr0b1, ipo4, lhcgr) and five male related candidate genes (FKBP5, apobb1, hbaa1, dmrt1, spata6) which are also expressed in juvenile zebrafish, 28 days post fertilisation (dpf). Following this, a literature review was performed to classify which of these early-expressed sex specific genes are already known to be affected by drug exposure in order to determine candidate genes to be used in pharmaceutical trials or environmental toxicology testing studies. Discovery of these early sex-determining genes in Danio rerio will allow identification of sex-related responses to drug testing to improve sex-specific healthcare and the medical treatment of human patients.
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Affiliation(s)
| | - Armin K. Zenker
- University of Applied Sciences and Arts North-Western Switzerland (FHNW), Muttenz, Switzerland
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15
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Petrelli B, Oztürk A, Pind M, Ayele H, Fainsod A, Hicks GG. Genetically programmed retinoic acid deficiency during gastrulation phenocopies most known developmental defects due to acute prenatal alcohol exposure in FASD. Front Cell Dev Biol 2023; 11:1208279. [PMID: 37397253 PMCID: PMC10311642 DOI: 10.3389/fcell.2023.1208279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 06/05/2023] [Indexed: 07/04/2023] Open
Abstract
Fetal Alcohol Spectrum Disorder (FASD) arises from maternal consumption of alcohol during pregnancy affecting 2%-5% of the Western population. In Xenopus laevis studies, we showed that alcohol exposure during early gastrulation reduces retinoic acid (RA) levels at this critical embryonic stage inducing craniofacial malformations associated with Fetal Alcohol Syndrome. A genetic mouse model that induces a transient RA deficiency in the node during gastrulation is described. These mice recapitulate the phenotypes characteristic of prenatal alcohol exposure (PAE) suggesting a molecular etiology for the craniofacial malformations seen in children with FASD. Gsc +/Cyp26A1 mouse embryos have a reduced RA domain and expression in the developing frontonasal prominence region and delayed HoxA1 and HoxB1 expression at E8.5. These embryos also show aberrant neurofilament expression during cranial nerve formation at E10.5 and have significant FASD sentinel-like craniofacial phenotypes at E18.5. Gsc +/Cyp26A1 mice develop severe maxillary malocclusions in adulthood. Phenocopying the PAE-induced developmental malformations with a genetic model inducing RA deficiency during early gastrulation strongly supports the alcohol/vitamin A competition model as a major molecular etiology for the neurodevelopmental defects and craniofacial malformations seen in children with FASD.
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Affiliation(s)
- B. Petrelli
- Department of Biochemistry and Medical Genetics, Regenerative Medicine Program, Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada
| | - A. Oztürk
- Department of Biochemistry and Medical Genetics, Regenerative Medicine Program, Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada
| | - M. Pind
- Department of Biochemistry and Medical Genetics, Regenerative Medicine Program, Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada
| | - H. Ayele
- Department of Biochemistry and Medical Genetics, Regenerative Medicine Program, Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada
| | - A. Fainsod
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel–Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - G. G. Hicks
- Department of Biochemistry and Medical Genetics, Regenerative Medicine Program, Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada
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16
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Harada T, Perez MW, Kalfon J, Braes FD, Batley R, Eagle K, Nabet B, Leifer B, Kruell J, Paralkar VR, Stegmaier K, Koehler AN, Orkin SH, Pimkin M. Rapid-kinetics degron benchmarking reveals off-target activities and mixed agonism-antagonism of MYB inhibitors. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.07.536032. [PMID: 37066194 PMCID: PMC10104119 DOI: 10.1101/2023.04.07.536032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/18/2023]
Abstract
Attenuating aberrant transcriptional circuits holds great promise for the treatment of numerous diseases, including cancer. However, development of transcriptional inhibitors is hampered by the lack of a generally accepted functional cellular readout to characterize their target specificity and on-target activity. We benchmarked the direct gene-regulatory signatures of six agents reported as inhibitors of the oncogenic transcription factor MYB against targeted MYB degradation in a nascent transcriptomics assay. The inhibitors demonstrated partial specificity for MYB target genes but displayed significant off-target activity. Unexpectedly, the inhibitors displayed bimodal on-target effects, acting as mixed agonists-antagonists. Our data uncover unforeseen agonist effects of small molecules originally developed as TF inhibitors and argue that rapid-kinetics benchmarking against degron models should be used for functional characterization of transcriptional modulators.
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Affiliation(s)
- Taku Harada
- Cancer and Blood Disorders Center, Dana-Farber Cancer Institute and Boston Children’s Hospital, Harvard Medical School, Boston, MA, 02215, USA
| | - Monika W. Perez
- Cancer and Blood Disorders Center, Dana-Farber Cancer Institute and Boston Children’s Hospital, Harvard Medical School, Boston, MA, 02215, USA
| | - Jérémie Kalfon
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, 02142, USA
| | - Flora Dievenich Braes
- Cancer and Blood Disorders Center, Dana-Farber Cancer Institute and Boston Children’s Hospital, Harvard Medical School, Boston, MA, 02215, USA
| | - Rashad Batley
- Cancer and Blood Disorders Center, Dana-Farber Cancer Institute and Boston Children’s Hospital, Harvard Medical School, Boston, MA, 02215, USA
| | - Kenneth Eagle
- Cancer and Blood Disorders Center, Dana-Farber Cancer Institute and Boston Children’s Hospital, Harvard Medical School, Boston, MA, 02215, USA
- Ken Eagle Consulting, Houston, TX, 77494, USA
| | - Behnam Nabet
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
| | - Becky Leifer
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Jasmin Kruell
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Vikram R. Paralkar
- Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Kimberly Stegmaier
- Cancer and Blood Disorders Center, Dana-Farber Cancer Institute and Boston Children’s Hospital, Harvard Medical School, Boston, MA, 02215, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, 02142, USA
| | - Angela N. Koehler
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, 02142, USA
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Stuart H. Orkin
- Cancer and Blood Disorders Center, Dana-Farber Cancer Institute and Boston Children’s Hospital, Harvard Medical School, Boston, MA, 02215, USA
- Howard Hughes Medical Institute, Boston, MA, 02215, USA
| | - Maxim Pimkin
- Cancer and Blood Disorders Center, Dana-Farber Cancer Institute and Boston Children’s Hospital, Harvard Medical School, Boston, MA, 02215, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, 02142, USA
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17
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Manna PR, Reddy AP, Pradeepkiran JA, Kshirsagar S, Reddy PH. Regulation of retinoid mediated StAR transcription and steroidogenesis in hippocampal neuronal cells: Implications for StAR in protecting Alzheimer's disease. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166596. [PMID: 36356843 PMCID: PMC9772146 DOI: 10.1016/j.bbadis.2022.166596] [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: 09/04/2022] [Revised: 10/30/2022] [Accepted: 10/31/2022] [Indexed: 11/09/2022]
Abstract
Retinoids (vitamin A and its derivatives) play pivotal roles in diverse processes, ranging from homeostasis to neurodegeneration, which are also influenced by steroid hormones. The rate-limiting step in steroid biosynthesis is mediated by the steroidogenic acute regulatory (StAR) protein. In the present study, we demonstrate that retinoids enhanced StAR expression and pregnenolone biosynthesis, and these parameters were markedly augmented by activation of the PKA pathway in mouse hippocampal neuronal HT22 cells. Deletion and mutational analyses of the 5'-flanking regions of the StAR gene revealed the importance of a retinoic acid receptor (RAR)/retinoid X receptor (RXR)-liver X receptor (LXR) heterodimeric motif at -200/-185 bp region in retinoid responsiveness. The RAR/RXR-LXR sequence motif can bind RARα and RXRα, and retinoid regulated transcription of the StAR gene was found to be influenced by the LXR pathway, representing signaling cross-talk in hippocampal neurosteroid biosynthesis. Steroidogenesis decreases during senescence due to declines in the central nervous system and the endocrine system, and results in hormone deficiencies, inferring the need for hormonal balance for healthy aging. Loss of neuronal cells, involving accumulation of amyloid beta (Aβ) and/or phosphorylated Tau within the brain, is the pathological hallmark of Alzheimer's disease (AD). HT22 cells overexpressing either mutant APP (mAPP) or mutant Tau (mTau), conditions mimetic to AD, enhanced toxicities, and resulted in attenuation of both basal and retinoid-responsive StAR and pregnenolone levels. Co-expression of StAR with either mAPP or mTau diminished cytotoxicity, and concomitantly elevated neurosteroid biosynthesis, pointing to a protective role of StAR in AD. These findings provide insights into the molecular events by which retinoid signaling upregulates StAR and steroid levels in hippocampal neuronal cells, and StAR, by rescuing mAPP and/or mTau-induced toxicities, modulates neurosteroidogenesis and restores hormonal balance, which may have important implications in protecting AD and age-related complications and diseases.
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Affiliation(s)
- Pulak R Manna
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
| | - Arubala P Reddy
- Nutritional Sciences Department, College of Human Sciences, Texas Tech University, 1301 Akron Ave, Lubbock, TX 79409, USA
| | | | - Sudhir Kshirsagar
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - P Hemachandra Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Nutritional Sciences Department, College of Human Sciences, Texas Tech University, 1301 Akron Ave, Lubbock, TX 79409, USA; Neurology, Departments of School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Public Health Department of Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Speech, Language and Hearing Sciences, School Health Professions, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
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18
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Guo Z, Zhao Y, Wu Y, Zhang Y, Wang R, Liu W, Zhang C, Yang X. Cellular retinol-binding protein 1: a therapeutic and diagnostic tumor marker. Mol Biol Rep 2023; 50:1885-1894. [PMID: 36515825 DOI: 10.1007/s11033-022-08179-2] [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: 09/18/2022] [Accepted: 12/06/2022] [Indexed: 12/15/2022]
Abstract
Cellular Retinol Binding Protein 1 (CRBP1) gene is a protein coding gene located on human chromosome 3q21, which codifies a protein named CRBP1. CRBP1 is widely expressed in many tissues as a chaperone protein to regulate the uptake, subsequent esterification and bioavailability of retinol. CRBP1 combines retinol and retinaldehyde with high affinity to protect retinoids from non-specific oxidation, and transports retinoids to specific enzymes to promote the biosynthesis of retinoic acid. The vital role of CRBP1 in retinoids metabolism has been gradually discovered, which has been implicated in tumorigenesis. However, the precise functions of CRBP1 in different diseases are still poorly understood. The purpose of this review is to provide an overview of the role of CRBP1 in various diseases, especially in both the promotion and inhibition of cancers, which may also offer a novel biomarker and potential therapeutic target for human diseases.
