|
1
|
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.
Collapse
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.
| |
Collapse
|
|
2
|
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.
Collapse
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.
| |
Collapse
|
|
3
|
Garattini SK, Basile D, De Re V, Brisotto G, Miolo G, Canzonieri V, Aprile G, Corvaja C, Buriolla S, Garattini E, Puglisi F. The potential of retinoic acid receptors as prognostic biomarkers and therapeutic targets in gastric cancer. Front Oncol 2024; 14:1453934. [PMID: 39323992 PMCID: PMC11422079 DOI: 10.3389/fonc.2024.1453934] [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: 06/24/2024] [Accepted: 08/06/2024] [Indexed: 09/27/2024] Open
Abstract
Background Gastric cancer is a heterogeneous collection of tumors characterized by low survival rates. All-trans retinoic acid (retinoic-acid) is a clinically useful therapeutic agent belonging to the chemical family of retinoids, which consists of both natural and synthetic derivatives of vitamin-A. Retinoids are essential components of the normal diet and they regulate different physiological processes. From a therapeutic point of view, retinoic-acid is the first example of clinically useful differentiating agent. Indeed, the differentiating properties of this compound have promoted the use of retinoic-acid as a standard of care in Acute-Promyelocytic-Leukemia, a rare form of acute myeloid leukemia. In this study, we determine the RNA expression of the six isoforms of Retinoic-Acid-Receptors (RARα/RARβ/RARγ/RXRα/RXRβ/RXRγ) in view of their potential use as gastric cancer progression markers and/or therapeutic targets. In addition, we evaluate associations between the expression of these receptors and a simplified molecular classification of stomach tumors as well as the clinical characteristics of the cohort of patients analyzed. Finally, we define the prognostic value of the various Retinoic-Acid-Receptors in gastric cancer. Methods In this single institution and retrospective RAR-GASTRIC study, we consider 55 consecutive gastric cancer patients. We extract total RNA from the pathological specimens and we perform a NanoString Assay using a customized panel of genes. This allows us to determine the expression levels of the RAR and RXR mRNAs as well as other transcripts of interest. Results Our data demonstrate ubiquitous expression of the RAR and RXR mRNAs in gastric cancers. High levels of RARα, RARβ, RXRα and RXRβ show a significant association with stage IV tumors, "de novo" metastatic disease, microsatellite-stable-status, epithelial-to-mesenchymal-transition, as well as PIK3CA and TP53 expression. Finally, we observe a worse overall-survival in gastric cancer patients characterized by high RARα/RARβ/RARγ/RXRβ mRNA levels. Conclusions In gastric cancer, high expression levels of RARα/RARβ/RARγ/RXRβ transcripts are associated with poor clinical and molecular characteristics as well as with reduced overall-survival. Our data are consistent with the idea that RARα, RARβ, RARγ and RXRβ represent potential prognostic markers and therapeutic targets of gastric cancer.
Collapse
Affiliation(s)
| | - Debora Basile
- Department of Medical Oncology, San Giovanni di Dio Hospital, Crotone, Italy
| | - Valli' De Re
- Immunopathology and Cancer Biomarkers/Bio-Proteomics Facility, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy
| | - Giulia Brisotto
- Immunopathology and Cancer Biomarkers/Bio-Proteomics Facility, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy
| | - Gianmaria Miolo
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Vincenzo Canzonieri
- Pathology Unit, IRCCS CRO National Cancer Institute, Aviano, Italy
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Giuseppe Aprile
- Department of Oncology, University and General Hospital, Udine, Italy
- Department of Oncology, San Bortolo General Hospital, Vicenza, Italy
| | - Carla Corvaja
- Division of Thoracic Oncology, European Institute of Oncology (IEO) IRCCS, Milano, Italy
| | - Silvia Buriolla
- Department of Oncology, ASUFC University Hospital, Udine, Italy
| | - Enrico Garattini
- Department of Biochemistry and Molecular Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy
| | - Fabio Puglisi
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
- Departiment of Medicine, University of Udine, Udine, Italy
| |
Collapse
|
|
4
|
Zhong R, Guo Y, Huang J, Yang Y, Ren S, Gu Y, Lei P, Gao Z. Insights into preeclampsia: a bioinformatics approach to deciphering genetic and immune contributions. Front Genet 2024; 15:1372164. [PMID: 39165753 PMCID: PMC11333266 DOI: 10.3389/fgene.2024.1372164] [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: 01/17/2024] [Accepted: 06/14/2024] [Indexed: 08/22/2024] Open
Abstract
Background Preeclampsia (PE) is a global pregnancy concern, characterized by hypertension with an unclear etiology. This study employs Mendelian randomization (MR) and single-cell RNA sequencing (scRNA-seq) to clarify its genetic and molecular roots, offering insights into diagnosis and treatment avenues. Methods We integrated PE-specific genome-wide association study (GWAS) data, expression and protein quantitative trait loci (eQTL and pQTL) data, and single-cell data from peripheral blood mononuclear cells (PBMCs). We identified highly variable genes using single-cell information and employed MR to determine potential causality. We also combined pQTL and GWAS data, discerned genes positively associated with PE through scRNA-seq, and leveraged the Enrichr platform to unearth drug-gene interactions. Results Our scRNA-seq pinpointed notable cell type distribution variances, especially in T helper cells (Th cells), between PE and control groups. We unveiled 591 highly variable genes and 6 directly PE-associated genes. Although MR revealed correlations with PE risk, pQTL analysis was inconclusive due to data constraints. Using DSigDB, 93 potential therapeutic agents, like Retinoic acid targeting core genes (IFITM3, NINJ1, COTL1, CD69, and YWHAZ), emerged as prospective multi-target treatments. Conclusion Utilizing MR and scRNA-seq, this study underscores significant cellular disparities, particularly in Th cells, and identifies crucial genes related to PE. Despite some limitations, these genes have been revealed in PE's underlying mechanism. Potential therapeutic agents, such as Retinoic acid, suggest promising treatment pathways.
Collapse
Affiliation(s)
- Rongrong Zhong
- Deparment of Geriatrics, Tianjin Medical University General Hospital, Tianjin, China
| | - Yifen Guo
- Department of Family Planning, The Second Hospital of Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Risk Assessment and Control Technology for Environment and Food Safety, Tianjin Institute of Environmental and Operational Medicine, Tianjin, China
| | - Jianxing Huang
- Medical Imaging and Nuclear Medicine, Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Yingao Yang
- Tianjin Key Laboratory of Risk Assessment and Control Technology for Environment and Food Safety, Tianjin Institute of Environmental and Operational Medicine, Tianjin, China
| | - Shuyue Ren
- Tianjin Key Laboratory of Risk Assessment and Control Technology for Environment and Food Safety, Tianjin Institute of Environmental and Operational Medicine, Tianjin, China
| | - Yan Gu
- Department of Family Planning, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Ping Lei
- Deparment of Geriatrics, Tianjin Medical University General Hospital, Tianjin, China
| | - Zhixian Gao
- Tianjin Key Laboratory of Risk Assessment and Control Technology for Environment and Food Safety, Tianjin Institute of Environmental and Operational Medicine, Tianjin, China
| |
Collapse
|
|
5
|
Stelloo S, Alejo-Vinogradova MT, van Gelder CAGH, Zijlmans DW, van Oostrom MJ, Valverde JM, Lamers LA, Rus T, Sobrevals Alcaraz P, Schäfers T, Furlan C, Jansen PWTC, Baltissen MPA, Sonnen KF, Burgering B, Altelaar MAFM, Vos HR, Vermeulen M. Deciphering lineage specification during early embryogenesis in mouse gastruloids using multilayered proteomics. Cell Stem Cell 2024; 31:1072-1090.e8. [PMID: 38754429 DOI: 10.1016/j.stem.2024.04.017] [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: 04/24/2023] [Revised: 01/10/2024] [Accepted: 04/19/2024] [Indexed: 05/18/2024]
Abstract
Gastrulation is a critical stage in embryonic development during which the germ layers are established. Advances in sequencing technologies led to the identification of gene regulatory programs that control the emergence of the germ layers and their derivatives. However, proteome-based studies of early mammalian development are scarce. To overcome this, we utilized gastruloids and a multilayered mass spectrometry-based proteomics approach to investigate the global dynamics of (phospho) protein expression during gastruloid differentiation. Our findings revealed many proteins with temporal expression and unique expression profiles for each germ layer, which we also validated using single-cell proteomics technology. Additionally, we profiled enhancer interaction landscapes using P300 proximity labeling, which revealed numerous gastruloid-specific transcription factors and chromatin remodelers. Subsequent degron-based perturbations combined with single-cell RNA sequencing (scRNA-seq) identified a critical role for ZEB2 in mouse and human somitogenesis. Overall, this study provides a rich resource for developmental and synthetic biology communities endeavoring to understand mammalian embryogenesis.
Collapse
Affiliation(s)
- Suzan Stelloo
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands.
| | - Maria Teresa Alejo-Vinogradova
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands
| | - Charlotte A G H van Gelder
- Molecular Cancer Research, Center for Molecular Medicine, Oncode Institute, University Medical Center Utrecht, Utrecht University, 3584 CG Utrecht, the Netherlands
| | - Dick W Zijlmans
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands
| | - Marek J van Oostrom
- Hubrecht Institute, KNAW (Royal Netherlands Academy of Arts and Sciences), University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands
| | - Juan Manuel Valverde
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CA Utrecht, the Netherlands; Netherlands Proteomics Center, 3584 CH Utrecht, the Netherlands
| | - Lieke A Lamers
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands
| | - Teja Rus
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands
| | - Paula Sobrevals Alcaraz
- Molecular Cancer Research, Center for Molecular Medicine, Oncode Institute, University Medical Center Utrecht, Utrecht University, 3584 CG Utrecht, the Netherlands
| | - Tilman Schäfers
- Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands
| | - Cristina Furlan
- Laboratory of Systems and Synthetic Biology, Wageningen University & Research, 6708 WE Wageningen, the Netherlands
| | - Pascal W T C Jansen
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands
| | - Marijke P A Baltissen
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands
| | - Katharina F Sonnen
- Hubrecht Institute, KNAW (Royal Netherlands Academy of Arts and Sciences), University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands
| | - Boudewijn Burgering
- Molecular Cancer Research, Center for Molecular Medicine, Oncode Institute, University Medical Center Utrecht, Utrecht University, 3584 CG Utrecht, the Netherlands
| | - Maarten A F M Altelaar
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CA Utrecht, the Netherlands; Netherlands Proteomics Center, 3584 CH Utrecht, the Netherlands
| | - Harmjan R Vos
- Molecular Cancer Research, Center for Molecular Medicine, Oncode Institute, University Medical Center Utrecht, Utrecht University, 3584 CG Utrecht, the Netherlands
| | - Michiel Vermeulen
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands; Division of Molecular Genetics, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
| |
Collapse
|
|
6
|
Vieiros M, Navarro-Tapia E, Ramos-Triguero A, García-Meseguer À, Martínez L, García-Algar Ó, Andreu-Fernández V. Analysis of alcohol-metabolizing enzymes genetic variants and RAR/RXR expression in patients diagnosed with fetal alcohol syndrome: a case-control study. BMC Genomics 2024; 25:610. [PMID: 38886650 PMCID: PMC11184718 DOI: 10.1186/s12864-024-10516-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 06/11/2024] [Indexed: 06/20/2024] Open
Abstract
Understanding the mechanisms underlying alcohol metabolism and its regulation, including the effect of polymorphisms in alcohol-metabolizing enzymes, is crucial for research on Fetal Alcohol Spectrum Disorders. The aim of this study was to identify specific single nucleotide polymorphisms in key alcohol-metabolizing enzymes in a cohort of 71 children, including children with fetal alcohol syndrome, children prenatally exposed to ethanol but without fetal alcohol spectrum disorder, and controls. We hypothesized that certain genetic variants related to alcohol metabolism may be fixed in these populations, giving them a particular alcohol metabolism profile. In addition, the difference in certain isoforms of these enzymes determines their affinity for alcohol, which also affects the metabolism of retinoic acid, which is key to the proper development of the central nervous system. Our results showed that children prenatally exposed to ethanol without fetal alcohol spectrum disorder traits had a higher frequency of the ADH1B*3 and ADH1C*1 alleles, which are associated with increased alcohol metabolism and therefore a protective factor against circulating alcohol in the fetus after maternal drinking, compared to FAS children who had an allele with a lower affinity for alcohol. This study also revealed the presence of an ADH4 variant in the FAS population that binds weakly to the teratogen, allowing increased circulation of the toxic agent and direct induction of developmental abnormalities in the fetus. However, both groups showed dysregulation in the expression of genes related to the retinoic acid pathway, such as retinoic acid receptor and retinoid X receptor, which are involved in the development, regeneration, and maintenance of the nervous system. These findings highlight the importance of understanding the interplay between alcohol metabolism, the retinoic acid pathway and genetic factors in the development of fetal alcohol syndrome.
