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Chen L, Shi Y, Xiao D, Huang Y, Jiang Y, Liang M, Liang F, Xue J, Chen H, Liu Z, Wang X, Zhuang F, Zhou G, Huo H, Cai Z, Shao Q, He B. NR4A1 deficiency promotes carotid plaque vulnerability by activating integrated stress response via targeting Bcat1. Cell Mol Life Sci 2025; 82:91. [PMID: 39985585 PMCID: PMC11846829 DOI: 10.1007/s00018-025-05602-2] [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: 11/14/2024] [Revised: 01/10/2025] [Accepted: 01/21/2025] [Indexed: 02/24/2025]
Abstract
Rupture of vulnerable carotid atherosclerotic plaque is one of the leading causes of ischemic stroke. However, the mechanisms driving the transition from stable to vulnerable plaques have not yet been elucidated. NR4A1 is an orphan nuclear receptor that functions in various inflammatory diseases. To explore the role of NR4A1 in vulnerable plaque formation, we generated a vulnerable plaque mouse model by combining partial ligation of the left common carotid artery and left renal artery in ApoE-/- and ApoE-/-;NR4A1-/- mice. Our research revealed that NR4A1 deficiency significantly worsened the pathology of vulnerable plaque, increasing intraplaque hemorrhage, rupture with thrombus, and the occurrence of multilayer with discontinuity. Moreover, NR4A1 deficiency exacerbated macrophage infiltration, inflammation, and oxidative stress. Mechanistically, we identified Bcat1 as the target of NR4A1. NR4A1 modulated the integrated stress response (ISR) in macrophages by transcriptionally inhibiting Bcat1, thus influencing the progression of vulnerable plaque. ISR inhibitor GSK2606414 or Bcat1 inhibitor ERG240 significantly ameliorated atherosclerotic plaque formation and increased plaque stability. Notably, supplementation with Celastrol, an herbal extract, stabilized atherosclerotic plaques in mice. These findings suggest that NR4A1 deficiency exacerbates vulnerable plaque by activating ISR via targeting Bcat1. The NR4A1/Bcat1/ISR axis is therefore an important therapeutic target for stabilizing atherosclerotic plaque.
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MESH Headings
- Animals
- Nuclear Receptor Subfamily 4, Group A, Member 1/deficiency
- Nuclear Receptor Subfamily 4, Group A, Member 1/genetics
- Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism
- Plaque, Atherosclerotic/pathology
- Plaque, Atherosclerotic/metabolism
- Plaque, Atherosclerotic/genetics
- Mice
- Mice, Inbred C57BL
- Macrophages/metabolism
- Disease Models, Animal
- Mice, Knockout
- Oxidative Stress
- Male
- Humans
- Apolipoproteins E/deficiency
- Apolipoproteins E/genetics
- Inflammation/pathology
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Affiliation(s)
- Long Chen
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Yiping Shi
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Danrui Xiao
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Yijie Huang
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Yangjing Jiang
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Min Liang
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Feng Liang
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Jieyuan Xue
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Haiping Chen
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Zhitong Liu
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Xia Wang
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Fei Zhuang
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Guo Zhou
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Huanhuan Huo
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Zhaohua Cai
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
| | - Qin Shao
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
| | - Ben He
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
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Parmar T, Parmar V, Malek G. Potential Role of NUR77 in the Aging Retinal Pigment Epithelium and Age-Related Macular Degeneration. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1468:165-169. [PMID: 39930190 DOI: 10.1007/978-3-031-76550-6_27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2025]
Abstract
The underlying mechanisms associated with age-related changes in the morphology and function of retinal pigmented epithelial (RPE) cells are poorly understood. The aging RPE progresses through several structural changes including loss of melanin granules, accumulation of lipofuscin, and cytoskeletal changes, among others. Extracellular to it, there is also thickening of Bruch's membrane and changes in the integrity of the choroid. Recent studies have revealed that aging also affects the metabolic ecosystem of the RPE. Aged mitochondria exhibit decreased rates of oxidative phosphorylation, increased reactive oxygen species generation, and increased number of mitochondrial mutations relative to baseline. These changes are also found in age-related macular degeneration (AMD), a late-onset vision-impairing disease, in which the RPE is particularly vulnerable. The orphan nuclear receptor NR4A1/NUR77 is an early response gene and regulator of various cellular processes during development, aging, and disease. Previously we observed decreased levels of Nur77/NUR77 in both mouse and human RPE as a function of age. Current knowledge of the function of this receptor in the RPE is limited. Herein, we discuss the putative roles of NUR77 in the RPE during aging and disease.
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Affiliation(s)
- Tanu Parmar
- Departments of Ophthalmology, Duke University School of Medicine, Durham, NC, USA.
- Albert Eye Research Institute, Durham, NC, USA.
| | - Vipul Parmar
- Departments of Ophthalmology, Duke University School of Medicine, Durham, NC, USA
| | - Goldis Malek
- Departments of Ophthalmology, Duke University School of Medicine, Durham, NC, USA.
- Albert Eye Research Institute, Durham, NC, USA.
- Departments of Pathology, Duke University School of Medicine, Durham, NC, USA.
- Departments of Cell Biology, Duke University School of Medicine, Durham, NC, USA.
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Chen JF, Wang J, Chai J, Jin W, Ren QL, Ma Q, Lu QX, Sun JJ, Mo DL, Zhang JQ, Xing BS. Transcriptome profiling of longissimus dorsi during different prenatal stages to identify genes involved in intramuscular fat deposition in lean and obese pig breeds. Mol Biol Rep 2024; 51:386. [PMID: 38441676 PMCID: PMC10914898 DOI: 10.1007/s11033-023-09088-8] [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: 05/13/2023] [Accepted: 11/29/2023] [Indexed: 03/07/2024]
Abstract
BACKGROUND There was significant difference in muscle development between fat-type and lean-type pig breeds. METHODS AND RESULTS In current study, transcriptome analysis and bioinformatics analysis were used to compare the difference in longissimus dorsi (LD) muscle at three time-points (38 days post coitus (dpc), 58 dpc, and 78 dpc ) between Huainan (HN) and Large white (LW) pig breeds. A total of 24500 transcripts were obtained in 18 samples, and 2319, 2799, and 3713 differently expressed genes (DEGs) were identified between these two breeds at 38 dpc, 58 dpc, and 78 dpc, respectively. And the number and foldchange of DEGs were increased, the alternative splice also increased. The cluster analysis of DEGs indicated the embryonic development progress of LD muscle between these two breeds was different. There were 539 shared DEGs between HN and LW at three stages, and the top-shared DEGs were associated with muscle development and lipid deposition, such as KLF4, NR4A1, HSP70, ZBTB16 and so on. CONCLUSIONS The results showed DEGs between Huainan (HN) and Large white (LW) pig breeds, and contributed to the understanding the muscle development difference between HN and LW, and provided basic materials for improvement of meat quality.
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Affiliation(s)
- Jun Feng Chen
- Henan Key Laboratory of Farm Animal Breeding and Nutritional Regulation, Institute of Animal Husbandry and Veterinary Science, Henan Academy of Agricultural Sciences, Huayuan Road No.116, Zhengzhou, 450002, Henan, China
| | - Jing Wang
- Henan Key Laboratory of Farm Animal Breeding and Nutritional Regulation, Institute of Animal Husbandry and Veterinary Science, Henan Academy of Agricultural Sciences, Huayuan Road No.116, Zhengzhou, 450002, Henan, China
| | - Jin Chai
- Agricultural Ministry Key Laboratory of Swine Breeding and Genetics & Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan, 430070, China
| | - Wei Jin
- Henan Key Laboratory of Farm Animal Breeding and Nutritional Regulation, Institute of Animal Husbandry and Veterinary Science, Henan Academy of Agricultural Sciences, Huayuan Road No.116, Zhengzhou, 450002, Henan, China
| | - Qiao Ling Ren
- Henan Key Laboratory of Farm Animal Breeding and Nutritional Regulation, Institute of Animal Husbandry and Veterinary Science, Henan Academy of Agricultural Sciences, Huayuan Road No.116, Zhengzhou, 450002, Henan, China
| | - Qiang Ma
- Henan Key Laboratory of Farm Animal Breeding and Nutritional Regulation, Institute of Animal Husbandry and Veterinary Science, Henan Academy of Agricultural Sciences, Huayuan Road No.116, Zhengzhou, 450002, Henan, China
| | - Qing Xia Lu
- Henan Key Laboratory of Farm Animal Breeding and Nutritional Regulation, Institute of Animal Husbandry and Veterinary Science, Henan Academy of Agricultural Sciences, Huayuan Road No.116, Zhengzhou, 450002, Henan, China
| | - Jia Jie Sun
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - De Lin Mo
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Jia Qing Zhang
- Henan Key Laboratory of Farm Animal Breeding and Nutritional Regulation, Institute of Animal Husbandry and Veterinary Science, Henan Academy of Agricultural Sciences, Huayuan Road No.116, Zhengzhou, 450002, Henan, China
| | - Bao Song Xing
- Henan Key Laboratory of Farm Animal Breeding and Nutritional Regulation, Institute of Animal Husbandry and Veterinary Science, Henan Academy of Agricultural Sciences, Huayuan Road No.116, Zhengzhou, 450002, Henan, China.