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Affiliation(s)
- Zhiyuan Guo
- College of Life Science, Henan Normal University, Xinxiang, 453007, China
- State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Henan Normal University, Xinxiang, 453007, China
| | - Yinshen Zhao
- College of Life Science, Henan Normal University, Xinxiang, 453007, China
- State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Henan Normal University, Xinxiang, 453007, China
| | - Yuqi Wu
- College of Life Science, Henan Normal University, Xinxiang, 453007, China
- State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Henan Normal University, Xinxiang, 453007, China
| | - Yuqi Zhang
- College of Life Science, Henan Normal University, Xinxiang, 453007, China
- State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Henan Normal University, Xinxiang, 453007, China
| | - Ruoyan Wang
- College of Life Science, Henan Normal University, Xinxiang, 453007, China
- State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Henan Normal University, Xinxiang, 453007, China
| | - Wan Liu
- College of Life Science, Henan Normal University, Xinxiang, 453007, China
- State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Henan Normal University, Xinxiang, 453007, China
| | - Chaoyang Zhang
- College of Life Science, Henan Normal University, Xinxiang, 453007, China
- State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Henan Normal University, Xinxiang, 453007, China
| | - Xianguang Yang
- College of Life Science, Henan Normal University, Xinxiang, 453007, China.
- State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Henan Normal University, Xinxiang, 453007, China.
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19
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Teletin M, Mark M, Wendling O, Vernet N, Féret B, Klopfenstein M, Herault Y, Ghyselinck NB. Timeline of Developmental Defects Generated upon Genetic Inhibition of the Retinoic Acid Receptor Signaling Pathway. Biomedicines 2023; 11:biomedicines11010198. [PMID: 36672706 PMCID: PMC9856201 DOI: 10.3390/biomedicines11010198] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 01/06/2023] [Indexed: 01/14/2023] Open
Abstract
It has been established for almost 30 years that the retinoic acid receptor (RAR) signalling pathway plays essential roles in the morphogenesis of a large variety of organs and systems. Here, we used a temporally controlled genetic ablation procedure to precisely determine the time windows requiring RAR functions. Our results indicate that from E8.5 to E9.5, RAR functions are critical for the axial rotation of the embryo, the appearance of the sinus venosus, the modelling of blood vessels, and the formation of forelimb buds, lung buds, dorsal pancreatic bud, lens, and otocyst. They also reveal that E9.5 to E10.5 spans a critical developmental period during which the RARs are required for trachea formation, lung branching morphogenesis, patterning of great arteries derived from aortic arches, closure of the optic fissure, and growth of inner ear structures and of facial processes. Comparing the phenotypes of mutants lacking the 3 RARs with that of mutants deprived of all-trans retinoic acid (ATRA) synthesising enzymes establishes that cardiac looping is the earliest known morphogenetic event requiring a functional ATRA-activated RAR signalling pathway.
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Affiliation(s)
- Marius Teletin
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS UMR7104), Institut National de la Sante et de la Recherche Médicale (INSERM U1258), Université de Strasbourg (UNISTRA), 1 Rue Laurent Fries, BP-10142, F-67404 Illkirch Graffenstaden, France
- Service de Biologie de la Reproduction, Hôpitaux Universitaires de Strasbourg (HUS), F-67000 Strasbourg, France
| | - Manuel Mark
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS UMR7104), Institut National de la Sante et de la Recherche Médicale (INSERM U1258), Université de Strasbourg (UNISTRA), 1 Rue Laurent Fries, BP-10142, F-67404 Illkirch Graffenstaden, France
- Service de Biologie de la Reproduction, Hôpitaux Universitaires de Strasbourg (HUS), F-67000 Strasbourg, France
- Institut Clinique de la Souris (ICS), Université de Strasbourg, CNRS, INSERM, CELPHEDIA, PHENOMIN, 1 Rue Laurent Fries, 67404 Illkirch Graffenstaden, France
- Correspondence:
| | - Olivia Wendling
- Institut Clinique de la Souris (ICS), Université de Strasbourg, CNRS, INSERM, CELPHEDIA, PHENOMIN, 1 Rue Laurent Fries, 67404 Illkirch Graffenstaden, France
| | - Nadège Vernet
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS UMR7104), Institut National de la Sante et de la Recherche Médicale (INSERM U1258), Université de Strasbourg (UNISTRA), 1 Rue Laurent Fries, BP-10142, F-67404 Illkirch Graffenstaden, France
| | - Betty Féret
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS UMR7104), Institut National de la Sante et de la Recherche Médicale (INSERM U1258), Université de Strasbourg (UNISTRA), 1 Rue Laurent Fries, BP-10142, F-67404 Illkirch Graffenstaden, France
| | - Muriel Klopfenstein
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS UMR7104), Institut National de la Sante et de la Recherche Médicale (INSERM U1258), Université de Strasbourg (UNISTRA), 1 Rue Laurent Fries, BP-10142, F-67404 Illkirch Graffenstaden, France
| | - Yann Herault
- Institut Clinique de la Souris (ICS), Université de Strasbourg, CNRS, INSERM, CELPHEDIA, PHENOMIN, 1 Rue Laurent Fries, 67404 Illkirch Graffenstaden, France
| | - Norbert B. Ghyselinck
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS UMR7104), Institut National de la Sante et de la Recherche Médicale (INSERM U1258), Université de Strasbourg (UNISTRA), 1 Rue Laurent Fries, BP-10142, F-67404 Illkirch Graffenstaden, France
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20
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Melo N, Belyaeva OV, Berger WK, Halasz L, Yu J, Pilli N, Yang Z, Klyuyeva AV, Elmets CA, Atigadda V, Muccio DD, Kane MA, Nagy L, Kedishvili NY, Renfrow MB. Next-generation retinoid X receptor agonists increase ATRA signaling in organotypic epithelium cultures and have distinct effects on receptor dynamics. J Biol Chem 2023; 299:102746. [PMID: 36436565 PMCID: PMC9807999 DOI: 10.1016/j.jbc.2022.102746] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 11/15/2022] [Accepted: 11/16/2022] [Indexed: 11/26/2022] Open
Abstract
Retinoid X receptors (RXRs) are nuclear transcription factors that partner with other nuclear receptors to regulate numerous physiological processes. Although RXR represents a valid therapeutic target, only a few RXR-specific ligands (rexinoids) have been identified, in part due to the lack of clarity on how rexinoids selectively modulate RXR response. Previously, we showed that rexinoid UAB30 potentiates all-trans-retinoic acid (ATRA) signaling in human keratinocytes, in part by stimulating ATRA biosynthesis. Here, we examined the mechanism of action of next-generation rexinoids UAB110 and UAB111 that are more potent in vitro than UAB30 and the FDA-approved Targretin. Both UAB110 and UAB111 enhanced ATRA signaling in human organotypic epithelium at a 50-fold lower concentration than UAB30. This was consistent with the 2- to 5- fold greater increase in ATRA in organotypic epidermis treated with UAB110/111 versus UAB30. Furthermore, at 0.2 μM, UAB110/111 increased the expression of ATRA genes up to 16-fold stronger than Targretin. The less toxic and more potent UAB110 also induced more changes in differential gene expression than Targretin. Additionally, our hydrogen deuterium exchange mass spectrometry analysis showed that both ligands reduced the dynamics of the ligand-binding pocket but also induced unique dynamic responses that were indicative of higher affinity binding relative to UAB30, especially for Helix 3. UAB110 binding also showed increased dynamics towards the dimer interface through the Helix 8 and Helix 9 regions. These data suggest that UAB110 and UAB111 are potent activators of RXR-RAR signaling pathways but accomplish activation through different molecular responses to ligand binding.
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Affiliation(s)
- Nathalia Melo
- O'Neil Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Olga V Belyaeva
- O'Neil Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Wilhelm K Berger
- Departments of Medicine and Biological Chemistry, Johns Hopkins University School of Medicine Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, St. Petersburg, Florida, USA
| | - Laszlo Halasz
- Departments of Medicine and Biological Chemistry, Johns Hopkins University School of Medicine Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, St. Petersburg, Florida, USA
| | - Jianshi Yu
- Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland, USA
| | - Nagesh Pilli
- Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland, USA
| | - Zhengrong Yang
- O'Neil Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Alla V Klyuyeva
- O'Neil Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Craig A Elmets
- O'Neil Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama, USA; Birmingham VA Medical Center, Birmingham, Alabama, USA
| | - Venkatram Atigadda
- O'Neil Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Donald D Muccio
- O'Neil Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Maureen A Kane
- Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland, USA
| | - Laszlo Nagy
- Departments of Medicine and Biological Chemistry, Johns Hopkins University School of Medicine Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, St. Petersburg, Florida, USA
| | - Natalia Y Kedishvili
- O'Neil Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
| | - Matthew B Renfrow
- O'Neil Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
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21
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Sung C, Jiao W, Park SY, Cooper M, Bouz A, Choi D, Jung E, Kim G, Hong YK, Wong AK. Lymphatic endothelial cell RXRα is critical for 9-cis-retinoic acid-mediated lymphangiogenesis and prevention of secondary lymphedema. FASEB J 2023; 37:e22674. [PMID: 36520015 DOI: 10.1096/fj.202200146rr] [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: 01/28/2022] [Revised: 11/11/2022] [Accepted: 11/16/2022] [Indexed: 12/23/2022]
Abstract
Secondary lymphedema is a debilitating disease characterized by abnormal soft tissue swelling and caused by lymphatic system dysfunction. Despite a high prevalence of secondary lymphedema after cancer treatments, current management is supportive and there are no approved therapeutic agents that can thwart disease progression. We have previously demonstrated that 9-cis-retinoic acid (9-cisRA) has the potential to be repurposed for lymphedema as it mitigates disease by promoting lymphangiogenesis at the site of lymphatic injury. Although the efficacy of 9-cisRA has been demonstrated in previous studies, the mechanism of action is not completely understood. In this study, we demonstrate that when RXRα is specifically deleted in lymphatic endothelial cells, 9-cisRA fails to induce lymphangiogenesis in vitro and prevent pathologic progression of postsurgical lymphedema in vivo. These findings demonstrate that downstream nuclear receptor RXRα plays a critical role in the therapeutic efficacy of 9-cisRA in postsurgical lymphedema.
