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Kimura S, Tagami S, Mano H, Kittaka A, Ida Y, Takagi Y, Nakagawa K, Arai T, Yokota S, Tsugawa N, Kamao M, Suhara Y, Sakaki T, Nakagawa K, Okano T, Hirota Y. Divergent roles of 25-hydroxyvitamin D 3 and 1α,25-dihydroxyvitamin D 3 in neural fate determination: A CYP27B1-dependent neuron formation and VDR-dependent astrocyte development. Biochem Biophys Res Commun 2025; 755:151547. [PMID: 40043620 DOI: 10.1016/j.bbrc.2025.151547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 02/20/2025] [Accepted: 02/25/2025] [Indexed: 03/17/2025]
Abstract
Vitamin D plays a crucial role in neural differentiation, yet its precise mechanisms remain unclear. In this study, we investigated the effects of vitamin D metabolites, 25-hydroxyvitamin D3 (25D3) and 1α,25-dihydroxyvitamin D3 (1α,25D3), on neural differentiation using Cyp27b1-/- and Vdr-/- knockout mice-derived neural stem cells. We found that 1α,25D3 promotes neuronal differentiation via vitamin D receptor (VDR), whereas some of its effects occur independently of VDR. Additionally, 25D3 requires conversion to 1α,25D3 by CYP27B1 to induce neuronal differentiation. In contrast, both 25D3 and 1α,25D3 promoted astrocyte differentiation regardless of CYP27B1 expression but required VDR. Furthermore, using vitamin D derivatives, we demonstrated that VDR binding affinity does not directly correlate with neurogenic potential. These findings reveal distinct VDR-dependent and VDR-independent pathways in neural differentiation, highlighting a previously unrecognized role of vitamin D metabolism in neural fate determination.
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Affiliation(s)
- Shusaku Kimura
- Laboratory of Hygienic Sciences, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, Japan
| | - Shintaro Tagami
- Laboratory of Biochemistry, Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, 307 Fukasaku, Minuma-ku, Saitama, Japan
| | - Hiroki Mano
- Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama, Japan
| | - Atsushi Kittaka
- Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo, Japan
| | - Yuka Ida
- Laboratory of Biochemistry, Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, 307 Fukasaku, Minuma-ku, Saitama, Japan
| | - Yuta Takagi
- Laboratory of Biochemistry, Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, 307 Fukasaku, Minuma-ku, Saitama, Japan
| | - Kurumi Nakagawa
- Laboratory of Biochemistry, Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, 307 Fukasaku, Minuma-ku, Saitama, Japan
| | - Tasuku Arai
- Laboratory of Biochemistry, Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, 307 Fukasaku, Minuma-ku, Saitama, Japan
| | - Satoshi Yokota
- Division of Cellular & Molecular Toxicology, Center for Biological Safety & Research, National Institute of Health Sciences, 3-25-26 Tono-machi, Kawasaki-ku, Kawasaki, Kanagawa, 210-9501, Japan
| | - Naoko Tsugawa
- Laboratory of Hygienic Sciences, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, Japan; Faculty of Nutrition, Kobe Gakuin University, 518 Ikawadanicho-Arise, Nishi, Kobe, 651-2180, Japan
| | - Maya Kamao
- Laboratory of Hygienic Sciences, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, Japan; Extension Center, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, Japan
| | - Yoshitomo Suhara
- Laboratory of Hygienic Sciences, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, Japan; Laboratory of Organic Synthesis and Medicinal Chemistry, Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, 307 Fukasaku, Minuma-ku, Saitama, Japan
| | - Toshiyuki Sakaki
- Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama, Japan
| | - Kimie Nakagawa
- Laboratory of Hygienic Sciences, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, Japan; Laboratory of Hygienic Sciences, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3, Minatojima, Chuo-ku, Kobe Hyogo, 650-8586, Japan.
| | - Toshio Okano
- Laboratory of Hygienic Sciences, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, Japan.
| | - Yoshihisa Hirota
- Laboratory of Hygienic Sciences, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, Japan; Laboratory of Biochemistry, Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, 307 Fukasaku, Minuma-ku, Saitama, Japan.
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Tizaoui K, Chikhaoui A, Yacoub-Youssef H. Role of VDR gene polymorphisms and environmental factors in the development of skin cancers: evidence by updated meta-analysis. Arch Dermatol Res 2025; 317:437. [PMID: 39969663 DOI: 10.1007/s00403-025-03975-9] [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: 12/28/2024] [Revised: 12/28/2024] [Accepted: 02/03/2025] [Indexed: 02/20/2025]
Abstract
The vitamin D and its receptor the VDR have pleiotropic effects on different biological mechanisms, including skin cancers. The sun UV radiation has confirmed effects on both skin cancers and on VD/VDR pathways. We aim to investigate the role of the VDR and its interaction with specific environmental factors to develop skin cancers. We conducted meta-analyses of published association studies on the VDR gene polymorphisms FokI, BsmI, TaqI and AapI and skin cancers. Subgroup analyses were performed to investigate the impact of environmental factors on skin cancers. Meta-analysis showed that the VDR Fok I polymorphism was associated with melanoma risk (CT vs. CC + TT, P = 0.020), with CT genotype as a significant risk factor. We found also significant association for the VDR BsmI polymorphism (AG vs. GG model, P = 0.020), as AG genotype having a protective effect against melanoma. However the VDR TaqI and ApaI polymorphisms were not associated with melanoma in the overall analysis. Met-analysis of studies on non-melanoma cancers (NMSC) showed significant effects of FokI (TT vs. CT + TT, P = 0.002, CC vs. CT, P = 0.017 and CC vs. TT, P = 0.001), with TT genotype as a risk factor, whereas the CC genotype was protective against NMSC. The TaqI showed also significant association with NMSK (T vs. C contrast allele: P = 0.006 and TT vs. CT + CC, P = 0.011), with T allele and TT genotype as having protective roles. Stratification according to geographic localisation showed that the FokI CC genotype had protective effect in both North America (CC vs. CT + TT, P = 0.003) and North Europe (CC vs. CT + TT, P = 0.010). Stratification according to the study period revealed that the FokI CT genotype had a highly significant risk (CT vs. TT, P < 0.001) in the last decade 2011-2020. VDR FokI and BsmI polymorphisms showed significant associations with melanoma, whereas FokI and TaqI were significantly associated with NMSC. Subgroup analysis revealed that factors such as the geographic localisation and study period influenced the association between the VDR gene and the risk of skin cancers.
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Affiliation(s)
- Kalthoum Tizaoui
- Laboratory of Biomedical Genomics and Oncogenetics (LR16IPT05), Institut Pasteur de Tunis, Université Tunis El Manar, El Manar I, 1002, Tunis, Tunisia.
| | - Asma Chikhaoui
- Laboratory of Biomedical Genomics and Oncogenetics (LR16IPT05), Institut Pasteur de Tunis, Université Tunis El Manar, El Manar I, 1002, Tunis, Tunisia
| | - Houda Yacoub-Youssef
- Laboratory of Biomedical Genomics and Oncogenetics (LR16IPT05), Institut Pasteur de Tunis, Université Tunis El Manar, El Manar I, 1002, Tunis, Tunisia
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Meng Z, Song L, Wang S, Duan G. Investigating Drug-Induced Thyroid Dysfunction Adverse Events Associated With Non-Selective RET Multi-Kinase Inhibitors: A Pharmacovigilance Analysis Utilizing FDA Adverse Event Reporting System Data. Clin Epidemiol 2025; 17:87-104. [PMID: 39989882 PMCID: PMC11844211 DOI: 10.2147/clep.s494215] [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: 10/17/2024] [Accepted: 01/17/2025] [Indexed: 02/25/2025] Open
Abstract
Purpose This study aims to investigate the potential association between non-selective RET kinase inhibitors and thyroid dysfunction (TD) by conducting a pharmacovigilance analysis using data from the US FDA Adverse Event Reporting System (FAERS). Methods Data for non-selective RET MKIs were obtained from the FAERS database, spanning the first quarter of 2015 to the fourth quarter of 2023. Disproportionality analysis was used to quantify the AE signals associated with non-selective RET MKIs and to identify TD AEs. Subgroup analyses and multivariate logistic regressions were used to assess the factors influencing the occurrence of TD AEs. Time-to-onset (TTO) analysis and the Weibull Shape Parameter (WSP) test were also performed. Results Descriptive analysis revealed an increasing trend in TD adverse events linked to non-selective RET MKIs, with a notable proportion of serious reactions reported. Disproportionality analysis using ROR, PRR, BCPNN, and EBGM algorithms consistently demonstrated a positive association between Sunitinib, Cabozantinib, and Lenvatinib with TD adverse events. Subgroup analyses highlighted differential susceptibility to TD based on age, gender, and weight, with varying patterns observed for each inhibitor. Logistic regression analyses identified factors independently influencing the occurrence of TD adverse events, emphasizing the importance of age, gender, and weight in patient stratification. Time-to-onset analysis indicated early manifestation of TD adverse events following treatment with non-selective RET MKIs, with a decreasing risk over time. Conclusion The results of our study indicate a correlation between the use of non-selective RET MKIs and the occurrence of TD AEs. This may provide support for the clinical monitoring and risk identification of non-selective RET MKIs. Nevertheless, further clinical studies are required to substantiate the findings of this study.
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Affiliation(s)
- Zhuda Meng
- Department of Thyroid Surgery, Changzhi People’s Hospital, Changzhi, People’s Republic of China
| | - Liying Song
- Department of Thyroid Surgery, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
| | - Shuang Wang
- Department of Gastroenterology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, People’s Republic of China
| | - Guosheng Duan
- Radiotherapy Department, Shanxi Provincial Peoples Hospital: Fifth Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
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Varshosaz P, O'Connor C, Moise AR. Feedback regulation of retinaldehyde reductase DHRS3, a critical determinant of retinoic acid homeostasis. FEBS Lett 2025; 599:340-351. [PMID: 39420244 PMCID: PMC11808460 DOI: 10.1002/1873-3468.15038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 09/13/2024] [Accepted: 09/18/2024] [Indexed: 10/19/2024]
Abstract
Retinoic acid is crucial for vertebrate embryogenesis, influencing anterior-posterior patterning and organogenesis through its interaction with nuclear hormone receptors comprising heterodimers of retinoic acid receptors (RARα, β, or γ) and retinoid X receptors (RXRα, β, or γ). Tissue retinoic acid levels are tightly regulated since both its excess and deficiency are deleterious. Dehydrogenase/reductase 3 (DHRS3) plays a critical role in this regulation by converting retinaldehyde to retinol, preventing excessive retinoic acid formation. Mutations in DHRS3 can result in embryonic lethality and congenital defects. This study shows that mouse Dhrs3 expression is responsive to vitamin A status and is directly regulated by the RAR/RXR complex through cis-regulatory elements. This highlights a negative feedback mechanism that ensures retinoic acid homeostasis.
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Affiliation(s)
- Parisa Varshosaz
- Biology and Biomolecular Sciences Ph.D. Program, Northern Ontario School of MedicineLaurentian UniversitySudburyCanada
| | - Catherine O'Connor
- Medical Sciences DivisionNorthern Ontario School of MedicineSudburyCanada
| | - Alexander R. Moise
- Medical Sciences DivisionNorthern Ontario School of MedicineSudburyCanada
- Department of Biology and Biomolecular Sciences ProgramLaurentian UniversitySudburyCanada
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Patalano SD, Fuxman Bass P, Fuxman Bass JI. Transcription factors in the development and treatment of immune disorders. Transcription 2025; 16:118-140. [PMID: 38100543 PMCID: PMC11970766 DOI: 10.1080/21541264.2023.2294623] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 12/05/2023] [Accepted: 12/08/2023] [Indexed: 12/17/2023] Open
Abstract
Immune function is highly controlled at the transcriptional level by the binding of transcription factors (TFs) to promoter and enhancer elements. Several TF families play major roles in immune gene expression, including NF-κB, STAT, IRF, AP-1, NRs, and NFAT, which trigger anti-pathogen responses, promote cell differentiation, and maintain immune system homeostasis. Aberrant expression, activation, or sequence of isoforms and variants of these TFs can result in autoimmune and inflammatory diseases as well as hematological and solid tumor cancers. For this reason, TFs have become attractive drug targets, even though most were previously deemed "undruggable" due to their lack of small molecule binding pockets and the presence of intrinsically disordered regions. However, several aspects of TF structure and function can be targeted for therapeutic intervention, such as ligand-binding domains, protein-protein interactions between TFs and with cofactors, TF-DNA binding, TF stability, upstream signaling pathways, and TF expression. In this review, we provide an overview of each of the important TF families, how they function in immunity, and some related diseases they are involved in. Additionally, we discuss the ways of targeting TFs with drugs along with recent research developments in these areas and their clinical applications, followed by the advantages and disadvantages of targeting TFs for the treatment of immune disorders.