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Upadhyay S, Hailemariam AE, Mariyam F, Hafiz Z, Martin G, Kothari J, Farkas E, Sivaram G, Bell L, Tjalkens R, Safe S. Bis-Indole Derivatives as Dual Nuclear Receptor 4A1 (NR4A1) and NR4A2 Ligands. Biomolecules 2024; 14:284. [PMID: 38540704 PMCID: PMC10967861 DOI: 10.3390/biom14030284] [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: 02/06/2024] [Revised: 02/22/2024] [Accepted: 02/23/2024] [Indexed: 06/27/2024] Open
Abstract
Bis-indole derived compounds such as 1,1-bis(3'-indolyl)-1-(3,5-disubstitutedphenyl) methane (DIM-3,5) and the corresponding 4-hydroxyl analogs (DIM8-3,5) are NR4A1 ligands that act as inverse NR4A1 agonists and are potent inhibitors of tumor growth. The high potency of several DIM-3,5 analogs (IC50 < 1 mg/kg/day), coupled with the >60% similarity of the ligand-binding domains (LBDs) of NR4A1 and NR4A2 and the pro-oncogenic activities of both receptors lead us to hypothesize that these compounds may act as dual NR4A1 and NR4A2 ligands. Using a fluorescence binding assay, it was shown that 22 synthetic DIM8-3,5 and DIM-3,5 analogs bound the LBD of NR4A1 and NR4A2 with most KD values in the low µM range. Moreover, the DIM-3,5 and DIM8-3,5 analogs also decreased NR4A1- and NR4A2-dependent transactivation in U87G glioblastoma cells transfected with GAL4-NR4A1 or GAL4-NR4A2 chimeras and a UAS-luciferase reporter gene construct. The DIM-3,5 and DIM8-3,5 analogs were cytotoxic to U87 glioblastoma and RKO colon cancer cells and the DIM-3,5 compounds were more cytotoxic than the DIM8-3,5 compounds. These studies show that both DIM-3,5 and DIM8-3,5 compounds previously identified as NR4A1 ligands bind both NR4A1 and NR4A2 and are dual NR4A1/2 ligands.
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Affiliation(s)
- Srijana Upadhyay
- Department of Veterinary Physiology, Texas A&M University, College Station, TX 77843, USA; (S.U.); (A.E.H.); (F.M.); (G.M.); (E.F.)
| | - Amanuel Esayas Hailemariam
- Department of Veterinary Physiology, Texas A&M University, College Station, TX 77843, USA; (S.U.); (A.E.H.); (F.M.); (G.M.); (E.F.)
| | - Fuada Mariyam
- Department of Veterinary Physiology, Texas A&M University, College Station, TX 77843, USA; (S.U.); (A.E.H.); (F.M.); (G.M.); (E.F.)
| | - Zahin Hafiz
- Department of Chemical Engineering, Texas A&M University, College Station, TX 77843, USA; (Z.H.); (J.K.)
| | - Gregory Martin
- Department of Veterinary Physiology, Texas A&M University, College Station, TX 77843, USA; (S.U.); (A.E.H.); (F.M.); (G.M.); (E.F.)
| | - Jainish Kothari
- Department of Chemical Engineering, Texas A&M University, College Station, TX 77843, USA; (Z.H.); (J.K.)
| | - Evan Farkas
- Department of Veterinary Physiology, Texas A&M University, College Station, TX 77843, USA; (S.U.); (A.E.H.); (F.M.); (G.M.); (E.F.)
| | - Gargi Sivaram
- Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA;
| | - Logan Bell
- Department of Chemistry, University of La Verne, La Verne, CA 91750, USA;
| | - Ronald Tjalkens
- Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80526, USA;
| | - Stephen Safe
- Department of Veterinary Physiology, Texas A&M University, College Station, TX 77843, USA; (S.U.); (A.E.H.); (F.M.); (G.M.); (E.F.)
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Zhang L, Martin G, Mohankumar K, Wright GA, Mariyam F, Safe S. Piperlongumine is a ligand for the orphan nuclear receptor 4A1 (NR4A1). Front Pharmacol 2023; 14:1223153. [PMID: 37808182 PMCID: PMC10551445 DOI: 10.3389/fphar.2023.1223153] [Citation(s) in RCA: 2] [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: 05/15/2023] [Accepted: 09/04/2023] [Indexed: 10/10/2023] Open
Abstract
Piperlongumine and derivatives are being developed as anticancer agents which act primarily as inducers of reactive oxygen species (ROS) in cancer cell lines. Many of the anticancer activities of piperlongumine resemble those observed for bis-indole derived compounds that bind the orphan nuclear receptor 4A1 (NR4A1) and act as inverse receptor agonists to inhibit NR4A1-regulated pro-oncogenic pathways and genes. In this study we show that like other NR4A1 inverse agonists piperlongumine inhibited RKO, SW480 and HCT116 colon cancer cell growth migration and invasion and induced apoptosis. Piperlongumine also downregulated the pro-reductant isocitrate dehydrogenase 1 (IDH1) and thioredoxin domain-containing 5 (TXNDC5) gene products resulting in the induction of ROS as previously observed for other inverse NR4A1 agonists. ROS also induced sestrin2 and this resulted in activation of AMPK phosphorylation and inhibition of mTOR pathway signaling. It has previously been reported that these pathways/genes are also regulated by inverse NR4A1 agonists or by knockdown of NR4A1. We also observed that piperlongumine directly bound NR4A1, inhibited NR4A1-dependent transactivation and interactions of the NR4A1/Sp1 complex bound to the GC-rich promoter of the NR4A1-regulated G9a gene.
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Affiliation(s)
- Lei Zhang
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, United States
| | - Greg Martin
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, United States
| | - Kumaravel Mohankumar
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, United States
| | - Gus A. Wright
- Department of Veterinary Pathobiology, Texas A&M University, College Station, TX, United States
| | - Fuada Mariyam
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, United States
| | - Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, United States
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Feng C, Yang Y, Lu A, Tan D, Lu Y, Qin L, He Y. Multi‑omics‑based analysis of the regulatory mechanism of gypenosides on bile acids in hypercholesterolemic mice. Exp Ther Med 2023; 26:438. [PMID: 37614436 PMCID: PMC10443059 DOI: 10.3892/etm.2023.12136] [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: 12/01/2022] [Accepted: 06/22/2023] [Indexed: 08/25/2023] Open
Abstract
Gynostemma pentaphyllum is a traditional medicine used by ethnic minorities in southwest China and gypenosides are currently recognized as essential components of the pharmacological substances of Gynostemma pentaphyllum, which are effective in regulating metabolic syndrome, especially in improving hepatic metabolic disorders. The present study randomly divided C57BL/6J male mice into the normal diet control group (ND), high-fat diet modeling group (HFD) and gypenosides group (GP). Liquid chromatography-mass spectrometry (UPLC-MS) was applied to quantify bile acids in the liver, bile and serum of mice in ND, HFD and GP groups. Liver proteins were extracted for trypsin hydrolysis and analyzed quantitatively using UPLC-MS + MS/MS (timsTOF Pro 2). Total mouse liver RNA was extracted from ND, HFD and GP groups respectively, cDNA sequencing libraries constructed and sequenced using BGISEQ-500 sequencing platform. The expression of key genes Fxr, Shp, Cyp7a1, Cyp8b1, and Abab11 was detected by RT-qPCR. The results showed that gypenosides accelerated free bile acid synthesis by promoting the expression of bile acid synthase CYP7A1 and CYP8B1 genes and proteins and accelerating the secretion of conjugated bile acids from the liver to the bile ducts. GP inhibited the bile acid transporters solute carrier organic anion transporter family member (SLCO) 1A1 and SLCO1A4, reducing the reabsorption of free bile acids and accelerating the excretion of free bile acids from the blood to the kidneys. It also promoted the metabolic enzyme CYP3A11, which accelerated the metabolism and clearance of bile acids, thus maintaining the balance of the bile acid internal environment.
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Affiliation(s)
- Chengcheng Feng
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Yanping Yang
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Anjing Lu
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Daopeng Tan
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Yanliu Lu
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Lin Qin
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Yuqi He
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
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Bizjak DA, Nussbaumer D, Winkert K, Treff G, Takabajashi K, Mentz L, Schober F, Buhl JL, John L, Dreyhaupt J, Steeb L, Harps LC, Parr MK, Diel P, Zügel M, Steinacker JM. Acute Effects of Single Versus Combined Inhaled β2-Agonists Salbutamol and Formoterol on Time Trial Performance, Lung Function, Metabolic and Endocrine Variables. SPORTS MEDICINE - OPEN 2023; 9:79. [PMID: 37640958 PMCID: PMC10462601 DOI: 10.1186/s40798-023-00630-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Accepted: 08/17/2023] [Indexed: 08/31/2023]
Abstract
BACKGROUND High prevalence rates of β2-agonist use among athletes in competitive sports makes it tempting to speculate that illegitimate use of β2-agonists boosts performance. However, data regarding the potential performance-enhancing effects of inhaled β2-agonists and its underlying molecular basis are scarce. METHODS In total, 24 competitive endurance athletes (12f/12m) participated in a clinical double-blinded balanced four-way block cross-over trial to investigate single versus combined effects of β2-agonists salbutamol (SAL) and formoterol (FOR), to evaluate the potential performance enhancement of SAL (1200 µg, Cyclocaps, Pb Pharma GmbH), FOR (36 µg, Sandoz, HEXAL AG) and SAL + FOR (1200 µg + 36 µg) compared to placebo (PLA, Gelatine capsules containing lactose monohydrate, Pharmacy of the University Hospital Ulm). Measurements included skeletal muscle gene and protein expression, endocrine regulation, urinary/serum β2-agonist concentrations, cardiac markers, cardiopulmonary and lung function testing and the 10-min time trial (TT) performance on a bicycle ergometer as outcome variables. Blood and urine samples were collected pre-, post-, 3 h post- and 24 h post-TT. RESULTS Mean power output during TT was not different between study arms. Treatment effects regarding lung function (p < 0.001), echocardiographic (left ventricular end-systolic volume p = 0.037; endocardial global longitudinal strain p < 0.001) and metabolic variables (e.g. NR4A2 and ATF3 pathway) were observed without any influence on performance. In female athletes, total serum β2-agonist concentrations for SAL and FOR were higher. Microarray muscle gene analysis showed a treatment effect for target genes in energy metabolism with strongest effect by SAL + FOR (NR4A2; p = 0.001). Of endocrine variables, follicle-stimulating hormone (3 h Post-Post-TT), luteinizing hormone (3 h Post-Pre-TT) and insulin (Post-Pre-TT) concentrations showed a treatment effect (all p < 0.05). CONCLUSIONS No endurance performance-enhancing effect for SAL, FOR or SAL + FOR within the permitted dosages compared to PLA was found despite an acute effect on lung and cardiac function as well as endocrine and metabolic variables in healthy participants. The impact of combined β2-agonists on performance and sex-specific thresholds on the molecular and cardiac level and their potential long-term performance enhancing or health effects have still to be determined. TRIAL REGISTRATION Registered at Eudra CT with the number: 2015-005598-19 (09.12.2015) and DRKS with number DRKS00010574 (16.11.2021, retrospectively registered).