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Affiliation(s)
- Cynthia Sung
- Division of Plastic Surgery, City of Hope National Medical Center, Duarte, California, USA.,Keck School of Medicine of USC, Los Angeles, California, USA
| | - Wan Jiao
- Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, California, USA
| | - Sun Young Park
- Division of Plastic Surgery, City of Hope National Medical Center, Duarte, California, USA.,Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, California, USA
| | - Michael Cooper
- Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, California, USA
| | - Antoun Bouz
- Herbert Wertheim College of Medicine of FIU, Miami, Florida, USA
| | - Dahae Choi
- Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Los Angeles, California, USA
| | - Eunson Jung
- Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Los Angeles, California, USA
| | - Gene Kim
- Keck School of Medicine of USC, Los Angeles, California, USA
| | - Young Kwon Hong
- Keck School of Medicine of USC, Los Angeles, California, USA.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Los Angeles, California, USA
| | - Alex K Wong
- Division of Plastic Surgery, City of Hope National Medical Center, Duarte, California, USA.,Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, California, USA
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22
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Wang Q, Miao J, Zhao A, Wu M, Pan L. Use of GAL4 factor-based yeast assay to quantify the effects of xenobiotics on RXR homodimer and RXR/PPAR heterodimer in scallop Chlamys farreri. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 852:158526. [PMID: 36063929 DOI: 10.1016/j.scitotenv.2022.158526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 08/30/2022] [Accepted: 08/31/2022] [Indexed: 06/15/2023]
Abstract
Retinoid X receptor (RXR) and peroxisome proliferators-activated receptors (PPAR) have been shown as important targets of endocrine disrupting effects caused by organotin compounds (OTCs). In vitro methods for non-model species are instrumental in revealing not only mechanism of toxicity but also basic biology. In the present study, we constructed the GAL4 factor-based recombinant yeast systems of RXRα/RXRα (RR), RXRα/PPARα (RPα) and RXRα/PPARγ (RPγ) of the scallop Chlamys farreri to investigate their transcriptional activity under the induction of OTCs (tributyltin chloride, triphenyltin chloride, tripropyltin chloride and bis(tributyltin)oxide), their spiked sediments and five other non‑tin compounds (Wy14643, rosiglitazone, benzyl butyl phthalate, dicyclohexyl phthalate and bis(2-ethylhexyl) phthalate). The results showed that the natural ligand of RXR, 9-cis-retinoic acid (9cRA), induces transcriptional activity in all three systems, while four OTCs induced the transcriptional activity of the RR and RPα systems. None of the five potential non‑tin endocrine disruptors induced effects on the RPα and RPγ systems. The spiked sediment experiment demonstrated the feasibility of the recombinant yeast systems constructed in this study for environmental sample detection. These results suggest that OTCs pose a threat to affect function of RXRα and PPARα of bivalve mollusks. The newly developed GAL4 factor-based yeast two-hybrid system can be used as a valuable tool for identification and quantification of compounds active in disturbing RXR and PPAR of bivalves.
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Affiliation(s)
- Qiaoqiao Wang
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao 266003, PR China
| | - Jingjing Miao
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao 266003, PR China.
| | - Anran Zhao
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao 266003, PR China
| | - Manni Wu
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao 266003, PR China
| | - Luqing Pan
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao 266003, PR China
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23
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Hirota A, Clément JE, Tanikawa S, Nonoyama T, Komatsuzaki T, Gong JP, Tanaka S, Imajo M. ERK MAP Kinase Signaling Regulates RAR Signaling to Confer Retinoid Resistance on Breast Cancer Cells. Cancers (Basel) 2022; 14:cancers14235890. [PMID: 36497371 PMCID: PMC9739577 DOI: 10.3390/cancers14235890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 11/18/2022] [Accepted: 11/24/2022] [Indexed: 12/05/2022] Open
Abstract
Retinoic acid (RA) and its synthetic derivatives, retinoids, have been established as promising anticancer agents based on their ability to regulate cell proliferation and survival. Clinical trials, however, have revealed that cancer cells often acquire resistance to retinoid therapy. Therefore, elucidation of underlying mechanisms of retinoid resistance has been considered key to developing more effective use of retinoids in cancer treatment. In this study, we show that constitutive activation of ERK MAP kinase signaling, which is often caused by oncogenic mutations in RAS or RAF genes, suppresses RA receptor (RAR) signaling in breast cancer cells. We show that activation of the ERK pathway suppresses, whereas its inhibition promotes, RA-induced transcriptional activation of RAR and the resultant upregulation of RAR-target genes in breast cancer cells. Importantly, ERK inhibition potentiates the tumor-suppressive activity of RA in breast cancer cells. Moreover, we also reveal that suppression of RAR signaling and activation of ERK signaling are associated with poor prognoses in breast cancer patients and represent hallmarks of specific subtypes of breast cancers, such as basal-like, HER2-enriched and luminal B. These results indicate that ERK-dependent suppression of RAR activity underlies retinoid resistance and is associated with cancer subtypes and patient prognosis in breast cancers.
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Affiliation(s)
- Akira Hirota
- Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo 001-0021, Japan
| | - Jean-Emmanuel Clément
- Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo 001-0021, Japan
- Research Center of Mathematics for Social Creativity, Research Institute for Electronic Science, Hokkaido University, Sapporo 001-0020, Japan
| | - Satoshi Tanikawa
- Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo 001-0021, Japan
| | - Takayuki Nonoyama
- Faculty of Advanced Life Science, Hokkaido University, Sapporo 001-0021, Japan
| | - Tamiki Komatsuzaki
- Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo 001-0021, Japan
- Research Center of Mathematics for Social Creativity, Research Institute for Electronic Science, Hokkaido University, Sapporo 001-0020, Japan
| | - Jian Ping Gong
- Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo 001-0021, Japan
- Faculty of Advanced Life Science, Hokkaido University, Sapporo 001-0021, Japan
| | - Shinya Tanaka
- Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo 001-0021, Japan
- Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Masamichi Imajo
- Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo 001-0021, Japan
- Correspondence: ; Tel.: +81-11-706-9683
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24
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le Maire A, Rey M, Vivat V, Guée L, Blanc P, Malosse C, Chamot-Rooke J, Germain P, Bourguet W. Design and in vitro characterization of RXR variants as tools to investigate the biological role of endogenous rexinoids. J Mol Endocrinol 2022; 69:377-390. [PMID: 35900852 DOI: 10.1530/jme-22-0021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 07/11/2022] [Indexed: 11/08/2022]
Abstract
Retinoid X receptors (RXRα, β, and γ) are essential members of the nuclear receptor (NR) superfamily of ligand-dependent transcriptional regulators that bind DNA response elements and control the expression of large gene networks. As obligate heterodimerization partners of many NRs, RXRs are involved in a variety of pathophysiological processes. However, despite this central role in NR signaling, there is still no consensus regarding the precise biological functions of RXRs and the putative role of the endogenous ligands (rexinoids) previously proposed for these receptors. Based on available crystal structures, we introduced a series of amino acid substitutions into the ligand-binding pocket of all three RXR subtypes in order to alter their binding properties. Subsequent characterization using a battery of cell-based and in vitro assays led to the identification of a double mutation abolishing the binding of any ligand while keeping the other receptor functions intact and a triple mutation that selectively impairs interaction with natural rexinoids but not with some synthetic ligands. We also report crystal structures that help understand the specific ligand-binding capabilities of both variants. These RXR variants, either fully disabled for ligand binding or retaining the property of being activated by synthetic compounds, represent unique tools that could be used in future studies to probe the presence of active endogenous rexinoids in tissues/organs and to investigate their role in vivo. Last, we provide data suggesting a possible involvement of fatty acids in the weak interaction of RXRs with corepressors.