Collapse
Affiliation(s)
- Melina Vieiros
- Grup de Recerca Infància i Entorn (GRIE), Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- IdiPAZ - Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain
- Department de Cirurgia i Especialitats Mèdico-Quirúrgiques, Universitat de Barcelona, Barcelona, Spain
| | - Elisabet Navarro-Tapia
- IdiPAZ - Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain.
- Faculty of Health Sciences, Valencian International University, Valencia, Spain.
| | - Anna Ramos-Triguero
- Grup de Recerca Infància i Entorn (GRIE), Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Àgueda García-Meseguer
- Grup de Recerca Infància i Entorn (GRIE), Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Leopoldo Martínez
- IdiPAZ - Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain
- Department of Pediatric Surgery, Hospital Universitario La Paz, Madrid, Spain
| | - Óscar García-Algar
- Grup de Recerca Infància i Entorn (GRIE), Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Department of Neonatology, Hospital Clínic-Maternitat, ICGON, BCNatal, Barcelona, Spain
| | - Vicente Andreu-Fernández
- Grup de Recerca Infància i Entorn (GRIE), Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
- Biosanitary Research Institute, Valencian International University, Valencia, Spain.
| |
Collapse
|
|
7
|
Jan N, Sofi S, Abo Mansoor A, Abdelrahim A, Ahmad I, Almilabairy A, Ahmad F, Mir MA. Exploring the role of trifarotene against RAR-α: an investigation of expression pattern and clinicopathological significance of RAR-α in breast cancer. Front Pharmacol 2024; 15:1361679. [PMID: 38910889 PMCID: PMC11190336 DOI: 10.3389/fphar.2024.1361679] [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: 12/26/2023] [Accepted: 05/06/2024] [Indexed: 06/25/2024] Open
Abstract
Introduction The members retinoic acid receptors (RARs) (α, β, and γ) and retinoid X receptors (RXRs) (α, β, and γ) belong to the retinoid receptor family. They regulate the biological action of classical retinoids through nuclear retinoid receptors, a transcription factor that is regulated by ligands. Through the binding of particular retinoic acid-responsive elements (RAREs) located in target gene promoters, RARs and members of the RXRs form heterodimers. By binding to its nuclear receptors and triggering the transcription of the target genes downstream, retinoic acid (RA) mediates the expression of certain genes. Retinoids so mainly control gene expression to carry out their biological actions. RARs are essential for many biological processes, such as development, immunity, reproduction, organogenesis, and homeostasis. Apart from their physiological functions, RARs are also linked to pathologies and tumors due to mutations, protein fusions, changes in expression levels, or abnormal post-translational changes that lead to aberrant functions and homeostasis breakdown. The oncogenic development of animal tissues or cultured cells is linked to altered expression of retinoid receptors. The RAR-α is over-expressed in several malignancies. Increased invasion and migration in several cancer forms, including HNSC carcinoma, pediatric low-grade gliomas, lung adenocarcinoma, and breast cancer, have been linked to its upregulated expression. Numerous approved therapeutic regimens targeting RAR-α have been developed, improving patient survival rates. Objective This study's main objective was to identify novel RAR-α-targeting drugs and evaluate the expression patterns of RAR-α in breast cancer patients. Methodology In-silico investigation using a variety of bioinformatics tools like UALCAN, TISCH, TIMER 2.0, ENRICHR, and others were employed to examine the expression of RAR-α. Further we evaluated in-silico inhibition of RAR-α with trifarotene and also tested the cytotoxicity of trifarotene in breast cancer cells. Results Our research indicates that RAR-α is upregulated in several malignancies including Breast Cancer. It regulates granulocyte differentiation and has an association with the retinoic acid receptor signaling pathway and cellular response to estrogen stimulus. Furthermore, trifarotene was found as a potential synthetic compound that targets RAR-α through in silico and in-vitro study. Discussion Overall, this research indicates that elevated expression of RAR-α enhances the onset of breast cancer. Using trifarotene medication to target RAR-α will significantly boost the response of breast cancer individuals to treatment and delay the development of resistance to drugs.
Collapse
Affiliation(s)
- Nusrat Jan
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, India
| | - Shazia Sofi
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, India
| | - Adel Abo Mansoor
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences (CAMS), King Khalid University, Abha, Saudi Arabia
| | - Adil Abdelrahim
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences (CAMS), King Khalid University, Abha, Saudi Arabia
| | - Irshad Ahmad
- Department of Medical Rehabilitation Sciences, College of Applied Medical Sciences (CAMS), King Khalid University, Abha, Saudi Arabia
| | - Abdullah Almilabairy
- Department of Family and Community Medicine, Faculty of Medicine, Al Baha University, Al Baha, Saudi Arabia
| | - Fuzail Ahmad
- College of Applied Sciences Almaarefa University, Riyadh, Saudi Arabia
| | - Manzoor Ahmad Mir
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, India
| |
Collapse
|
|
8
|
Replogle MR, Thompson S, Reis LM, Semina EV. A De Novo Noncoding RARB Variant Associated with Complex Microphthalmia Alters a Putative Regulatory Element. Hum Mutat 2024; 2024:6619280. [PMID: 39450403 PMCID: PMC11501074 DOI: 10.1155/2024/6619280] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2024]
Abstract
Retinoic acid receptor beta (RARB) is a transcriptional regulator crucial for coordinating retinoic acid- (RA-) mediated morphogenic movements, cell growth, and differentiation during eye development. Loss- or gain-of-function RARB coding variants have been associated with microphthalmia, coloboma, and anterior segment defects. We identified a de novo variant c.157+1895G>A located within a conserved region (CR1) in the first intron of RARB in an individual with complex microphthalmia and significant global developmental delay. Based on the phenotypic overlap, we further investigated the possible effects of the variant on mRNA splicing and/or transcriptional regulation through in silico and functional studies. In silico analysis identified the possibility of alternative splicing, suggested by one out of three (HSF, SpliceAI, and MaxEntScan) splicing prediction programs, and a strong indication of regulatory function based on publicly available DNase hypersensitivity, histone modification, chromatin folding, and ChIP-seq data sets. Consistent with the predictions of SpliceAI and MaxEntScan, in vitro minigene assays showed no effect on RARB mRNA splicing. Evaluation of CR1 for a regulatory role using luciferase reporter assays in human lens epithelial cells demonstrated a significant increase in the activity of the RARB promoter in the presence of wild-type CR1. This activity was further significantly increased in the presence of CR1 carrying the c.157+1895G>A variant, suggesting that the variant may promote RARB overexpression in human cells. Induction of RARB overexpression in human lens epithelial cells resulted in increased cell proliferation and elevated expression of FOXC1, a known downstream target of RA signaling and a transcription factor whose down- and upregulation is associated with ocular phenotypes overlapping the RARB spectrum. These results support a regulatory role for the CR1 element and suggest that the de novo c.157+1895G>A variant affecting this region may alter the proper regulation of RARB and, as a result, its downstream genes, possibly leading to abnormal development.
Collapse
Affiliation(s)
- Maria R. Replogle
- Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Samuel Thompson
- Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Linda M. Reis
- Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Elena V. Semina
- Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, WI, USA
- Department of Pediatrics and Children’s Research Institute, Medical College of Wisconsin and Children’s Hospital of Wisconsin, Milwaukee, WI, USA
| |
Collapse
|
|
9
|
Dutta S, Pal D, Rao MRS. Retinoic Acid-Mediated Differentiation of Mouse Embryonic Stem Cells to Neuronal Cells. Methods Mol Biol 2024; 2736:39-51. [PMID: 37140812 DOI: 10.1007/7651_2023_480] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
The capability of pluripotent embryonic stem cells (ESCs) to proliferate and differentiate into specific lineages makes them an important avenue of research in the field of cell therapy as well as a useful model to study patterns of differentiation and gene expression, recapitulating many events that occur during the very early stages of development of the mammalian embryo. With striking similarities that exist between inherently programmed embryonic development of the nervous system in vivo and the differentiation of ESCs in vitro, they have already been used to treat locomotive and cognitive deficits caused by brain injury in rodents. A suitable differentiation model thus empowers us with all these opportunities. In this chapter, we describe a neural differentiation model from mouse embryonic stem cells using retinoic acid as the inducer. This method is among the most commonly used one to acquire a homogeneous population of neuronal progenitor cells or mature neurons as desired. The method is scalable, efficient, and results in production of ~70% neural progenitor cells within 4-6 days.
Collapse
Affiliation(s)
- Sangeeta Dutta
- Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India
| | - Debosree Pal
- Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India
- UCL Cancer Institute, University College London, London, UK
| | - M R S Rao
- Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India.
| |
Collapse
|
|
10
|
Vo HVT, Nguyen YT, Kim N, Lee HJ. Vitamin A, D, E, and K as Matrix Metalloproteinase-2/9 Regulators That Affect Expression and Enzymatic Activity. Int J Mol Sci 2023; 24:17038. [PMID: 38069361 PMCID: PMC10707015 DOI: 10.3390/ijms242317038] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 11/25/2023] [Accepted: 11/29/2023] [Indexed: 12/18/2023] Open
Abstract
Fat-soluble vitamins (vitamin A, D, E, and K) assume a pivotal role in maintaining human homeostasis by virtue of their enzymatic functions. The daily inclusion of these vitamins is imperative to the upkeep of various physiological processes including vision, bone health, immunity, and protection against oxidative stress. Current research highlights fat-soluble vitamins as potential therapeutics for human diseases, especially cancer. Fat-soluble vitamins exert their therapeutic effects through multiple pathways, including regulation of matrix metalloproteinases' (MMPs) expression and enzymatic activity. As MMPs have been reported to be involved in the pathology of various diseases, such as cancers, cardiovascular diseases, and neurological disorders, regulating the expression and/or activity of MMPs could be considered as a potent therapeutic strategy. Here, we summarize the properties of fat-soluble vitamins and their potential as promising candidates capable of effectively modulating MMPs through multiple pathways to treat human diseases.
Collapse
Affiliation(s)
- Ha Vy Thi Vo
- Department of Chemistry Education, Kongju National University, Gongju 32588, Republic of Korea;
| | - Yen Thi Nguyen
- Department of Chemistry, Kongju National University, Gongju 32588, Republic of Korea;
| | - Namdoo Kim
- Department of Chemistry, Kongju National University, Gongju 32588, Republic of Korea;
| | - Hyuck Jin Lee
- Department of Chemistry Education, Kongju National University, Gongju 32588, Republic of Korea;
- Kongju National University Institute of Science Education, Kongju National University, Gongju 32588, Republic of Korea
- Kongju National University’s Physical Fitness for Health Research Lab (KNUPFHR), Kongju National University, Gongju 32588, Republic of Korea
| |
Collapse
|
|
11
|
Abstract
Retinoic acid (RA) is a metabolite of vitamin A and is essential for development and growth as well as cellular metabolism. Through genomic and nongenomic actions, RA regulates a variety of physiological functions. Dysregulation of RA signaling is associated with many diseases. Targeting RA signaling has been proven valuable to human health. All-trans retinoic acid (AtRA) and anthracycline-based chemotherapy are the standard treatment of acute promyelocytic leukemia (APL). Both human and animal studies have shown a significant relationship between RA signaling and the development and progression of nonalcoholic fatty liver disease (NAFLD). In this review article, we will first summarize vitamin A metabolism and then focus on the role of RA signaling in NAFLD. AtRA inhibits the development and progression of NAFLD via regulating lipid metabolism, inflammation, thermogenesis, etc.