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Affiliation(s)
- Samantha D. Patalano
- Biology Department, Boston University, Boston, MA, USA
- Molecular Biology, Cellular Biology and Biochemistry Program, Boston University, Boston, MA, USA
| | - Paula Fuxman Bass
- Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
| | - Juan I. Fuxman Bass
- Biology Department, Boston University, Boston, MA, USA
- Molecular Biology, Cellular Biology and Biochemistry Program, Boston University, Boston, MA, USA
- Bioinformatics Program, Boston University, Boston, MA, USA
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Murugesan H, Sampath P, A VK, R S, Veerasamy A, Ranganathan UD, Paramasivam S, Bethunaickan R. Association of CYP27B1 gene polymorphisms with pulmonary tuberculosis and vitamin D levels. Gene 2024; 927:148679. [PMID: 38876405 DOI: 10.1016/j.gene.2024.148679] [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: 01/25/2024] [Revised: 05/08/2024] [Accepted: 06/10/2024] [Indexed: 06/16/2024]
Abstract
BACKGROUND AND OBJECTIVES Genetic factors are reported to be connected with tuberculosis (TB) infection. Studies have shown that genetic variations in genes involved in the vitamin D pathway influence the levels of vitamin D found in the bloodstream (serum). Cyp27b1 (1α-hydroxylase) is an enzyme that activates the synthesis of bioactive vitamin D3 by hydroxylation of 25(OH)D3.The in vitro studies reported rare gene variants of Cyp27b1 such as rs118204011 and rs118204012, associated with loss of Cyp27b1 function and lower serum vitamin D levels. Globally, a critical gap exists in understanding the link between these gene variants with TB and vitamin D levels. Hence, the study objective is to comprehend the association of Cyp27b1 rs118204009 (G/A), rs118204011 (C/T), and rs118204012 (A/G) with tuberculosis susceptibility/protection and to assess the influence of gene variants on vitamin D levels in both healthy controls (HCs) and those with pulmonary tuberculosis (PTB) in South India. METHODS Genomic DNA extraction was performed by salting-out procedure and subsequently genotyped through polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. Vitamin D level was measured by Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS In rs118204012 (A/G), a substantial association was found with PTB susceptibility in allele 'A' [Odds Ratio (OR): 1.52 (1.02-2.26); p = 0.044] and 'AA' genotype [OR: 1.69 (1.02-2.81); p = 0.040] through the dominant model. Allele 'G' [OR: 0.66 (0.44-0.98); p = 0.044) was found to be associated with protection against TB. Males were associated with increased susceptibility towards TB compared to females in the rs118204011 "CC" [OR: 3.94 (1.94-7.98); p = 0.002] and rs118204012 'AA' [OR: 4.57 (2.13-9.79); p = 0.0001] genotypes. Vitamin D insufficiency (<30 ng/ml) was more prevalent in PTB patients (66.67 %) with the rs118201012 'AA' genotype compared with healthy controls (57.14 %). This genotype was associated with disease susceptible odds ratio of 1.5. CONCLUSION Cyp27b1 rs118204012 'AA' genotype was found to have association with vitamin D insufficiency and TB susceptibility. In terms of gender, our findings suggest that male individuals are correlated with a higher TB risk. This suggest that the gene variants may be involved in the downstream processing of serum Vitamin D levels and its association with the disease.
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Affiliation(s)
- Harishankar Murugesan
- Department of Immunology, ICMR-National Institute for Research in Tuberculosis, Chennai, India
| | - Pavithra Sampath
- Department of Immunology, ICMR-National Institute for Research in Tuberculosis, Chennai, India
| | - Vamsi Kumar A
- Department of Immunology, ICMR-National Institute for Research in Tuberculosis, Chennai, India
| | - Srividhya R
- Department of Immunology, ICMR-National Institute for Research in Tuberculosis, Chennai, India
| | - Athikesavan Veerasamy
- Department of Immunology, ICMR-National Institute for Research in Tuberculosis, Chennai, India
| | - Uma Devi Ranganathan
- Department of Immunology, ICMR-National Institute for Research in Tuberculosis, Chennai, India
| | - Selvaraj Paramasivam
- Department of Immunology, ICMR-National Institute for Research in Tuberculosis, Chennai, India
| | - Ramalingam Bethunaickan
- Department of Immunology, ICMR-National Institute for Research in Tuberculosis, Chennai, India.
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Doost ME, Hong J, Broatch JE, Applegate MT, Wagner CE, Marshall PA, Jurutka PW. Synergistic Activation of VDR-RXR Heterodimers by Vitamin D and Rexinoids in Human Kidney and Brain Cells. Cells 2024; 13:1878. [PMID: 39594626 PMCID: PMC11592939 DOI: 10.3390/cells13221878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 11/07/2024] [Accepted: 11/07/2024] [Indexed: 11/28/2024] Open
Abstract
The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D), binds to the vitamin D receptor (VDR) with high affinity. The VDR then heterodimerizes with the retinoid X receptor (RXR) and associates with vitamin D response elements (VDREs) to regulate the transcription of target genes. Bexarotene (Bex) is an RXR ligand (rexinoid) developed to treat cutaneous T-cell lymphoma and is a putative therapeutic for other diseases. We postulate that VDR ligands (1,25D) and RXR ligands (Bex/analogs) can "synergize" to "super-activate" the VDR-RXR heterodimer. This "cross-talk" could allow disorders treated with high-dose Bex therapy (leading to significant adverse side effects) to instead be treated using both low-dose Bex and vitamin D. Thus, we designed experiments to examine the effect of both VDR and RXR ligands, alone and in combination, to activate VDR-RXR-mediated transcription. The goal was to determine if selected RXR-specific ligands can synergize with vitamin D to amplify RXR-VDR activity. The results demonstrate a synergistic effect with both Bex and 1,25D which could be further modulated by (1) the protein levels (or polymorphic version) of VDR present in the cell, (2) the concentration of the ligands, (3) the cellular "background" (e.g., brain cells versus kidney cells), (4) the nature of the VDRE platform, or (5) the type of rexinoid (Bex analogs). Our findings suggest that diseases that respond to treatment with either vitamin D, or with rexinoids, may be amenable to enhanced therapeutic potential by employing multi-ligand dosing via combinatorial therapy.
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Affiliation(s)
| | | | | | | | | | - Pamela A. Marshall
- School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA; (M.E.D.); (J.H.); (J.E.B.); (M.T.A.); (C.E.W.); (P.W.J.)
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Jain SK, Justin Margret J, Abrams SA, Levine SN, Bhusal K. The Impact of Vitamin D and L-Cysteine Co-Supplementation on Upregulating Glutathione and Vitamin D-Metabolizing Genes and in the Treatment of Circulating 25-Hydroxy Vitamin D Deficiency. Nutrients 2024; 16:2004. [PMID: 38999752 PMCID: PMC11243476 DOI: 10.3390/nu16132004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 06/18/2024] [Accepted: 06/21/2024] [Indexed: 07/14/2024] Open
Abstract
Vitamin D receptors are expressed in many organs and tissues, which suggests that vitamin D (VD) affects physiological functions beyond its role in maintaining bone health. Deficiency or inadequacy of 25(OH)VD is widespread globally. Population studies demonstrate that a positive association exists between a high incidence of VD deficiency and a high incidence of chronic diseases, including dementia, diabetes, and heart disease. However, many subjects have difficulty achieving the required circulating levels of 25(OH)VD even after high-dose VD supplementation, and randomized controlled clinical trials have reported limited therapeutic success post-VD supplementation. Thus, there is a discordance between the benefits of VD supplementation and the prevention of chronic diseases in those with VD deficiency. Why this dissociation exists is currently under debate and is of significant public interest. This review discusses the downregulation of VD-metabolizing genes needed to convert consumed VD into 25(OH)VD to enable its metabolic action exhibited by subjects with metabolic syndrome, obesity, and other chronic diseases. Research findings indicate a positive correlation between the levels of 25(OH)VD and glutathione (GSH) in both healthy and diabetic individuals. Cell culture and animal experiments reveal a novel mechanism through which the status of GSH can positively impact the expression of VD metabolism genes. This review highlights that for better success, VD deficiency needs to be corrected at multiple levels: (i) VD supplements and/or VD-rich foods need to be consumed to provide adequate VD, and (ii) the body needs to be able to upregulate VD-metabolizing genes to convert VD into 25(OH)VD and then to 1,25(OH)2VD to enhance its metabolic action. This review outlines the association between 25(OH)VD deficiency/inadequacy and decreased GSH levels, highlighting the positive impact of combined VD+LC supplementation on upregulating GSH, VD-metabolizing genes, and VDR. These effects have the potential to enhance 25(OH)VD levels and its therapeutic efficacy.
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Affiliation(s)
- Sushil K. Jain
- Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USA;
| | - Jeffrey Justin Margret
- Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USA;
| | - Steven A. Abrams
- Department of Pediatrics and Dell Pediatric Research Institute, Dell Medical School at the University of Texas at Austin, Austin, TX 78723, USA;
| | - Steven N. Levine
- Department of Medicine, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USA; (S.N.L.); (K.B.)
| | - Kamal Bhusal
- Department of Medicine, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USA; (S.N.L.); (K.B.)
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Sinclair-Black M, Garcia-Mejia RA, Blair LR, Angel R, Arbe X, Cavero D, Ellestad LE. Circadian regulation of calcium and phosphorus homeostasis during the oviposition cycle in laying hens. Poult Sci 2024; 103:103209. [PMID: 38052129 PMCID: PMC10746567 DOI: 10.1016/j.psj.2023.103209] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 10/12/2023] [Accepted: 10/13/2023] [Indexed: 12/07/2023] Open
Abstract
Maintenance of calcium and phosphorus homeostasis in laying hens is crucial for preservation of skeletal integrity and eggshell quality, though physiological regulation of these systems is incompletely defined. To investigate changes in mineral and vitamin D3 homeostasis during the 24-h egg formation cycle, 32-wk-old commercial laying hens were sampled at 1, 3, 4, 6, 7, 8, 12, 15, 18, 21, 23, and 24 h post-oviposition (HPOP; n ≥ 4). Ovum location and egg calcification stage were recorded, and blood chemistry, plasma vitamin D3 metabolites, circulating parathyroid hormone (PTH), and expression of genes mediating uptake and utilization of calcium and phosphorus were evaluated. Elevated levels of renal 25-hydroxylase from 12 to 23 HPOP suggest this tissue might play a role in vitamin D3 25-hydroxylation during eggshell calcification. In shell gland, retinoid-x-receptor gamma upregulation between 6 and 8 HPOP followed by subsequently increased vitamin D receptor indicate that vitamin D3 signaling is important for eggshell calcification. Increased expression of PTH, calcitonin, and fibroblast growth factor 23 (FGF23) receptors in the shell gland between 18 and 24 HPOP suggest elevated sensitivity to these hormones toward the end of eggshell calcification. Shell gland sodium-calcium exchanger 1 was upregulated between 4 and 7 HPOP and plasma membrane calcium ATPase 1 increased throughout eggshell calcification, suggesting the primary calcium transporter may differ according to eggshell calcification stage. Expression in shell gland further indicated that bicarbonate synthesis precedes transport, where genes peaked at 6 to 7 and 12 to 18 HPOP, respectively. Inorganic phosphorus transporter 1 (PiT-1) expression peaked in kidney between 12 and 15 HPOP, likely to excrete excess circulating phosphorus, and in shell gland between 18 and 21 HPOP. Upregulation of FGF23 receptors and PiT-1 during late eggshell calcification suggest shell gland phosphorus uptake is important at this time. Together, these findings identified potentially novel hormonal pathways involved in calcium and phosphorus homeostasis along with associated circadian patterns in gene expression that can be used to devise strategies aimed at improving eggshell and skeletal strength in laying hens.
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Affiliation(s)
| | | | - Lyssa R Blair
- Department of Poultry Science, University of Georgia, Athens, GA 30602, USA
| | - Roselina Angel
- Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA
| | | | | | - Laura E Ellestad
- Department of Poultry Science, University of Georgia, Athens, GA 30602, USA.
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van Driel M, Muñoz A, van Leeuwen JP. Overview of vitamin D actions in cancer. FELDMAN AND PIKE'S VITAMIN D 2024:679-718. [DOI: 10.1016/b978-0-323-91338-6.00034-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Kesharwani D, Brown AC. Navigating the Adipocyte Precursor Niche: Cell-Cell Interactions, Regulatory Mechanisms and Implications for Adipose Tissue Homeostasis. JOURNAL OF CELLULAR SIGNALING 2024; 5:65-86. [PMID: 38826152 PMCID: PMC11141760 DOI: 10.33696/signaling.5.114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/04/2024]
Abstract
Support for stem cell self-renewal and differentiation hinges upon the intricate microenvironment termed the stem cell 'niche'. Within the adipose tissue stem cell niche, diverse cell types, such as endothelial cells, immune cells, mural cells, and adipocytes, intricately regulate the function of adipocyte precursors. These interactions, whether direct or indirect, play a pivotal role in governing the balance between self-renewal and differentiation of adipocyte precursors into adipocytes. The mechanisms orchestrating the maintenance and coordination of this niche are still in the early stages of comprehension, despite their crucial role in regulating adipose tissue homeostasis. The complexity of understanding adipocyte precursor renewal and differentiation is amplified due to the challenges posed by the absence of suitable surface receptors for identification, limitations in creating optimal ex vivo culture conditions for expansion and constraints in conducting in vivo studies. This review delves into the current landscape of knowledge surrounding adipocyte precursors within the adipose stem cell niche. We will review the identification of adipocyte precursors, the cell-cell interactions they engage in, the factors influencing their renewal and commitment toward adipocytes and the transformations they undergo during instances of obesity.