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Affiliation(s)
- Albane le Maire
- CBS (Centre de Biologie Structurale), Univ Montpellier, CNRS, Inserm, Montpellier, France
| | - Martial Rey
- Institut Pasteur, Université de Paris, CNRS USR2000, Mass Spectrometry for Biology Unit, Paris, France
| | - Valérie Vivat
- IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Univ Strasbourg, CNRS, Inserm, Illkirch, France
| | - Laura Guée
- CBS (Centre de Biologie Structurale), Univ Montpellier, CNRS, Inserm, Montpellier, France
| | - Pauline Blanc
- CBS (Centre de Biologie Structurale), Univ Montpellier, CNRS, Inserm, Montpellier, France
| | - Christian Malosse
- Institut Pasteur, Université de Paris, CNRS USR2000, Mass Spectrometry for Biology Unit, Paris, France
| | - Julia Chamot-Rooke
- Institut Pasteur, Université de Paris, CNRS USR2000, Mass Spectrometry for Biology Unit, Paris, France
| | - Pierre Germain
- CBS (Centre de Biologie Structurale), Univ Montpellier, CNRS, Inserm, Montpellier, France
| | - William Bourguet
- CBS (Centre de Biologie Structurale), Univ Montpellier, CNRS, Inserm, Montpellier, France
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25
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Pierro JD, Ahir BK, Baker NC, Kleinstreuer NC, Xia M, Knudsen TB. Computational model for fetal skeletal defects potentially linked to disruption of retinoic acid signaling. Front Pharmacol 2022; 13:971296. [PMID: 36172177 PMCID: PMC9511990 DOI: 10.3389/fphar.2022.971296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 07/21/2022] [Indexed: 11/13/2022] Open
Abstract
All-trans retinoic acid (ATRA) gradients determine skeletal patterning morphogenesis and can be disrupted by diverse genetic or environmental factors during pregnancy, leading to fetal skeleton defects. Adverse Outcome Pathway (AOP) frameworks for ATRA metabolism, signaling, and homeostasis allow for the development of new approach methods (NAMs) for predictive toxicology with less reliance on animal testing. Here, a data-driven model was constructed to identify chemicals associated with both ATRA pathway bioactivity and prenatal skeletal defects. The phenotype data was culled from ToxRefDB prenatal developmental toxicity studies and produced a list of 363 ToxRefDB chemicals with altered skeletal observations. Defects were classified regionally as cranial, post-cranial axial, appendicular, and other (unspecified) features based on ToxRefDB descriptors. To build a multivariate statistical model, high-throughput screening bioactivity data from >8,070 chemicals in ToxCast/Tox21 across 10 in vitro assays relevant to the retinoid signaling system were evaluated and compared to literature-based candidate reference chemicals in the dataset. There were 48 chemicals identified for effects on both in vivo skeletal defects and in vitro ATRA pathway targets for computational modeling. The list included 28 chemicals with prior evidence of skeletal defects linked to retinoid toxicity and 20 chemicals without prior evidence. The combination of thoracic cage defects and DR5 (direct repeats of 5 nucleotides for RAR/RXR transactivation) disruption was the most frequently occurring phenotypic and target disturbance, respectively. This data model provides valuable AOP elucidation and validates current mechanistic understanding. These findings also shed light on potential avenues for new mechanistic discoveries related to ATRA pathway disruption and associated skeletal dysmorphogenesis due to environmental exposures.
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Affiliation(s)
- Jocylin D. Pierro
- Center for Computational Toxicology and Exposure (CCTE), Computational Toxicology and Bioinformatics Branch (CTBB), Office of Research and Development (ORD), U.S. Environmental Protection Agency (USEPA), Research Triangle Park, NC, United States
| | - Bhavesh K. Ahir
- Eurofins Medical Device Testing, Lancaster, PA, United States
| | - Nancy C. Baker
- Scientific Computing and Data Curation Division (SCDCD), Leidos Contractor, Center for Computational Toxicology and Exposure (CCTE), USEPA/ORD, Research Triangle Park, NC, United States
| | - Nicole C. Kleinstreuer
- Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), National Toxicology Program, National Institutes of Health, Research Triangle Park, NC, United States
| | - Menghang Xia
- Division for Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, United States
| | - Thomas B. Knudsen
- Center for Computational Toxicology and Exposure (CCTE), Computational Toxicology and Bioinformatics Branch (CTBB), Office of Research and Development (ORD), U.S. Environmental Protection Agency (USEPA), Research Triangle Park, NC, United States
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26
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Behl T, Kaur D, Sehgal A, Singla RK, Makeen HA, Albratty M, Alhazmi HA, Meraya AM, Bungau S. Therapeutic insights elaborating the potential of retinoids in Alzheimer’s disease. Front Pharmacol 2022; 13:976799. [PMID: 36091826 PMCID: PMC9453874 DOI: 10.3389/fphar.2022.976799] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 07/18/2022] [Indexed: 11/24/2022] Open
Abstract
Alzheimer’s disease (AD) is perceived with various pathophysiological characteristics such oxidative stress, senile plaques, neuroinflammation, altered neurotransmission immunological changes, neurodegenerative pathways, and age-linked alterations. A great deal of studies even now are carried out for comprehensive understanding of pathological processes of AD, though many agents are in clinical trials for the treatment of AD. Retinoids and retinoic acid receptors (RARs) are pertinent to such attributes of the disease. Retinoids support the proper functioning of the immunological pathways, and are very potent immunomodulators. The nervous system relies heavily on retinoic acid signaling. The disruption of retinoid signaling relates to several pathogenic mechanisms in the normal brain. Retinoids play critical functions in the neuronal organization, differentiation, and axonal growth in the normal functioning of the brain. Disturbed retinoic acid signaling causes inflammatory responses, mitochondrial impairment, oxidative stress, and neurodegeneration, leading to Alzheimer’s disease (AD) progression. Retinoids interfere with the production and release of neuroinflammatory chemokines and cytokines which are located to be activated in the pathogenesis of AD. Also, stimulating nuclear retinoid receptors reduces amyloid aggregation, lowers neurodegeneration, and thus restricts Alzheimer’s disease progression in preclinical studies. We outlined the physiology of retinoids in this review, focusing on their possible neuroprotective actions, which will aid in elucidating the critical function of such receptors in AD pathogenesis.
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Affiliation(s)
- Tapan Behl
- School of Health Sciences, University of Petroleum and Energy Studies, Dehradun, Uttarakhand, India
- *Correspondence: Tapan Behl, ; Simona Bungau,
| | - Dapinder Kaur
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Rajeev K. Singla
- Institutes for Sytems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- iGlobal Research and Publishing Foundation, New Delhi, India
| | - Hafiz A. Makeen
- Pharmacy Practice Research Unit, Clinical Pharmacy Department, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | - Mohammed Albratty
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | - Hassan A. Alhazmi
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
- Substance Abuse and Toxicology Research Center, Jazan University, Jazan, Saudi Arabia
| | - Abdulkarim M. Meraya
- Pharmacy Practice Research Unit, Department of Clinical Pharmacy, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
- Doctoral School of Biomedical Sciences, University of Oradea, Oradea, Romania
- *Correspondence: Tapan Behl, ; Simona Bungau,
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27
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Targeting Nuclear Receptors in Lung Cancer—Novel Therapeutic Prospects. Pharmaceuticals (Basel) 2022; 15:ph15050624. [PMID: 35631448 PMCID: PMC9145966 DOI: 10.3390/ph15050624] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/10/2022] [Accepted: 05/13/2022] [Indexed: 01/27/2023] Open
Abstract
Lung cancer, the second most commonly diagnosed cancer, is the major cause of fatalities worldwide for both men and women, with an estimated 2.2 million new incidences and 1.8 million deaths, according to GLOBOCAN 2020. Although various risk factors for lung cancer pathogenesis have been reported, controlling smoking alone has a significant value as a preventive measure. In spite of decades of extensive research, mechanistic cues and targets need to be profoundly explored to develop potential diagnostics, treatments, and reliable therapies for this disease. Nuclear receptors (NRs) function as transcription factors that control diverse biological processes such as cell growth, differentiation, development, and metabolism. The aberrant expression of NRs has been involved in a variety of disorders, including cancer. Deregulation of distinct NRs in lung cancer has been associated with numerous events, including mutations, epigenetic modifications, and different signaling cascades. Substantial efforts have been made to develop several small molecules as agonists or antagonists directed to target specific NRs for inhibiting tumor cell growth, migration, and invasion and inducing apoptosis in lung cancer, which makes NRs promising candidates for reliable lung cancer therapeutics. The current work focuses on the importance of various NRs in the development and progression of lung cancer and highlights the different small molecules (e.g., agonist or antagonist) that influence NR expression, with the goal of establishing them as viable therapeutics to combat lung cancer.
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28
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Gur M, Bendelac-Kapon L, Shabtai Y, Pillemer G, Fainsod A. Reduced Retinoic Acid Signaling During Gastrulation Induces Developmental Microcephaly. Front Cell Dev Biol 2022; 10:844619. [PMID: 35372345 PMCID: PMC8967241 DOI: 10.3389/fcell.2022.844619] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 02/24/2022] [Indexed: 12/21/2022] Open
Abstract
Retinoic acid (RA) is a central signaling molecule regulating multiple developmental decisions during embryogenesis. Excess RA induces head malformations, primarily by expansion of posterior brain structures at the expense of anterior head regions, i.e., hindbrain expansion. Despite this extensively studied RA teratogenic effect, a number of syndromes exhibiting microcephaly, such as DiGeorge, Vitamin A Deficiency, Fetal Alcohol Syndrome, and others, have been attributed to reduced RA signaling. This causative link suggests a requirement for RA signaling during normal head development in all these syndromes. To characterize this novel RA function, we studied the involvement of RA in the early events leading to head formation in Xenopus embryos. This effect was mapped to the earliest RA biosynthesis in the embryo within the gastrula Spemann-Mangold organizer. Head malformations were observed when reduced RA signaling was induced in the endogenous Spemann-Mangold organizer and in the ectopic organizer of twinned embryos. Two embryonic retinaldehyde dehydrogenases, ALDH1A2 (RALDH2) and ALDH1A3 (RALDH3) are initially expressed in the organizer and subsequently mark the trunk and the migrating leading edge mesendoderm, respectively. Gene-specific knockdowns and CRISPR/Cas9 targeting show that RALDH3 is a key enzyme involved in RA production required for head formation. These observations indicate that in addition to the teratogenic effect of excess RA on head development, RA signaling also has a positive and required regulatory role in the early formation of the head during gastrula stages. These results identify a novel RA activity that concurs with its proposed reduction in syndromes exhibiting microcephaly.