Collapse
Affiliation(s)
- Fathima N Cassim Bawa
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA 44272
| | - Yanqiao Zhang
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA 44272
| |
Collapse
|
|
12
|
Korzekwa AJ, Kononiuk A, Kordan W, Orzołek A. Retinoic acid alters metalloproteinase action in red deer antler stem cells. PLoS One 2023; 18:e0287782. [PMID: 37428795 DOI: 10.1371/journal.pone.0287782] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 06/13/2023] [Indexed: 07/12/2023] Open
Abstract
Metalloproteinases (MMP)s regulate developmental processes, control angiogenesis and wound healing, participate in the formation of immune receptors, and are expressed in stem cells. Retinoic acid (RA) is a potential modulator of these proteinases. The aim was to determine (1) MMPs' action in antler stem cells (ASCs) before and after differentiation into adipo-, osteo-, and chondrocytes and (2) the effect of RA on modifying MMP action in ASCs. Antler tissue from pedicle was collected approximately 40 days after antler casting, post mortem from healthy breeding five year old males (N = 7). The cells were isolated from the pedicle layer of periosteum after skin separation and cultured. The pluripotency of the ASCs was evaluated by mRNA expression for NANOG, SOX2, and OCT4. ASCs were stimulated with RA (100nM) and differentiated for 14 days. The MMP (1-3) and TIMP(1-3) (tissue inhibitor of MMPs) mRNA expression was determined in the ASCs, their concentrations in the ASCs and the medium after RA stimulation as well as profiles of mRNA expression for MMPs: 1-3 and TIMPs: 1-3 during differentiation of ASC to osteocytes, adipocytes and chondrocytes. RA increased MMP-3 and TIMP-3 mRNA expression and output (P < 0.05) and not influenced on MMP-1 and TIMP-1 mRNA expression and output in ASC (P > 0.05). Depending on differentiation of ASC to osteocytes, adipocytes or chondrocytes, MMPs`and TIMPs`expression profile fluctuates for all studied proteases and its inhibitors. The studies demand continuation considering the role of proteases in stem cells physiology and differentiation. The results may be relevant for the study of cellular processes during the cancerogenesis of tumor stem cells.
Collapse
Affiliation(s)
- Anna J Korzekwa
- Department of Biodiversity Protection (DBP), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences (IAR&FR PAS), Olsztyn, Poland
| | - Anna Kononiuk
- Department of Biodiversity Protection (DBP), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences (IAR&FR PAS), Olsztyn, Poland
| | - Władysław Kordan
- Department of Animal Biochemistry and Biotechnology, Faculty of Animal Bioengineering, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Aleksandra Orzołek
- Department of Animal Biochemistry and Biotechnology, Faculty of Animal Bioengineering, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| |
Collapse
|
|
13
|
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.
Collapse
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.
| |
Collapse
|
|
14
|
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.
Collapse
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
| |
Collapse
|
|
15
|
Fang J, Wang D, Kramer NI, Rietjens IMCM, Boogaard PJ, Kamelia L. The role of receptor-mediated activities of 4- and 5-ring unsubstituted and methylated polycyclic aromatic hydrocarbons (PAHs) in developmental toxicity. J Appl Toxicol 2022; 43:845-861. [PMID: 36585251 DOI: 10.1002/jat.4428] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 12/11/2022] [Accepted: 12/22/2022] [Indexed: 01/01/2023]
Abstract
The present study evaluated the aryl hydrocarbon receptor (AhR), estrogen receptor-α (ER-α), and retinoic acid receptor (RAR) mediated activities of nine 4- and 5-ring unsubstituted and monomethylated polycyclic aromatic hydrocarbons (PAHs) using a series of Chemical-Activated LUciferase gene eXpression (CALUX) assays. The potential role of these aforementioned receptors in relation to the developmental toxicity of these PAHs was further assessed in the zebrafish embryotoxicity test (ZET). The results show that all nine tested PAHs were AhR agonists, benz[a]anthracene (BaA) and 8-methyl-benz[a]anthracene (8-MeBaA) were ER-α agonists, and none of the tested PAHs induced ER-α antagonistic or RAR (ant)agonistic activities. In the AhR CALUX assay, all the methylated PAHs showed higher potency (lower EC50) in activating the AhR than their respective unsubstituted PAHs, implying that the addition of a methyl substituent on the aromatic ring of PAHs could enhance their AhR-mediated activities. Co-exposure of zebrafish embryos with each individual PAH and an AhR antagonist (CH223191) counteracted the observed developmental retardations and embryo lethality to a certain extent, except for 8-methyl-benzo[a]pyrene (8-MeBaP). Co-exposure of zebrafish embryos with either of the two estrogenic PAHs (i.e., BaA and 8-MeBaA) and an ER-α antagonist (fulvestrant) neutralized embryo lethality induced by 50 μM BaA and the developmental retardations induced by 15 μM 8-MeBaA. Altogether, our findings suggest that the observed developmental retardations in zebrafish embryos by the PAH tested may partially be AhR- and/or ER-α-mediated, whereas the RAR seems not to be relevant for the PAH-induced developmental toxicity in the ZET.
Collapse
Affiliation(s)
- Jing Fang
- Division of Toxicology, Wageningen University and Research, Wageningen, 6708 WE, The Netherlands
| | - Danlei Wang
- Division of Toxicology, Wageningen University and Research, Wageningen, 6708 WE, The Netherlands
| | - Nynke I Kramer
- Division of Toxicology, Wageningen University and Research, Wageningen, 6708 WE, The Netherlands
| | - Ivonne M C M Rietjens
- Division of Toxicology, Wageningen University and Research, Wageningen, 6708 WE, The Netherlands
| | - Peter J Boogaard
- Division of Toxicology, Wageningen University and Research, Wageningen, 6708 WE, The Netherlands
| | - Lenny Kamelia
- Shell Global Solutions International B.V., The Hague, The Netherlands
| |
Collapse
|
|
16
|
Jayaprakash S, Hegde M, Girisa S, Alqahtani MS, Abbas M, Lee EHC, Yap KCH, Sethi G, Kumar AP, Kunnumakkara AB. Demystifying the Functional Role of Nuclear Receptors in Esophageal Cancer. Int J Mol Sci 2022; 23:ijms231810952. [PMID: 36142861 PMCID: PMC9501100 DOI: 10.3390/ijms231810952] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 09/14/2022] [Accepted: 09/14/2022] [Indexed: 11/16/2022] Open
Abstract
Esophageal cancer (EC), an aggressive and poorly understood disease, is one of the top causes of cancer-related fatalities. GLOBOCAN 2020 reports that there are 544,076 deaths and 604,100 new cases expected worldwide. Even though there are various advancements in treatment procedures, this cancer has been reported as one of the most difficult cancers to cure, and to increase patient survival; treatment targets still need to be established. Nuclear receptors (NRs) are a type of transcription factor, which has a key role in several biological processes such as reproduction, development, cellular differentiation, stress response, immunity, metabolism, lipids, and drugs, and are essential regulators of several diseases, including cancer. Numerous studies have demonstrated the importance of NRs in tumor immunology and proved the well-known roles of multiple NRs in modulating proliferation, differentiation, and apoptosis. There are surplus of studies conducted on NRs and their implications in EC, but only a few studies have demonstrated the diagnostic and prognostic potential of NRs. Therefore, there is still a paucity of the role of NRs and different ways to target them in EC cells to stop them from spreading malignancy. This review emphasizes the significance of NRs in EC by discussing their diverse agonists as well as antagonists and their response to tumor progression. Additionally, we emphasize NRs’ potential to serve as a novel therapeutic target and their capacity to treat and prevent EC.
Collapse
Affiliation(s)
- Sujitha Jayaprakash
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati 781039, Assam, India
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati 781039, Assam, India
| | - Sosmitha Girisa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati 781039, Assam, India
| | - Mohammed S. Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha 61421, Saudi Arabia
- BioImaging Unit, Space Research Centre, Michael Atiyah Building, University of Leicester, Leicester LE1 7RH, UK
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha 61421, Saudi Arabia
- Electronics and Communications Department, College of Engineering, Delta University for Science and Technology, Gamasa 35712, Egypt
| | - E. Hui Clarissa Lee
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
| | - Kenneth Chun-Hong Yap
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
- Correspondence: (A.P.K.); (A.B.K.)
| | - Ajaikumar B. Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati 781039, Assam, India
- Correspondence: (A.P.K.); (A.B.K.)
| |
Collapse
|
|
17
|
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.
Collapse
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
| |
Collapse
|
|
18
|
Baker NC, Pierro JD, Taylor LW, Knudsen TB. Identifying candidate reference chemicals for in vitro testing of the retinoid pathway for predictive developmental toxicity. ALTEX 2022; 40:217–236. [PMID: 35796328 PMCID: PMC10765368 DOI: 10.14573/altex.2202231] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 06/21/2022] [Indexed: 11/23/2022]
Abstract
Evaluating chemicals for potential in vivo toxicity based on their in vitro bioactivity profile is an important step toward animal- free testing. A compendium of reference chemicals and data describing their bioactivity on specific molecular targets, cellular pathways, and biological processes is needed to bolster confidence in the predictive value of in vitro hazard detection. Endogenous signaling by all-trans retinoic acid (ATRA) is an important pathway in developmental processes and toxicities. Employing data extraction methods and advanced literature extraction tools, we assembled a set of candidate reference chemicals with demonstrated activity on ten protein family targets in the retinoid system. The compendium was culled from Protein Data Bank, ChEMBL, ToxCast/Tox21, and the biomedical literature in PubMed. Finally, we performed a case study on one chemical in our collection, citral, an inhibitor of endogenous ATRA production, to determine whether the literature supports an adverse outcome pathway explaining the compound’s developmental toxicity initiated by disruption of the retinoid pathway. We also deliver an updated Abstract Sifter tool populated with these reference compounds and complex search terms designed to query the literature for the downstream consequences to support concordance with targeted retinoid pathway disruption.
Collapse
Affiliation(s)
| | - Jocylin D. Pierro
- Center for Computational Toxicology and Exposure, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA
| | - Laura W. Taylor
- Center for Computational Toxicology and Exposure, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA
| | - Thomas B. Knudsen
- Center for Computational Toxicology and Exposure, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA
| |
Collapse
|
|
19
|
O’Connor C, Varshosaz P, Moise AR. Mechanisms of Feedback Regulation of Vitamin A Metabolism. Nutrients 2022; 14:1312. [PMID: 35334970 PMCID: PMC8950952 DOI: 10.3390/nu14061312] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/15/2022] [Accepted: 03/17/2022] [Indexed: 02/06/2023] Open
Abstract
Vitamin A is an essential nutrient required throughout life. Through its various metabolites, vitamin A sustains fetal development, immunity, vision, and the maintenance, regulation, and repair of adult tissues. Abnormal tissue levels of the vitamin A metabolite, retinoic acid, can result in detrimental effects which can include congenital defects, immune deficiencies, proliferative defects, and toxicity. For this reason, intricate feedback mechanisms have evolved to allow tissues to generate appropriate levels of active retinoid metabolites despite variations in the level and format, or in the absorption and conversion efficiency of dietary vitamin A precursors. Here, we review basic mechanisms that govern vitamin A signaling and metabolism, and we focus on retinoic acid-controlled feedback mechanisms that contribute to vitamin A homeostasis. Several approaches to investigate mechanistic details of the vitamin A homeostatic regulation using genomic, gene editing, and chromatin capture technologies are also discussed.