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Affiliation(s)
- Daniel A Bizjak
- Department of Internal Medicine, Division of Sports and Rehabilitation Medicine, University Hospital Ulm, 89075, Ulm, Germany.
| | - Dorle Nussbaumer
- Department of Internal Medicine, Division of Sports and Rehabilitation Medicine, University Hospital Ulm, 89075, Ulm, Germany
| | - Kay Winkert
- Department of Internal Medicine, Division of Sports and Rehabilitation Medicine, University Hospital Ulm, 89075, Ulm, Germany
| | - Gunnar Treff
- Department of Internal Medicine, Division of Sports and Rehabilitation Medicine, University Hospital Ulm, 89075, Ulm, Germany
- Institute of Sports Medicine, Paracelsus Medical University Salzburg, 5020, Salzburg, Austria
| | - Kensuke Takabajashi
- Department of Internal Medicine, Division of Sports and Rehabilitation Medicine, University Hospital Ulm, 89075, Ulm, Germany
| | - Lennart Mentz
- Department of Internal Medicine, Division of Sports and Rehabilitation Medicine, University Hospital Ulm, 89075, Ulm, Germany
| | - Franziska Schober
- Department of Internal Medicine, Division of Sports and Rehabilitation Medicine, University Hospital Ulm, 89075, Ulm, Germany
| | - Jasmine-Lèonike Buhl
- Department of Internal Medicine, Division of Sports and Rehabilitation Medicine, University Hospital Ulm, 89075, Ulm, Germany
| | - Lucas John
- Department of Internal Medicine, Division of Sports and Rehabilitation Medicine, University Hospital Ulm, 89075, Ulm, Germany
| | - Jens Dreyhaupt
- Institute of Epidemiology and Medical Biometry, Ulm University, 89075, Ulm, Germany
| | - Luise Steeb
- Institute of Epidemiology and Medical Biometry, Ulm University, 89075, Ulm, Germany
| | - Lukas C Harps
- Pharmaceutical Analysis and Metabolism, Institute of Pharmacy, Freie Universität Berlin, 14195, Berlin, Germany
| | - Maria K Parr
- Pharmaceutical Analysis and Metabolism, Institute of Pharmacy, Freie Universität Berlin, 14195, Berlin, Germany
| | - Patrick Diel
- Institute of Cardiovascular Research and Sports Medicine, Molecular and Cellular Sports Medicine, German Sport University Cologne, 50933, Cologne, Germany
| | - Martina Zügel
- Department of Internal Medicine, Division of Sports and Rehabilitation Medicine, University Hospital Ulm, 89075, Ulm, Germany
| | - Jürgen M Steinacker
- Department of Internal Medicine, Division of Sports and Rehabilitation Medicine, University Hospital Ulm, 89075, Ulm, Germany
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Hosseini SF, Bakhtiarizadeh MR, Salehi A. Meta-analysis of RNA-Seq datasets highlights novel genes/pathways involved in fat deposition in fat-tail of sheep. Front Vet Sci 2023; 10:1159921. [PMID: 37252399 PMCID: PMC10213422 DOI: 10.3389/fvets.2023.1159921] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 04/11/2023] [Indexed: 05/31/2023] Open
Abstract
Introduction Fat-tail in sheep is considered as an important energy reservoir to provide energy as a survival buffer during harsh challenges. However, fat-tail is losing its importance in modern sheep industry systems and thin-tailed breeds are more desirable. Using comparative transcriptome analysis to compare fat-tail tissue between fat- and thin-tailed sheep breeds provides a valuable approach to study the complex genetic factors associated with fat-tail development. However, transcriptomic studies often suffer from issues with reproducibility, which can be improved by integrating multiple studies based on a meta-analysis. Methods Hence, for the first time, an RNA-Seq meta-analysis on sheep fat-tail transcriptomes was performed using six publicly available datasets. Results and discussion A total of 500 genes (221 up-regulated, 279 down-regulated) were identified as differentially expressed genes (DEGs). A jackknife sensitivity analysis confirmed the robustness of the DEGs. Moreover, QTL and functional enrichment analysis reinforced the importance of the DEGs in the underlying molecular mechanisms of fat deposition. Protein-protein interactions (PPIs) network analysis revealed the functional interactions among the DEGs and the subsequent sub-network analysis led to identify six functional sub-networks. According to the results of the network analysis, down-regulated DEGs in green and pink sub-networks (like collagen subunits IV, V, and VI, integrins 1 and 2, SCD, SCD5, ELOVL6, ACLY, SLC27A2, and LPIN1) may impair lipolysis or fatty acid oxidation and cause fat accumulation in tail. On the other hand, up-regulated DEGs, especially those are presented in green and pink sub-networks (like IL6, RBP4, LEPR, PAI-1, EPHX1, HSD11B1, and FMO2), might contribute to a network controlling fat accumulation in the tail of sheep breed through mediating adipogenesis and fatty acid biosynthesis. Our results highlighted a set of known and novel genes/pathways associated with fat-tail development, which could improve the understanding of molecular mechanisms behind fat deposition in sheep fat-tail.
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9
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Tao G, Liu F, Jin Z, Liu B, Wang H, Li D, Tang W, Chen Y, He Q, Qin S. A strategy of local hydrogen capture and catalytic hydrogenation for enhanced therapy of chronic liver diseases. Theranostics 2023; 13:2455-2470. [PMID: 37215568 PMCID: PMC10196827 DOI: 10.7150/thno.80494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 04/08/2023] [Indexed: 05/24/2023] Open
Abstract
Background: Chronic liver diseases (CLD) frequently derive from hepatic steatosis, inflammation and fibrosis, and become a leading inducement of cirrhosis and hepatocarcinoma. Molecular hydrogen (H2) is an emerging wide-spectrum anti-inflammatory molecule which is able to improve hepatic inflammation and metabolic dysfunction, and holds obvious advantages in biosafety over traditional anti-CLD drugs, but existing H2 administration routes cannot realize the liver-targeted high-dose delivery of H2, severely limiting its anti-CLD efficacy. Method: In this work, a concept of local hydrogen capture and catalytic hydroxyl radical (·OH) hydrogenation is proposed for CLD treatment. The mild and moderate non-alcoholic steatohepatitis (NASH) model mice were intravenously injected with PdH nanoparticles firstly, and then daily inhaled 4% hydrogen gas for 3 h throughout the whole treatment period. After the end of treatment, glutathione (GSH) was intramuscularly injected every day to assist the Pd excretion. Results: In vitro and in vivo proof-of-concept experiments have confirmed that Pd nanoparticles can accumulate in liver in a targeted manner post intravenous injection, and play a dual role of hydrogen captor and ·OH filter to locally capture/store the liver-passing H2 during daily hydrogen gas inhalation and rapidly catalyze the ·OH hydrogenation into H2O. The proposed therapy significantly improves the outcomes of hydrogen therapy in the prevention and treatment of NASH by exhibiting a wide range of bioactivity including the regulation of lipid metabolism and anti-inflammation. Pd can be mostly eliminated after the end of treatment under the assistance of GSH. Conclusion: Our study verified a catalytic strategy of combining PdH nanoparticles and hydrogen inhalation, which exhibited enhanced anti-inflammatory effect for CLD treatment. The proposed catalytic strategy will open a new window to realize safe and efficient CLD treatment.