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29
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Gangwar SK, Kumar A, Jose S, Alqahtani MS, Abbas M, Sethi G, Kunnumakkara AB. Nuclear receptors in oral cancer-emerging players in tumorigenesis. Cancer Lett 2022; 536:215666. [DOI: 10.1016/j.canlet.2022.215666] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 03/25/2022] [Accepted: 03/25/2022] [Indexed: 12/24/2022]
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30
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Vitamin A and Viral Infection in Critical Care. JORJANI BIOMEDICINE JOURNAL 2022. [DOI: 10.52547/jorjanibiomedj.10.1.67] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/17/2023]
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31
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Vitória JJM, Trigo D, da Cruz E Silva OAB. Revisiting APP secretases: an overview on the holistic effects of retinoic acid receptor stimulation in APP processing. Cell Mol Life Sci 2022; 79:101. [PMID: 35089425 PMCID: PMC11073327 DOI: 10.1007/s00018-021-04090-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Revised: 11/18/2021] [Accepted: 12/01/2021] [Indexed: 01/03/2023]
Abstract
Alzheimer's disease (AD) is the leading cause of dementia worldwide and is characterized by the accumulation of the β-amyloid peptide (Aβ) in the brain, along with profound alterations in phosphorylation-related events and regulatory pathways. The production of the neurotoxic Aβ peptide via amyloid precursor protein (APP) proteolysis is a crucial step in AD development. APP is highly expressed in the brain and is complexly metabolized by a series of sequential secretases, commonly denoted the α-, β-, and γ-cleavages. The toxicity of resulting fragments is a direct consequence of the first cleaving event. β-secretase (BACE1) induces amyloidogenic cleavages, while α-secretases (ADAM10 and ADAM17) result in less pathological peptides. Hence this first cleavage event is a prime therapeutic target for preventing or reverting initial biochemical events involved in AD. The subsequent cleavage by γ-secretase has a reduced impact on Aβ formation but affects the peptides' aggregating capacity. An array of therapeutic strategies are being explored, among them targeting Retinoic Acid (RA) signalling, which has long been associated with neuronal health. Additionally, several studies have described altered RA levels in AD patients, reinforcing RA Receptor (RAR) signalling as a promising therapeutic strategy. In this review we provide a holistic approach focussing on the effects of isoform-specific RAR modulation with respect to APP secretases and discuss its advantages and drawbacks in subcellular AD related events.
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Affiliation(s)
- José J M Vitória
- Department of Medical Sciences, Neurosciences and Signalling Group, Institute of Biomedicine, University of Aveiro, 3810-193, Aveiro, Portugal
| | - Diogo Trigo
- Department of Medical Sciences, Neurosciences and Signalling Group, Institute of Biomedicine, University of Aveiro, 3810-193, Aveiro, Portugal
| | - Odete A B da Cruz E Silva
- Department of Medical Sciences, Neurosciences and Signalling Group, Institute of Biomedicine, University of Aveiro, 3810-193, Aveiro, Portugal.
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32
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Enhanced Loss of Retinoic Acid Network Genes in Xenopus laevis Achieves a Tighter Signal Regulation. Cells 2022; 11:cells11030327. [PMID: 35159137 PMCID: PMC8834563 DOI: 10.3390/cells11030327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/13/2022] [Accepted: 01/17/2022] [Indexed: 12/10/2022] Open
Abstract
Retinoic acid (RA) is a major regulatory signal during embryogenesis produced from vitamin A (retinol) by an extensive, autoregulating metabolic and signaling network to prevent fluctuations that result in developmental malformations. Xenopus laevis is an allotetraploid hybrid frog species whose genome includes L (long) and S (short) chromosomes from the originating species. Evolutionarily, the X. laevis subgenomes have been losing either L or S homoeologs in about 43% of genes to generate singletons. In the RA network, out of the 47 genes, about 47% have lost one of the homoeologs, like the genome average. Interestingly, RA metabolism genes from storage (retinyl esters) to retinaldehyde production exhibit enhanced gene loss with 75% singletons out of 28 genes. The effect of this gene loss on RA signaling autoregulation was studied. Employing transient RA manipulations, homoeolog gene pairs were identified in which one homoeolog exhibits enhanced responses or looser regulation than the other, while in other pairs both homoeologs exhibit similar RA responses. CRISPR/Cas9 targeting of individual homoeologs to reduce their activity supports the hypothesis where the RA metabolic network gene loss results in tighter network regulation and more efficient RA robustness responses to overcome complex regulation conditions.
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Sharma S, Shen T, Chitranshi N, Gupta V, Basavarajappa D, Mirzaei M, You Y, Krezel W, Graham SL, Gupta V. Retinoid X Receptor: Cellular and Biochemical Roles of Nuclear Receptor with a Focus on Neuropathological Involvement. Mol Neurobiol 2022; 59:2027-2050. [PMID: 35015251 PMCID: PMC9015987 DOI: 10.1007/s12035-021-02709-y] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 12/21/2021] [Indexed: 12/13/2022]
Abstract
Retinoid X receptors (RXRs) present a subgroup of the nuclear receptor superfamily with particularly high evolutionary conservation of ligand binding domain. The receptor exists in α, β, and γ isotypes that form homo-/heterodimeric complexes with other permissive and non-permissive receptors. While research has identified the biochemical roles of several nuclear receptor family members, the roles of RXRs in various neurological disorders remain relatively under-investigated. RXR acts as ligand-regulated transcription factor, modulating the expression of genes that plays a critical role in mediating several developmental, metabolic, and biochemical processes. Cumulative evidence indicates that abnormal RXR signalling affects neuronal stress and neuroinflammatory networks in several neuropathological conditions. Protective effects of targeting RXRs through pharmacological ligands have been established in various cell and animal models of neuronal injury including Alzheimer disease, Parkinson disease, glaucoma, multiple sclerosis, and stroke. This review summarises the existing knowledge about the roles of RXR, its interacting partners, and ligands in CNS disorders. Future research will determine the importance of structural and functional heterogeneity amongst various RXR isotypes as well as elucidate functional links between RXR homo- or heterodimers and specific physiological conditions to increase drug targeting efficiency in pathological conditions.
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Affiliation(s)
- Samridhi Sharma
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.
| | - Ting Shen
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
| | - Nitin Chitranshi
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
| | - Veer Gupta
- School of Medicine, Deakin University, Melbourne, VIC, Australia
| | - Devaraj Basavarajappa
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
| | - Mehdi Mirzaei
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
| | - Yuyi You
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.,Save Sight Institute, University of Sydney, Sydney, NSW, Australia
| | - Wojciech Krezel
- Institut de Génétique Et de Biologie Moléculaire Et Cellulaire, INSERM U1258, CNRS UMR 7104, Unistra, 67404, Illkirch-Graffenstaden, France
| | - Stuart L Graham
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.,Save Sight Institute, University of Sydney, Sydney, NSW, Australia
| | - Vivek Gupta
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.
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Kim N, Priefer R. Retinol binding protein 4 antagonists and protein synthesis inhibitors: Potential for therapeutic development. Eur J Med Chem 2021; 226:113856. [PMID: 34547506 DOI: 10.1016/j.ejmech.2021.113856] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 09/07/2021] [Accepted: 09/13/2021] [Indexed: 12/12/2022]
Abstract
Retinol-binding protein 4 (RBP4) is a serum protein that transports Vitamin A. RBP4 is correlated with numerous diseases and metabolic syndromes, including insulin resistance in type 2 diabetes, cardiovascular diseases, obesity, and macular degeneration. Recently, RBP4 antagonists and protein synthesis inhibitors are under development to regulate the effect of RBP4. Several RBP4 antagonists, especially BPN-14136, have demonstrated promising safety profiles and potential therapeutic benefits in animal studies. Two RBP4 antagonists, specifically tinlarebant (Belite Bio) and STG-001 (Stargazer) are currently undergoing clinical trials. Some antidiabetic drugs and nutraceuticals have been reported to reduce RBP4 expression, but more clinical data is needed to evaluate their therapeutical benefits. As regulating RBP4 levels or its activities would benefit a wide range of patients, further research is highly recommended to develop clinically useful RBP4 antagonists or protein synthesis inhibitors.
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Affiliation(s)
- Noheul Kim
- Massachusetts College of Pharmacy and Health Sciences University, Boston, MA, USA
| | - Ronny Priefer
- Massachusetts College of Pharmacy and Health Sciences University, Boston, MA, USA.
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Nasri A, Foisset F, Ahmed E, Lahmar Z, Vachier I, Jorgensen C, Assou S, Bourdin A, De Vos J. Roles of Mesenchymal Cells in the Lung: From Lung Development to Chronic Obstructive Pulmonary Disease. Cells 2021; 10:3467. [PMID: 34943975 PMCID: PMC8700565 DOI: 10.3390/cells10123467] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 12/02/2021] [Accepted: 12/07/2021] [Indexed: 12/28/2022] Open
Abstract
Mesenchymal cells are an essential cell type because of their role in tissue support, their multilineage differentiation capacities and their potential clinical applications. They play a crucial role during lung development by interacting with airway epithelium, and also during lung regeneration and remodeling after injury. However, much less is known about their function in lung disease. In this review, we discuss the origins of mesenchymal cells during lung development, their crosstalk with the epithelium, and their role in lung diseases, particularly in chronic obstructive pulmonary disease.
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Affiliation(s)
- Amel Nasri
- Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM, Centre Hospitalier Universitaire de Montpellier, 34000 Montpellier, France; (A.N.); (F.F.); (C.J.); (S.A.)
| | - Florent Foisset
- Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM, Centre Hospitalier Universitaire de Montpellier, 34000 Montpellier, France; (A.N.); (F.F.); (C.J.); (S.A.)
| | - Engi Ahmed
- Department of Respiratory Diseases, Université de Montpellier, INSERM, Centre Hospitalier Universitaire de Montpellier, 34090 Montpellier, France; (E.A.); (Z.L.); (I.V.); (A.B.)
- PhyMedExp, Université de Montpellier, INSERM, Centre Hospitalier Universitaire de Montpellier, 34295 Montpellier, France
| | - Zakaria Lahmar
- Department of Respiratory Diseases, Université de Montpellier, INSERM, Centre Hospitalier Universitaire de Montpellier, 34090 Montpellier, France; (E.A.); (Z.L.); (I.V.); (A.B.)