Collapse
Affiliation(s)
- Catherine O’Connor
- MD Program, Northern Ontario School of Medicine, 317-MSE Bldg., 935 Ramsey Lake Rd., Sudbury, ON P3E 2C6, Canada;
| | - Parisa Varshosaz
- Biology and Biomolecular Sciences Ph.D. Program, Northern Ontario School of Medicine, Laurentian University, Sudbury, ON P3E 2C6, Canada;
| | - Alexander R. Moise
- Medical Sciences Division, Northern Ontario School of Medicine, 317-MSE Bldg., 935 Ramsey Lake Rd., Sudbury, ON P3E 2C6, Canada
- Department of Chemistry and Biochemistry, Biology and Biomolecular Sciences Program, Laurentian University, Sudbury, ON P3E 2C6, Canada
| |
Collapse
|
|
20
|
Steinhoff JS, Lass A, Schupp M. Retinoid Homeostasis and Beyond: How Retinol Binding Protein 4 Contributes to Health and Disease. Nutrients 2022; 14:1236. [PMID: 35334893 PMCID: PMC8951293 DOI: 10.3390/nu14061236] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/09/2022] [Accepted: 03/11/2022] [Indexed: 02/06/2023] Open
Abstract
Retinol binding protein 4 (RBP4) is the specific transport protein of the lipophilic vitamin A, retinol, in blood. Circulating RBP4 originates from the liver. It is secreted by hepatocytes after it has been loaded with retinol and binding to transthyretin (TTR). TTR association prevents renal filtration due to the formation of a higher molecular weight complex. In the circulation, RBP4 binds to specific membrane receptors, thereby delivering retinol to target cells, rendering liver-secreted RBP4 the major mechanism to distribute hepatic vitamin A stores to extrahepatic tissues. In particular, binding of RBP4 to 'stimulated by retinoic acid 6' (STRA6) is required to balance tissue retinoid responses in a highly homeostatic manner. Consequently, defects/mutations in RBP4 can cause a variety of conditions and diseases due to dysregulated retinoid homeostasis and cover embryonic development, vision, metabolism, and cardiovascular diseases. Aside from the effects related to retinol transport, non-canonical functions of RBP4 have also been reported. In this review, we summarize the current knowledge on the regulation and function of RBP4 in health and disease derived from murine models and human mutations.
Collapse
Affiliation(s)
- Julia S. Steinhoff
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pharmacology, Cardiovascular Metabolic Renal (CMR)-Research Center, 10115 Berlin, Germany;
| | - Achim Lass
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Heinrichstraße 31/II, A-8010 Graz, Austria;
- Field of Excellence BioHealth, University of Graz, Heinrichstraße 31/II, A-8010 Graz, Austria
| | - Michael Schupp
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pharmacology, Cardiovascular Metabolic Renal (CMR)-Research Center, 10115 Berlin, Germany;
| |
Collapse
|
|
21
|
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.
Collapse
|
|
22
|
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.
Collapse
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.
| |
Collapse
|
|
23
|
Li H, Liu Q, Li L, Qin X, Wang S, Hu J, Lu X, Song J, Nie J, Zhang Q, Wang L, Niu Q. Aluminum inhibits non-amyloid pathways via retinoic acid receptor. J Trace Elem Med Biol 2022; 69:126902. [PMID: 34837756 DOI: 10.1016/j.jtemb.2021.126902] [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: 02/22/2021] [Revised: 11/04/2021] [Accepted: 11/15/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Aluminium neurotoxicity has been widely confirmed and mainly manifests as cognitive impairment. Al3+ can inhibit the expression of ADAM10, a key enzyme of the nonamyloid pathway, but its mechanism of toxicity has not been fully elucidated. Studies have shown that RARs can regulate ADAM10 expression. METHODS We explored whether Al3+ affects the expression of ADAM10 through RARs, thereby affecting the nonamyloid pathway. RESULTS Al3+ reduced the expressions of RARα, RARβ and ADAM10. The expression levels of the RARα, RARβ and ADAM10 proteins were upregulated in the RA group compared with the control group. In the RA + 200 μmol Al(mal)3 group, the downregulation of RARα, RARβ and ADAM10 was weaker than that of the 200 μmol Al(mal)3 group, which indicated that RA participated in and upregulated the expression of ADAM10 through RARα and RARβ. CONCLUSION Al3+ inhibits ADAM10 expression through RARα and RARβ and results in a decrease in the nonamyloid pathway.
Collapse
Affiliation(s)
- Huan Li
- Department of Occupational Health, School of Public Health, Shanxi Medical University, China; Department of Occupational Health, School of Public Health, Jining Medical University, China
| | - Qun Liu
- Department of Occupational Health, School of Public Health, Shanxi Medical University, China
| | - Liang Li
- Department of Occupational Health, School of Public Health, Shanxi Medical University, China
| | - Xiujun Qin
- Department of Occupational Health, School of Public Health, Shanxi Medical University, China
| | - ShanShan Wang
- Department of Occupational Health, School of Public Health, Shanxi Medical University, China
| | - Jiali Hu
- Department of Occupational Health, School of Public Health, Shanxi Medical University, China
| | - Xiaoting Lu
- Department of Occupational Health, School of Public Health, Shanxi Medical University, China; Key Lab of Environmental Hazard and Health of Shanxi Province, Shanxi Medical University, China
| | - Jing Song
- Department of Occupational Health, School of Public Health, Shanxi Medical University, China; Key Lab of Environmental Hazard and Health of Shanxi Province, Shanxi Medical University, China
| | - JiSheng Nie
- Department of Occupational Health, School of Public Health, Shanxi Medical University, China; Key Lab of Environmental Hazard and Health of Shanxi Province, Shanxi Medical University, China
| | - Qinli Zhang
- Department of Occupational Health, School of Public Health, Shanxi Medical University, China; Key Lab of Environmental Hazard and Health of Shanxi Province, Shanxi Medical University, China; Department of Pathology, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Linping Wang
- Department of Occupational Health, School of Public Health, Shanxi Medical University, China; Key Lab of Environmental Hazard and Health of Shanxi Province, Shanxi Medical University, China.
| | - Qiao Niu
- Department of Occupational Health, School of Public Health, Shanxi Medical University, China; Department of Occupational Health, School of Public Health, Xuzhou Medical University, China; Key Lab of Environmental Hazard and Health of Shanxi Province, Shanxi Medical University, China.
| |
Collapse
|
|
24
|
Ometere Boyi J, Stokholm I, Hillmann M, Søndergaard J, Persson S, de Wit CA, Siebert U, Kristina L. Relationships between gene transcription and contaminant concentrations in Baltic ringed seals: A comparison between tissue matrices. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2022; 242:106035. [PMID: 34856463 DOI: 10.1016/j.aquatox.2021.106035] [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: 06/22/2021] [Revised: 11/10/2021] [Accepted: 11/13/2021] [Indexed: 06/13/2023]
Abstract
Ringed seals (Pusa hispida) are slowly recovering in the eastern and northern parts of the Baltic Sea after years of hunting pressure and contaminant exposure. Still, consequences of anthropogenic activities such as contaminant exposure and increasing temperatures are stressors that continue to have deleterious effects on their habitat and health. Transcription profiles of seven health-related genes involved in xenobiotic metabolism, endocrine disruption and stress were evaluated in blood, blubber, and liver of Baltic ringed seals in a multi-tissue approach. Selected persistent organic pollutants and total mercury concentrations were measured in blubber and liver, and muscle and liver of these animals, respectively. Concentrations of contaminants varied across tissues on a lipid weight basis but not with sex. mRNA transcript levels for all seven target genes did not vary between sexes or age classes. Transcript levels of thyroid hormone receptor alpha (TRα), retinoic acid receptor alpha (RARα) and heat shock protein 70 (HSP70) correlated with levels of persistent organic pollutants. TRα transcript levels also correlated positively with mercury concentrations in the liver. Of the three tissues assessed in this multi-tissue approach, blubber showed highest transcription levels of aryl hydrocarbon receptor nuclear translocator (ARNT), thyroid stimulating hormone receptor beta (TSHβ), oestrogen receptor alpha (ESR1) and peroxisome proliferator activated receptor alpha (PPARα). The wide range of genes expressed highlights the value of minimally invasive sampling (e.g. biopsies) for assessing health endpoints in free-ranging marine wildlife and the importance of identifying optimal matrices for targeted gene expression studies. This gene transcript profile study has provided baseline information on transcript levels of biomarkers for early on-set health effects in ringed seals and will be a useful guide to assess the impacts of environmental change in Baltic pinnipeds for conservation and management.
Collapse
Affiliation(s)
- Joy Ometere Boyi
- Institute for Terrestrial and Aquatic Wildlife Research, University of Veterinary Medicine Hannover, Foundation, Werftstrasse 6, Buesum D-25761, Germany
| | - Iben Stokholm
- Institute for Terrestrial and Aquatic Wildlife Research, University of Veterinary Medicine Hannover, Foundation, Werftstrasse 6, Buesum D-25761, Germany
| | - Miriam Hillmann
- Institute for Terrestrial and Aquatic Wildlife Research, University of Veterinary Medicine Hannover, Foundation, Werftstrasse 6, Buesum D-25761, Germany
| | - Jens Søndergaard
- Department of Bioscience, Aarhus University, Roskilde DK-4000, Denmark
| | - Sara Persson
- Swedish Museum of Natural History, Department of Environmental Research and Monitoring, Stockholm SE-10405, Sweden
| | - Cynthia A de Wit
- Department of Environmental Science, Stockholm University, Stockholm SE-10691, Sweden
| | - Ursula Siebert
- Institute for Terrestrial and Aquatic Wildlife Research, University of Veterinary Medicine Hannover, Foundation, Werftstrasse 6, Buesum D-25761, Germany
| | - Lehnert Kristina
- Institute for Terrestrial and Aquatic Wildlife Research, University of Veterinary Medicine Hannover, Foundation, Werftstrasse 6, Buesum D-25761, Germany.
| |
Collapse
|
|
25
|
Pignolo RJ, Pacifici M. Retinoid Agonists in the Targeting of Heterotopic Ossification. Cells 2021; 10:cells10113245. [PMID: 34831466 PMCID: PMC8617746 DOI: 10.3390/cells10113245] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/17/2021] [Accepted: 11/17/2021] [Indexed: 12/25/2022] Open
Abstract
Retinoids are metabolic derivatives of vitamin A and regulate the function of many tissues and organs both prenatally and postnatally. Active retinoids, such as all trans-retinoic acid, are produced in the cytoplasm and then interact with nuclear retinoic acid receptors (RARs) to up-regulate the transcription of target genes. The RARs can also interact with target gene response elements in the absence of retinoids and exert a transcriptional repression function. Studies from several labs, including ours, showed that chondrogenic cell differentiation and cartilage maturation require (i) the absence of retinoid signaling and (ii) the repression function by unliganded RARs. These and related insights led to the proposition that synthetic retinoid agonists could thus represent pharmacological agents to inhibit heterotopic ossification (HO), a process that recapitulates developmental skeletogenesis and involves chondrogenesis, cartilage maturation, and endochondral ossification. One form of HO is acquired and is caused by injury, and another severe and often fatal form of it is genetic and occurs in patients with fibrodysplasia ossificans progressiva (FOP). Mouse models of FOP bearing mutant ACVR1R206H, characteristic of most FOP patients, were used to test the ability of the retinoid agonists selective for RARα and RARγ against spontaneous and injury-induced HO. The RARγ agonists were found to be most effective, and one such compound, palovarotene, was selected for testing in FOP patients. The safety and effectiveness data from recent and ongoing phase II and phase III clinical trials support the notion that palovarotene may represent a disease-modifying treatment for patients with FOP. The post hoc analyses showed substantial efficacy but also revealed side effects and complications, including premature growth plate closure in some patients. Skeletally immature patients will need to be carefully weighed in any future regulatory indications of palovarotene as an important therapeutic option in FOP.