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Affiliation(s)
- Devesh Kesharwani
- Center for Molecular Medicine, MaineHealth Institute for Research, 81 Research Drive, Scarborough, ME 04074, USA
| | - Aaron C. Brown
- Center for Molecular Medicine, MaineHealth Institute for Research, 81 Research Drive, Scarborough, ME 04074, USA
- School of Biomedical Sciences and Engineering, The University of Maine, Orono, Maine 04469, USA
- Tufts University School of Medicine, 145 Harrison Ave, Boston, MA 02111, USA
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12
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Kim MJ, Kulkarni V, Goode MA, Sivesind TE. Exploring the interactions of antihistamine with retinoic acid receptor beta (RARB) by molecular dynamics simulations and genome-wide meta-analysis. J Mol Graph Model 2023; 124:108539. [PMID: 37331258 PMCID: PMC10529808 DOI: 10.1016/j.jmgm.2023.108539] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 06/03/2023] [Accepted: 06/05/2023] [Indexed: 06/20/2023]
Abstract
Kaposi sarcoma (KS) is one of the most common AIDS-related malignant neoplasms, which can leave lesions on the skin among HIV patients. These lesions can be treated with 9-cis-retinoic acid (9-cis-RA), an endogenous ligand of retinoic acid receptors that has been FDA-approved for treatment of KS. However, topical application of 9-cis-RA can induce several unpleasant side effects, like headache, hyperlipidemia, and nausea. Hence, alternative therapeutics with less side effects are desirable. There are case reports associating over-the-counter antihistamine usage with regression of KS. Antihistamines competitively bind to H1 receptor and block the action of histamine, best known for being released in response to allergens. Furthermore, there are already dozens of antihistamines that are FDA-approved with less side effects than 9-cis-RA. This led our team to conduct a series of in-silico assays to determine whether antihistamines can activate retinoic acid receptors. First, we utilized high-throughput virtual screening and molecular dynamics simulations to model high-affinity interactions between antihistamines and retinoic acid receptor beta (RARβ). We then performed systems genetics analysis to identify a genetic association between H1 receptor itself and molecular pathways involved in KS. Together, these findings advocate for exploration of antihistamines against KS, starting with our two promising hit compounds, bepotastine and hydroxyzine, for experimental validation study in the future.
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Affiliation(s)
- Minjae J Kim
- University of Tennessee Health Sciences Center School of Medicine, Memphis, TN, USA.
| | | | - Micah A Goode
- University of Tennessee Health Sciences Center School of Medicine, Memphis, TN, USA.
| | - Torunn E Sivesind
- Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
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13
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Pike JW, Lee SM, Meyer MB. Molecular insights into mineralotropic hormone inter-regulation. Front Endocrinol (Lausanne) 2023; 14:1213361. [PMID: 37441497 PMCID: PMC10334211 DOI: 10.3389/fendo.2023.1213361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 06/13/2023] [Indexed: 07/15/2023] Open
Abstract
The regulation of mineral homeostasis involves the three mineralotropic hormones PTH, FGF23 and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Early research efforts focused on PTH and 1,25(OH)2D3 and more recently on FGF23 have revealed that each of these hormones regulates the expression of the other two. Despite early suggestions of transcriptional processes, it has been only recently that research effort have begun to delineate the genomic mechanisms underpinning this regulation for 1,25(OH)2D3 and FGF23; the regulation of PTH by 1,25(OH)2D3, however, remains obscure. We review here our molecular understanding of how PTH induces Cyp27b1 expression, the gene encoding the enzyme responsible for the synthesis of 1,25(OH)2D3. FGF23 and 1,25(OH)2D3, on the other hand, function by suppressing production of 1,25(OH)2D3. PTH stimulates the PKA-induced recruitment of CREB and its coactivator CBP at CREB occupied sites within the kidney-specific regulatory regions of Cyp27b1. PKA activation also promotes the nuclear translocation of SIK bound coactivators such as CRTC2, where it similarly interacts with CREB occupied Cyp27b1 sites. The negative actions of both FGF23 and 1,25(OH)2D3 appear to suppress Cyp27b1 expression by opposing the recruitment of CREB coactivators at this gene. Reciprocal gene actions are seen at Cyp24a1, the gene encoding the enzyme that degrades 1,25(OH)2D3, thereby contributing to the overall regulation of blood levels of 1,25(OH)2D3. Relative to PTH regulation, we summarize what is known of how 1,25(OH)2D3 regulates PTH suppression. These studies suggest that it is not 1,25(OH)2D3 that controls PTH levels in healthy subjects, but rather calcium itself. Finally, we describe current progress using an in vivo approach that furthers our understanding of the regulation of Fgf23 expression by PTH and 1,25(OH)2D3 and provide the first evidence that P may act to induce Fgf23 expression via a complex transcriptional mechanism in bone. It is clear, however, that additional advances will need to be made to further our understanding of the inter-regulation of each of these hormonal genes.
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Affiliation(s)
- J. Wesley Pike
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, United States
| | - Seong Min Lee
- Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, United States
| | - Mark B. Meyer
- Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, United States
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14
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Wang B, Gu B, Zhang T, Li X, Wang N, Ma C, Xiang L, Wang Y, Gao L, Yu Y, Song K, He P, Wang Y, Zhu J, Chen H. Good or bad: Paradox of plasminogen activator inhibitor 1 (PAI-1) in digestive system tumors. Cancer Lett 2023; 559:216117. [PMID: 36889376 DOI: 10.1016/j.canlet.2023.216117] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 02/17/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023]
Abstract
The fibrinolytic system is involved in many physiological functions, among which the important members can interact with each other, either synergistically or antagonistically to participate in the pathogenesis of many diseases. Plasminogen activator inhibitor 1 (PAI-1) acts as a crucial element of the fibrinolytic system and functions in an anti-fibrinolytic manner in the normal coagulation process. It inhibits plasminogen activator, and affects the relationship between cells and extracellular matrix. PAI-1 not only involved in blood diseases, inflammation, obesity and metabolic syndrome but also in tumor pathology. Especially PAI-1 plays a different role in different digestive tumors as an oncogene or cancer suppressor, even a dual role for the same cancer. We term this phenomenon "PAI-1 paradox". PAI-1 is acknowledged to have both uPA-dependent and -independent effects, and its different actions can result in both beneficial and adverse consequences. Therefore, this review will elaborate on PAI-1 structure, the dual value of PAI-1 in different digestive system tumors, gene polymorphisms, the uPA-dependent and -independent mechanisms of regulatory networks, and the drugs targeted by PAI-1 to deepen the comprehensive understanding of PAI-1 in digestive system tumors.
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Affiliation(s)
- Bofang Wang
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Baohong Gu
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Tao Zhang
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Xuemei Li
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Na Wang
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Chenhui Ma
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Lin Xiang
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Yunpeng Wang
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Lei Gao
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Yang Yu
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Kewei Song
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Puyi He
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Yueyan Wang
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Jingyu Zhu
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Hao Chen
- Lanzhou University Second Hospital, Lanzhou, Gansu, China; Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou, Gansu, China; Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, Gansu, China.
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15
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Kotsopoulou I, Vyas AK, Cory MJ, Chan CS, Jagarapu J, Gill S, Mudduluru M, Angelis D. Developmental changes of the fetal and neonatal thyroid gland and functional consequences on the cardiovascular system. J Perinatol 2022; 42:1576-1586. [PMID: 36376450 DOI: 10.1038/s41372-022-01559-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 10/29/2022] [Accepted: 11/01/2022] [Indexed: 11/16/2022]
Abstract
Thyroid hormones play an important role in the development and function of the cardiac myocyte. Dysregulation of the thyroid hormone milieu affects the fetal cardiac cells via complex molecular mechanisms, either by altering gene expression or directly by affecting post-translational processes. This review offers a comprehensive summary of the effects of thyroid hormones on the developing cardiovascular system and its adaptation. Furthermore, we will highlight the gaps in knowledge and provide suggestions for future research.
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Affiliation(s)
- Ioanna Kotsopoulou
- Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Arpita K Vyas
- Division of Pediatrics and Endocrinology, College of Medicine, California Northstate University, Elk Grove, CA, USA
| | - Melinda J Cory
- Division of Cardiology, Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Christina S Chan
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Jawahar Jagarapu
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Shamaila Gill
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Manjula Mudduluru
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Dimitrios Angelis
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
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Rastinejad F. Retinoic acid receptor structures: the journey from single domains to full-length complex. J Mol Endocrinol 2022; 69:T25-T36. [PMID: 36069789 PMCID: PMC11376212 DOI: 10.1530/jme-22-0113] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 09/07/2022] [Indexed: 11/08/2022]
Abstract
The retinoic acid receptors (RARα, β, and γ) are multi-domain polypeptides that heterodimerize with retinoid X receptors (RXRα, β, and γ) to form functional transcription factors. Understanding the three-dimensional molecular organization of these nuclear receptors (NRs) began with RAR and RXR DNA-binding domains (DBDs), and were followed with studies on isolated ligand-binding domains (LBDs). The more complete picture emerged in 2017 with the multi-domain crystal structure of RXRα-RARβ on its response element with retinoic acid molecules and coactivator segments on both proteins. The analysis of that structure and its complementary studies have clarified the direct communication pathways within RXR-RAR polypeptides, through which DNA binding, protein-ligand, and protein-protein interactions are integrated for overall functional responses. Understanding the molecular connections in the RXR-RAR complex has benefited from direct observations of the multi-domain structures of RXRα-PPARγ, RXRα-LXRβ, HNF-4α homodimer, and androgen receptor homodimer, each bound to its response element. These comprehensive NR structures show unique quaternary architectures, yet all have DBD-DBD, LBD-LBD, and DBD-LBD domain-domain contacts within them. These convergence zones allow signals from discrete domains of their polypeptides to be propagated and integrated across their entire complex, shaping their overall responses in an allosteric fashion.
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Affiliation(s)
- Fraydoon Rastinejad
- Nuffield Department of Medicine, University of Oxford, Target Discovery Institute (NDM RB), Oxford, UK
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17
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Giguère V, Evans RM. Chronicle of a discovery: the retinoic acid receptor. J Mol Endocrinol 2022; 69:T1-T11. [PMID: 35900848 DOI: 10.1530/jme-22-0117] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 06/18/2022] [Indexed: 11/08/2022]
Abstract
The landmark 1987 discovery of the retinoic acid receptor (RAR) came as a surprise, uncovering a genomic kinship between the fields of vitamin A biology and steroid receptors. This stunning breakthrough triggered a cascade of studies to deconstruct the roles played by the RAR and its natural and synthetic ligands in embryonic development, skin, growth, physiology, vision, and disease as well as providing a template to elucidate the molecular mechanisms by which nuclear receptors regulate gene expression. In this review, written from historic and personal perspectives, we highlight the milestones that led to the discovery of the RAR and the subsequent studies that enriched our knowledge of the molecular mechanisms by which a low-abundant dietary compound could be so essential to the generation and maintenance of life itself.
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Affiliation(s)
- Vincent Giguère
- Goodman Cancer Institute, McGill University, Montréal, Quebec, Canada
- Department of Biochemistry, McGill University, Montréal, Quebec, Canada
| | - Ronald M Evans
- The Salk Institute for Biological Studies, La Jolla, California, USA
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Balbuena E, Cheng J, Eroglu A. Carotenoids in orange carrots mitigate non-alcoholic fatty liver disease progression. Front Nutr 2022; 9:987103. [PMID: 36225879 PMCID: PMC9549209 DOI: 10.3389/fnut.2022.987103] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 09/02/2022] [Indexed: 11/23/2022] Open
Abstract
Background Carotenoids are abundant in colored fruits and vegetables. Non-alcoholic fatty liver disease (NAFLD) is a global burden and risk factor for end-stage hepatic diseases. This study aims to compare the anti-NAFLD efficacy between carotenoid-rich and carotenoid-deficient vegetables. Materials and methods Male C57BL/6J mice were randomized to one of four experimental diets for 15 weeks (n = 12 animals/group): Low-fat diet (LFD, 10% calories from fat), high-fat diet (HFD, 60% calories from fat), HFD with 20% white carrot powders (HFD + WC), or with 20% orange carrot powders (HFD + OC). Results We observed that carotenoids in the orange carrots reduced HFD-induced weight gain, better than white carrots. Histological and triglyceride (TG) analyses revealed significantly decreased HFD-induced hepatic lipid deposition and TG content in the HFD + WC group, which was further reduced in the HFD + OC group. Western blot analysis demonstrated inconsistent changes of fatty acid synthesis-related proteins but significantly improved ACOX-1 and CPT-II, indicating that orange carrot carotenoids had the potential to inhibit NAFLD by improving β-oxidation. Further investigation showed significantly higher mRNA and protein levels of PPARα and its transcription factor activity. Conclusion Carotenoid-rich foods may display more potent efficacy in mitigating NAFLD than those with low carotenoid levels.
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Affiliation(s)
- Emilio Balbuena
- Plants for Human Health Institute, North Carolina State University, Kannapolis, NC, United States
- Department of Molecular and Structural Biochemistry, College of Agriculture and Life Sciences, North Carolina State University, Raleigh, NC, United States
| | - Junrui Cheng
- Plants for Human Health Institute, North Carolina State University, Kannapolis, NC, United States
| | - Abdulkerim Eroglu
- Plants for Human Health Institute, North Carolina State University, Kannapolis, NC, United States
- Department of Molecular and Structural Biochemistry, College of Agriculture and Life Sciences, North Carolina State University, Raleigh, NC, United States
- *Correspondence: Abdulkerim Eroglu,
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19
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Wu XY, Nie L, Lu XJ, Fei CJ, Chen J. Molecular characterization, expression and functional analysis of large yellow croaker (Larimichthys crocea) peroxisome proliferator-activated receptor gamma. FISH & SHELLFISH IMMUNOLOGY 2022; 123:50-60. [PMID: 35227879 DOI: 10.1016/j.fsi.2022.02.021] [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: 01/20/2022] [Revised: 02/11/2022] [Accepted: 02/12/2022] [Indexed: 06/14/2023]
Abstract
The peroxisome proliferator-activated receptor gamma (PPARγ) are nuclear receptors with distinct roles in energy metabolism and immunity. Although extensively studied in mammals, immunomodulatory roles of this molecule in teleost fish remain to be investigated. In this study, large yellow croaker (Larimichthys crocea) PPARγ (LcPPARγ) sequence was cloned, which encodes a polypeptide of 541 amino acids that include signature domains belonging to the nuclear receptor superfamily. Phylogenetically, LcPPARγ was most closely related to PPARγ derived from European sea bass (Dicentrarchus labrax). Quantitative analysis shown a ubiquitous expression of this molecule, with highest expression level detected in the intestine. The expression of LcPPARγ was decreased in the intestine, muscle, body kidney, spleen and head kidney-derived monocytes/macrophages (MO/MФs) over the course of Vibrio alginolyticus (V. alginolyticus) infection. In contrast, an up-regulation of LcPPARγ was observed in head kidney-derived MO/MФs following docosahexaenoic acid (DHA) treatment. This increase in LcPPARγ leads to an up-regulation of LcCD11b and LcCD18 and an enhancement of complement-mediated phagocytosis. Furthermore, cytokine secretions of V. alginolyticus-stimulated MO/MФs were modulated following LcPPARγ activations that up-regulated the expression of LcIL-10, while decreased the expression of LcIL-1β, LcTNF-α and LcTGF-β1. Overall, our results indicated that LcPPARγ plays a role in regulating functions of MO/MФs and likely contribute to MO/MФs polarization.