- PhyMedExp, Université de Montpellier, INSERM, Centre Hospitalier Universitaire de Montpellier, 34295 Montpellier, France
| | - Isabelle Vachier
- Department of Respiratory Diseases, Université de Montpellier, INSERM, Centre Hospitalier Universitaire de Montpellier, 34090 Montpellier, France; (E.A.); (Z.L.); (I.V.); (A.B.)
| | - Christian Jorgensen
- Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM, Centre Hospitalier Universitaire de Montpellier, 34000 Montpellier, France; (A.N.); (F.F.); (C.J.); (S.A.)
| | - Said Assou
- Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM, Centre Hospitalier Universitaire de Montpellier, 34000 Montpellier, France; (A.N.); (F.F.); (C.J.); (S.A.)
| | - Arnaud Bourdin
- Department of Respiratory Diseases, Université de Montpellier, INSERM, Centre Hospitalier Universitaire de Montpellier, 34090 Montpellier, France; (E.A.); (Z.L.); (I.V.); (A.B.)
- PhyMedExp, Université de Montpellier, INSERM, Centre Hospitalier Universitaire de Montpellier, 34295 Montpellier, France
| | - John De Vos
- Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM, Centre Hospitalier Universitaire de Montpellier, 34000 Montpellier, France; (A.N.); (F.F.); (C.J.); (S.A.)
- Department of Cell and Tissue Engineering, Université de Montpellier, Centre Hospitalier Universitaire de Montpellier, 34000 Montpellier, France
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Liu X, Shan W, Li T, Gao X, Kong F, You H, Kong D, Qiao S, Tang R. Cellular retinol binding protein-1 inhibits cancer stemness via upregulating WIF1 to suppress Wnt/β-catenin pathway in hepatocellular carcinoma. BMC Cancer 2021; 21:1224. [PMID: 34775955 PMCID: PMC8590789 DOI: 10.1186/s12885-021-08967-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 10/27/2021] [Indexed: 12/25/2022] Open
Abstract
Background CRBP-1, a cytosolic chaperone of vitamin A, is identified in a serious number of cancers; however, its biological role in hepatocellular carcinoma (HCC) needs to be further explored. The aim of our present study is to explore the roles and mechanisms of CRBP-1 in regulating liver cancer by using in vitro and in vivo biology approaches. Methods The expression level of CRBP-1 was detected using immunohistochemistry in HCC and matching adjacent non-tumorous liver tissues. Following established stable CRBP-1 overexpressed HCC cell lines, the cell growth and tumorigenicity were investigated both in vitro and in vivo. Intracellular retinoic acid was quantified by ELISA. The relationship between CRBP-1 and WIF1 was validated by using dual luciferase and ChIP analyses. Results The low expression of CRBP-1 was observed in HCC tissues compared to the normal liver tissues, while high CRBP-1 expression correlated with clinicopathological characteristics and increased overall survival in HCC patients. Overexpression of CRBP-1 significantly inhibited cell growth and tumorigenicity both in vitro and in vivo. Moreover, overexpression of CRBP-1 suppressed tumorsphere formation and cancer stemness related genes expression in HCC. Mechanically, CRBP-1 inhibited Wnt/β-catenin signaling pathway to suppress cancer cell stemness of HCC. Furthermore, our results revealed that CRBP-1 could increase the intracellular levels of retinoic acid, which induced the activation of RARs/RXRs leading to the transcriptional expression of WIF1, a secreted antagonist of the Wnt/β-catenin signaling pathway, by physically interacting with the region on WIF1 promoter. Conclusion Our findings reveal that CRBP-1 is a crucial player in the initiation and progression of HCC, which provide a novel independent prognostic biomarker and therapeutic target for the diagnosis and treatment of HCC. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08967-2.
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Affiliation(s)
- Xiangye Liu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, People's Republic of China.
| | - Wenhua Shan
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China
| | - Tingting Li
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, People's Republic of China
| | - Xiaoge Gao
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China
| | - Fanyun Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, People's Republic of China
| | - Hongjuan You
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, People's Republic of China
| | - Delong Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, People's Republic of China
| | - Shuxi Qiao
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China
| | - Renxian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, People's Republic of China.
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Cwiek A, Suzuki M, deRonde K, Conaway M, Bennett KM, El Dahr S, Reidy KJ, Charlton JR. Premature differentiation of nephron progenitor cell and dysregulation of gene pathways critical to kidney development in a model of preterm birth. Sci Rep 2021; 11:21667. [PMID: 34737344 PMCID: PMC8569166 DOI: 10.1038/s41598-021-00489-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 10/05/2021] [Indexed: 12/31/2022] Open
Abstract
Preterm birth is a leading cause of neonatal morbidity. Survivors have a greater risk for kidney dysfunction and hypertension. Little is known about the molecular changes that occur in the kidney of individuals born preterm. Here, we demonstrate that mice delivered two days prior to full term gestation undergo premature cessation of nephrogenesis, resulting in a lower glomerular density. Kidneys from preterm and term groups exhibited differences in gene expression profiles at 20- and 27-days post-conception, including significant differences in the expression of fat-soluble vitamin-related genes. Kidneys of the preterm mice exhibited decreased proportions of endothelial cells and a lower expression of genes promoting angiogenesis compared to the term group. Kidneys from the preterm mice also had altered nephron progenitor subpopulations, early Six2 depletion, and altered Jag1 expression in the nephrogenic zone, consistent with premature differentiation of nephron progenitor cells. In conclusion, preterm birth alone was sufficient to shorten the duration of nephrogenesis and cause premature differentiation of nephron progenitor cells. These candidate genes and pathways may provide targets to improve kidney health in preterm infants.
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Affiliation(s)
- Aleksandra Cwiek
- Division of Nephrology, Department of Pediatrics, University of Virginia, Box 800386, Charlottesville, VA, 22903, USA
- Cell & Developmental Biology Graduate Program, University of Virginia School of Medicine, Charlottesville, VA, 22903, USA
| | - Masako Suzuki
- Department of Genetics, Albert Einstein College of Medicine, New York, NY, USA
| | - Kimberly deRonde
- Division of Nephrology, Department of Pediatrics, University of Virginia, Box 800386, Charlottesville, VA, 22903, USA
| | - Mark Conaway
- University of Virginia Health System, Charlottesville, VA, USA
- Division of Translational Research and Applied Statistics, Department of Public Health Sciences, University of Virginia School of Medicine, University of Virginia, Charlottesville, VA, USA
| | - Kevin M Bennett
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA
| | - Samir El Dahr
- Department of Pediatrics, Tulane University School of Medicine and Children's Hospital of New Orleans, New Orleans, LA, USA
| | - Kimberly J Reidy
- Division of Nephrology, Department of Pediatrics, Children's Hospital at Montefiore, New York, NY, USA
| | - Jennifer R Charlton
- Division of Nephrology, Department of Pediatrics, University of Virginia, Box 800386, Charlottesville, VA, 22903, USA.
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RXR – centralny regulator wielu ścieżek sygnałowych w organizmie. POSTEP HIG MED DOSW 2021. [DOI: 10.2478/ahem-2021-0005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Abstrakt
Receptory jądrowe (NRs) tworzą największą nadrodzinę czynników transkrypcyjnych, które odgrywają ważną rolę w regulacji wielu procesów biologicznych. Receptor kwasu 9-cis-retinowego (RXR) wydaje się odgrywać szczególną rolę wśród tej grupy białek, a to ma związek z jego zdolnością do tworzenia dimerów z innymi NRs. Ze względu na kontrolę ekspresji wielu genów, RXR stanowi bardzo dobry cel licznych terapii. Nieprawidłowości w szlakach modulowanych przez RXR są powiązane m.in. z chorobami neurodegeneracyjnymi, otyłością, cukrzycą, a także nowotworami. Istnieje wiele związków mogących regulować aktywność transkrypcyjną RXR. Jednak obecnie dopuszczonych do użytku klinicznego jest tylko kilka z nich. Retinoidy normalizują wzrost i różnicowanie komórek skóry i błon śluzowych, ponadto działają immunomodulująco oraz przeciwzapalnie. Stąd są stosowane przede wszystkim w chorobach skóry i w terapii niektórych chorób nowotworowych. W artykule przedstawiono ogólne wiadomości na temat RXR, jego budowy, ligandów i mechanizmu działania oraz potencjalnej roli w terapii nowotworów i zespołu metabolicznego.
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Da Silva F, Jian Motamedi F, Weerasinghe Arachchige LC, Tison A, Bradford ST, Lefebvre J, Dolle P, Ghyselinck NB, Wagner KD, Schedl A. Retinoic acid signaling is directly activated in cardiomyocytes and protects mouse hearts from apoptosis after myocardial infarction. eLife 2021; 10:68280. [PMID: 34623260 PMCID: PMC8530512 DOI: 10.7554/elife.68280] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 10/07/2021] [Indexed: 12/22/2022] Open
Abstract
Retinoic acid (RA) is an essential signaling molecule for cardiac development and plays a protective role in the heart after myocardial infarction (MI). In both cases, the effect of RA signaling on cardiomyocytes, the principle cell type of the heart, has been reported to be indirect. Here we have developed an inducible murine transgenic RA-reporter line using CreERT2 technology that permits lineage tracing of RA-responsive cells and faithfully recapitulates endogenous RA activity in multiple organs during embryonic development. Strikingly, we have observed a direct RA response in cardiomyocytes during mid-late gestation and after MI. Ablation of RA signaling through deletion of the Aldh1a1/a2/a3 genes encoding RA-synthesizing enzymes leads to increased cardiomyocyte apoptosis in adults subjected to MI. RNA sequencing analysis reveals Tgm2 and Ace1, two genes with well-established links to cardiac repair, as potential targets of RA signaling in primary cardiomyocytes, thereby providing novel links between the RA pathway and heart disease.