Collapse
Affiliation(s)
- Robert J. Pignolo
- Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Correspondence:
| | - Maurizio Pacifici
- Translational Research Program in Pediatric Orthopedics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA;
| |
Collapse
|
|
26
|
Affiliation(s)
- Helen Håkansson
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
| |
Collapse
|
|
27
|
Takei M, Okada N, Nakamura S, Kagawa K, Fujii S, Miki H, Ishizawa K, Abe M, Sato Y. A genome-wide association study predicts the onset of dysgeusia due to anti-cancer drug treatment. Biol Pharm Bull 2021; 45:114-117. [PMID: 34657909 DOI: 10.1248/bpb.b21-00745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Dysgeusia is a major side effect of anti-cancer drug treatment. Since dysgeusia significantly lowers the patient's quality of life, predicting and avoiding its onset in advance is desirable. Accordingly, aims of the present study were to use a genome-wide association study (GWAS) to identify genes associated with the development of dysgeusia in patients taking anti-cancer drugs and to predict the development of dysgeusia using associated SNPs. GWAS was conducted on 76 patients admitted to the Department of Hematology, Tokushima University Hospital. Using Sanger sequencing for 23 separately collected validation samples, the top two single nucleotide polymorphisms (SNPs) associated with the development of dysgeusia were determined. GWAS identified rs73049478 and rs41396146 SNPs on the RARB gene associated with dysgeusia development due to the administration of anti-cancer drugs. Evaluation of the two SNPs using 23 validation samples indicated that the accuracy rate of rs73049478 was relatively high (87.0%). Thus, the findings of the present study suggest that the rs73049478 SNP of RARB can be used to predict the onset of dysgeusia caused by the administration of anti-cancer drugs.
Collapse
Affiliation(s)
- Minori Takei
- Department of Pharmaceutical Information Science, Institute of Biomedical Sciences, Tokushima University Graduate School
| | - Naoto Okada
- Department of Pharmacy, Tokushima University Hospital
| | - Shingen Nakamura
- Department of Community Medicine and Medical Science, Tokushima University Graduate School of Biomedical Sciences
| | - Kumiko Kagawa
- Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School
| | - Shiro Fujii
- Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School
| | - Hirokazu Miki
- Division of Transfusion Medicine and Cell Therapy, Tokushima University Hospital
| | - Keisuke Ishizawa
- Department of Pharmacy, Tokushima University Hospital.,Department of Clinical Pharmacology and Therapeutics, Institute of Biomedical Sciences, Tokushima University Graduate School
| | - Masahiro Abe
- Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School
| | - Youichi Sato
- Department of Pharmaceutical Information Science, Institute of Biomedical Sciences, Tokushima University Graduate School
| |
Collapse
|
|
28
|
Morita T, Miyakawa K, Jeremiah SS, Yamaoka Y, Sada M, Kuniyoshi T, Yang J, Kimura H, Ryo A. All-Trans Retinoic Acid Exhibits Antiviral Effect against SARS-CoV-2 by Inhibiting 3CLpro Activity. Viruses 2021; 13:1669. [PMID: 34452533 PMCID: PMC8402917 DOI: 10.3390/v13081669] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 08/18/2021] [Accepted: 08/20/2021] [Indexed: 12/24/2022] Open
Abstract
The pandemic of COVID-19 caused by SARS-CoV-2 continues to spread despite the global efforts taken to control it. The 3C-like protease (3CLpro), the major protease of SARS-CoV-2, is one of the most interesting targets for antiviral drug development because it is highly conserved among SARS-CoVs and plays an important role in viral replication. Herein, we developed high throughput screening for SARS-CoV-2 3CLpro inhibitor based on AlphaScreen. We screened 91 natural product compounds and found that all-trans retinoic acid (ATRA), an FDA-approved drug, inhibited 3CLpro activity. The 3CLpro inhibitory effect of ATRA was confirmed in vitro by both immunoblotting and AlphaScreen with a 50% inhibition concentration (IC50) of 24.7 ± 1.65 µM. ATRA inhibited the replication of SARS-CoV-2 in VeroE6/TMPRSS2 and Calu-3 cells, with IC50 = 2.69 ± 0.09 µM in the former and 0.82 ± 0.01 µM in the latter. Further, we showed the anti-SARS-CoV-2 effect of ATRA on the currently circulating variants of concern (VOC); alpha, beta, gamma, and delta. These results suggest that ATRA may be considered as a potential therapeutic agent against SARS-CoV-2.
Collapse
Affiliation(s)
- Takeshi Morita
- Department of Microbiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (T.M.); (K.M.); (S.S.J.); (Y.Y.)
| | - Kei Miyakawa
- Department of Microbiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (T.M.); (K.M.); (S.S.J.); (Y.Y.)
| | - Sundararaj Stanleyraj Jeremiah
- Department of Microbiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (T.M.); (K.M.); (S.S.J.); (Y.Y.)
| | - Yutaro Yamaoka
- Department of Microbiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (T.M.); (K.M.); (S.S.J.); (Y.Y.)
- Life Science Laboratory, Technology and Development Division, Kanto Chemical Co., Inc., Isehara 259-1146, Japan
| | - Mitsuru Sada
- Advanced Medical Science Research Center, Gunma Paz University, Shibukawa 377-0008, Japan;
| | - Tomoko Kuniyoshi
- R&D Department, TOKIWA Phytochemical Co., Ltd., Sakura, Chiba 285-0801, Japan; (T.K.); (J.Y.)
| | - Jinwei Yang
- R&D Department, TOKIWA Phytochemical Co., Ltd., Sakura, Chiba 285-0801, Japan; (T.K.); (J.Y.)
| | - Hirokazu Kimura
- Department of Health Science, Gunma Paz University Graduate School, Takasaki 370-0006, Japan;
| | - Akihide Ryo
- Department of Microbiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (T.M.); (K.M.); (S.S.J.); (Y.Y.)
| |
Collapse
|
|
29
|
Hunsu VO, Facey COB, Fields JZ, Boman BM. Retinoids as Chemo-Preventive and Molecular-Targeted Anti-Cancer Therapies. Int J Mol Sci 2021; 22:7731. [PMID: 34299349 PMCID: PMC8304138 DOI: 10.3390/ijms22147731] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/11/2021] [Accepted: 07/13/2021] [Indexed: 02/06/2023] Open
Abstract
Retinoic acid (RA) agents possess anti-tumor activity through their ability to induce cellular differentiation. However, retinoids have not yet been translated into effective systemic treatments for most solid tumors. RA signaling is mediated by the following two nuclear retinoic receptor subtypes: the retinoic acid receptor (RAR) and the retinoic X receptor (RXR), and their isoforms. The identification of mutations in retinoid receptors and other RA signaling pathway genes in human cancers offers opportunities for target discovery, drug design, and personalized medicine for distinct molecular retinoid subtypes. For example, chromosomal translocation involving RARA occurs in acute promyelocytic leukemia (APL), and all-trans retinoic acid (ATRA) is a highly effective and even curative therapeutic for APL patients. Thus, retinoid-based target discovery presents an important line of attack toward designing new, more effective strategies for treating other cancer types. Here, we review retinoid signaling, provide an update on retinoid agents and the current clinical research on retinoids in cancer, and discuss how the retinoid pathway genotype affects the ability of retinoid agents to inhibit the growth of colorectal cancer (CRC) cells. We also deliberate on why retinoid agents have not shown clinical efficacy against solid tumors and discuss alternative strategies that could overcome the lack of efficacy.
Collapse
Affiliation(s)
- Victoria O. Hunsu
- Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Newark, DE 19713, USA; (V.O.H.); (C.O.B.F.)
- Department of Biological Sciences, University of Delaware, Newark, DE 19713, USA
| | - Caroline O. B. Facey
- Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Newark, DE 19713, USA; (V.O.H.); (C.O.B.F.)
| | | | - Bruce M. Boman
- Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Newark, DE 19713, USA; (V.O.H.); (C.O.B.F.)
- Department of Biological Sciences, University of Delaware, Newark, DE 19713, USA
- Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA
| |
Collapse
|
|
30
|
Sun JL, Shi JY, Yin B, Lin YS, Shi B, Jia ZL. Association analysis of SNPs in GRHL3, FAF1, and KCNJ2 with NSCPO sub-phenotypes in Han Chinese. Oral Dis 2021; 28:2204-2214. [PMID: 34255421 DOI: 10.1111/odi.13961] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 07/06/2021] [Accepted: 07/08/2021] [Indexed: 02/05/2023]
Abstract
OBJECTIVES Non-syndromic cleft palate only (NSCPO) is a common congenital deformity with complex etiologies. GRHL3, FAF1, and KCNJ2 have been reported to be involved in the pathogenesis of NSCPO. Up till now, there have been no replication studies based on large Han Chinese. Therefore, this study aimed to investigate associations between GRHL3, FAF1, KCNJ2, and NSCPO sub-phenotypes patients in Han Chinese. MATERIALS AND METHODS Firstly, we selected 2 SNPs based on previous literatures: FAF1 (rs3827730) and GRHL3 (rs41268753). Also, we selected 8 tagSNPs in GRHL3 (rs557811, rs609352, rs10903078, rs6659209, rs12401714, rs12568599, rs3887581, rs12024148) and 2 tagSNPs in KCNJ2 (rs75855040 and rs236514). Afterward, we evaluated these SNPs among 1668 NSCPO patients and 1811 normal controls from Han Chinese. Following data were analyzed by PLINK and Haploview program. RESULTS Association analysis under additive model showed that allele A at rs12568599 in GRHL3 gene is significantly associated with NSCPO (p = 0.0034, OR = 1.38 and 95%CI: 1.11-1.72) and its sub-phenotype incomplete cleft palate (ICP) (p = 0.0039, OR = 1.4 and 95%CI: 1.11-1.75), and it could increase the risk of both NSCPO and ICP. CONCLUSIONS This study firstly found that rs12568599 in GRHL3 is associated with NSCPO and ICP in Han Chinese, indicating that sub-phenotypes of NSCPO have different etiologies.
Collapse
Affiliation(s)
- Jia-Lin Sun
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Cleft Lip and Palate, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jia-Yu Shi
- Division of Growth and Development and Section of Orthodontics, School of Dentistry, University of California, Los Angeles, California, USA
| | - Bin Yin
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Cleft Lip and Palate, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yan-Song Lin
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Cleft Lip and Palate, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Bing Shi
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Cleft Lip and Palate, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Zhong-Lin Jia
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Cleft Lip and Palate, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| |
Collapse
|
|
31
|
Wang Q, Xu L, Miura J, Saha MK, Uemura Y, Sandell LL, Trainor PA, Yamashiro T, Kurosaka H. Branchiomeric Muscle Development Requires Proper Retinoic Acid Signaling. Front Cell Dev Biol 2021; 9:596838. [PMID: 34307338 PMCID: PMC8299418 DOI: 10.3389/fcell.2021.596838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 05/12/2021] [Indexed: 11/30/2022] Open
Abstract
The first and second branchiomeric (branchial arch) muscles are craniofacial muscles that derive from branchial arch mesoderm. In mammals, this set of muscles is indispensable for jaw movement and facial expression. Defects during embryonic development that result in congenital partial absence of these muscles can have significant impact on patients’ quality of life. However, the detailed molecular and cellular mechanisms that regulate branchiomeric muscle development remains poorly understood. Herein we investigated the role of retinoic acid (RA) signaling in developing branchiomeric muscles using mice as a model. We administered all-trans RA (25 mg/kg body weight) to Institute of Cancer Research (ICR) pregnant mice by gastric intubation from E8.5 to E10.5. In their embryos at E13.5, we found that muscles derived from the first branchial arch (temporalis, masseter) and second branchial arch (frontalis, orbicularis oculi) were severely affected or undetectable, while other craniofacial muscles were hypoplastic. We detected elevated cell death in the branchial arch mesoderm cells in RA-treated embryos, suggesting that excessive RA signaling reduces the survival of precursor cells of branchiomeric muscles, resulting in the development of hypoplastic craniofacial muscles. In order to uncover the signaling pathway(s) underlying this etiology, we focused on Pitx2, Tbx1, and MyoD1, which are critical for cranial muscle development. Noticeably reduced expression of all these genes was detected in the first and second branchial arch of RA-treated embryos. Moreover, elevated RA signaling resulted in a reduction in Dlx5 and Dlx6 expression in cranial neural crest cells (CNCCs), which disturbed their interactions with branchiomeric mesoderm cells. Altogether, we discovered that embryonic craniofacial muscle defects caused by excessive RA signaling were associated with the downregulation of Pitx2, Tbx1, MyoD1, and Dlx5/6, and reduced survival of cranial myogenic precursor cells.