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Affiliation(s)
- Xiang-Yu Wu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo City, China; Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Meishan Campus, Ningbo University, Ningbo City, China; Collaborative Innovation Center for Zhejiang Marine High-efficiency and Healthy Aquaculture, School of Marine Sciences, Ningbo University, Ningbo City, China
| | - Li Nie
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Meishan Campus, Ningbo University, Ningbo City, China; Collaborative Innovation Center for Zhejiang Marine High-efficiency and Healthy Aquaculture, School of Marine Sciences, Ningbo University, Ningbo City, China
| | - Xin-Jiang Lu
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Meishan Campus, Ningbo University, Ningbo City, China
| | - Chen-Jie Fei
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Meishan Campus, Ningbo University, Ningbo City, China; Collaborative Innovation Center for Zhejiang Marine High-efficiency and Healthy Aquaculture, School of Marine Sciences, Ningbo University, Ningbo City, China.
| | - Jiong Chen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo City, China; Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Meishan Campus, Ningbo University, Ningbo City, China; Collaborative Innovation Center for Zhejiang Marine High-efficiency and Healthy Aquaculture, School of Marine Sciences, Ningbo University, Ningbo City, China.
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20
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Yu B, Wang CY. Osteoporosis and periodontal diseases - An update on their association and mechanistic links. Periodontol 2000 2022; 89:99-113. [PMID: 35244945 DOI: 10.1111/prd.12422] [Citation(s) in RCA: 162] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Periodontitis and osteoporosis are prevalent inflammation-associated skeletal disorders that pose significant public health challenges to our aging population. Both periodontitis and osteoporosis are bone disorders closely associated with inflammation and aging. There has been consistent intrigue on whether a systemic skeletal disease such as osteoporosis will amplify the alveolar bone loss in periodontitis. A survey of the literature published in the past 25 years indicates that systemic low bone mineral density (BMD) is associated with alveolar bone loss, while recent evidence also suggests a correlation between clinical attachment loss and other parameters of periodontitis. Inflammation and its influence on bone remodeling play critical roles in the pathogenesis of both osteoporosis and periodontitis and could serve as the central mechanistic link between these disorders. Enhanced cytokine production and elevated inflammatory response exacerbate osteoclastic bone resorption while inhibiting osteoblastic bone formation, resulting in a net bone loss. With aging, accumulation of oxidative stress and cellular senescence drive the progression of osteoporosis and exacerbation of periodontitis. Vitamin D deficiency and smoking are shared risk factors and may mediate the connection between osteoporosis and periodontitis, through increasing oxidative stress and impairing host response to inflammation. With the connection between systemic and localized bone loss in mind, routine dental exams and intraoral radiographs may serve as a low-cost screening tool for low systemic BMD and increased fracture risk. Conversely, patients with fracture risk beyond the intervention threshold are at greater risk for developing severe periodontitis and undergo tooth loss. Various Food and Drug Administration-approved therapies for osteoporosis have shown promising results for treating periodontitis. Understanding the molecular mechanisms underlying their connection sheds light on potential therapeutic strategies that may facilitate co-management of systemic and localized bone loss.
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Affiliation(s)
- Bo Yu
- Division of Regenerative and Constitutive Sciences, School of Dentistry, University of California at Los Angeles, Los Angeles, California, USA
| | - Cun-Yu Wang
- Division of Oral Biology and Medicine, School of Dentistry, University of California at Los Angeles, Los Angeles, California, USA.,Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, Broad Stem Cell Research Center and Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA
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21
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Lo CSC, Kiang KMY, Leung GKK. Anti-tumor effects of vitamin D in glioblastoma: mechanism and therapeutic implications. J Transl Med 2022; 102:118-125. [PMID: 34504307 DOI: 10.1038/s41374-021-00673-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/24/2021] [Accepted: 08/26/2021] [Indexed: 11/09/2022] Open
Abstract
Glioma is the most prevalent primary brain tumor in adults among which glioblastoma is the most malignant and lethal subtype. Its common resistance to conventional chemotherapeutics calls for the development of alternative or concomitant treatment. Taking advantage of its endocrine function as a neurosteroid, vitamin D has become a target of interest to be used in conjunction with different chemotherapies. In this article, we review the mechanisms through which vitamin D and its analogs induce anti-tumor activity in glioblastoma, and the practical issues relevant to their potential application based on in vitro and in vivo studies. Vitamin D has largely been reported to promote cell cycle arrest and induce cell death to suppress tumor growth in glioblastoma. Glioblastoma cells treated with vitamin D have also shown reduced migratory and invasive phenotypes, and reduced stemness. It is worth noting that vitamin D analogs are able to produce similar inhibitory actions without causing adverse effects such as hypercalcemia in vivo. Upregulation of vitamin D receptors by vitamin D and its analogs may also play a role in enhancing its anti-tumor activity. Based on current findings and taking into consideration its potential cancer-protective effects, the clinical application of vitamin D in glioblastoma treatment and prevention will be discussed. With some study findings subject to controversy, further investigation is warranted to elucidate the mechanism of action of vitamin D and to evaluate relevant issues regarding its treatment efficacy and potential clinical application.
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Affiliation(s)
- Carmen Sze-Ching Lo
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong
| | - Karrie Mei-Yee Kiang
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong
| | - Gilberto Ka-Kit Leung
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong.
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22
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Manhas KR, Marshall PA, Wagner CE, Jurutka PW, Mancenido MV, Debray HZ, Blattman JN. Rexinoids Modulate Effector T Cell Expression of Mucosal Homing Markers CCR9 and α4β7 Integrin and Direct Their Migration In Vitro. Front Immunol 2022; 13:746484. [PMID: 35154092 PMCID: PMC8829570 DOI: 10.3389/fimmu.2022.746484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 01/03/2022] [Indexed: 11/19/2022] Open
Abstract
Altering T cell trafficking to mucosal regions can enhance immune responses towards pathogenic infections and cancers at these sites, leading to better outcomes. All-trans-retinoic acid (ATRA) promotes T cell migration to mucosal surfaces by inducing transcription of the mucosal-homing receptors CCR9 and α4β7 via binding to retinoic acid receptors (RARs), which heterodimerize with retinoid X receptors (RXRs) to function. However, the unstable nature and toxicity of ATRA limit its use as a widespread treatment modality for mucosal diseases. Therefore, identifying alternatives that could reduce or eliminate the use of ATRA are needed. Rexinoids are synthetically derived compounds structurally similar to ATRA. Originally named for their ability to bind RXRs, rexinoids can enhance RAR-mediated gene transcription. Furthermore, rexinoids are more stable than ATRA and possess an improved safety profile, making them attractive candidates for use in clinical settings. Here we show that select novel rexinoids act as ATRA mimics, as they cause increased CCR9 and α4β7 expression and enhanced migration to the CCR9 ligand, CCL25 in vitro, even in the absence of ATRA. Conversely, other rexinoids act synergistically with ATRA, as culturing cells with suboptimal doses of both compounds resulted in CCR9 expression and migration to CCL25. Overall, our findings show that rexinoids can be used independently or synergistically with ATRA to promote mucosal homing of T cells in vitro, and lends support for the prospective clinical use of these compounds in immunotherapeutic approaches for pathogenic infections or cancers at mucosal surfaces.
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Affiliation(s)
- Kavita R. Manhas
- Biodesign Center for Immunotherapy, Vaccines, and Virotherapy, Arizona State University, Tempe, AZ, United States
| | - Pamela A. Marshall
- School of Mathematical and Natural Sciences, Arizona State University West Campus, Glendale, AZ, United States
| | - Carl E. Wagner
- School of Mathematical and Natural Sciences, Arizona State University West Campus, Glendale, AZ, United States
| | - Peter W. Jurutka
- School of Mathematical and Natural Sciences, Arizona State University West Campus, Glendale, AZ, United States
| | - Michelle V. Mancenido
- School of Mathematical and Natural Sciences, Arizona State University West Campus, Glendale, AZ, United States
| | - Hannah Z. Debray
- Biodesign Center for Immunotherapy, Vaccines, and Virotherapy, Arizona State University, Tempe, AZ, United States
| | - Joseph N. Blattman
- Biodesign Center for Immunotherapy, Vaccines, and Virotherapy, Arizona State University, Tempe, AZ, United States
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Blackmur JP, Vaughan-Shaw PG, Donnelly K, Harris BT, Svinti V, Ochocka-Fox AM, Freile P, Walker M, Gurran T, Reid S, Semple CA, Din FVN, Timofeeva M, Dunlop MG, Farrington SM. Gene Co-Expression Network Analysis Identifies Vitamin D-Associated Gene Modules in Adult Normal Rectal Epithelium Following Supplementation. Front Genet 2022; 12:783970. [PMID: 35096006 PMCID: PMC8790603 DOI: 10.3389/fgene.2021.783970] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 12/02/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is a common, multifactorial disease. While observational studies have identified an association between lower vitamin D and higher CRC risk, supplementation trials have been inconclusive and the mechanisms by which vitamin D may modulate CRC risk are not well understood. We sought to perform a weighted gene co-expression network analysis (WGCNA) to identify modules present after vitamin D supplementation (when plasma vitamin D level was sufficient) which were absent before supplementation, and then to identify influential genes in those modules. The transcriptome from normal rectal mucosa biopsies of 49 individuals free from CRC were assessed before and after 12 weeks of 3200IU/day vitamin D (Fultium-D3) supplementation using paired-end total RNAseq. While the effects on expression patterns following vitamin D supplementation were subtle, WGCNA identified highly correlated genes forming gene modules. Four of the 17 modules identified in the post-vitamin D network were not preserved in the pre-vitamin D network, shedding new light on the biochemical impact of supplementation. These modules were enriched for GO terms related to the immune system, hormone metabolism, cell growth and RNA metabolism. Across the four treatment-associated modules, 51 hub genes were identified, with enrichment of 40 different transcription factor motifs in promoter regions of those genes, including VDR:RXR. Six of the hub genes were nominally differentially expressed in studies of vitamin D effects on adult normal mucosa organoids: LCN2, HLA-C, AIF1L, PTPRU, PDE4B and IFI6. By taking a gene-correlation network approach, we have described vitamin D induced changes to gene modules in normal human rectal epithelium in vivo, the target tissue from which CRC develops.
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Affiliation(s)
- James P. Blackmur
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
| | - Peter G. Vaughan-Shaw
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
| | - Kevin Donnelly
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
| | - Bradley T. Harris
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
| | - Victoria Svinti
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
| | - Anna-Maria Ochocka-Fox
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
| | - Paz Freile
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
| | - Marion Walker
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
| | - Toby Gurran
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
| | - Stuart Reid
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
| | - Colin A. Semple
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
| | - Farhat V. N. Din
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
| | - Maria Timofeeva
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
- Department of Public Health, Danish Institute for Advanced Study, University of Southern Denmark, Odense, Denmark
| | - Malcolm G. Dunlop
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
| | - Susan M. Farrington
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
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Pike JW, Meyer MB. New Approaches to Assess Mechanisms of Action of Selective Vitamin D Analogues. Int J Mol Sci 2021; 22:ijms222212352. [PMID: 34830234 PMCID: PMC8619157 DOI: 10.3390/ijms222212352] [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: 10/14/2021] [Revised: 11/05/2021] [Accepted: 11/11/2021] [Indexed: 12/28/2022] Open
Abstract
Recent studies of transcription have revealed an advanced set of overarching principles that govern vitamin D action on a genome-wide scale. These tenets of vitamin D transcription have emerged as a result of the application of now well-established techniques of chromatin immunoprecipitation coupled to next-generation DNA sequencing that have now been linked directly to CRISPR-Cas9 genomic editing in culture cells and in mouse tissues in vivo. Accordingly, these techniques have established that the vitamin D hormone modulates sets of cell-type specific genes via an initial action that involves rapid binding of the VDR-ligand complex to multiple enhancer elements at open chromatin sites that drive the expression of individual genes. Importantly, a sequential set of downstream events follows this initial binding that results in rapid histone acetylation at these sites, the recruitment of additional histone modifiers across the gene locus, and in many cases, the appearance of H3K36me3 and RNA polymerase II across gene bodies. The measured recruitment of these factors and/or activities and their presence at specific regions in the gene locus correlate with the emerging presence of cognate transcripts, thereby highlighting sequential molecular events that occur during activation of most genes both in vitro and in vivo. These features provide a novel approach to the study of vitamin D analogs and their actions in vivo and suggest that they can be used for synthetic compound evaluation and to select for novel tissue- and gene-specific features. This may be particularly useful for ligand activation of nuclear receptors given the targeting of these factors directly to genetic sites in the nucleus.