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Affiliation(s)
| | | | | | - Amelie Tison
- Université Côte d'Azur, Inserm, CNRS, iBV, Nice, France
| | | | | | - Pascal Dolle
- IGBMC, Inserm U1258, UNISTRA CNRS, Illkirch, France
| | | | - Kay D Wagner
- Université Côte d'Azur, Inserm, CNRS, iBV, Nice, France
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Abstract
While the uses of retinoids for cancer treatment continue to evolve, this review focuses on other therapeutic areas in which retinoids [retinol (vitamin A), all-trans retinoic acid (RA), and synthetic retinoic acid receptor (RAR)α-, β-, and γ-selective agonists] are being used and on promising new research that suggests additional uses for retinoids for the treatment of disorders of the kidneys, skeletal muscles, heart, pancreas, liver, nervous system, skin, and other organs. The most mature area, in terms of US Food and Drug Administration-approved, RAR-selective agonists, is for treatment of various skin diseases. Synthetic retinoid agonists have major advantages over endogenous RAR agonists such as RA. Because they act through a specific RAR, side effects may be minimized, and synthetic retinoids often have better pharmaceutical properties than does RA. Based on our increasing knowledge of the multiple roles of retinoids in development, epigenetic regulation, and tissue repair, other exciting therapeutic areas are emerging. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Lorraine J Gudas
- Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA;
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Retinoid X Receptor α Regulates DHA-Dependent Spinogenesis and Functional Synapse Formation In Vivo. Cell Rep 2021; 31:107649. [PMID: 32433958 DOI: 10.1016/j.celrep.2020.107649] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Revised: 02/01/2020] [Accepted: 04/22/2020] [Indexed: 12/23/2022] Open
Abstract
Coordinated intracellular and extracellular signaling is critical to synapse development and functional neural circuit wiring. Here, we report that unesterified docosahexaenoic acid (DHA) regulates functional synapse formation in vivo via retinoid X receptor α (Rxra) signaling. Using Rxra conditional knockout (cKO) mice and virus-mediated transient gene expression, we show that endogenous Rxra plays important roles in regulating spinogenesis and excitatory synaptic transmission in cortical pyramidal neurons. We further show that the effects of RXRA are mediated through its DNA-binding domain in a cell-autonomous and reversible manner. Moreover, unesterified DHA increases spine formation and excitatory synaptic transmission in vivo in an Rxra-dependent fashion. Rxra cKO mice generally behave normally but show deficits in behavior tasks associated with social memory. Together, these results demonstrate that unesterified DHA signals through RXRA to regulate spinogenesis and functional synapse formation, providing insight into the mechanism through which DHA promotes brain development and cognitive function.
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Ozgun G, Senturk S, Erkek-Ozhan S. Retinoic acid signaling and bladder cancer: Epigenetic deregulation, therapy and beyond. Int J Cancer 2021; 148:2364-2374. [PMID: 33128775 DOI: 10.1002/ijc.33374] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 10/10/2020] [Accepted: 10/21/2020] [Indexed: 12/13/2022]
Abstract
Retinoic acid (RA) signaling is a crucial developmental pathway involved in urothelium development, differentiation and regeneration. Deregulation of the RA signaling is highly implicated in several cancers, including bladder cancer, underlying the need to unravel the complete regulatory aspects of the retinoids in bladder tumorigenesis. Given the fact that RA receptors are transcription factors functioning at the chromatin level and act in close cooperation with chromatin modifiers, it is known that retinoids show their efficacy by changing the epigenome. Bladder cancer can be defined as a "disease of chromatin" with mutations identified in the genes involved in chromatin regulation in 80% of the patients. Therefore, a careful examination of the epigenetic backgrounds and the breakdown of the emerging and highly underexplored field of RA dependent regulation of the epigenome is essential to fully understand the retinoid-dependent effects on bladder cancer. With this motivation, in this review, we evaluate the role of RA signaling in bladder cancer with a focus on the regulatory and mutational aspects, emphasizing the deregulatory characteristics in bladder cancer and highlighting the potential treatment opportunities with the RA and derivatives alone or in combination with epigenetic drugs.
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Affiliation(s)
- Gizem Ozgun
- Izmir Biomedicine and Genome Center, Izmir, Turkey
- Dokuz Eylül University Izmir International Biomedicine and Genome Institute, Izmir, Turkey
| | - Serif Senturk
- Izmir Biomedicine and Genome Center, Izmir, Turkey
- Dokuz Eylül University Izmir International Biomedicine and Genome Institute, Izmir, Turkey
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Fang M, Li Y, Ren J, Hu R, Gao X, Chen L. Epilepsy-Associated UBE3A Deficiency Downregulates Retinoic Acid Signalling Pathway. Front Genet 2021; 12:681295. [PMID: 33995501 PMCID: PMC8113777 DOI: 10.3389/fgene.2021.681295] [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: 03/16/2021] [Accepted: 03/29/2021] [Indexed: 01/11/2023] Open
Abstract
Ubiquitin-protein ligase E3A (UBE3A) has dual functions as a E3 ubiquitin-protein ligase and coactivator of nuclear hormone receptors. Mutations or deletions of the maternally inherited UBE3A gene cause Angelman syndrome. Here, we performed transcriptome profiling in the hippocampus of Ube3am+/p+ and Ube3am–/p+ mice, and determined that the expression of the retinoic acid (RA) signalling pathway was downregulated in Ube3a-deficient mice compared to WT mice. Furthermore, we demonstrated that UBE3A directly interacts with RARα and may function as a coactivator of the nuclear receptor RARα to participate in the regulation of gene expression. Loss of UBE3A expression caused the downregulation of the expression of RA-related genes, including Erbb4, Dpysl3, Calb1, Pten, and Arhgap5 in Ube3am–/p+ mice brain tissues. This work revealed a new role for UBE3A in regulating retinoic acid (RA) signalling downstream genes and hopefully to shed light on the potential drug target of AS.
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Affiliation(s)
- Meimiao Fang
- School of Medicine, Guizhou University, Guiyang, China
| | - Yali Li
- State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Jin Ren
- School of Medicine, Guizhou University, Guiyang, China
| | - Ronggui Hu
- School of Medicine, Guizhou University, Guiyang, China.,State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Xiaobo Gao
- Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
| | - Liang Chen
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
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Shojaeian A, Mehri-Ghahfarrokhi A, Banitalebi-Dehkordi M. Monophosphoryl Lipid A and Retinoic Acid Combinations Increased Germ Cell Differentiation Markers Expression in Human Umbilical Cord-derived Mesenchymal Stromal Cells in an In vitro Ovine Acellular Testis Scaffold. INTERNATIONAL JOURNAL OF MOLECULAR AND CELLULAR MEDICINE 2021; 9:288-296. [PMID: 33688486 PMCID: PMC7936076 DOI: 10.22088/ijmcm.bums.9.4.288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 01/17/2021] [Indexed: 11/22/2022]
Abstract
Infertility is known as one of the most common problems among couples. In this regard, generation of male germ cells from adult stem ones are among the current promising priorities of researchers. Mesenchymal stromal cells (MSCs) were previously induced to differentiate into germ-like progenitors in vitro. Monophosphoryl lipid A (MPLA) is a detoxified derivative of lipopolysaccharides (LPS) that lacks many of the endotoxic properties of LPS. Our present study aimed to investigate the expression of migration genes (CXCR4, VCAM1, VEGF, MMP2, and VLA4), and differentiation markers during human umbilical mesenchymal stromal cells (hUMSCs) culture in the presence of retinoic acid (RA) and MPLA-treated acellular testis. Accordingly, the high expression levels of deleted in azoospermia-like (DAZL), piwi-like RNA-mediated gene silencing 2 (PIWIL2) transcripts as well as protein were consequently observed in treated hUMSCs. It was concluded that combination treatment (i.e., MPLA/RA) had more prominent results than each of the treatments alone, even though MPLA and RA could be regarded as inducer of migration and differentiation, respectively. Ultimately, it was suggested to introduce the use of combination treatment as a more effective strategy to improve therapies in regenerative medicine.
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Affiliation(s)
- Ali Shojaeian
- Department of Molecular Medicine, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Ameneh Mehri-Ghahfarrokhi
- Department of Molecular Medicine, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mehdi Banitalebi-Dehkordi
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
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Feng CW, Burnet G, Spiller CM, Cheung FKM, Chawengsaksophak K, Koopman P, Bowles J. Identification of regulatory elements required for Stra8 expression in fetal ovarian germ cells of the mouse. Development 2021; 148:dev.194977. [PMID: 33574039 DOI: 10.1242/dev.194977] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 02/04/2021] [Indexed: 12/14/2022]
Abstract
In mice, the entry of germ cells into meiosis crucially depends on the expression of stimulated by retinoic acid gene 8 (Stra8). Stra8 is expressed specifically in pre-meiotic germ cells of females and males, at fetal and postnatal stages, respectively, but the mechanistic details of its spatiotemporal regulation are yet to be defined. In particular, there has been considerable debate regarding whether retinoic acid is required, in vivo, to initiate Stra8 expression in the mouse fetal ovary. We show that the distinctive anterior-to-posterior pattern of Stra8 initiation, characteristic of germ cells in the fetal ovary, is faithfully recapitulated when 2.9 kb of the Stra8 promoter is used to drive eGFP expression. Using in vitro transfection assays of cutdown and mutant constructs, we identified two functional retinoic acid responsive elements (RAREs) within this 2.9 kb regulatory element. We also show that the transcription factor DMRT1 enhances Stra8 expression, but only in the presence of RA and the most proximal RARE. Finally, we used CRISPR/Cas9-mediated targeted mutation studies to demonstrate that both RAREs are required for optimal Stra8 expression levels in vivo.