Collapse
Affiliation(s)
- Qi Wang
- Department of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Osaka University, Suita, Japan.,The Affiliated Stomatology Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Oral Biomedical Research of Zhejiang Province, Zhejiang University School of Stomatology, Hangzhou, China
| | - Lin Xu
- Department of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Osaka University, Suita, Japan
| | - Jiro Miura
- Division for Interdisciplinary Dentistry, Osaka University Graduate School of Dentistry, Suita, Japan
| | - Mithun Kumar Saha
- Department of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Osaka University, Suita, Japan
| | - Yume Uemura
- Department of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Osaka University, Suita, Japan
| | - Lisa L Sandell
- Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, KY, United States
| | - Paul A Trainor
- Stowers Institute for Medical Research, Kansas City, MO, United States.,Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Takashi Yamashiro
- Department of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Osaka University, Suita, Japan
| | - Hiroshi Kurosaka
- Department of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Osaka University, Suita, Japan
| |
Collapse
|
|
32
|
Mark M, Teletin M, Wendling O, Vonesch JL, Féret B, Hérault Y, Ghyselinck NB. Pathogenesis of Anorectal Malformations in Retinoic Acid Receptor Knockout Mice Studied by HREM. Biomedicines 2021; 9:742. [PMID: 34203310 PMCID: PMC8301324 DOI: 10.3390/biomedicines9070742] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/22/2021] [Accepted: 06/23/2021] [Indexed: 12/12/2022] Open
Abstract
Anorectal malformations (ARMs) are relatively common congenital abnormalities, but their pathogenesis is poorly understood. Previous gene knockout studies indicated that the signalling pathway mediated by the retinoic acid receptors (RAR) is instrumental to the formation of the anorectal canal and of various urogenital structures. Here, we show that simultaneous ablation of the three RARs in the mouse embryo results in a spectrum of malformations of the pelvic organs in which anorectal and urinary bladder ageneses are consistently associated. We found that these ageneses could be accounted for by defects in the processes of growth and migration of the cloaca, the embryonic structure from which the anorectal canal and urinary bladder originate. We further show that these defects are preceded by a failure of the lateral shift of the umbilical arteries and propose vascular abnormalities as a possible cause of ARM. Through the comparisons of these phenotypes with those of other mutant mice and of human patients, we would like to suggest that morphological data may provide a solid base to test molecular as well as clinical hypotheses.
Collapse
Affiliation(s)
- Manuel Mark
- CNRS, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France; (M.T.); (O.W.); (J.-L.V.); (B.F.); (Y.H.); (N.B.G.)
- Service de Biologie de la Reproduction, Hôpitaux Universitaires de Strasbourg (HUS), 67300 Schiltigheim, France
- CNRS, INSERM, CELPHEDIA, PHENOMIN-Institut Clinique de la Souris (ICS), Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France
| | - Marius Teletin
- CNRS, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France; (M.T.); (O.W.); (J.-L.V.); (B.F.); (Y.H.); (N.B.G.)
- Service de Biologie de la Reproduction, Hôpitaux Universitaires de Strasbourg (HUS), 67300 Schiltigheim, France
| | - Olivia Wendling
- CNRS, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France; (M.T.); (O.W.); (J.-L.V.); (B.F.); (Y.H.); (N.B.G.)
- CNRS, INSERM, CELPHEDIA, PHENOMIN-Institut Clinique de la Souris (ICS), Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France
| | - Jean-Luc Vonesch
- CNRS, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France; (M.T.); (O.W.); (J.-L.V.); (B.F.); (Y.H.); (N.B.G.)
| | - Betty Féret
- CNRS, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France; (M.T.); (O.W.); (J.-L.V.); (B.F.); (Y.H.); (N.B.G.)
| | - Yann Hérault
- CNRS, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France; (M.T.); (O.W.); (J.-L.V.); (B.F.); (Y.H.); (N.B.G.)
- CNRS, INSERM, CELPHEDIA, PHENOMIN-Institut Clinique de la Souris (ICS), Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France
| | - Norbert B. Ghyselinck
- CNRS, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France; (M.T.); (O.W.); (J.-L.V.); (B.F.); (Y.H.); (N.B.G.)
| |
Collapse
|
|
33
|
Iturbide A, Ruiz Tejada Segura ML, Noll C, Schorpp K, Rothenaigner I, Ruiz-Morales ER, Lubatti G, Agami A, Hadian K, Scialdone A, Torres-Padilla ME. Retinoic acid signaling is critical during the totipotency window in early mammalian development. Nat Struct Mol Biol 2021; 28:521-532. [PMID: 34045724 PMCID: PMC8195742 DOI: 10.1038/s41594-021-00590-w] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 04/07/2021] [Indexed: 12/15/2022]
Abstract
Totipotent cells hold enormous potential for regenerative medicine. Thus, the development of cellular models recapitulating totipotent-like features is of paramount importance. Cells resembling the totipotent cells of early embryos arise spontaneously in mouse embryonic stem (ES) cell cultures. Such '2-cell-like-cells' (2CLCs) recapitulate 2-cell-stage features and display expanded cell potential. Here, we used 2CLCs to perform a small-molecule screen to identify new pathways regulating the 2-cell-stage program. We identified retinoids as robust inducers of 2CLCs and the retinoic acid (RA)-signaling pathway as a key component of the regulatory circuitry of totipotent cells in embryos. Using single-cell RNA-seq, we reveal the transcriptional dynamics of 2CLC reprogramming and show that ES cells undergo distinct cellular trajectories in response to RA. Importantly, endogenous RA activity in early embryos is essential for zygotic genome activation and developmental progression. Overall, our data shed light on the gene regulatory networks controlling cellular plasticity and the totipotency program.
Collapse
MESH Headings
- Acitretin/pharmacology
- Animals
- Blastocyst Inner Cell Mass/cytology
- Cell Differentiation
- Cells, Cultured
- Dose-Response Relationship, Drug
- Embryonic Stem Cells/cytology
- Embryonic Stem Cells/drug effects
- Female
- Gene Expression Regulation, Developmental
- Gene Regulatory Networks/genetics
- Genes, Reporter
- Isotretinoin/pharmacology
- Male
- Mice/embryology
- Mice, Inbred C57BL
- Mice, Inbred CBA
- Piperazines/pharmacology
- Pyrazoles/pharmacology
- RNA Interference
- RNA, Messenger/biosynthesis
- RNA, Messenger/genetics
- RNA, Small Interfering/pharmacology
- RNA-Seq
- Receptors, Retinoic Acid/antagonists & inhibitors
- Receptors, Retinoic Acid/physiology
- Signal Transduction/drug effects
- Totipotent Stem Cells/cytology
- Totipotent Stem Cells/drug effects
- Transcription, Genetic
- Tretinoin/antagonists & inhibitors
- Tretinoin/pharmacology
- Tretinoin/physiology
- Retinoic Acid Receptor gamma
Collapse
Affiliation(s)
- Ane Iturbide
- Institute of Epigenetics and Stem Cells (IES), Helmholtz Zentrum München, Munich, Germany
| | - Mayra L Ruiz Tejada Segura
- Institute of Epigenetics and Stem Cells (IES), Helmholtz Zentrum München, Munich, Germany
- Institute of Functional Epigenetics (IFE), Helmholtz Zentrum München, Neuherberg, Germany
- Institute of Computational Biology (ICB), Helmholtz Zentrum München, Neuherberg, Germany
| | - Camille Noll
- Institute of Epigenetics and Stem Cells (IES), Helmholtz Zentrum München, Munich, Germany
| | - Kenji Schorpp
- Assay Development & Screening Platform, Institute of Molecular Toxicology & Pharmacology (TOXI), Helmholtz Zentrum München, Neuherberg, Germany
| | - Ina Rothenaigner
- Assay Development & Screening Platform, Institute of Molecular Toxicology & Pharmacology (TOXI), Helmholtz Zentrum München, Neuherberg, Germany
| | - Elias R Ruiz-Morales
- Institute of Epigenetics and Stem Cells (IES), Helmholtz Zentrum München, Munich, Germany
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
| | - Gabriele Lubatti
- Institute of Epigenetics and Stem Cells (IES), Helmholtz Zentrum München, Munich, Germany
- Institute of Functional Epigenetics (IFE), Helmholtz Zentrum München, Neuherberg, Germany
- Institute of Computational Biology (ICB), Helmholtz Zentrum München, Neuherberg, Germany
| | - Ahmed Agami
- Institute of Epigenetics and Stem Cells (IES), Helmholtz Zentrum München, Munich, Germany
| | - Kamyar Hadian
- Assay Development & Screening Platform, Institute of Molecular Toxicology & Pharmacology (TOXI), Helmholtz Zentrum München, Neuherberg, Germany
| | - Antonio Scialdone
- Institute of Epigenetics and Stem Cells (IES), Helmholtz Zentrum München, Munich, Germany
- Institute of Functional Epigenetics (IFE), Helmholtz Zentrum München, Neuherberg, Germany
- Institute of Computational Biology (ICB), Helmholtz Zentrum München, Neuherberg, Germany
| | - Maria-Elena Torres-Padilla
- Institute of Epigenetics and Stem Cells (IES), Helmholtz Zentrum München, Munich, Germany.
- Faculty of Biology, Ludwig-Maximilians Universität, Munich, Germany.
| |
Collapse
|
|
34
|
Li Y, Ma H, Chen R, Zhang H, Nakanishi T, Hu J. Maternal Transfer of 2-Ethylhexyl Diphenyl Phosphate Leads to Developmental Toxicity Possibly by Blocking the Retinoic Acid Receptor and Retinoic X Receptor in Japanese Medaka ( Oryzias latipes). ENVIRONMENTAL SCIENCE & TECHNOLOGY 2021; 55:5056-5064. [PMID: 33685123 DOI: 10.1021/acs.est.0c06809] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
2-Ethylhexyl diphenyl phosphate (EHDPP) has been detected in wild fish with high concentrations, which may pose a risk in the embryo development considering its potential maternal transfer. In this study, EHDPP was demonstrated to elicit antagonistic activity to medaka retinoic acid receptor (mRAR) and retinoic X receptor (mRXR) with 50% inhibitory concentration of 18 and 36 μM, respectively. After adult female medaka were exposed to EHDPP at 156, 405, and 1161 ng/L for 35 days, the embryonic EHDPP concentrations (364-4824 ng/g lipid weight (lw)) were higher than those in the maternal tissues (15.0-4166 ng/g lw), showing notable maternal transfer. The embryonic concentration of EHDPP decreased limitedly during 1-2 day post-fertilization (dpf, the main developmental window of eye) but then decreased sharply after 2 dpf. The transcript abundance of cyp26a1 was inhibited and subsequent increasing embryonic all-trans RA level was observed in embryos, showing RAR/RXR antagonistic activity. These results may specifically contribute to the increased eye deformity incidences in all exposure groups (up to 8.0%; 51/637) relative to the control (1.0%, 7/733). The response behavior of the larvae to light stimulation was impaired in a dose-dependent manner, demonstrating a vision disorder. Because such developmental toxicities were observed at the environmental level, EHDPP may pose a threat to the survival of wild larvae and therefore a population risk for wild fish.