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Affiliation(s)
- Geru Tao
- Key Laboratory of Major Diseases and Hydrogen Medical Translational Applications in Universities of Shandong Province & Key Laboratory of Hydrogen Biomedical Research of Health Commission of Shandong Province, The Second Affiliated Hospital of Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an 271000, China
- Taishan Institute for Hydrogen Biomedical Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an 271000, China
| | - Feng Liu
- Key Laboratory of Major Diseases and Hydrogen Medical Translational Applications in Universities of Shandong Province & Key Laboratory of Hydrogen Biomedical Research of Health Commission of Shandong Province, The Second Affiliated Hospital of Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an 271000, China
- Taishan Institute for Hydrogen Biomedical Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an 271000, China
| | - Zhaokui Jin
- School of Biomedical Engineering, Guangzhou Medical University, Guangdong, 511495 China
| | - Boyan Liu
- Key Laboratory of Major Diseases and Hydrogen Medical Translational Applications in Universities of Shandong Province & Key Laboratory of Hydrogen Biomedical Research of Health Commission of Shandong Province, The Second Affiliated Hospital of Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an 271000, China
- Taishan Institute for Hydrogen Biomedical Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an 271000, China
| | - Hao Wang
- Key Laboratory of Major Diseases and Hydrogen Medical Translational Applications in Universities of Shandong Province & Key Laboratory of Hydrogen Biomedical Research of Health Commission of Shandong Province, The Second Affiliated Hospital of Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an 271000, China
- Taishan Institute for Hydrogen Biomedical Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an 271000, China
| | - Daosheng Li
- Pathology Department of Tai'an City Central Hospital, Tai'an 271016, China
| | - Wei Tang
- Key Laboratory of Human-Machine-Intelligence Synergic System, Research Center for Neural Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, Guangdong, China
| | - Yuan Chen
- Key Laboratory of Major Diseases and Hydrogen Medical Translational Applications in Universities of Shandong Province & Key Laboratory of Hydrogen Biomedical Research of Health Commission of Shandong Province, The Second Affiliated Hospital of Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an 271000, China
- Taishan Institute for Hydrogen Biomedical Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an 271000, China
| | - Qianjun He
- Shanghai Key Laboratory of Hydrogen Science & Center of Hydrogen Science, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
- Shenzhen Research Institute, Shanghai Jiao Tong University, Shenzhen 518057, China
| | - Shucun Qin
- Key Laboratory of Major Diseases and Hydrogen Medical Translational Applications in Universities of Shandong Province & Key Laboratory of Hydrogen Biomedical Research of Health Commission of Shandong Province, The Second Affiliated Hospital of Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an 271000, China
- Taishan Institute for Hydrogen Biomedical Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an 271000, China
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10
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Raths F, Karimzadeh M, Ing N, Martinez A, Yang Y, Qu Y, Lee TY, Mulligan B, Devkota S, Tilley WT, Hickey TE, Wang B, Giuliano AE, Bose S, Goodarzi H, Ray EC, Cui X, Knott SR. The molecular consequences of androgen activity in the human breast. CELL GENOMICS 2023; 3:100272. [PMID: 36950379 PMCID: PMC10025454 DOI: 10.1016/j.xgen.2023.100272] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 10/20/2022] [Accepted: 01/30/2023] [Indexed: 03/24/2023]
Abstract
Estrogen and progesterone have been extensively studied in the mammary gland, but the molecular effects of androgen remain largely unexplored. Transgender men are recorded as female at birth but identify as male and may undergo gender-affirming androgen therapy to align their physical characteristics and gender identity. Here we perform single-cell-resolution transcriptome, chromatin, and spatial profiling of breast tissues from transgender men following androgen therapy. We find canonical androgen receptor gene targets are upregulated in cells expressing the androgen receptor and that paracrine signaling likely drives sex-relevant androgenic effects in other cell types. We also observe involution of the epithelium and a spatial reconfiguration of immune, fibroblast, and vascular cells, and identify a gene regulatory network associated with androgen-induced fat loss. This work elucidates the molecular consequences of androgen activity in the human breast at single-cell resolution.
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Affiliation(s)
- Florian Raths
- Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Mehran Karimzadeh
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
- Vector Institute, Toronto, ON, Canada
- Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada
- Department of Urology, University of California, San Francisco, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
- Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA
| | - Nathan Ing
- Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Andrew Martinez
- Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Yoona Yang
- Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ying Qu
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Tian-Yu Lee
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Brianna Mulligan
- Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Suzanne Devkota
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Wayne T. Tilley
- Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
- Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, SA, Australia
| | - Theresa E. Hickey
- Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
| | - Bo Wang
- Vector Institute, Toronto, ON, Canada
- Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Computer Science, University of Toronto, Toronto, ON, Canada
| | | | - Shikha Bose
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Hani Goodarzi
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
- Department of Urology, University of California, San Francisco, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
- Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA
| | - Edward C. Ray
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Transgender Surgery and Health Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Xiaojiang Cui
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Simon R.V. Knott
- Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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11
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Wang H, Zhang M, Fang F, Xu C, Liu J, Gao L, Zhao C, Wang Z, Zhong Y, Wang X. The nuclear receptor subfamily 4 group A1 in human disease. Biochem Cell Biol 2023; 101:148-159. [PMID: 36861809 DOI: 10.1139/bcb-2022-0331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/03/2023] Open
Abstract
Nuclear receptor 4A1 (NR4A1), a member of the NR4A subfamily, acts as a gene regulator in a wide range of signaling pathways and responses to human diseases. Here, we provide a brief overview of the current functions of NR4A1 in human diseases and the factors involved in its function. A deeper understanding of these mechanisms can potentially improve drug development and disease therapy.
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Affiliation(s)
- Hongshuang Wang
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang 050091, China
| | - Mengjuan Zhang
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang 050091, China
| | - Fang Fang
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang 050091, China
| | - Chang Xu
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang 050091, China
| | - Jiazhi Liu
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang 050091, China
| | - Lanjun Gao
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang 050091, China
| | - Chenchen Zhao
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang 050091, China
| | - Zheng Wang
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns Research, Shijiazhuang 050091, China.,Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Yan Zhong
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns Research, Shijiazhuang 050091, China.,Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Xiangting Wang
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns Research, Shijiazhuang 050091, China
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12
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Go S, Masuda H, Tsuru M, Inden M, Hozumi I, Kurita H. Exposure to a low concentration of methylmercury in neural differentiation downregulates NR4A1 expression with altered epigenetic modifications and inhibits neuronal spike activity in vitro. Toxicol Lett 2023; 374:68-76. [PMID: 36565944 DOI: 10.1016/j.toxlet.2022.12.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 10/31/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022]
Abstract
Methylmercury (MeHg) is a well-known developmental neurotoxin. Our previous research showed that the inhibition of neurite extension by exposure to a low level of MeHg (1 nM) was attributed to the decrease of acetylation of histone H3 and the increase of DNA methylation. However, the target molecules responsible for the neurological dysfunctions caused by MeHg exposure have not been identified. This study focused on a nuclear receptor subfamily 4 group A member 1 (NR4A1), which is reported to be related to synaptic plasticity and neurite extension. LUHMES cells, which are derived from human fetal brain, were treated with 0.1 and 1 nM MeHg beginning at two days of differentiation and continued for 6 consecutive days. The present study showed that exposure to a 1 nM MeHg during neural differentiation inhibited neuronal spike activity and neurite extension. Furthermore, MeHg exposure increased DNA methylation, and altered histone modifications for transcriptional repression in the NR4A1 promoter region to decrease the levels of NR4A1 expression. In addition, MeHg exposure inhibited the mobilization of cAMP response element-binding protein (CREB) and CREB binding protein (CBP) in the NR4A1 promoter region. These results suggest that MeHg inhibits the recruitment of the CREB-CBP complex to the NR4A1 promoter region and impairs neuronal functions associated with NR4A1 repression via a decrease in acetylation of histone H3 lysine 14 levels. Conclusively, this study demonstrated that MeHg exposure during neuronal differentiation could induce neurological dysfunctions even at a low concentration in vitro. These dysfunctions could be associated with the transcriptional repression of NR4A1 by the dissociation of CREB and CBP from the NR4A1 promoter region due to the alterations of epigenetic modifications.
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Affiliation(s)
- Suzuna Go
- Laboratory of Medical Therapeutics and Molecular Therapeutics, Department Biomedical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu city, Gifu, 501-1196, Japan
| | - Haruka Masuda
- Laboratory of Medical Therapeutics and Molecular Therapeutics, Department Biomedical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu city, Gifu, 501-1196, Japan
| | - Mizuki Tsuru
- Laboratory of Medical Therapeutics and Molecular Therapeutics, Department Biomedical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu city, Gifu, 501-1196, Japan
| | - Masatoshi Inden
- Laboratory of Medical Therapeutics and Molecular Therapeutics, Department Biomedical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu city, Gifu, 501-1196, Japan
| | - Isao Hozumi
- Laboratory of Medical Therapeutics and Molecular Therapeutics, Department Biomedical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu city, Gifu, 501-1196, Japan.
| | - Hisaka Kurita
- Laboratory of Medical Therapeutics and Molecular Therapeutics, Department Biomedical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu city, Gifu, 501-1196, Japan.
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13
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Yu T, Wu F, Jia Y, Zhang X, Qi X, Jin Z, Hao T, Zhao J, Liu Z, Wang C, Niu M, Yue Q, Li M, Liu Y. RNA N 6-methyladenosine modification mediates downregulation of NR4A1 to facilitate malignancy of cervical cancer. Cell Biosci 2022; 12:207. [PMID: 36566195 DOI: 10.1186/s13578-022-00937-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 12/05/2022] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND N6-methyladenosine is the most abundant eukaryotic mRNA modification and alters a wide range of cellular processes in cancer. Therefore, defining the molecular details are critical for understanding the regulatory mechanism of m6A modification. RESULTS We found that METTL3, a core m6A methyltransferase component, is upregulated and functions as an oncogene in cervical cancer. Mechanistically, METTL3 induces the degradation of m6A-modified transcripts of NR4A1 though YTHDF2-DDX6 pathway. In addition, NR4A1 overexpression attenuates the malignant progression through recruiting the LSD1/HDAC1/CoREST transcriptional repression complex to AKT1 promoter. CONCLUSIONS Our findings reveal that m6A regulates cervical cancer cellular progression through manipulating NR4A1 pathway.
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Affiliation(s)
- Tao Yu
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
| | - Fuxia Wu
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Yan Jia
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Xue Zhang
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Xiaozhen Qi
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Zeyuan Jin
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Tongxin Hao
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Jianing Zhao
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Ziyu Liu
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Chaokun Wang
- Department of Integrative Chinese and Western Medicine, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Minmin Niu
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Qin Yue
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Min Li
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Yankun Liu
- Department of Molecular Diagnosis, Tangshan People's Hospital, Tangshan, 063001, China.