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Affiliation(s)
- Chun-Wei Feng
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia.,Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Guillaume Burnet
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Cassy M Spiller
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia.,Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Fiona Ka Man Cheung
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Kallayanee Chawengsaksophak
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.,Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i. Vídenská 1083, 4 14220 Prague, Czech Republic
| | - Peter Koopman
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Josephine Bowles
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia .,Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
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Leal AS, Reich LA, Moerland JA, Zhang D, Liby KT. Potential therapeutic uses of rexinoids. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2021; 91:141-183. [PMID: 34099107 DOI: 10.1016/bs.apha.2021.01.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The discovery of nuclear receptors, particularly retinoid X receptors (RXR), and their involvement in numerous pathways related to development sparked interest in their immunomodulatory properties. Genetic models using deletion or overexpression of RXR and the subsequent development of several small molecules that are agonists or antagonists of this receptor support a promising therapeutic role for these receptors in immunology. Bexarotene was approved in 1999 for the treatment of cutaneous T cell lymphoma. Several other small molecule RXR agonists have since been synthesized with limited preclinical development, but none have yet achieved FDA approval. Cancer treatment has recently been revolutionized with the introduction of immune checkpoint inhibitors, but their success has been restricted to a minority of patients. This review showcases the emerging immunomodulatory effects of RXR and the potential of small molecules that target this receptor as therapies for cancer and other diseases. Here we describe the essential roles that RXR and partner receptors play in T cells, dendritic cells, macrophages and epithelial cells, especially within the tumor microenvironment. Most of these effects are site and cancer type dependent but skew immune cells toward an anti-inflammatory and anti-tumor effect. This beneficial effect on immune cells supports the promise of combining rexinoids with approved checkpoint blockade therapies in order to enhance efficacy of the latter and to delay or potentially eliminate drug resistance. The data compiled in this review strongly suggest that targeting RXR nuclear receptors is a promising new avenue in immunomodulation for cancer and other chronic inflammatory diseases.
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Affiliation(s)
- Ana S Leal
- Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI, United States
| | - Lyndsey A Reich
- Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI, United States
| | - Jessica A Moerland
- Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI, United States
| | - Di Zhang
- Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI, United States
| | - Karen T Liby
- Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI, United States.
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Structural Insights into the Interaction of the Intrinsically Disordered Co-activator TIF2 with Retinoic Acid Receptor Heterodimer (RXR/RAR). J Mol Biol 2021; 433:166899. [PMID: 33647291 DOI: 10.1016/j.jmb.2021.166899] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 02/02/2021] [Accepted: 02/22/2021] [Indexed: 12/19/2022]
Abstract
Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) form heterodimers that activate target gene transcription by recruiting co-activator complexes in response to ligand binding. The nuclear receptor (NR) co-activator TIF2 mediates this recruitment by interacting with the ligand-binding domain (LBD) of NRs trough the nuclear receptor interaction domain (TIF2NRID) containing three highly conserved α-helical LxxLL motifs (NR-boxes). The precise binding mode of this domain to RXR/RAR is not clear due to the disordered nature of TIF2. Here we present the structural characterization of TIF2NRID by integrating several experimental (NMR, SAXS, Far-UV CD, SEC-MALS) and computational data. Collectively, the data are in agreement with a largely disordered protein with partially structured regions, including the NR-boxes and their flanking regions, which are evolutionary conserved. NMR and X-ray crystallographic data on TIF2NRID in complex with RXR/RAR reveal a multisite binding of the three NR-boxes as well as an active role of their flanking regions in the interaction.
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Zhou H, Chen Y, Hu Y, Gao S, Lu W, He Y. Administration of All-Trans Retinoic Acid to Pregnant Sows Improves the Developmental Defects of Hoxa1 -/- Fetal Pigs. Front Vet Sci 2021; 7:618660. [PMID: 33506002 PMCID: PMC7829359 DOI: 10.3389/fvets.2020.618660] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Accepted: 12/09/2020] [Indexed: 12/16/2022] Open
Abstract
Hoxa1 mutation adversely affect fetal pig development, but whether all-trans retinoic acid (ATRA) administration to Hoxa1+/− pregnant sows can improve Hoxa1−/− fetal pig development defects has not been reported. A total of 24 healthy Hoxa1+/− sows were mated with a healthy Hoxa1+/− boar and randomly assigned to one control group and nine experiment groups. ATRA was orally administered to pregnant sows at the doses of 0, 4, 5, or 6 mg/kg maternal body weight on 12, 13, and 14 days post coitum (dpc), respectively, and a total of 146 live piglets were delivered including 37 Hoxa1−/− piglets and 109 non-Hoxa1−/− piglets. Results indicated that Hoxa1−/− piglets delivered by sows in control group had bilateral microtia, canal atresia and ear's internal defects, and had lower birth liveweight and external ear score than non-Hoxa1−/− neonatal piglets (P < 0.05). Maternal administration with ATRA can effectively correct the development defects of Hoxa1−/− fetal pigs, Hoxa1−/− neonatal piglets delivered by sows administered ATRA at a dose of 4 mg/kg body weight on 14 dpc had higher birth liveweight (P > 0.05) and higher scores of external ear (P < 0.05) compared to Hoxa1−/− neonatal piglets from the control group, but had no significantly difference in terms of birth liveweight and external ear integrity than non-Hoxa1−/− piglets from the control group (P > 0.05). The time of ATRA administration significantly affected Hoxa1−/− fetal development (P < 0.05). Administration of ATRA to Hoxa1+/− pregnant sows at 4 mg/kg body weight on 14 dpc can effectively improve the birth liveweight and ear defects of Hoxa1−/− piglets.
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Affiliation(s)
- Haimei Zhou
- Jiangxi Province Key Laboratory of Animal Nutrition/Engineering Research Center of Feed Development, Jiangxi Agricultural University, Nanchang, China.,Department of Animal Science, Jiangxi Agricultural Engineering College, Zhangshu, China
| | - Yixin Chen
- Jiangxi Province Key Laboratory of Animal Nutrition/Engineering Research Center of Feed Development, Jiangxi Agricultural University, Nanchang, China
| | - Yongqiang Hu
- Jiangxi Province Key Laboratory of Animal Nutrition/Engineering Research Center of Feed Development, Jiangxi Agricultural University, Nanchang, China
| | - Shan Gao
- Jiangxi Province Key Laboratory of Animal Nutrition/Engineering Research Center of Feed Development, Jiangxi Agricultural University, Nanchang, China
| | - Wei Lu
- Jiangxi Province Key Laboratory of Animal Nutrition/Engineering Research Center of Feed Development, Jiangxi Agricultural University, Nanchang, China
| | - Yuyong He
- Jiangxi Province Key Laboratory of Animal Nutrition/Engineering Research Center of Feed Development, Jiangxi Agricultural University, Nanchang, China
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49
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Friesen L, Gu B, Kim C. A ligand-independent fast function of RARα promotes exit from metabolic quiescence upon T cell activation and controls T cell differentiation. Mucosal Immunol 2021; 14:100-112. [PMID: 32518366 PMCID: PMC7725911 DOI: 10.1038/s41385-020-0311-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 04/22/2020] [Accepted: 05/20/2020] [Indexed: 02/04/2023]
Abstract
Vitamin A metabolites play important roles in T cell activation and differentiation. A conventional model of RARα function relies upon retinoic acid (RA)-liganded RARα binding to specific DNA motifs to regulate gene expression in the nucleus. However, this genomic function fails to explain many of the biological responses of the RA-RARα axis on T cells. We generated a mouse line where RARα is over-expressed in T cells to probe RARα function with unprecedented sensitivity. Using this model together with mice specifically lacking RARα in T cells, we found that RARα is required for prompt exit from metabolic quiescence in resting T cells upon T cell activation. The positive effect of RARα on metabolism is mediated through PI3K and subsequent activation of the Akt and mTOR signaling pathway. This largely non-genomic function of RARα is surprisingly ligand-independent and controls the differentiation of effector and regulatory T cell subsets.
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Affiliation(s)
- L.R. Friesen
- Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109,Mary H. Weiser Food Allergy Center, University of Michigan School of Medicine, Ann Arbor, MI 48109
| | - B. Gu
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47906
| | - C.H. Kim
- Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109,Mary H. Weiser Food Allergy Center, University of Michigan School of Medicine, Ann Arbor, MI 48109,Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI 48109
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50
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Knudsen TB, Pierro JD, Baker NC. Retinoid signaling in skeletal development: Scoping the system for predictive toxicology. Reprod Toxicol 2021; 99:109-130. [PMID: 33202217 PMCID: PMC11451096 DOI: 10.1016/j.reprotox.2020.10.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 10/15/2020] [Accepted: 10/27/2020] [Indexed: 02/06/2023]
Abstract
All-trans retinoic acid (ATRA), the biologically active form of vitamin A, is instrumental in regulating the patterning and specification of the vertebrate embryo. Various animal models demonstrate adverse developmental phenotypes following experimental retinoid depletion or excess during pregnancy. Windows of vulnerability for altered skeletal patterning coincide with early specification of the body plan (gastrulation) and regional specification of precursor cell populations forming the facial skeleton (cranial neural crest), vertebral column (somites), and limbs (lateral plate mesoderm) during organogenesis. A common theme in physiological roles of ATRA signaling is mutual antagonism with FGF signaling. Consequences of genetic errors or environmental disruption of retinoid signaling include stage- and region-specific homeotic transformations to severe deficiencies for various skeletal elements. This review derives from an annex in Detailed Review Paper (DRP) of the OECD Test Guidelines Programme (Project 4.97) to support recommendations regarding assay development for the retinoid system and the use of resulting data in a regulatory context for developmental and reproductive toxicity (DART) testing.
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Affiliation(s)
- Thomas B Knudsen
- Center for Computational Toxicology and Exposure (CCTE), Biomolecular and Computational Toxicology Division (BCTD), Computational Toxicology and Bioinformatics Branch (CTBB), Office of Research and Development (ORD), U.S. Environmental Protection Agency (USEPA), Research Triangle Park, NC, 27711, United States.
| | - Jocylin D Pierro
- Center for Computational Toxicology and Exposure (CCTE), Biomolecular and Computational Toxicology Division (BCTD), Computational Toxicology and Bioinformatics Branch (CTBB), Office of Research and Development (ORD), U.S. Environmental Protection Agency (USEPA), Research Triangle Park, NC, 27711, United States.
| | - Nancy C Baker
- Leidos, Contractor to CCTE, Research Triangle Park, NC, 27711, United States.
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