Collapse
Affiliation(s)
- Yu Li
- MOE Laboratory for Earth Surface Process, College of Urban and Environmental Sciences, Peking University, Beijing 100871, China
- State Environmental Protection Key Laboratory of Integrated Surface Water-Groundwater Pollution Control, School of Environmental Science and Engineering, Southern University of Science and Technology, Shenzhen 518055, China
| | - Haojia Ma
- MOE Laboratory for Earth Surface Process, College of Urban and Environmental Sciences, Peking University, Beijing 100871, China
| | - Ruichao Chen
- MOE Laboratory for Earth Surface Process, College of Urban and Environmental Sciences, Peking University, Beijing 100871, China
| | - Hong Zhang
- MOE Laboratory for Earth Surface Process, College of Urban and Environmental Sciences, Peking University, Beijing 100871, China
| | - Tsuyoshi Nakanishi
- Laboratory of Hygienic Chemistry and Molecular Toxicology, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Gifu 501-1196, Japan
| | - Jianying Hu
- MOE Laboratory for Earth Surface Process, College of Urban and Environmental Sciences, Peking University, Beijing 100871, China
| |
Collapse
|
|
35
|
Esteban J, Sánchez-Pérez I, Hamscher G, Miettinen HM, Korkalainen M, Viluksela M, Pohjanvirta R, Håkansson H. Role of aryl hydrocarbon receptor (AHR) in overall retinoid metabolism: Response comparisons to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure between wild-type and AHR knockout mice. Reprod Toxicol 2021; 101:33-49. [PMID: 33607186 DOI: 10.1016/j.reprotox.2021.02.004] [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: 10/14/2020] [Revised: 01/20/2021] [Accepted: 02/10/2021] [Indexed: 02/06/2023]
Abstract
Young adult wild-type and aryl hydrocarbon receptor knockout (AHRKO) mice of both sexes and the C57BL/6J background were exposed to 10 weekly oral doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; total dose of 200 μg/kg bw) to further characterize the observed impacts of AHR as well as TCDD on the retinoid system. Unexposed AHRKO mice harboured heavier kidneys, lighter livers and lower serum all-trans retinoic acid (ATRA) and retinol (REOH) concentrations than wild-type mice. Results from the present study also point to a role for the murine AHR in the control of circulating REOH and ATRA concentrations. In wild-type mice, TCDD elevated liver weight and reduced thymus weight, and drastically reduced the hepatic concentrations of 9-cis-4-oxo-13,14-dihydro-retinoic acid (CORA) and retinyl palmitate (REPA). In female wild-type mice, TCDD increased the hepatic concentration of ATRA as well as the renal and circulating REOH concentrations. Renal CORA concentrations were substantially diminished in wild-type male mice exclusively following TCDD-exposure, with a similar tendency in serum. In contrast, TCDD did not affect any of these toxicity or retinoid system parameters in AHRKO mice. Finally, a distinct sex difference occurred in kidney concentrations of all the analysed retinoid forms. Together, these results strengthen the evidence of a mandatory role of AHR in TCDD-induced retinoid disruption, and suggest that the previously reported accumulation of several retinoid forms in the liver of AHRKO mice is a line-specific phenomenon. Our data further support participation of AHR in the control of liver and kidney development in mice.
Collapse
Affiliation(s)
- Javier Esteban
- Instituto De Bioingeniería, Universidad Miguel Hernández De Elche, Elche, Alicante, Spain.
| | - Ismael Sánchez-Pérez
- Instituto De Bioingeniería, Universidad Miguel Hernández De Elche, Elche, Alicante, Spain.
| | - Gerd Hamscher
- Institute of Food Chemistry and Food Biotechnology, Justus Liebig University Giessen, Giessen, Germany.
| | - Hanna M Miettinen
- School of Pharmacy (Toxicology) and Department of Environmental and Biological Sciences, University of Eastern Finland, Kuopio, Finland.
| | - Merja Korkalainen
- Environmental Health Unit, Finnish Insitute for Health and Welfare (THL), Kuopio, Finland.
| | - Matti Viluksela
- School of Pharmacy (Toxicology) and Department of Environmental and Biological Sciences, University of Eastern Finland, Kuopio, Finland; Environmental Health Unit, Finnish Insitute for Health and Welfare (THL), Kuopio, Finland.
| | - Raimo Pohjanvirta
- Department of Food Hygiene & Environmental Health, Faculty of Veterinary Medicine, University of Helsinki, Mustialankatu 1, FI-00790 Helsinki, Finland.
| | - Helen Håkansson
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
| |
Collapse
|
|
36
|
Steinhoff JS, Lass A, Schupp M. Biological Functions of RBP4 and Its Relevance for Human Diseases. Front Physiol 2021; 12:659977. [PMID: 33790810 PMCID: PMC8006376 DOI: 10.3389/fphys.2021.659977] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 02/22/2021] [Indexed: 12/13/2022] Open
Abstract
Retinol binding protein 4 (RBP4) is a member of the lipocalin family and the major transport protein of the hydrophobic molecule retinol, also known as vitamin A, in the circulation. Expression of RBP4 is highest in the liver, where most of the body’s vitamin A reserves are stored as retinyl esters. For the mobilization of vitamin A from the liver, retinyl esters are hydrolyzed to retinol, which then binds to RBP4 in the hepatocyte. After associating with transthyretin (TTR), the retinol/RBP4/TTR complex is released into the bloodstream and delivers retinol to tissues via binding to specific membrane receptors. So far, two distinct RBP4 receptors have been identified that mediate the uptake of retinol across the cell membrane and, under specific conditions, bi-directional retinol transport. Although most of RBP4’s actions depend on its role in retinoid homeostasis, functions independent of retinol transport have been described. In this review, we summarize and discuss the recent findings on the structure, regulation, and functions of RBP4 and lay out the biological relevance of this lipocalin for human diseases.
Collapse
Affiliation(s)
- Julia S Steinhoff
- Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Achim Lass
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.,BioTechMed-Graz, Graz, Austria
| | - Michael Schupp
- Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| |
Collapse
|
|
37
|
Goliusova DV, Klementieva NV, Panova AV, Mokrysheva NG, Kiselev SL. The Role of Genetic Factors in Endocrine Tissues Development and Its Regulation In Vivo and In Vitro. RUSS J GENET+ 2021; 57:273-281. [DOI: 10.1134/s102279542103008x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/13/2020] [Accepted: 06/16/2020] [Indexed: 02/05/2023]
|
|
38
|
Fischer C, Koblmüller S, Börger C, Michelitsch G, Trajanoski S, Schlötterer C, Guelly C, Thallinger GG, Sturmbauer C. Genome sequences of Tropheus moorii and Petrochromis trewavasae, two eco-morphologically divergent cichlid fishes endemic to Lake Tanganyika. Sci Rep 2021; 11:4309. [PMID: 33619328 PMCID: PMC7900123 DOI: 10.1038/s41598-021-81030-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 12/28/2020] [Indexed: 01/01/2023] Open
Abstract
With more than 1000 species, East African cichlid fishes represent the fastest and most species-rich vertebrate radiation known, providing an ideal model to tackle molecular mechanisms underlying recurrent adaptive diversification. We add high-quality genome reconstructions for two phylogenetic key species of a lineage that diverged about ~ 3-9 million years ago (mya), representing the earliest split of the so-called modern haplochromines that seeded additional radiations such as those in Lake Malawi and Victoria. Along with the annotated genomes we analysed discriminating genomic features of the study species, each representing an extreme trophic morphology, one being an algae browser and the other an algae grazer. The genomes of Tropheus moorii (TM) and Petrochromis trewavasae (PT) comprise 911 and 918 Mbp with 40,300 and 39,600 predicted genes, respectively. Our DNA sequence data are based on 5 and 6 individuals of TM and PT, and the transcriptomic sequences of one individual per species and sex, respectively. Concerning variation, on average we observed 1 variant per 220 bp (interspecific), and 1 variant per 2540 bp (PT vs PT)/1561 bp (TM vs TM) (intraspecific). GO enrichment analysis of gene regions affected by variants revealed several candidates which may influence phenotype modifications related to facial and jaw morphology, such as genes belonging to the Hedgehog pathway (SHH, SMO, WNT9A) and the BMP and GLI families.
Collapse
Affiliation(s)
- C Fischer
- Institute of Biology, University of Graz, Graz, Austria
- Institute of Biomedical Informatics, Graz University of Technology, Graz, Austria
| | - S Koblmüller
- Institute of Biology, University of Graz, Graz, Austria
| | - C Börger
- Institute of Biology, University of Graz, Graz, Austria
| | - G Michelitsch
- Center for Medical Research, Medical University of Graz, Graz, Austria
| | - S Trajanoski
- Center for Medical Research, Medical University of Graz, Graz, Austria
| | - C Schlötterer
- Institut für Populationsgenetik, Vetmeduni Vienna, Vienna, Austria
| | - C Guelly
- Center for Medical Research, Medical University of Graz, Graz, Austria
| | - G G Thallinger
- Institute of Biomedical Informatics, Graz University of Technology, Graz, Austria.
- BioTechMed-Graz, Graz, Austria.
| | - C Sturmbauer
- Institute of Biology, University of Graz, Graz, Austria.
- BioTechMed-Graz, Graz, Austria.
| |
Collapse
|
|
39
|
Assessment of the in vitro developmental toxicity of diethylstilbestrol and estradiol in the zebrafish embryotoxicity test. Toxicol In Vitro 2021; 72:105088. [PMID: 33429043 DOI: 10.1016/j.tiv.2021.105088] [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: 11/30/2020] [Accepted: 01/06/2021] [Indexed: 11/20/2022]
Abstract
The present study investigated the developmental toxicity of diethylstilbestrol (DES) in the zebrafish embryotoxicity test (ZET). This was done to investigate whether the ZET would better capture the developmental toxicity of DES than the embryonic stem cells test (EST) that was previously shown to underpredict the DES-induced developmental toxicity as compared to in vivo data, potentially because the EST does not capture late events in the developmental process. The ZET results showed DES-induced growth retardation, cumulative mortality and dysmorphisms (i.e. induction of pericardial edema) in zebrafish embryos while the endogenous ERα agonist 17β-estradiol (E2) showed only growth retardation and cumulative mortality with lower potency compared to DES. Furthermore, the DES-induced pericardial edema formation in zebrafish embryos could be counteracted by co-exposure with ERα antagonist fulvestrant, indicating that the ZET captures the role of ERα in the mode of action underlying the developmental toxicity of DES. Altogether, it is concluded that the ZET differentiates DES from E2 with respect to their developmental toxicity effects, while confirming the role of ERα in mediating the developmental toxicity of DES. Furthermore, comparison to in vivo data revealed that, like the EST, in a quantitative way also the ZET did not capture the relatively high in vivo potency of DES as a developmental toxicant.
Collapse
|
|
40
|
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.
Collapse
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
| |
Collapse
|
|
41
|
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.
Collapse
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.
| |
Collapse
|
|
42
|
Vitamin A as a Transcriptional Regulator of Cardiovascular Disease. HEARTS 2020. [DOI: 10.3390/hearts1020013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Vitamin A is a micronutrient and signaling molecule that regulates transcription, cellular differentiation, and organ homeostasis. Additionally, metabolites of Vitamin A are utilized as differentiation agents in the treatment of hematological cancers and skin disorders, necessitating further study into the effects of both nutrient deficiency and the exogenous delivery of Vitamin A and its metabolites on cardiovascular phenotypes. Though vitamin A/retinoids are well-known regulators of cardiac formation, recent evidence has emerged that supports their role as regulators of cardiac regeneration, postnatal cardiac function, and cardiovascular disease progression. We here review findings from genetic and pharmacological studies describing the regulation of both myocyte- and vascular-driven cardiac phenotypes by vitamin A signaling. We identify the relationship between retinoids and maladaptive processes during the pathological hypertrophy of the heart, with a focus on the activation of neurohormonal signaling and fetal transcription factors (Gata4, Tbx5). Finally, we assess how this information might be leveraged to develop novel therapeutic avenues.