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Affiliation(s)
- John Wesley Pike
- Correspondence: ; Tel.: +1-(608)-262-8229; Fax: +1-(608)-263-7609
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25
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Chen A, Han Y, Poss KD. Regulation of zebrafish fin regeneration by vitamin D signaling. Dev Dyn 2021; 250:1330-1339. [PMID: 33064344 PMCID: PMC8050121 DOI: 10.1002/dvdy.261] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 10/10/2020] [Accepted: 10/12/2020] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Vitamin D is an essential nutrient that has long been known to regulate skeletal growth and integrity. In models of major appendage regeneration, treatment with vitamin D analogs has been reported to improve aspects of zebrafish fin regeneration in specific disease or gene misexpression contexts, but also to disrupt pattern in regenerating salamander limbs. Recently, we reported strong mitogenic roles for vitamin D signaling in several zebrafish tissues throughout life stages, including epidermal cells and osteoblasts of adult fins. To our knowledge, molecular genetic approaches to dissect vitamin D function in appendage regeneration have not been described. RESULTS Using a knock-in GFP reporter for the expression of the vitamin D target gene and negative regulator cyp24a1, we identified active vitamin D signaling in adult zebrafish fins during tissue homeostasis and regeneration. Transgenic expression of cyp24a1 or a dominant-negative vitamin D receptor (VDR) inhibited regeneration of amputated fins, whereas global vitamin D treatment accelerated regeneration. Using tissue regeneration enhancer elements, we found that local enhancement of VDR expression could improve regeneration with low doses of a vitamin D analog. CONCLUSIONS Vitamin D signaling enhances the efficacy of fin regeneration in zebrafish.
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Affiliation(s)
- Anzhi Chen
- Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, 27710, USA
- Regeneration Next, Duke University, Durham, North Carolina, 27710, USA
| | - Yanchao Han
- Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, 27710, USA
- Regeneration Next, Duke University, Durham, North Carolina, 27710, USA
- Institute for Cardiovascular Science, Medical College, Soochow University, Suzhou, China
| | - Kenneth D. Poss
- Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, 27710, USA
- Regeneration Next, Duke University, Durham, North Carolina, 27710, USA
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Abstract
The present review traces the road leading to discovery of L-thyroxine, thyroid hormone (3,5,3´-triiodo-L-thyronine, T3) and its cognate nuclear receptors. Thyroid hormone is a pleio-tropic regulator of growth, differentiation, and tissue homeostasis in higher organisms. The major site of the thyroid hormone action is predominantly a cell nucleus. T3 specific binding sites in the cell nuclei have opened a new era in the field of the thyroid hormone receptors (TRs) discovery. T3 actions are mediated by high affinity nuclear TRs, TRalpha and TRbeta, which function as T3-activated transcription factors playing an essential role as transcription-modulating proteins affecting the transcriptional responses in target genes. Discovery and characterization of nuclear retinoid X receptors (RXRs), which form with TRs a heterodimer RXR/TR, positioned RXRs at the epicenter of molecular endocrinology. Transcriptional control via nuclear RXR/TR heterodimer represents a direct action of thyroid hormone. T3 plays a crucial role in the development of brain, it exerts significant effects on the cardiovascular system, skeletal muscle contractile function, bone development and growth, both female and male reproductive systems, and skin. It plays an important role in maintaining the hepatic, kidney and intestine homeostasis and in pancreas, it stimulates the beta-cell proliferation and survival. The TRs cross-talk with other signaling pathways intensifies the T3 action at cellular level. The role of thyroid hormone in human cancers, acting via its cognate nuclear receptors, has not been fully elucidated yet. This review is aimed to describe the history of T3 receptors, starting from discovery of T3 binding sites in the cell nuclei to revelation of T3 receptors as T3-inducible transcription factors in relation to T3 action at cellular level. It also focuses on milestones of investigation, comprising RXR/TR dimerization, cross-talk between T3 receptors, and other regulatory pathways within the cell and mainly on genomic action of T3. This review also focuses on novel directions of investigation on relationships between T3 receptors and cancer. Based on the update of available literature and the author's experimental experience, it is devoted to clinicians and medical students.
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A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in the liver. Genes Dev 2021; 35:367-378. [PMID: 33602873 PMCID: PMC7919419 DOI: 10.1101/gad.345686.120] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 01/12/2021] [Indexed: 12/14/2022]
Abstract
In this study, Shabtai et al. investigated the mechanism of thyroid hormone (TH)-dependent gene repression, generated a mouse line in which endogenous thyroid hormone receptor TRβ1 was epitope-tagged to allow precise chromatin immunoprecipitation at the low physiological levels of thyroid hormone receptors (TR), and defined high-confidence binding sites where TR functioned at enhancers regulated in the same direction as the nearest gene in a TRβ-dependent manner. Their results demonstrate that, in contrast to the canonical “all or none” coregulator switch model, TH regulates gene expression by orchestrating a shift in the relative binding of corepressors and coactivators. Thyroid hormones (THs) are powerful regulators of metabolism with major effects on body weight, cholesterol, and liver fat that have been exploited pharmacologically for many years. Activation of gene expression by TH action is canonically ascribed to a hormone-dependent “switch” from corepressor to activator binding to thyroid hormone receptors (TRs), while the mechanism of TH-dependent repression is controversial. To address this, we generated a mouse line in which endogenous TRβ1 was epitope-tagged to allow precise chromatin immunoprecipitation at the low physiological levels of TR and defined high-confidence binding sites where TRs functioned at enhancers regulated in the same direction as the nearest gene in a TRβ-dependent manner. Remarkably, although positive and negative regulation by THs have been ascribed to different mechanisms, TR binding was highly enriched at canonical DR4 motifs irrespective of the transcriptional direction of the enhancer. The canonical NCoR1/HDAC3 corepressor complex was reduced but not completely dismissed by TH and, surprisingly, similar effects were seen at enhancers associated with negatively as well as positively regulated genes. Conversely, coactivator CBP was found at all TH-regulated enhancers, with transcriptional activity correlating with the ratio of CBP to NCoR rather than their presence or absence. These results demonstrate that, in contrast to the canonical “all or none” coregulator switch model, THs regulate gene expression by orchestrating a shift in the relative binding of corepressors and coactivators.
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Abdallah A, Ezzeldein S, Eisa E, Raouf MAE, Bayoumi Y. Obstructive urolithiasis in buffalo calves ( Bubalus bubalis): Serum changes of Vitamins A and D and efficacy of surgical management using tube cystostomy. Vet World 2021; 14:129-136. [PMID: 33642796 PMCID: PMC7896912 DOI: 10.14202/vetworld.2021.129-136] [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: 08/30/2020] [Accepted: 12/01/2020] [Indexed: 11/16/2022] Open
Abstract
Background and Aim: Obstructive urolithiasis is one of the major health problems in livestock animals, mainly in young calves. The present study was designed first to investigate the changes in the serum levels of Vitamins A and D in buffalo calves (Bubalus bubalis) with obstructive urolithiasis and second to investigate the efficacy of tube cystostomy technique in management of such condition. Materials and Methods: One hundred and forty-nine buffalo calves of variable ages ranged from 3 to 7 months with a history of retained urine were examined clinically and ultrasonographically. Then, they were subjected to surgical treatment using the tube cystostomy technique. The serum levels of Vitamins A and D were investigated in retained urine calves in addition to 10 clinically healthy calves of the same age used as a control group. Results: Based on clinical and ultrasonographic findings, the calves were diagnosed as obstructive urolithiasis with intact bladder (n=64 calves) or with bladder rupture (n=85 calves) with the peak incidence in winter months. Tube cystostomy was an efficient and quick surgical technique for the management of such condition and 95.3% of calves returned their normal urination within 7–14 days after surgery. Significant hypovitaminoses A and D were found between retained urine calves and control ones (p= 0.01 and 0.002, respectively). Conclusion: Hypovitaminoses A and D suggested predisposing obstructive urolithiasis in buffalo calves, but further clinical studies are recommended for more confirmation. Surgical treatment using tube cystostomy technique is recommended for the management of obstructive urolithiasis in buffalo calves.
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Affiliation(s)
- Abdelmonem Abdallah
- Department of Animal Medicine, Faculty of Veterinary Medicine, Zagazig University, 44519, Zagazig, Sharkia, Egypt
| | - Shimaa Ezzeldein
- Department of Surgery, Anesthesiology and Radiology, Faculty of Veterinary Medicine, Zagazig University, 44519, Zagazig, Sharkia, Egypt
| | - Eslam Eisa
- Department of Surgery, Anesthesiology and Radiology, Faculty of Veterinary Medicine, Zagazig University, 44519, Zagazig, Sharkia, Egypt
| | - Mustafa Abd El Raouf
- Department of Surgery, Anesthesiology and Radiology, Faculty of Veterinary Medicine, Zagazig University, 44519, Zagazig, Sharkia, Egypt
| | - Yasmin Bayoumi
- Department of Animal Medicine, Faculty of Veterinary Medicine, Zagazig University, 44519, Zagazig, Sharkia, Egypt
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Basolo A, Matrone A, Elisei R, Santini F. Effects of tyrosine kinase inhibitors on thyroid function and thyroid hormone metabolism. Semin Cancer Biol 2021; 79:197-202. [PMID: 33476722 DOI: 10.1016/j.semcancer.2020.12.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 12/14/2020] [Indexed: 02/06/2023]
Abstract
The increasing knowledge of the molecular mechanisms in the cell signaling pathways of malignant cells, has recently led to the discovery of several tyrosine kinases (TKs), mainly TK receptors (TKR), which play a major role in the pathogenesis of many types of cancer. These receptors, physiologically involved in cell growth and angiogenesis, may harbor mutations or be overexpressed in malignant cells, and represent a target for anticancer therapy. Indeed, several therapeutic agents targeting specific altered pathways such as RET, BRAF, RAS, EGFR and VEGFR, have been identified. Tyrosine kinase inhibitors (TKIs) affect TK dependent oncogenic pathways by competing with ATP binding sites of the TK domain, thus blocking the activity of the enzyme, and thereby inhibiting the growth and spread of several cancers. Although the therapeutic action may be very effective, these molecules, due to their mechanism of multitargeted inhibition, may produce adverse events involving several biological systems. Both hypothyroidism and thyrotoxicosis have been reported during treatment with TKI, as well as an effect on the activity of enzymes involved in thyroid hormone metabolism. The pathogenic mechanisms leading to thyroid dysfunction and changes in serum thyroid function tests occurring in patients on TKI are reviewed and discussed in this manuscript.
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Affiliation(s)
- Alessio Basolo
- Department of Clinical and Experimental Medicine, Endocrinology Unit, University Hospital of Pisa, Via Paradisa 2, 56124, Pisa, Italy.
| | - Antonio Matrone
- Department of Clinical and Experimental Medicine, Endocrinology Unit, University Hospital of Pisa, Via Paradisa 2, 56124, Pisa, Italy.
| | - Rossella Elisei
- Department of Clinical and Experimental Medicine, Endocrinology Unit, University Hospital of Pisa, Via Paradisa 2, 56124, Pisa, Italy.
| | - Ferruccio Santini
- Department of Clinical and Experimental Medicine, Endocrinology Unit, University Hospital of Pisa, Via Paradisa 2, 56124, Pisa, Italy.
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A review of species differences in the control of, and response to, chemical-induced thyroid hormone perturbations leading to thyroid cancer. Arch Toxicol 2021; 95:807-836. [PMID: 33398420 DOI: 10.1007/s00204-020-02961-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 11/26/2020] [Indexed: 12/13/2022]
Abstract
This review summarises the current state of knowledge regarding the physiology and control of production of thyroid hormones, the effects of chemicals in perturbing their synthesis and release that result in thyroid cancer. It does not consider the potential neurodevelopmental consequences of low thyroid hormones. There are a number of known molecular initiating events (MIEs) that affect thyroid hormone synthesis in mammals and many chemicals are able to activate multiple MIEs simultaneously. AOP analysis of chemical-induced thyroid cancer in rodents has defined the key events that predispose to the development of rodent cancer and many of these will operate in humans under appropriate conditions, if they were exposed to high enough concentrations of the affecting chemicals. There are conditions however that, at the very least, would indicate significant quantitative differences in the sensitivity of humans to these effects, with rodents being considerably more sensitive to thyroid effects by virtue of differences in the biology, transport and control of thyroid hormones in these species as opposed to humans where turnover is appreciably lower and where serum transport of T4/T3 is different to that operating in rodents. There is heated debate around claimed qualitative differences between the rodent and human thyroid physiology, and significant reservations, both scientific and regulatory, still exist in terms of the potential neurodevelopmental consequences of low thyroid hormone levels at critical windows of time. In contrast, the situation for the chemical induction of thyroid cancer, through effects on thyroid hormone production and release, is less ambiguous with both theoretical, and actual data, showing clear dose-related thresholds for the key events predisposing to chemically induced thyroid cancer in rodents. In addition, qualitative differences in transport, and quantitative differences in half life, catabolism and turnover of thyroid hormones, exist that would not operate under normal situations in humans.