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14
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Szczepanski HE, Flannigan KL, Mainoli B, Alston L, Baruta GM, Lee JW, Venu VKP, Shearer J, Dufour A, Hirota SA. NR4A1 modulates intestinal smooth muscle cell phenotype and dampens inflammation-associated intestinal remodeling. FASEB J 2022; 36:e22609. [PMID: 36250380 DOI: 10.1096/fj.202101817rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 09/16/2022] [Accepted: 09/30/2022] [Indexed: 11/11/2022]
Abstract
Stricture formation is a common complication of Crohn's disease (CD), driven by enhanced deposition of extracellular matrix (ECM) and expansion of the intestinal smooth muscle layers. Nuclear receptor subfamily 4 group A member 1 (NR4A1) is an orphan nuclear receptor that exhibits anti-proliferative effects in smooth muscle cells (SMCs). We hypothesized that NR4A1 regulates intestinal SMC proliferation and muscle thickening in the context of inflammation. Intestinal SMCs isolated from Nr4a1+/+ and Nr4a1-/- littermates were subjected to shotgun proteomic analysis, proliferation, and bioenergetic assays. Proliferation was assessed in the presence and absence of NR4A1 agonists, cytosporone-B (Csn-B) and 6-mercaptopurine (6-MP). In vivo, we compared colonic smooth muscle thickening in Nr4a1+/+ and Nr4a1-/- mice using the chronic dextran sulfate sodium (DSS) model of colitis. Second, SAMP1/YitFc mice (a model of spontaneous ileitis) were treated with Csn-B and small intestinal smooth muscle thickening was assessed. SMCs isolated from Nr4a1-/- mice exhibited increased abundance of proteins related to cell proliferation, metabolism, and ECM production, whereas Nr4a1+/+ SMCs highly expressed proteins related to the regulation of the actin cytoskeleton and contractile processes. SMCs isolated from Nr4a1-/- mice exhibited increased proliferation and alterations in cellular metabolism, whereas activation of NR4A1 attenuated proliferation. In vivo, Nr4a1-/- mice exhibited increased colonic smooth muscle thickness following repeated cycles of DSS. Activating NR4A1 with Csn-B, in the context of established inflammation, reduced ileal smooth muscle thickening in SAMP1/YitFc mice. Targeting NR4A1 may provide a novel approach to regulate intestinal SMC phenotype, limiting excessive proliferation that contributes to stricture development in CD.
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Affiliation(s)
- Holly E Szczepanski
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Kyle L Flannigan
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Barbara Mainoli
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.,Department of Biochemistry & Molecular Biology, University of Calgary, Calgary, Alberta, Canada
| | - Laurie Alston
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Grace M Baruta
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Joshua W Lee
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Vivek Krishna Pulakazhi Venu
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Jane Shearer
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.,Department of Biochemistry & Molecular Biology, University of Calgary, Calgary, Alberta, Canada.,Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
| | - Antoine Dufour
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.,Department of Biochemistry & Molecular Biology, University of Calgary, Calgary, Alberta, Canada.,McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Alberta, Canada
| | - Simon A Hirota
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.,Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.,Department of Immunology, Microbiology & Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
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15
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Guo J, Zhou Y, Liu D, Wang M, Wu Y, Tang D, Liu X. Mitochondria as multifaceted regulators of ferroptosis. LIFE METABOLISM 2022; 1:134-148. [PMID: 39872359 PMCID: PMC11749789 DOI: 10.1093/lifemeta/loac035] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 11/21/2022] [Accepted: 11/22/2022] [Indexed: 01/30/2025]
Abstract
Mitochondria are well known to be "energy factories" of the cell as they provide intracellular ATP via oxidative phosphorylation. Interestingly, they also function as a "cellular suicidal weapon store" by acting as a key mediator of various forms of regulated cell death, including apoptosis, pyroptosis, necroptosis, and ferroptosis. Ferroptosis, distinct from the other types of regulated cell death, is characterized by iron-dependent lipid peroxidation and subsequent plasma membrane rupture. Growing evidence suggests that an impaired ferroptotic response is implicated in various diseases and pathological conditions, and this impaired response is associated with dramatic changes in mitochondrial morphology and function. Mitochondria are the center of iron metabolism and energy production, leading to altered lipid peroxidation sensitivity. Although a growing number of studies have explored the inextricable link between mitochondria and ferroptosis, the role of this organelle in regulating ferroptosis remains unclear. Here, we review recent advances in our understanding of the role of mitochondria in ferroptosis and summarize the characteristics of this novel iron-based cellular suicide weapon and its arsenal. We also discuss the importance of ferroptosis in pathophysiology, including the need for further understanding of the relationship between mitochondria and ferroptosis to identify combinatorial targets that are essential for the development of successful drug discovery.
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Affiliation(s)
- Jingyi Guo
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences; Guangzhou Medical University, Guangzhou, Guangdong 510530, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China-New Zealand Joint Laboratory on Biomedicine and Health, CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, Institute for Stem Cell and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China
| | - Yunhao Zhou
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences; Guangzhou Medical University, Guangzhou, Guangdong 510530, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China-New Zealand Joint Laboratory on Biomedicine and Health, CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, Institute for Stem Cell and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China
- University of Chinese Academy of Sciences, Beijing 100093, China
| | - Dingfei Liu
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences; Guangzhou Medical University, Guangzhou, Guangdong 510530, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China-New Zealand Joint Laboratory on Biomedicine and Health, CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, Institute for Stem Cell and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China
- University of Chinese Academy of Sciences, Beijing 100093, China
| | - Mengfei Wang
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences; Guangzhou Medical University, Guangzhou, Guangdong 510530, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China-New Zealand Joint Laboratory on Biomedicine and Health, CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, Institute for Stem Cell and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China
- University of Chinese Academy of Sciences, Beijing 100093, China
| | - Yi Wu
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences; Guangzhou Medical University, Guangzhou, Guangdong 510530, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China-New Zealand Joint Laboratory on Biomedicine and Health, CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, Institute for Stem Cell and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Xingguo Liu
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences; Guangzhou Medical University, Guangzhou, Guangdong 510530, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China-New Zealand Joint Laboratory on Biomedicine and Health, CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, Institute for Stem Cell and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong, China
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16
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Narrative Review: Glucocorticoids in Alcoholic Hepatitis—Benefits, Side Effects, and Mechanisms. J Xenobiot 2022; 12:266-288. [PMID: 36278756 PMCID: PMC9589945 DOI: 10.3390/jox12040019] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 09/03/2022] [Accepted: 09/05/2022] [Indexed: 11/17/2022] Open
Abstract
Alcoholic hepatitis is a major health and economic burden worldwide. Glucocorticoids (GCs) are the only first-line drugs recommended to treat severe alcoholic hepatitis (sAH), with limited short-term efficacy and significant side effects. In this review, I summarize the major benefits and side effects of GC therapy in sAH and the potential underlying mechanisms. The review of the literature and data mining clearly indicate that the hepatic signaling of glucocorticoid receptor (GR) is markedly impaired in sAH patients. The impaired GR signaling causes hepatic down-regulation of genes essential for gluconeogenesis, lipid catabolism, cytoprotection, and anti-inflammation in sAH patients. The efficacy of GCs in sAH may be compromised by GC resistance and/or GC’s extrahepatic side effects, particularly the side effects of intestinal epithelial GR on gut permeability and inflammation in AH. Prednisolone, a major GC used for sAH, activates both the GR and mineralocorticoid receptor (MR). When GC non-responsiveness occurs in sAH patients, the activation of MR by prednisolone might increase the risk of alcohol abuse, liver fibrosis, and acute kidney injury. To improve the GC therapy of sAH, the effort should be focused on developing the biomarker(s) for GC responsiveness, liver-targeting GR agonists, and strategies to overcome GC non-responsiveness and prevent alcohol relapse in sAH patients.
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17
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Puttabyatappa M, Saadat N, Elangovan VR, Dou J, Bakulski K, Padmanabhan V. Developmental programming: Impact of prenatal bisphenol-A exposure on liver and muscle transcriptome of female sheep. Toxicol Appl Pharmacol 2022; 451:116161. [PMID: 35817127 PMCID: PMC9618258 DOI: 10.1016/j.taap.2022.116161] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 06/21/2022] [Accepted: 07/05/2022] [Indexed: 11/21/2022]
Abstract
Gestational Bisphenol A (BPA) exposure leads to peripheral insulin resistance, and hepatic and skeletal muscle oxidative stress and lipotoxicity during adulthood in the female sheep offspring. To investigate transcriptional changes underlying the metabolic outcomes, coding and non-coding (nc) RNA in liver and muscle from 21-month-old control and prenatal BPA-treated (0.5 mg/kg/day from days 30 to 90 of gestation; Term: 147 days) female sheep were sequenced. Prenatal BPA-treatment dysregulated: expression of 194 genes (138 down, 56 up) in liver and 112 genes (32 down, 80 up) in muscle (FDR < 0.05 and abs log2FC > 0.5); 155 common gene pathways including mitochondrial-related genes in both tissues; 1415 gene pathways including oxidative stress and lipid biosynthetic process specifically in the liver (FDR < 0.01); 192 gene pathways including RNA biosynthetic processes in muscle (FDR < 0.01); 77 lncRNA (49 down, 28 up), 14 microRNAs (6 down, 8 up), 127 snoRNAs (63 down, 64 up) and 55 snRNAs (15 down, 40 up) in the liver while upregulating 6 lncRNA and dysregulating 65 snoRNAs (47 down, 18 up) in muscle (FDR < 0.1, abs log2FC > 0.5). Multiple ncRNA correlated with LCORL, MED17 and ZNF41 mRNA in liver but none of them in the muscle. Discriminant analysis identified (p < 0.05) PECAM, RDH11, ABCA6, MIR200B, and MIR30B in liver and CAST, NOS1, FASN, MIR26B, and MIR29A in muscle as gene signatures of gestational BPA exposure. These findings provide mechanistic clues into the development and/or maintenance of the oxidative stress and lipid accumulation and potential for development of mitochondrial and fibrotic defects contributing to the prenatal BPA-induced metabolic dysfunctions.