Collapse
|
|
43
|
Hewitt SC, Grimm SA, Wu SP, DeMayo FJ, Korach KS. Estrogen receptor α (ERα)-binding super-enhancers drive key mediators that control uterine estrogen responses in mice. J Biol Chem 2020; 295:8387-8400. [PMID: 32354741 DOI: 10.1074/jbc.ra120.013666] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 04/27/2020] [Indexed: 12/13/2022] Open
Abstract
Estrogen receptor α (ERα) modulates gene expression by interacting with chromatin regions that are frequently distal from the promoters of estrogen-regulated genes. Active chromatin-enriched "super-enhancer" (SE) regions, mainly observed in in vitro culture systems, often control production of key cell type-determining transcription factors. Here, we defined super-enhancers that bind to ERα in vivo within hormone-responsive uterine tissue in mice. We found that SEs are already formed prior to estrogen exposure at the onset of puberty. The genes at SEs encoded critical developmental factors, including retinoic acid receptor α (RARA) and homeobox D (HOXD). Using high-throughput chromosome conformation capture (Hi-C) along with DNA sequence analysis, we demonstrate that most SEs are located at a chromatin loop end and that most uterine genes in loop ends associated with these SEs are regulated by estrogen. Although the SEs were formed before puberty, SE-associated genes acquired optimal ERα-dependent expression after reproductive maturity, indicating that pubertal processes that occur after SE assembly and ERα binding are needed for gene responses. Genes associated with these SEs affected key estrogen-mediated uterine functions, including transforming growth factor β (TGFβ) and LIF interleukin-6 family cytokine (LIF) signaling pathways. To the best of our knowledge, this is the first identification of SE interactions that underlie hormonal regulation of genes in uterine tissue and optimal development of estrogen responses in this tissue.
Collapse
Affiliation(s)
- Sylvia C Hewitt
- Reproductive and Developmental Biology Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina, USA
| | - Sara A Grimm
- Integrative Bioinformatics Support Group, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina, USA
| | - San-Pin Wu
- Reproductive and Developmental Biology Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina, USA
| | - Francesco J DeMayo
- Reproductive and Developmental Biology Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina, USA
| | - Kenneth S Korach
- Reproductive and Developmental Biology Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina, USA
| |
Collapse
|
|
44
|
Grignard E, Håkansson H, Munn S. Regulatory needs and activities to address the retinoid system in the context of endocrine disruption: The European viewpoint. Reprod Toxicol 2020; 93:250-258. [PMID: 32171711 PMCID: PMC7322530 DOI: 10.1016/j.reprotox.2020.03.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 03/02/2020] [Accepted: 03/06/2020] [Indexed: 01/01/2023]
Abstract
Endocrine disruption continues to be a matter of high concern, and a subject of intensive activities at the public, political, regulatory and academic levels. Currently, available regulatory test guidelines (TGs) relevant to the identification of endocrine disrupters are largely limited to estrogen, androgen, thyroid and steroidogenesis (EATS) pathways. Thus, there is an increasing interest and need to develop test methods, biomarkers, and Adverse Outcome Pathways (AOPs), for identification and evaluation of endocrine disrupters in addition to the EATS pathways. An activity focusing on the retinoid system has been jointly initiated by the Swedish Chemicals Agency and the European Commission. The retinoid system is involved in fundamental life processes and has been described, in previous work at the OECD, as a system susceptible to environmental endocrine disruption, the disruption of which could contribute to the increasing incidence of certain disorders in humans and wildlife populations.
Collapse
Affiliation(s)
- Elise Grignard
- European Commission, Joint Research Centre (JRC), Italy.
| | - Helen Håkansson
- Institute of Environmental Medicine (IMM), Karolinska Institutet, Sweden.
| | - Sharon Munn
- European Commission, Joint Research Centre (JRC), Italy.
| |
Collapse
|
|
45
|
Roberts C. Regulating Retinoic Acid Availability during Development and Regeneration: The Role of the CYP26 Enzymes. J Dev Biol 2020; 8:jdb8010006. [PMID: 32151018 PMCID: PMC7151129 DOI: 10.3390/jdb8010006] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 02/17/2020] [Accepted: 02/17/2020] [Indexed: 12/16/2022] Open
Abstract
This review focuses on the role of the Cytochrome p450 subfamily 26 (CYP26) retinoic acid (RA) degrading enzymes during development and regeneration. Cyp26 enzymes, along with retinoic acid synthesising enzymes, are absolutely required for RA homeostasis in these processes by regulating availability of RA for receptor binding and signalling. Cyp26 enzymes are necessary to generate RA gradients and to protect specific tissues from RA signalling. Disruption of RA homeostasis leads to a wide variety of embryonic defects affecting many tissues. Here, the function of CYP26 enzymes is discussed in the context of the RA signalling pathway, enzymatic structure and biochemistry, human genetic disease, and function in development and regeneration as elucidated from animal model studies.
Collapse
Affiliation(s)
- Catherine Roberts
- Developmental Biology of Birth Defects, UCL-GOS Institute of Child Health, 30 Guilford St, London WC1N 1EH, UK;
- Institute of Medical and Biomedical Education St George’s, University of London, Cranmer Terrace, Tooting, London SW17 0RE, UK
| |
Collapse
|
|
46
|
Adam AHB, de Haan LHJ, Estruch IM, Hooiveld GJEJ, Louisse J, Rietjens IMCM. Estrogen receptor alpha (ERα)-mediated coregulator binding and gene expression discriminates the toxic ERα agonist diethylstilbestrol (DES) from the endogenous ERα agonist 17β-estradiol (E2). Cell Biol Toxicol 2020; 36:417-435. [PMID: 32088792 PMCID: PMC7505815 DOI: 10.1007/s10565-020-09516-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 01/28/2020] [Indexed: 12/29/2022]
Abstract
Diethylstilbestrol (DES) is a synthetic estrogen and proven human teratogen and carcinogen reported to act via the estrogen receptor α (ERα). Since the endogenous ERα ligand 17β-estradiol (E2) does not show these adverse effects to a similar extent, we hypothesized that DES' interaction with the ERα differs from that of E2. The current study aimed to investigate possible differences between DES and E2 using in vitro assays that detect ERα-mediated effects, including ERα-mediated reporter gene expression, ERα-mediated breast cancer cell (T47D) proliferation and ERα-coregulator interactions and gene expression in T47D cells. Results obtained indicate that DES and E2 activate ERα-mediated reporter gene transcription and T47D cell proliferation in a similar way. However, significant differences between DES- and E2-induced binding of the ERα to 15 coregulator motifs and in transcriptomic signatures obtained in the T47D cells were observed. It is concluded that differences observed in binding of the ERα with several co-repressor motifs, in downregulation of genes involved in histone deacetylation and DNA methylation and in upregulation of CYP26A1 and CYP26B1 contribute to the differential effects reported for DES and E2.
Collapse
Affiliation(s)
- Aziza Hussein Bakheit Adam
- Division of Toxicology, Wageningen University and Research, PO Box 8000, 6700 EA, Wageningen, The Netherlands.
| | - Laura H J de Haan
- Division of Toxicology, Wageningen University and Research, PO Box 8000, 6700 EA, Wageningen, The Netherlands
| | - Ignacio Miro Estruch
- Division of Toxicology, Wageningen University and Research, PO Box 8000, 6700 EA, Wageningen, The Netherlands
| | - Guido J E J Hooiveld
- Division of Human Nutrition and Health, Wageningen University and Research, PO Box 17, 6700 AA, Wageningen, The Netherlands
| | - Jochem Louisse
- Division of Toxicology, Wageningen University and Research, PO Box 8000, 6700 EA, Wageningen, The Netherlands
| | - Ivonne M C M Rietjens
- Division of Toxicology, Wageningen University and Research, PO Box 8000, 6700 EA, Wageningen, The Netherlands
| |
Collapse
|
|
47
|
Vitamin A: its many roles-from vision and synaptic plasticity to infant mortality. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 2020; 206:389-399. [PMID: 32034476 DOI: 10.1007/s00359-020-01403-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 11/06/2019] [Accepted: 01/15/2020] [Indexed: 10/25/2022]
Abstract
The recognition that a dietary factor is essential to maintain good and sensitive vision as well as overall health goes back over 3,000 years to the ancient Egyptians. With the discovery of the vitamins at the turn of the twentieth century, fat-soluble vitamin A was soon shown to be the essential factor. In the first half of the twentieth century, the role vitamin A plays in vision, as precursor to the light-sensitive visual pigment molecules in the photoreceptors was elegantly worked out, especially by George Wald and his colleagues. Beginning in the 1960s, with the recognition of the active metabolite of vitamin A, its acid form now called retinoic acid, the roles of vitamin A in maintaining overall health of an organism began to be explored, and this research continues to this day. Receptors activated by retinoic acid, the RARs and RXRs have been shown to regulate gene transcription in a surprisingly wide variety of biological processes from early growth and development to the maintenance of epithelial tissues in many organs, the regulation of the immune system, and even the modulation of synaptic function in the brain involved in mechanisms underlying memory and learning. Therapeutic uses for retinoic acid have been developed, including one for a specific form of leukemia. The story is by no means complete and it is likely more surprises await with regard to this remarkable molecule.
Collapse
|
|
48
|
Miller AP, Coronel J, Amengual J. The role of β-carotene and vitamin A in atherogenesis: Evidences from preclinical and clinical studies. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158635. [PMID: 31978554 DOI: 10.1016/j.bbalip.2020.158635] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 01/14/2020] [Accepted: 01/16/2020] [Indexed: 02/07/2023]
Abstract
Atherosclerotic cardiovascular disease (ASCVD) is the principal contributor to myocardial infarction, the leading cause of death worldwide. Epidemiological and mechanistic studies indicate that β-carotene and its vitamin A derivatives stimulate lipid catabolism in several tissues to reduce the incidence of obesity, but their roles within ASCVD are elusive. Herein, we review the mechanisms by which β-carotene and vitamin A modulate ASCVD. First, we summarize the current knowledge linking these nutrients with epidemiological studies and lipoprotein metabolism as one of the initiating factors of ASCVD. Next, we focus on different aspects of vitamin A metabolism in immune cells such as the mechanisms of carotenoid uptake and conversion to the vitamin A metabolite, retinoic acid. Lastly, we review the effects of retinoic acid on immuno-metabolism, differentiation, and function of macrophages and T cells, the two pillars of the innate and adaptive immune response in ASCVD, respectively. This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro.
Collapse
Affiliation(s)
- Anthony P Miller
- Department of Food Science and Human Nutrition, University of Illinois Urbana Champaign, Urbana, IL 61801, United States of America
| | - Johana Coronel
- Department of Food Science and Human Nutrition, University of Illinois Urbana Champaign, Urbana, IL 61801, United States of America
| | - Jaume Amengual
- Department of Food Science and Human Nutrition, University of Illinois Urbana Champaign, Urbana, IL 61801, United States of America; Division of Nutritional Sciences, University of Illinois Urbana Champaign, Urbana, IL 61801, United States of America.
| |
Collapse
|
|
49
|
Fainsod A, Bendelac-Kapon L, Shabtai Y. Fetal Alcohol Spectrum Disorder: Embryogenesis Under Reduced Retinoic Acid Signaling Conditions. Subcell Biochem 2020; 95:197-225. [PMID: 32297301 DOI: 10.1007/978-3-030-42282-0_8] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Fetal Alcohol Spectrum Disorder (FASD) is a complex set of developmental malformations, neurobehavioral anomalies and mental disabilities induced by exposing human embryos to alcohol during fetal development. Several experimental models and a series of developmental and biochemical approaches have established a strong link between FASD and reduced retinoic acid (RA) signaling. RA signaling is involved in the regulation of numerous developmental decisions from patterning of the anterior-posterior axis, starting at gastrulation, to the differentiation of specific cell types within developing organs, to adult tissue homeostasis. Being such an important regulatory signal during embryonic development, mutations or environmental perturbations that affect the level, timing or location of the RA signal can induce multiple and severe developmental malformations. The evidence connecting human syndromes to reduced RA signaling is presented here and the resulting phenotypes are compared to FASD. Available data suggest that competition between ethanol clearance and RA biosynthesis is a major etiological component in FASD.
Collapse
Affiliation(s)
- Abraham Fainsod
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem, POB 12271, 9112102, Jerusalem, Israel.
| | - Liat Bendelac-Kapon
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem, POB 12271, 9112102, Jerusalem, Israel
| | - Yehuda Shabtai
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem, POB 12271, 9112102, Jerusalem, Israel
| |
Collapse
|
|
50
|
Xu A, Zhang N, Cao J, Zhu H, Yang B, He Q, Shao X, Ying M. Post-translational modification of retinoic acid receptor alpha and its roles in tumor cell differentiation. Biochem Pharmacol 2020; 171:113696. [DOI: 10.1016/j.bcp.2019.113696] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 11/05/2019] [Indexed: 12/22/2022]
|