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Duez H, Pourcet B. Nuclear Receptors in the Control of the NLRP3 Inflammasome Pathway. Front Endocrinol (Lausanne) 2021; 12:630536. [PMID: 33716981 PMCID: PMC7947301 DOI: 10.3389/fendo.2021.630536] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 01/04/2021] [Indexed: 12/13/2022] Open
Abstract
The innate immune system is the first line of defense specialized in the clearing of invaders whether foreign elements like microbes or self-elements that accumulate abnormally including cellular debris. Inflammasomes are master regulators of the innate immune system, especially in macrophages, and are key sensors involved in maintaining cellular health in response to cytolytic pathogens or stress signals. Inflammasomes are cytoplasmic complexes typically composed of a sensor molecule such as NOD-Like Receptors (NLRs), an adaptor protein including ASC and an effector protein such as caspase 1. Upon stimulation, inflammasome complex components associate to promote the cleavage of the pro-caspase 1 into active caspase-1 and the subsequent activation of pro-inflammatory cytokines including IL-18 and IL-1β. Deficiency or overactivation of such important sensors leads to critical diseases including Alzheimer diseases, chronic inflammatory diseases, cancers, acute liver diseases, and cardiometabolic diseases. Inflammasomes are tightly controlled by a two-step activation regulatory process consisting in a priming step, which activates the transcription of inflammasome components, and an activation step which leads to the inflammasome complex formation and the subsequent cleavage of pro-IL1 cytokines. Apart from the NF-κB pathway, nuclear receptors have recently been proposed as additional regulators of this pathway. This review will discuss the role of nuclear receptors in the control of the NLRP3 inflammasome and the putative beneficial effect of new modulators of inflammasomes in the treatment of inflammatory diseases including colitis, fulminant hepatitis, cardiac ischemia-reperfusion and brain diseases.
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32
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Xie G, Zhou Y, Tu X, Ye X, Xu L, Xiao Z, Wang Q, Wang X, Du M, Chen Z, Chi X, Zhang X, Xia J, Zhang X, Zhou Y, Li Z, Xie C, Sheng L, Zeng Z, Zhou H, Yin Z, Su Y, Xu Y, Zhang XK. Centrosomal Localization of RXRα Promotes PLK1 Activation and Mitotic Progression and Constitutes a Tumor Vulnerability. Dev Cell 2020; 55:707-722.e9. [PMID: 33321102 DOI: 10.1016/j.devcel.2020.11.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 08/15/2020] [Accepted: 11/09/2020] [Indexed: 02/06/2023]
Abstract
Retinoid X receptor alpha (RXRα), a nuclear receptor of transcription factor, controls various physiological and pathological pathways including cellular growth, proliferation, differentiation, and apoptosis. Here, we report that RXRα is phosphorylated at its N-terminal A/B domain by cyclin-dependent kinase 1 (Cdk1) at the onset of mitosis, triggering its translocation to the centrosome, where phosphorylated-RXRα (p-RXRα) interacts with polo-like kinase 1 (PLK1) through its N-terminal A/B domain by a unique mechanism. The interaction promotes PLK1 activation, centrosome maturation, and mitotic progression. Levels of p-RXRα are abnormally elevated in cancer cell lines, during carcinogenesis in animals, and in clinical tumor tissues. An RXRα ligand XS060, which specifically inhibits p-RXRα/PLK1 interaction but not RXRα heterodimerization, promotes mitotic arrest and catastrophe in a tumor-specific manner. These findings unravel a transcription-independent action of RXRα at the centrosome during mitosis and identify p-RXRα as a tumor-specific vulnerability for developing mitotic drugs with improved therapeutic index.
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Affiliation(s)
- Guobin Xie
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China
| | - Yuqi Zhou
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China; NucMito Pharmaceuticals Co. Ltd., Xiamen 361101, Fujian, China
| | - Xuhuang Tu
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China
| | - Xiaohong Ye
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China
| | - Lin Xu
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China
| | - Zhijian Xiao
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China
| | - Qiqiang Wang
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China
| | - Xin Wang
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China
| | - Mingxuan Du
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China
| | - Ziwen Chen
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China; NucMito Pharmaceuticals Co. Ltd., Xiamen 361101, Fujian, China
| | - Xiaoqin Chi
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital Xiamen University, Xiamen 361004, Fujian, China
| | - Xiaoli Zhang
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China
| | - Ji Xia
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China
| | - Xiaowei Zhang
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China
| | - Yunxia Zhou
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China
| | - Zongxi Li
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China
| | - Chengrong Xie
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital Xiamen University, Xiamen 361004, Fujian, China
| | - Luoyan Sheng
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China
| | - Zhiping Zeng
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China
| | - Hu Zhou
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China
| | - Zhenyu Yin
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital Xiamen University, Xiamen 361004, Fujian, China
| | - Ying Su
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China; NucMito Pharmaceuticals Co. Ltd., Xiamen 361101, Fujian, China
| | - Yang Xu
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China
| | - Xiao-Kun Zhang
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China.
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Zhao LF, Iwasaki Y, Han BL, Wang J, Zhang Y, Han J, Liu GY, Jiang X. TRIIODOTHYRONINE ACTIVATES GLYCEROL-3-PHOSPHATE ACYLTRANSFERASE 3 VIA AGGTCA-LIKE-DIRECT-REPEAT-4 TYPE THYROID HORMONE RESPONSE ELEMENT. ACTA ENDOCRINOLOGICA-BUCHAREST 2020; 16:129-135. [PMID: 33029227 DOI: 10.4183/aeb.2020.129] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Background Thyroid hormone participates in lipid metabolism regulation. However, the effects on triacyleride or triacylglycerol metabolism are complex and not fully clarified yet. In this study, we try to identify novel thyroid hormone-targeting lipogenic metabolic genes and analyze their molecular regulative mechanism. Method Thirty-five promoters of twenty-nine human lipogenic regulative enzyme genes were constructed into pXP1 luciferase reporter plasmid (PFK2/FBP2-luc) and transfected into HeGP2 cells, respectively. Gene expression induced by triiodothyronine (T3) was detected by luciferase assay. The T3-activated gene promoter was then analyzed by sequence analysis, deletion and mutation, and electrophoretic mobility shift assay (EMSA). Results After 10 nM T3 stimulation for 36 h, phosphogluconate dehydrogenase, malic enzyme, Glycerol-3-phosphate acyltransferase (GPAT) 3, and 1-acylglycerol-3-phosphate O-acyltransferase (AGPAT) 2 were significantly activated, respectively. A AGGTCA-like-direct-repeat-4 consensus thyroid hormone response element (DR4-TRE)-like sequence was found in the GPAT3 promoter, which was then verified to be necessary for T3-induced GPAT3 activation by gene deletion and mutation analysis. EMSA further identified that T3-thyroid receptor (TR) α-retinoid-X receptor (RXR) complex directly bound on the GPAT3 promoter. Conclusion Triiodothyronine could activate the GPAT3 through DR4-TRE-like sequence binding to participate in lipogenic regulation. AGPAT2 may be another thyroid hormone target enzyme.
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Affiliation(s)
- L F Zhao
- Tianjin First Center Hospital, Department of Endocrinology, Tianjin, China
| | - Y Iwasaki
- Kochi University, The Health Care Center, Kochi, Japan
| | - B L Han
- Tianjin First Center Hospital, Department of Endocrinology, Tianjin, China
| | - J Wang
- Tianjin First Center Hospital, Department of Endocrinology, Tianjin, China
| | - Y Zhang
- Tianjin First Center Hospital, Department of Endocrinology, Tianjin, China
| | - J Han
- Tianjin First Center Hospital, Department of Endocrinology, Tianjin, China
| | - G Y Liu
- Tianjin First Center Hospital, Department of Endocrinology, Tianjin, China
| | - X Jiang
- Tianjin First Center Hospital, Department of Endocrinology, Tianjin, China
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Paus R, Ramot Y, Kirsner RS, Tomic-Canic M. Topical L-thyroxine: The Cinderella among hormones waiting to dance on the floor of dermatological therapy? Exp Dermatol 2020; 29:910-923. [PMID: 32682336 PMCID: PMC7722149 DOI: 10.1111/exd.14156] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 06/28/2020] [Accepted: 07/13/2020] [Indexed: 12/15/2022]
Abstract
Topical hormone therapy with natural or synthetic ligands of nuclear hormone receptors such as glucocorticoids, vitamin D analogues and retinoids has a long and highly successful tradition in dermatology. Yet the dermatological potential of thyroid hormone receptor (TR) agonists has been widely ignored, despite abundant clinical, cell and molecular biology, mouse in vivo, and human skin and hair follicle organ culture data documenting a role of TR-mediated signalling in skin physiology and pathology. Here, we review this evidence, with emphasis on wound healing and hair growth, and specifically highlight the therapeutic potential of repurposing topical L-thyroxine (T4) for selected applications in future dermatological therapy. We underscore the known systemic safety and efficacy profile of T4 in clinical medicine, and the well-documented impact of thyroid hormones on, for example, human epidermal and hair follicle physiology, hair follicle epithelial stem cells and pigmentation, keratin expression, mitochondrial energy metabolism and wound healing. On this background, we argue that short-term topical T4 treatment deserves careful further preclinical and clinical exploration for repurposing as a low-cost, effective and widely available dermatotherapeutic, namely in the management of skin ulcers and telogen effluvium, and that its predictable adverse effects are well-manageable.
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Affiliation(s)
- Ralf Paus
- Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
- Centre for Dermatology Research, University of Manchester & NIHR Manchester Biomedical Research Centre, Manchester, UK
- Monasterium Laboratory, Münster, Germany
| | - Yuval Ramot
- Department of Dermatology, Hadassah Medical Center, The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Robert S. Kirsner
- Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Marjana Tomic-Canic
- Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
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Jones BG, Penkert RR, Surman SL, Sealy RE, Hurwitz JL. Nuclear Receptors, Ligands and the Mammalian B Cell. Int J Mol Sci 2020; 21:E4997. [PMID: 32679815 PMCID: PMC7404052 DOI: 10.3390/ijms21144997] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 07/07/2020] [Accepted: 07/08/2020] [Indexed: 12/22/2022] Open
Abstract
Questions concerning the influences of nuclear receptors and their ligands on mammalian B cells are vast in number. Here, we briefly review the effects of nuclear receptor ligands, including estrogen and vitamins, on immunoglobulin production and protection from infectious diseases. We describe nuclear receptor interactions with the B cell genome and the potential mechanisms of gene regulation. Attention to the nuclear receptor/ligand regulation of B cell function may help optimize B cell responses, improve pathogen clearance, and prevent damaging responses toward inert- and self-antigens.
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Affiliation(s)
- Bart G. Jones
- Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; (B.G.J.); (R.R.P.); (S.L.S.); (R.E.S.)
| | - Rhiannon R. Penkert
- Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; (B.G.J.); (R.R.P.); (S.L.S.); (R.E.S.)
| | - Sherri L. Surman
- Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; (B.G.J.); (R.R.P.); (S.L.S.); (R.E.S.)
| | - Robert E. Sealy
- Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; (B.G.J.); (R.R.P.); (S.L.S.); (R.E.S.)
| | - Julia L. Hurwitz
- Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; (B.G.J.); (R.R.P.); (S.L.S.); (R.E.S.)
- Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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Zeng Y, Luo M, Pan L, Chen Y, Guo S, Luo D, Zhu L, Liu Y, Pan L, Xu S, Zhang R, Zhang C, Wu P, Ge L, Noureddin M, Pandol SJ, Han YP. Vitamin D signaling maintains intestinal innate immunity and gut microbiota: potential intervention for metabolic syndrome and NAFLD. Am J Physiol Gastrointest Liver Physiol 2020; 318:G542-G553. [PMID: 31984787 PMCID: PMC7099486 DOI: 10.1152/ajpgi.00286.2019] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 12/13/2019] [Accepted: 01/19/2020] [Indexed: 01/31/2023]
Abstract
A lack of sunlight exposure, residence in the northern latitudes, and dietary vitamin D insufficiency are coprevalent with metabolic syndrome (MetS), Type 2 diabetes (T2D), and nonalcoholic fatty liver diseases (NAFLD), implying a potential causality and underlying mechanism. Whether vitamin D supplementation or treatment can improve these disorders is controversial, in part, because of the absence of large-scale trials. Experimental investigations, on the other hand, have uncovered novel biological functions of vitamin D in development, tumor suppression, and immune regulation, far beyond its original role as a vitamin that maintained calcium homeostasis. While the large intestine harbors massive numbers of microbes, the small intestine has a minimal quantity of bacteria, indicating the existence of a gating system located in the distal region of the small intestine that may restrain bacterial translocation to the small intestine. Vitamin D receptor (VDR) was found to be highly expressed at the distal region of small intestine, where the vitamin D signaling promotes innate immunity, including the expression of α-defensins by Paneth cells, and maintains the intestinal tight junctions. Thus, a new hypothesis is emerging, indicating that vitamin D deficiency may impair the intestinal innate immunity, including downregulation of Paneth cell defensins, leading to bacterial translocation, endotoxemia, systemic inflammation, insulin resistance, and hepatic steatosis. Here, we review the studies for vitamin D for innate immunity and metabolic homeostasis, and we outline the clinical trials of vitamin D for mitigating MetS, T2D, and NAFLD.