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Affiliation(s)
- Muraly Puttabyatappa
- Department of Pediatrics, University of Michigan, Ann Arbor, MI, United States of America
| | - Nadia Saadat
- Department of Pediatrics, University of Michigan, Ann Arbor, MI, United States of America
| | | | - John Dou
- Department of Epidemiology, University of Michigan, Ann Arbor, MI, United States of America
| | - Kelly Bakulski
- Department of Epidemiology, University of Michigan, Ann Arbor, MI, United States of America
| | - Vasantha Padmanabhan
- Department of Pediatrics, University of Michigan, Ann Arbor, MI, United States of America.
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18
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Zhang Y, Pang Y, Feng W, Jin Y, Chen S, Ding S, Wang Z, Zou Y, Li Y, Wang T, Sun P, Gao J, Zhu Y, Ke X, Marshall C, Huang H, Sheng C, Xiao M. miR-124 regulates early isolation-induced social abnormalities via inhibiting myelinogenesis in the medial prefrontal cortex. Cell Mol Life Sci 2022; 79:507. [PMID: 36059036 PMCID: PMC11803008 DOI: 10.1007/s00018-022-04533-6] [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: 05/14/2022] [Revised: 08/18/2022] [Accepted: 08/18/2022] [Indexed: 01/10/2023]
Abstract
Patients with autism spectrum disorder (ASD) typically experience substantial social isolation, which may cause secondary adverse effects on their brain development. miR-124 is the most abundant miRNA in the human brain, acting as a pivotal molecule regulating neuronal fate determination. Alterations of miR-124 maturation or expression are observed in various neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. In the present study, we analyzed a panel of brain-enriched microRNAs in serums from 2 to 6 year old boys diagnosed with ASD. The hsa-miR-124 level was found significantly elevated in ASD boys than in age and sex-matched healthy controls. In an isolation-reared weanling mouse model, we evidenced elevated mmu-miR-124 level in the serum and the medial prefrontal cortex (mPFC). These mice displayed significant sociability deficits, as well as myelin abnormality in the mPFC, which was partially rescued by expressing the miR-124 sponge in the bilateral mPFC, ubiquitously or specifically in oligodendroglia. In cultured mouse oligodendrocyte precursor cells, introducing a synthetic mmu-miR-124 inhibited the differentiation process through suppressing expression of nuclear receptor subfamily 4 group A member 1 (Nr4a1). Overexpressing Nr4a1 in the bilateral mPFC also corrected the social behavioral deficits and myelin impairments in the isolation-reared mice. This study revealed an unanticipated role of the miR-124/Nr4a1 signaling in regulating early social experience-dependent mPFC myelination, which may serve as a potential therapy target for social neglect or social isolation-related neuropsychiatric disorders.
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Affiliation(s)
- Yanli Zhang
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China
- Brain Institute, Nanjing Brain Hospital, Nanjing Medical University, Nanjing, 210029, China
| | - Yingting Pang
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China
- Center for Global Health, Nanjing Medical University, Nanjing, 211166, China
| | - Weixi Feng
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China
- Center for Global Health, Nanjing Medical University, Nanjing, 211166, China
| | - Yuxi Jin
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China
- Brain Institute, Nanjing Brain Hospital, Nanjing Medical University, Nanjing, 210029, China
| | - Sijia Chen
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China
- Brain Institute, Nanjing Brain Hospital, Nanjing Medical University, Nanjing, 210029, China
| | - Shixin Ding
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China
- Brain Institute, Nanjing Brain Hospital, Nanjing Medical University, Nanjing, 210029, China
| | - Ze Wang
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China
| | - Ying Zou
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China
- Center for Global Health, Nanjing Medical University, Nanjing, 211166, China
| | - Yun Li
- Brain Institute, Nanjing Brain Hospital, Nanjing Medical University, Nanjing, 210029, China
| | - Tianqi Wang
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China
- Center for Global Health, Nanjing Medical University, Nanjing, 211166, China
| | - Peng Sun
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China
- Center for Global Health, Nanjing Medical University, Nanjing, 211166, China
| | - Junying Gao
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China
- Center for Global Health, Nanjing Medical University, Nanjing, 211166, China
| | - Yi Zhu
- Department of Rehabilitation, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Xiaoyan Ke
- Brain Institute, Nanjing Brain Hospital, Nanjing Medical University, Nanjing, 210029, China
| | - Charles Marshall
- Department of Rehabilitation Sciences, University of Kentucky Center of Excellence in Rural Health, Hazard, KY, USA
| | - Huang Huang
- Department of Neurology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211166, China.
| | - Chengyu Sheng
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China.
| | - Ming Xiao
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China.
- Brain Institute, Nanjing Brain Hospital, Nanjing Medical University, Nanjing, 210029, China.
- Center for Global Health, Nanjing Medical University, Nanjing, 211166, China.
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19
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Fischer F, Grigolon G, Benner C, Ristow M. Evolutionarily conserved transcription factors as regulators of longevity and targets for geroprotection. Physiol Rev 2022; 102:1449-1494. [PMID: 35343830 DOI: 10.1152/physrev.00017.2021] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Aging is the single largest risk factor for many debilitating conditions, including heart diseases, stroke, cancer, diabetes, and neurodegenerative disorders. While far from understood in its full complexity, it is scientifically well-established that aging is influenced by genetic and environmental factors, and can be modulated by various interventions. One of aging's early hallmarks are aberrations in transcriptional networks, controlling for example metabolic homeostasis or the response to stress. Evidence in different model organisms abounds that a number of evolutionarily conserved transcription factors, which control such networks, can affect lifespan and healthspan across species. These transcription factors thus potentially represent conserved regulators of longevity and are emerging as important targets in the challenging quest to develop treatments to mitigate age-related diseases, and possibly even to slow aging itself. This review provides an overview of evolutionarily conserved transcription factors that impact longevity or age-related diseases in at least one multicellular model organism (nematodes, flies, or mice), and/or are tentatively linked to human aging. Discussed is the general evidence for transcriptional regulation of aging and disease, followed by a more detailed look at selected transcription factor families, the common metabolic pathways involved, and the targeting of transcription factors as a strategy for geroprotective interventions.
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Affiliation(s)
- Fabian Fischer
- Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, Switzerland
| | - Giovanna Grigolon
- Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, Switzerland
| | - Christoph Benner
- Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, Switzerland
| | - Michael Ristow
- Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, Switzerland
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20
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Peng X, Wang W, Wang W, Qi J. NR4A1 promotes oxidative stresses after myocardial ischemia reperfusion injury in aged mice. Exp Gerontol 2022; 162:111742. [PMID: 35182611 DOI: 10.1016/j.exger.2022.111742] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 01/27/2022] [Accepted: 02/11/2022] [Indexed: 11/19/2022]
Abstract
Myocardial infarction (MI) is a serious disease which is responsible for major death in the elderly. Myocardial oxidative stress contributes to pathophysiology of MI. The nuclear receptor subfamily 4 group A member 1 (NR4A1) has been shown to regulate oxidative stress in several diseases. However, the precise roles of NR4A1 in MI-induced oxidative stress in elderly remain unknown. In present study, the effects of NR4A1 deficiency on oxidative stress were evaluated in aged MI mice. A MI aged mice model was established in wide-type (WT) and NR4A1 deficient mice. The expression of NR4A1, oxidative stress markers was measured. The myocardial functions were monitored. NR4A1 was upregulated in aged MI WT mice, which was positively correlated to the elevated oxidative stress. NR4A1 deficient MI mice had significantly decreased expression of oxidative stress markers malondialdehyde and hydrogen peroxide while had improved myocardial function. In summary, NR4A1 deficiency could attenuate oxidative stress in aged MI mice.
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Affiliation(s)
- Xue Peng
- Department of Gerontology, Cangzhou Central Hospital, No. 16 Xinhua West Road, Cangzhou, Hebei 061000, China.
| | - Wenjuan Wang
- Department of Gerontology, Cangzhou Central Hospital, No. 16 Xinhua West Road, Cangzhou, Hebei 061000, China
| | - Wenhao Wang
- Department of Gerontology, Cangzhou Central Hospital, No. 16 Xinhua West Road, Cangzhou, Hebei 061000, China
| | - Jingrui Qi
- Department of Gerontology, Cangzhou Central Hospital, No. 16 Xinhua West Road, Cangzhou, Hebei 061000, China
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21
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Evaluating whole-genome expression differences in idiopathic and diabetic adhesive capsulitis. J Shoulder Elbow Surg 2022; 31:e1-e13. [PMID: 34352401 PMCID: PMC8665043 DOI: 10.1016/j.jse.2021.06.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 06/18/2021] [Accepted: 06/28/2021] [Indexed: 02/01/2023]
Abstract
BACKGROUND Diabetic patients have a greater incidence of adhesive capsulitis (AC) and a more protracted disease course than patients with idiopathic AC. The purpose of this study was to compare gene expression differences between AC with diabetes mellitus and AC without diabetes mellitus. METHODS Shoulder capsule samples were prospectively obtained from diabetic or nondiabetic patients who presented with shoulder dysfunction and underwent arthroscopy (N = 16). Shoulder samples of AC with and without diabetes (n = 8) were compared with normal shoulder samples with and without diabetes as the control group (n = 8). Shoulder capsule samples were subjected to whole-transcriptome RNA sequencing, and differential expression was analyzed with EdgeR. Only genes with a false discovery rate < 5% were included for further functional enrichment analysis. RESULTS The sample population had a mean age of 47 years (range, 24-62 years), and the mean hemoglobin A1c level for nondiabetic and diabetic patients was 5.18% and 8.71%, respectively. RNA-sequencing analysis revealed that 66 genes were differentially expressed between diabetic patients and nondiabetic patients with AC whereas only 3 genes were differentially expressed when control patients with and without diabetes were compared. Furthermore, 286 genes were differentially expressed in idiopathic AC patients, and 61 genes were differentially expressed in diabetic AC patients. On gene clustering analysis, idiopathic AC was enriched with multiple structural and muscle-related pathways, such as muscle filament sliding, whereas diabetic AC included a greater number of hormonal and inflammatory signaling pathways, such as cellular response to corticotropin-releasing factor. CONCLUSIONS Whole-transcriptome expression profiles demonstrate a fundamentally different underlying pathophysiology when comparing diabetic AC with idiopathic AC, suggesting that these conditions are distinct clinical entities. The new genes expressed explain the differences in the disease course and suggest new therapeutic targets that may lead to different treatment paradigms in these 2 subsets.
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22
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Safe S, Shrestha R, Mohankumar K. Orphan nuclear receptor 4A1 (NR4A1) and novel ligands. Essays Biochem 2021; 65:877-886. [PMID: 34096590 PMCID: PMC11410023 DOI: 10.1042/ebc20200164] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/20/2021] [Accepted: 05/06/2021] [Indexed: 12/14/2022]
Abstract
The nuclear receptor (NR) superfamily of transcription factors encodes expression of 48 human genes that are important for maintaining cellular homeostasis and in pathophysiology, and this has been observed for all sub-families including orphan receptors for which endogenous ligands have not yet been identified. The orphan NR4A1 (Nur77 and TR3) and other members of this sub-family (NR4A2 and NR4A3) are immediate early genes induced by diverse stressors, and these receptors play an important role in the immune function and are up-regulated in some inflammatory diseases including solid tumors. Although endogenous ligands for NR4A have not been identified, several different classes of compounds have been characterized as NR4A1 ligands that bind the receptor. These compounds include cytosporone B and structurally related analogs, bis-indole derived (CDIM) compounds, the triterpenoid celastrol and a number of other chemicals including polyunsaturated fatty acids. NR4A1 ligands bind different regions/surfaces of NR4A1 and exhibit selective NR4A1 modulator (SNR4AM) activities that are dependent on ligand structure and cell/tissue context. NR4A1 ligands exhibit pharmacologic activities in studies on cancer, endometriosis metabolic and inflammatory diseases and are promising agents with clinical potential for treating multiple diseases.
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Affiliation(s)
- Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843 USA
| | - Rupesh Shrestha
- Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA, 77843
| | - Kumaravel Mohankumar
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843 USA
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23
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The New Role of AMP-Activated Protein Kinase in Regulating Fat Metabolism and Energy Expenditure in Adipose Tissue. Biomolecules 2021; 11:biom11121757. [PMID: 34944402 PMCID: PMC8698496 DOI: 10.3390/biom11121757] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/21/2021] [Accepted: 11/23/2021] [Indexed: 12/12/2022] Open
Abstract
Obesity is characterized by excessive accumulation of fat in the body, which is triggered by a body energy intake larger than body energy consumption. Due to complications such as cardiovascular diseases, type 2 diabetes (T2DM), obstructive pneumonia and arthritis, as well as high mortality, morbidity and economic cost, obesity has become a major health problem. The global prevalence of obesity, and its comorbidities is escalating at alarming rates, demanding the development of additional classes of therapeutics to reduce the burden of disease further. As a central energy sensor, the AMP-activated protein kinase (AMPK) has recently been elucidated to play a paramount role in fat synthesis and catabolism, especially in regulating the energy expenditure of brown/beige adipose tissue and the browning of white adipose tissue (WAT). This review discussed the role of AMPK in fat metabolism in adipose tissue, emphasizing its role in the energy expenditure of brown/beige adipose tissue and browning of WAT. A deeper understanding of the role of AMPK in regulating fat metabolism and energy expenditure can provide new insights into obesity research and treatment.
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24
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Bizjak DA, Zügel M, Treff G, Winkert K, Jerg A, Hudemann J, Mooren FC, Krüger K, Nieß A, Steinacker JM. Effects of Training Status and Exercise Mode on Global Gene Expression in Skeletal Muscle. Int J Mol Sci 2021; 22:ijms222212578. [PMID: 34830458 PMCID: PMC8674764 DOI: 10.3390/ijms222212578] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/14/2021] [Accepted: 11/17/2021] [Indexed: 12/29/2022] Open
Abstract
The aim of this study was to investigate differences in skeletal muscle gene expression of highly trained endurance and strength athletes in comparison to untrained individuals at rest and in response to either an acute bout of endurance or strength exercise. Endurance (ET, n = 8, VO2max 67 ± 9 mL/kg/min) and strength athletes (ST, n = 8, 5.8 ± 3.0 training years) as well as untrained controls (E-UT and S-UT, each n = 8) performed an acute endurance or strength exercise test. One day before testing (Pre), 30 min (30'Post) and 3 h (180'Post) afterwards, a skeletal muscle biopsy was obtained from the m. vastus lateralis. Skeletal muscle mRNA was isolated and analyzed by Affymetrix-microarray technology. Pathway analyses were performed to evaluate the effects of training status (trained vs. untrained) and exercise mode-specific (ET vs. ST) transcriptional responses. Differences in global skeletal muscle gene expression between trained and untrained were smaller compared to differences in exercise mode. Maximum differences between ET and ST were found between Pre and 180'Post. Pathway analyses showed increased expression of exercise-related genes, such as nuclear transcription factors (NR4A family), metabolism and vascularization (PGC1-α and VEGF-A), and muscle growth/structure (myostatin, IRS1/2 and HIF1-α. The most upregulated genes in response to acute endurance or strength exercise were the NR4A genes (NR4A1, NR4A2, NR4A3). The mode of acute exercise had a significant effect on transcriptional regulation Pre vs. 180'Post. In contrast, the effect of training status on human skeletal muscle gene expression profiles was negligible compared to strength or endurance specialization. The highest variability in gene expression, especially for the NR4A-family, was observed in trained individuals at 180'Post. Assessment of these receptors might be suitable to obtain a deeper understanding of skeletal muscle adaptive processes to develop optimized training strategies.
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Affiliation(s)
- Daniel A. Bizjak
- Division of Sports and Rehabilitation Medicine, Department of Internal Medicine II, University of Ulm, 89075 Ulm, Germany; (M.Z.); (G.T.); (K.W.); (A.J.); (J.M.S.)
- Correspondence: ; Tel.: +49-73150045368; Fax: +49-73150045301
| | - Martina Zügel
- Division of Sports and Rehabilitation Medicine, Department of Internal Medicine II, University of Ulm, 89075 Ulm, Germany; (M.Z.); (G.T.); (K.W.); (A.J.); (J.M.S.)
| | - Gunnar Treff
- Division of Sports and Rehabilitation Medicine, Department of Internal Medicine II, University of Ulm, 89075 Ulm, Germany; (M.Z.); (G.T.); (K.W.); (A.J.); (J.M.S.)
| | - Kay Winkert
- Division of Sports and Rehabilitation Medicine, Department of Internal Medicine II, University of Ulm, 89075 Ulm, Germany; (M.Z.); (G.T.); (K.W.); (A.J.); (J.M.S.)
| | - Achim Jerg
- Division of Sports and Rehabilitation Medicine, Department of Internal Medicine II, University of Ulm, 89075 Ulm, Germany; (M.Z.); (G.T.); (K.W.); (A.J.); (J.M.S.)
| | - Jens Hudemann
- Department of Sports Medicine, University Hospital Tübingen, 72074 Tübingen, Germany; (J.H.); (A.N.)
| | - Frank C. Mooren
- Department of Medicine, Faculty of Health, University of Witten/Herdecke, 58455 Witten, Germany;
| | - Karsten Krüger
- Department of Exercise Physiology and Sports Therapy, University of Gießen, 35394 Gießen, Germany;
| | - Andreas Nieß
- Department of Sports Medicine, University Hospital Tübingen, 72074 Tübingen, Germany; (J.H.); (A.N.)
| | - Jürgen M. Steinacker
- Division of Sports and Rehabilitation Medicine, Department of Internal Medicine II, University of Ulm, 89075 Ulm, Germany; (M.Z.); (G.T.); (K.W.); (A.J.); (J.M.S.)