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Affiliation(s)
- Yilan Zeng
- Chengdu Public Health Clinical Center, Chengdu, China
| | - Mei Luo
- Chengdu Public Health Clinical Center, Chengdu, China
| | - Liwei Pan
- The Center for Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, China
| | - Yuan Chen
- The Center for Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, China
| | - Siqi Guo
- The Center for Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, China
| | - Dongxia Luo
- Chengdu Public Health Clinical Center, Chengdu, China
| | - Li Zhu
- Chengdu Public Health Clinical Center, Chengdu, China
| | - Yong Liu
- Chengdu Public Health Clinical Center, Chengdu, China
| | - Lisha Pan
- The Center for Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, China
| | - Siya Xu
- The Center for Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, China
| | - Ruofei Zhang
- The Center for Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, China
| | - Chunyan Zhang
- The Center for Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, China
| | - Pengfei Wu
- The Center for Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, China
| | - Liangpeng Ge
- Chongqing Academy of Animal Sciences, Chongqing, China
| | | | | | - Yuan-Ping Han
- The Center for Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, China
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Mahendra A, Karishma, Choudhury BK, Sharma T, Bansal N, Bansal R, Gupta S. Vitamin D and gastrointestinal cancer. J Lab Physicians 2020; 10:1-5. [PMID: 29403195 PMCID: PMC5784277 DOI: 10.4103/jlp.jlp_49_17] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Vitamin D serves as a precursor to the potent steroid hormone calcitriol, which has widespread actions throughout the body. Calcitriol regulates numerous cellular pathways that could have a role in determining cancer risk and prognosis. Low Vitamin D levels have been implicated in numerous disease processes including fracture risk, falls, cardiovascular disease, hypertension, diabetes mellitus, and cancers. Metabolite of 1, 25-dihydroxyvitamin D3 (1,25[OH]2D3) regulates numerous genes that control gut physiology and homeostasis. 1,25(OH)2D3 serves various functions such as maintaining the integrity of epithelial barrier and absorption of calcium and phosphate, and the host's defense against pathogens, and the inflammatory response by several types of secretory and immune cells. Although epidemiological data remain inconsistent, and randomized control trials in humans do not yet exist to conclusively support a beneficial role for Vitamin D, results from some correlating studies strongly suggest that Vitamin D deficiency increases the risk of developing cancer and that avoiding deficiency and adding Vitamin D supplements might be an economical and safe way to reduce cancer incidence and improve cancer prognosis and outcome. The present review highlights the role of Vitamin D in cancer of the gastrointestinal tract including esophagus, gastric (stomach), liver, pancreas, and colon.
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Affiliation(s)
- Ashish Mahendra
- Department of Oral Pathology, Chandra Dental College, Barabanki, India
| | - Karishma
- Department Oral Medicine and Radiology, Sardar Patel Postgraduate Institute of Medical and Dental Sciences, Lucknow, Uttar Pradesh, India
| | - Basanta Kumar Choudhury
- Department Oral Medicine and Radiology, Institute of Dental Sciences and Sum Hospital, Kalinga Nagar, Shampur, Bhubaneswar, Odisha, India
| | - Tamanna Sharma
- Department of Oral Pathology, Himachal Dental College, Sundernagar, Mandi, Himachal Pradesh, India
| | - Neha Bansal
- Department Oral Medicine and Radiology, Dr HS Judge Institute of Dental Sciences, PU, Chandigarh, India
| | - Richa Bansal
- Department of Oral Pathology, Seema Dental College and Hospital, Rishikesh, Uttarakhand, India
| | - Shivangi Gupta
- Department of Periodontics and Implantology, Bhojia Dental College and Hospital, Nalagarh, Himachal Pradesh, India
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Yoshikawa Y, Yoshizawa T, Domae E, Hirai Y, Kamada A, Okazaki T, Ikeo T. Knockdown of sphingomyelin synthase 2 inhibits osteoclastogenesis by decreasing RANKL expression in mouse primary osteoblasts. Biomed Res 2020; 40:189-196. [PMID: 31597904 DOI: 10.2220/biomedres.40.189] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Sphingomyelin is a major lipid of the plasma membrane and is enriched in microdomains of the plasma membrane that are critical for signal transduction. However, the function of sphingomyelin in the cell membrane of osteoblasts has not been clarified. Therefore, we examined how sphingomyelin synthase 2 (SMS2) affects osteoclast differentiation by osteoblasts. We knocked down the expression of SMS2 with siRNA targeting the Sgms2 gene in mouse primary osteoblasts. The effects of SMS2 knockdown in osteoblasts were examined using polymerase chain reaction and western blotting. The knockdown of SMS2 suppressed the formation of TRAP-positive multinucleated cells by co-culture of osteoblasts and bone marrow cells compared to the control. We found that receptor activator of nuclear factor κB ligand (RANKL) mRNA expression was significantly reduced by 1,25(OH)2D3 stimulation in SMS2 siRNA osteoblasts. The knockdown of SMS2 repressed the expression of retinoid-X-receptor-α (RXRα) regardless of 1,25(OH)2D3 stimulation. TRAP-positive multinucleated cell formation was significantly reduced by RXRα siRNA in osteoblasts in a co-culture system. These results suggest that SMS2 regulates osteoclast differentiation by inducing RANKL expression via RXRα.
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Affiliation(s)
| | - Tatsuya Yoshizawa
- Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University
| | - Eisuke Domae
- Department of Biochemistry, Osaka Dental University
| | - Yuya Hirai
- Department of Biology, Osaka Dental University
| | - Aiko Kamada
- Department of Biochemistry, Osaka Dental University
| | - Toshiro Okazaki
- The Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University
| | - Takashi Ikeo
- Department of Biochemistry, Osaka Dental University
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Sirbu IO, Chiş AR, Moise AR. Role of carotenoids and retinoids during heart development. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158636. [PMID: 31978553 DOI: 10.1016/j.bbalip.2020.158636] [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: 12/03/2019] [Revised: 01/15/2020] [Accepted: 01/16/2020] [Indexed: 02/08/2023]
Abstract
The nutritional requirements of the developing embryo are complex. In the case of dietary vitamin A (retinol, retinyl esters and provitamin A carotenoids), maternal derived nutrients serve as precursors to signaling molecules such as retinoic acid, which is required for embryonic patterning and organogenesis. Despite variations in the composition and levels of maternal vitamin A, embryonic tissues need to generate a precise amount of retinoic acid to avoid congenital malformations. Here, we summarize recent findings regarding the role and metabolism of vitamin A during heart development and we survey the association of genes known to affect retinoid metabolism or signaling with various inherited disorders. A better understanding of the roles of vitamin A in the heart and of the factors that affect retinoid metabolism and signaling can help design strategies to meet nutritional needs and to prevent birth defects and disorders associated with altered retinoid metabolism. 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.
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Affiliation(s)
- Ioan Ovidiu Sirbu
- Biochemistry Department, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Nr. 2, 300041 Timisoara, Romania; Timisoara Institute of Complex Systems, V. Lucaciu 18, 300044 Timisoara, Romania.
| | - Aimée Rodica Chiş
- Biochemistry Department, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Nr. 2, 300041 Timisoara, Romania
| | - Alexander Radu Moise
- Medical Sciences Division, Northern Ontario School of Medicine, Sudbury, ON P3E 2C6, Canada; Department of Chemistry and Biochemistry, Biology and Biomolecular Sciences Program, Laurentian University, Sudbury, ON P3E 2C6, Canada.
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Mrowka P, Glodkowska-Mrowka E. PPARγ Agonists in Combination Cancer Therapies. Curr Cancer Drug Targets 2019; 20:197-215. [PMID: 31814555 DOI: 10.2174/1568009619666191209102015] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 10/03/2019] [Accepted: 11/01/2019] [Indexed: 12/15/2022]
Abstract
Peroxisome proliferator-activated receptor-gamma (PPARγ) is a nuclear receptor acting as a transcription factor involved in the regulation of energy metabolism, cell cycle, cell differentiation, and apoptosis. These unique properties constitute a strong therapeutic potential that place PPARγ agonists as one of the most interesting and widely studied anticancer molecules. Although PPARγ agonists exert significant, antiproliferative and tumoricidal activity in vitro, their anticancer efficacy in animal models is ambiguous, and their effectiveness in clinical trials in monotherapy is unsatisfactory. However, due to pleiotropic effects of PPARγ activation in normal and tumor cells, PPARγ ligands interact with many antitumor treatment modalities and synergistically potentiate their effectiveness. The most spectacular example is a combination of PPARγ ligands with tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). In this setting, PPARγ activation sensitizes leukemic stem cells, resistant to any previous form of treatment, to targeted therapy. Thus, this combination is believed to be the first pharmacological therapy able to cure CML patients. Within the last decade, a significant body of data confirming the benefits of the addition of PPARγ ligands to various antitumor therapies, including chemotherapy, hormonotherapy, targeted therapy, and immunotherapy, has been published. Although the majority of these studies have been carried out in vitro or animal tumor models, a few successful attempts to introduce PPARγ ligands into anticancer therapy in humans have been recently made. In this review, we aim to summarize shines and shadows of targeting PPARγ in antitumor therapies.
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Affiliation(s)
- Piotr Mrowka
- Department of Biophysics and Human Physiology, Medical University of Warsaw, Warsaw, Poland
| | - Eliza Glodkowska-Mrowka
- Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age, Medical University of Warsaw, Warsaw, Poland.,Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
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Wang S, Yu J, Kane MA, Moise AR. Modulation of retinoid signaling: therapeutic opportunities in organ fibrosis and repair. Pharmacol Ther 2019; 205:107415. [PMID: 31629008 DOI: 10.1016/j.pharmthera.2019.107415] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 09/17/2019] [Indexed: 02/08/2023]
Abstract
The vitamin A metabolite, retinoic acid, is an important signaling molecule during embryonic development serving critical roles in morphogenesis, organ patterning and skeletal and neural development. Retinoic acid is also important in postnatal life in the maintenance of tissue homeostasis, while retinoid-based therapies have long been used in the treatment of a variety of cancers and skin disorders. As the number of people living with chronic disorders continues to increase, there is great interest in extending the use of retinoid therapies in promoting the maintenance and repair of adult tissues. However, there are still many conflicting results as we struggle to understand the role of retinoic acid in the multitude of processes that contribute to tissue injury and repair. This review will assess our current knowledge of the role retinoic acid signaling in the development of fibroblasts, and their transformation to myofibroblasts, and of the potential use of retinoid therapies in the treatment of organ fibrosis.
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Affiliation(s)
- Suya Wang
- Department of Cardiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Jianshi Yu
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, 21201, USA
| | - Maureen A Kane
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, 21201, USA.
| | - Alexander R Moise
- Medical Sciences Division, Northern Ontario School of Medicine, Sudbury, ON P3E 2C6, Canada; Departments of Chemistry and Biochemistry, and Biology and Biomolecular Sciences Program, Laurentian University, Sudbury, ON, P3E 2C6, Canada.
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Rühl R, Krezel W, de Lera AR. 9-Cis-13,14-dihydroretinoic acid, a new endogenous mammalian ligand of retinoid X receptor and the active ligand of a potential new vitamin A category: vitamin A5. Nutr Rev 2019; 76:929-941. [PMID: 30358857 DOI: 10.1093/nutrit/nuy057] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The identity of the endogenous RXR ligand has not been conclusively determined, even though several compounds of natural origin, including retinoids and fatty acids, have been postulated to fulfill this role. Filling this gap, 9-cis-13,14-dihydroretinoic acid (9CDHRA) was identified as an endogenous RXR ligand in mice. This review examines the physiological relevance of various potential endogenous RXR ligands, especially 9CDHRA. The elusive steps in the metabolic synthesis of 9CDHRA, as well as the nutritional/nutrimetabolic origin of 9CDHRA, are also explored, along with the suitability of the ligand to be the representative member of a novel vitamin A class (vitamin A5).
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Affiliation(s)
- Ralph Rühl
- Paprika Bioanalytics BT, Debrecen, Hungary
| | - Wojciech Krezel
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Inserm, Centre National Recherche Scientifique (CNRS), Université de Strasbourg, Illkirch, France.,Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France
| | - Angel R de Lera
- Departamento de Química Orgánica, Facultad de Química, Centro De Investigaciones Biomédicasand Instituto de Investigación Biomédica de Vigo, Universidade de Vigo, Campus Lagoas-Marcosende, Vigo, Spain
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Lüsebrink E, Warm V, Pircher J, Ehrlich A, Zhang Z, Strecker J, Chambon P, Massberg S, Schulz C, Petzold T. Role of RXRβ in platelet function and arterial thrombosis. J Thromb Haemost 2019; 17:1489-1499. [PMID: 31172692 DOI: 10.1111/jth.14531] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 05/28/2019] [Accepted: 05/31/2019] [Indexed: 12/22/2022]
Abstract
OBJECTIVE Retinoid X receptors (RXR) are a family of nuclear receptors that play critical roles in the regulation of numerous fundamental biological processes including cell proliferation, differentiation, and death. Earlier studies suggested that treatment with RXR agonists attenuates platelet activation in all adults (male and femal) and mice; however, the underlying molecular mechanisms have remained insufficiently understood. To elaborate further on this issue, we characterized megakaryocyte and platelet-specific RXR knockout mice to study platelet function in vitro and arterial thrombosis in vivo. APPROACH AND RESULTS First, we identified RXRβ as the dominant RXR receptor in mouse platelets, prompting us to generate a megakaryocyte and platelet-specific PF4Cre ;RXRβflox/flox mouse. Second, we studied activation, spreading, and aggregation of platelets from C57Bl/6 wild-type mice (WT), PF4Cre+ ;RXRβflox/flox mice, and PF4Cre- ;RXRβflox/flox littermate controls in the presence or absence of RXR ligands, that is, 9-cis-retinoic acid (9cRA) and methoprene acid (MA). We found that in vitro treatment with RXR ligands attenuates spreading and aggregation of platelets and increases proplatelet particle formation from megakaryocytes (MK). However, these effects are also observed in RXRβ-deficient platelets and MKs and are thus independent of RXRβ. Third, we investigated arterial thrombus formation in an iron chloride (FeCl3)-induced vascular injury model in vivo, which is also not affected by the absence of RXRβ in platelets. CONCLUSIONS Absence of the most abundant RXR receptor in mouse platelets, RXRβ, does not affect platelet function in vitro and thrombus formation in vivo. Furthermore, RXR agonists' mediated effects on platelet function are independent of RXRβ expression. Hence, our data do not support a significant contribution of RXRβ to arterial thrombosis in mice.
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Affiliation(s)
- Enzo Lüsebrink
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | - Verena Warm
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | - Joachim Pircher
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | - Andreas Ehrlich
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | - Zhe Zhang
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | - Jan Strecker
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | - Pierre Chambon
- Département de Biologie, Cellulaire and Développement, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Strasbourg, France
| | - Steffen Massberg
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | - Christian Schulz
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | - Tobias Petzold
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
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Wang S, Moise AR. Recent insights on the role and regulation of retinoic acid signaling during epicardial development. Genesis 2019; 57:e23303. [PMID: 31066193 PMCID: PMC6682438 DOI: 10.1002/dvg.23303] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 04/23/2019] [Accepted: 04/24/2019] [Indexed: 12/18/2022]
Abstract
The vitamin A metabolite, retinoic acid, carries out essential and conserved roles in vertebrate heart development. Retinoic acid signals via retinoic acid receptors (RAR)/retinoid X receptors (RXRs) heterodimers to induce the expression of genes that control cell fate specification, proliferation, and differentiation. Alterations in retinoic acid levels are often associated with congenital heart defects. Therefore, embryonic levels of retinoic acid need to be carefully regulated through the activity of enzymes, binding proteins and transporters involved in vitamin A metabolism. Here, we review evidence of the complex mechanisms that control the fetal uptake and synthesis of retinoic acid from vitamin A precursors. Next, we highlight recent evidence of the role of retinoic acid in orchestrating myocardial compact zone growth and coronary vascular development.
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Affiliation(s)
- Suya Wang
- Department of Cardiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Alexander R. Moise
- Medical Sciences Division, Northern Ontario School of Medicine, Sudbury, ON P3E 2C6, Canada
- Departments of Chemistry and Biochemistry, and Biology and Biomolecular Sciences Program, Laurentian University, Sudbury, ON, P3E 2C6 Canada
- Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, 66045, USA
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Veras Ribeiro Filho H, Tambones IL, Mariano Gonçalves Dias M, Bernardi Videira N, Bruder M, Amorim Amato A, Migliorini Figueira AC. Modulation of nuclear receptor function: Targeting the protein-DNA interface. Mol Cell Endocrinol 2019; 484:1-14. [PMID: 30703486 DOI: 10.1016/j.mce.2019.01.023] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 01/25/2019] [Accepted: 01/25/2019] [Indexed: 02/02/2023]
Abstract
Nuclear receptors (NRs) are a superfamily of ligand-dependent transcription factors that modulate several biological processes. Traditionally, modulation of NRs has been focused on the development of ligands that recognize and bind to the ligand binding domain (LBD), resulting in activation or repression of transcription through the recruitment of coregulators. However, for more severe diseases, such as breast and prostate cancer, the conventional treatment addressing LBD modulation is not always successful, due to tumor resistance. To overcome these challenges and aiming to modulate NR activity by inhibiting the NR-DNA interaction, new studies focus on the development of molecules targeting alternative sites and domains on NRs. Here, we discuss two different approaches for this alternative NR modulation: one targeting the NR DNA binding domain (DBD); and the other targeting the DNA sites recognized by NRs. Our aim is to present the challenges and perspectives for developing specific inhibitors for each purpose, alongside with already reported examples.
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Affiliation(s)
- Helder Veras Ribeiro Filho
- Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, SP, 13083-970, Brazil; Graduate Program in Biosciences and Technology of Bioactive Products, Institute of Biology, State University of Campinas (Unicamp), Campinas, 13083-970, Brazil
| | - Izabella Luisa Tambones
- Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, SP, 13083-970, Brazil; Graduate Program in Biosciences and Technology of Bioactive Products, Institute of Biology, State University of Campinas (Unicamp), Campinas, 13083-970, Brazil
| | - Marieli Mariano Gonçalves Dias
- Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, SP, 13083-970, Brazil; Graduate Program in Molecular and Functional Biology, Institute of Biology, State University of Campinas (Unicamp), Campinas, SP, 13083-970, Brazil
| | - Natalia Bernardi Videira
- Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, SP, 13083-970, Brazil
| | - Marjorie Bruder
- Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, SP, 13083-970, Brazil
| | - Angélica Amorim Amato
- Laboratory of Molecular Pharmacology, Department of Pharmaceutical Science, University of Brasilia (UnB), Brasília, DF, 70910-900, Brazil
| | - Ana Carolina Migliorini Figueira
- Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, SP, 13083-970, Brazil.
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Bellan M, Marzullo P. New Insights on Low Vitamin D Plasma Concentration as a Potential Cardiovascular Risk Factor. Open Rheumatol J 2018. [DOI: 10.2174/1874312901812010261] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The role of Vitamin D hormone in human health and disease is still debated. Recently, growing attention has been paid to its putative role in cardiovascular system homeostasis with several studies that suggested a correlation between low vitamin D levels and increased cardiovascular risk. Several mechanisms are involved in the development of cardiovascular diseases: systemic inflammation, endothelial dysfunction, arterial hypertension and insulin resistance. In the present paper, we have revised the current literature supporting a role for vitamin D in the development of these pathogenetic processes. Finally, we have evaluated the current evidence linking vitamin D to atherosclerosis and its natural consequence, cardiovascular diseases.
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Abstract
Patients with Rheumatoid Arthritis (RA) commonly develop osteoporosis and fragility fractures. This fact cannot be explained only with the use of glucocorticoids, known to be detrimental for bone health. RA is characterized by a chronic inflammation caused by the continuous activation of innate and adaptive immunity with proinflammatory cytokines overproduction. This process is detrimental for several organs and physiological processes, including the impairment of bone remodeling. We will briefly review the pathogenesis of inflammation-related bone loss in RA, describing well-known and new molecular pathways and focusing on vitamin D and Parathyroid Hormone role.
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Qu Z, Bendena WG, Tobe SS, Hui JHL. Juvenile hormone and sesquiterpenoids in arthropods: Biosynthesis, signaling, and role of MicroRNA. J Steroid Biochem Mol Biol 2018; 184:69-76. [PMID: 29355708 DOI: 10.1016/j.jsbmb.2018.01.013] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Revised: 01/03/2018] [Accepted: 01/16/2018] [Indexed: 12/21/2022]
Abstract
Arthropod molting and reproduction are precisely controlled by the levels of sesquiterpenoids, a class of C15 hormones derived from three isoprene units. The two major functional arthropod sesquiterpenoids are juvenile hormone (JH) and methyl farnesoate (MF). In hemimetabolous insects (such as the aphids, bugs, and cockroaches) and holometabolous insects (such as beetles, bees, butterflies, and flies), dramatic decrease in the titers of JH and/or MF promote metamorphosis from larvae to adults either directly or through an intermediate pupal stage, respectively. JH is absent in crustaceans (lobster, shrimp, crab) and other arthropods (chelicerates such as ticks, mites, spiders, scorpions and myriapods such as millipede and centipedes). In some crustaceans, molting and reproduction is dependent on changing levels of MF. The regulation of sesquiterpenoid production is thus crucial in the life cycle of arthropods. Dynamic and complex mechanisms have evolved to regulate sesquiterpenoid production. Noncoding RNAs such as the microRNAs are primary regulators. This article provides an overview of microRNAs that are known to regulate sesquiterpenoid production in arthropods.
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Affiliation(s)
- Zhe Qu
- School of Life Sciences, Simon F.S. Li Marine Science Laboratory, Partner State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong
| | | | - Stephen S Tobe
- Department of Cell and Systems Biology, University of Toronto, Canada.
| | - Jerome H L Hui
- School of Life Sciences, Simon F.S. Li Marine Science Laboratory, Partner State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong.
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Hirota Y, Nakagawa K, Isomoto K, Sakaki T, Kubodera N, Kamao M, Osakabe N, Suhara Y, Okano T. Eldecalcitol is more effective in promoting osteogenesis than alfacalcidol in Cyp27b1-knockout mice. PLoS One 2018; 13:e0199856. [PMID: 30281599 PMCID: PMC6169848 DOI: 10.1371/journal.pone.0199856] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 09/01/2018] [Indexed: 01/29/2023] Open
Abstract
Calcium (Ca) absorption from the intestinal tract is promoted by active vitamin D (1α,25D3). Vitamin D not only promotes Ca homeostasis, but it also inhibits bone resorption and promotes osteogenesis, thus playing a role in the maintenance of normal bone metabolism. Because 1α,25D3 plays an important role in osteogenesis, vitamin D formulations, such as alfacalcidol (ALF) and eldecalcitol (ELD), are used for treating osteoporosis. While it is known that, in contrast to ALF, ELD is an active ligand that directly acts on bone, the reason for its superior osteogenesis effects is unknown. Cyp27b1-knockout mice (Cyp27b1-/-mice) are congenitally deficient in 1α,25D3 and exhibit marked hypocalcemia and high parathyroid hormone levels, resulting in osteodystrophy involving bone hypocalcification and growth plate cartilage hypertrophy. However, because the vitamin D receptor is expressed normally in Cyp27b1-/-mice, they respond normally to 1α,25D3. Accordingly, in Cyp27b1-/-mice, the pharmacological effects of exogenously administered active vitamin D derivatives can be analyzed without being affected by 1α,25D3. We used Cyp27b1-/-mice to characterize and clarify the superior osteogenic effects of ELD on the bone in comparison with ALF. The results indicated that compared to ALF, ELD strongly induces ECaC2, calbindin-D9k, and CYP24A1 in the duodenum, promoting Ca absorption and decreasing the plasma concentration of 1α,25D3, resulting in improved osteogenesis. Because bone morphological measurements demonstrated that ELD has stronger effects on bone calcification, trabecular formation, and cancellous bone density than ALF, ELD appears to be a more effective therapeutic agent for treating postmenopausal osteoporosis, in which cancellous bone density decreases markedly. By using Cyp27b1-/-mice, this study was the first to succeed in clarifying the osteogenic effect of ELD without any influence of endogenous 1α,25D3. Furthermore, ELD more strongly enhanced bone mineralization, trabecular proliferation, and cancellous bone density than did ALF. Thus, ELD is expected to show an effect on postmenopausal osteoporosis, in which cancellous bone mineral density decreases markedly. In the future, this study may enable the development of next-generation active vitamin D derivatives with higher affinity for bone than ELD.
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Affiliation(s)
- Yoshihisa Hirota
- Laboratory of Biochemistry, Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, Fukasaku, Minuma-ku, Saitama, Japan
- Laboratory of Hygienic Sciences, Kobe Pharmaceutical University, Motoyamakita-machi, Higashinada-ku, Kobe, Japan
| | - Kimie Nakagawa
- Laboratory of Hygienic Sciences, Kobe Pharmaceutical University, Motoyamakita-machi, Higashinada-ku, Kobe, Japan
| | - Keigo Isomoto
- Laboratory of Hygienic Sciences, Kobe Pharmaceutical University, Motoyamakita-machi, Higashinada-ku, Kobe, Japan
| | - Toshiyuki Sakaki
- Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, Kurokawa, Imizu, Toyama, Japan
| | - Noboru Kubodera
- International Institute of Active Vitamin D Analogs, Sankeidai, Mishima, Shizuoka, Japan
| | - Maya Kamao
- Laboratory of Hygienic Sciences, Kobe Pharmaceutical University, Motoyamakita-machi, Higashinada-ku, Kobe, Japan
| | - Naomi Osakabe
- Food and Nutrition Laboratory, Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, Fukasaku, Minuma-ku, Saitama, Japan
| | - Yoshitomo Suhara
- Laboratory of Organic Synthesis and Medicinal Chemistry, Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, Fukasaku, Minuma-ku, Saitama, Japan
| | - Toshio Okano
- Laboratory of Hygienic Sciences, Kobe Pharmaceutical University, Motoyamakita-machi, Higashinada-ku, Kobe, Japan
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Vieira WA, Wells KM, Milgrom R, McCusker CD. Exogenous Vitamin D signaling alters skeletal patterning, differentiation, and tissue integration during limb regeneration in the axolotl. Mech Dev 2018; 153:1-9. [PMID: 30096415 PMCID: PMC6727847 DOI: 10.1016/j.mod.2018.08.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2017] [Revised: 03/22/2018] [Accepted: 08/06/2018] [Indexed: 12/19/2022]
Abstract
Urodele amphibians such as the axolotl regenerate complete limbs as adults, and understanding how the "blueprint", or pattern, of the regenerate is established and manipulated are areas of intense interest. Nutrient signaling plays an important role in pattern formation during regeneration. Retinoic acid signaling is the most characterized pathway during this process. Exogenous retinoic acid (RA) reprograms the pattern information in regenerating cells to a more posterior, ventral, and proximal identity. Vitamin D signaling shares several molecular similarities with RA and has been shown to alter pattern formation during zebrafish pectoral fin regeneration. To determine if exogenous Vitamin D signaling is capable of reprograming pattern in the axolotl limb blastema, we treated regenerating limbs with a potent Vitamin D agonist. Under the studied conditions, exogenous Vitamin D did not act in a manner similar to RA and failed to proximalize the pattern of the resulting regenerates. The Vitamin D treatment did result in several skeletal defects during regeneration, including carpal fusions along the A/P axis; failure to integrate the newly regenerated tissue with the existing tissue, formation of ectopic nodules of cartilage at the site of amputation, and altered bone morphology in uninjured skeletal tissue.
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Affiliation(s)
- Warren A Vieira
- Department of Biology, University of Massachusetts Boston, Boston, MA, USA
| | - Kaylee M Wells
- Department of Biology, University of Massachusetts Boston, Boston, MA, USA
| | - Roni Milgrom
- Department of Biology, University of Massachusetts Boston, Boston, MA, USA
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