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25
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Venu VKP, Saifeddine M, Mihara K, Faiza M, Gorobets E, Flewelling AJ, Derksen DJ, Hirota SA, Marei I, Al-Majid D, Motahhary M, Ding H, Triggle CR, Hollenberg MD. Metformin Prevents Hyperglycemia-Associated, Oxidative Stress-Induced Vascular Endothelial Dysfunction: Essential Role for the Orphan Nuclear Receptor Human Nuclear Receptor 4A1 (Nur77). Mol Pharmacol 2021; 100:428-455. [PMID: 34452975 DOI: 10.1124/molpharm.120.000148] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 08/17/2021] [Indexed: 01/22/2023] Open
Abstract
Vascular pathology is increased in diabetes because of reactive-oxygen-species (ROS)-induced endothelial cell damage. We found that in vitro and in a streptozotocin diabetes model in vivo, metformin at diabetes-therapeutic concentrations (1-50 µM) protects tissue-intact and cultured vascular endothelial cells from hyperglycemia/ROS-induced dysfunction typified by reduced agonist-stimulated endothelium-dependent, nitric oxide-mediated vasorelaxation in response to muscarinic or proteinase-activated-receptor 2 agonists. Metformin not only attenuated hyperglycemia-induced ROS production in aorta-derived endothelial cell cultures but also prevented hyperglycemia-induced endothelial mitochondrial dysfunction (reduced oxygen consumption rate). These endothelium-protective effects of metformin were absent in orphan-nuclear-receptor Nr4a1-null murine aorta tissues in accord with our observing a direct metformin-Nr4a1 interaction. Using in silico modeling of metformin-NR4A1 interactions, Nr4a1-mutagenesis, and a transfected human embryonic kidney 293T cell functional assay for metformin-activated Nr4a1, we identified two Nr4a1 prolines, P505/P549 (mouse sequences corresponding to human P501/P546), as key residues for enabling metformin to affect mitochondrial function. Our data indicate a critical role for Nr4a1 in metformin's endothelial-protective effects observed at micromolar concentrations, which activate AMPKinase but do not affect mitochondrial complex-I or complex-III oxygen consumption rates, as does 0.5 mM metformin. Thus, therapeutic metformin concentrations requiring the expression of Nr4a1 protect the vasculature from hyperglycemia-induced dysfunction in addition to metformin's action to enhance insulin action in patients with diabetes. SIGNIFICANCE STATEMENT: Metformin improves diabetic vasodilator function, having cardioprotective effects beyond glycemic control, but its mechanism to do so is unknown. We found that metformin at therapeutic concentrations (1-50µM) prevents hyperglycemia-induced endothelial dysfunction by attenuating reactive oxygen species-induced damage, whereas high metformin (>250 µM) impairs vascular function. However, metformin's action requires the expression of the orphan nuclear receptor NR4A1/Nur77. Our data reveal a novel mechanism whereby metformin preserves diabetic vascular endothelial function, with implications for developing new metformin-related therapeutic agents.
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Affiliation(s)
- Vivek Krishna Pulakazhi Venu
- Inflammation Research Network and Snyder Institute for Chronic Diseases, Department of Physiology & Pharmacology (V.K.P.V, M.S., K.M., M.M., S.A.H., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary AB, Canada; Alberta Children's Hospital Research Institute and Department of Chemistry, University of Calgary AB, Canada (E.G., A.J.F., D.D.); Departments of Pharmacology and Medical Education, Weill Cornell Medicine in Qatar, Al-Rayyan, Doha, Qatar (I. M., D. A-M., H.D., C.R.T.) and Bioinformatics (M.F.), Jamia Millia Islamia (Central University), Jaima Nagar, Okhla New Delhi, India
| | - Mahmoud Saifeddine
- Inflammation Research Network and Snyder Institute for Chronic Diseases, Department of Physiology & Pharmacology (V.K.P.V, M.S., K.M., M.M., S.A.H., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary AB, Canada; Alberta Children's Hospital Research Institute and Department of Chemistry, University of Calgary AB, Canada (E.G., A.J.F., D.D.); Departments of Pharmacology and Medical Education, Weill Cornell Medicine in Qatar, Al-Rayyan, Doha, Qatar (I. M., D. A-M., H.D., C.R.T.) and Bioinformatics (M.F.), Jamia Millia Islamia (Central University), Jaima Nagar, Okhla New Delhi, India
| | - Koichiro Mihara
- Inflammation Research Network and Snyder Institute for Chronic Diseases, Department of Physiology & Pharmacology (V.K.P.V, M.S., K.M., M.M., S.A.H., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary AB, Canada; Alberta Children's Hospital Research Institute and Department of Chemistry, University of Calgary AB, Canada (E.G., A.J.F., D.D.); Departments of Pharmacology and Medical Education, Weill Cornell Medicine in Qatar, Al-Rayyan, Doha, Qatar (I. M., D. A-M., H.D., C.R.T.) and Bioinformatics (M.F.), Jamia Millia Islamia (Central University), Jaima Nagar, Okhla New Delhi, India
| | - Muniba Faiza
- Inflammation Research Network and Snyder Institute for Chronic Diseases, Department of Physiology & Pharmacology (V.K.P.V, M.S., K.M., M.M., S.A.H., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary AB, Canada; Alberta Children's Hospital Research Institute and Department of Chemistry, University of Calgary AB, Canada (E.G., A.J.F., D.D.); Departments of Pharmacology and Medical Education, Weill Cornell Medicine in Qatar, Al-Rayyan, Doha, Qatar (I. M., D. A-M., H.D., C.R.T.) and Bioinformatics (M.F.), Jamia Millia Islamia (Central University), Jaima Nagar, Okhla New Delhi, India
| | - Evgueni Gorobets
- Inflammation Research Network and Snyder Institute for Chronic Diseases, Department of Physiology & Pharmacology (V.K.P.V, M.S., K.M., M.M., S.A.H., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary AB, Canada; Alberta Children's Hospital Research Institute and Department of Chemistry, University of Calgary AB, Canada (E.G., A.J.F., D.D.); Departments of Pharmacology and Medical Education, Weill Cornell Medicine in Qatar, Al-Rayyan, Doha, Qatar (I. M., D. A-M., H.D., C.R.T.) and Bioinformatics (M.F.), Jamia Millia Islamia (Central University), Jaima Nagar, Okhla New Delhi, India
| | - Andrew J Flewelling
- Inflammation Research Network and Snyder Institute for Chronic Diseases, Department of Physiology & Pharmacology (V.K.P.V, M.S., K.M., M.M., S.A.H., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary AB, Canada; Alberta Children's Hospital Research Institute and Department of Chemistry, University of Calgary AB, Canada (E.G., A.J.F., D.D.); Departments of Pharmacology and Medical Education, Weill Cornell Medicine in Qatar, Al-Rayyan, Doha, Qatar (I. M., D. A-M., H.D., C.R.T.) and Bioinformatics (M.F.), Jamia Millia Islamia (Central University), Jaima Nagar, Okhla New Delhi, India
| | - Darren J Derksen
- Inflammation Research Network and Snyder Institute for Chronic Diseases, Department of Physiology & Pharmacology (V.K.P.V, M.S., K.M., M.M., S.A.H., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary AB, Canada; Alberta Children's Hospital Research Institute and Department of Chemistry, University of Calgary AB, Canada (E.G., A.J.F., D.D.); Departments of Pharmacology and Medical Education, Weill Cornell Medicine in Qatar, Al-Rayyan, Doha, Qatar (I. M., D. A-M., H.D., C.R.T.) and Bioinformatics (M.F.), Jamia Millia Islamia (Central University), Jaima Nagar, Okhla New Delhi, India
| | - Simon A Hirota
- Inflammation Research Network and Snyder Institute for Chronic Diseases, Department of Physiology & Pharmacology (V.K.P.V, M.S., K.M., M.M., S.A.H., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary AB, Canada; Alberta Children's Hospital Research Institute and Department of Chemistry, University of Calgary AB, Canada (E.G., A.J.F., D.D.); Departments of Pharmacology and Medical Education, Weill Cornell Medicine in Qatar, Al-Rayyan, Doha, Qatar (I. M., D. A-M., H.D., C.R.T.) and Bioinformatics (M.F.), Jamia Millia Islamia (Central University), Jaima Nagar, Okhla New Delhi, India
| | - Isra Marei
- Inflammation Research Network and Snyder Institute for Chronic Diseases, Department of Physiology & Pharmacology (V.K.P.V, M.S., K.M., M.M., S.A.H., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary AB, Canada; Alberta Children's Hospital Research Institute and Department of Chemistry, University of Calgary AB, Canada (E.G., A.J.F., D.D.); Departments of Pharmacology and Medical Education, Weill Cornell Medicine in Qatar, Al-Rayyan, Doha, Qatar (I. M., D. A-M., H.D., C.R.T.) and Bioinformatics (M.F.), Jamia Millia Islamia (Central University), Jaima Nagar, Okhla New Delhi, India
| | - Dana Al-Majid
- Inflammation Research Network and Snyder Institute for Chronic Diseases, Department of Physiology & Pharmacology (V.K.P.V, M.S., K.M., M.M., S.A.H., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary AB, Canada; Alberta Children's Hospital Research Institute and Department of Chemistry, University of Calgary AB, Canada (E.G., A.J.F., D.D.); Departments of Pharmacology and Medical Education, Weill Cornell Medicine in Qatar, Al-Rayyan, Doha, Qatar (I. M., D. A-M., H.D., C.R.T.) and Bioinformatics (M.F.), Jamia Millia Islamia (Central University), Jaima Nagar, Okhla New Delhi, India
| | - Majid Motahhary
- Inflammation Research Network and Snyder Institute for Chronic Diseases, Department of Physiology & Pharmacology (V.K.P.V, M.S., K.M., M.M., S.A.H., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary AB, Canada; Alberta Children's Hospital Research Institute and Department of Chemistry, University of Calgary AB, Canada (E.G., A.J.F., D.D.); Departments of Pharmacology and Medical Education, Weill Cornell Medicine in Qatar, Al-Rayyan, Doha, Qatar (I. M., D. A-M., H.D., C.R.T.) and Bioinformatics (M.F.), Jamia Millia Islamia (Central University), Jaima Nagar, Okhla New Delhi, India
| | - Hong Ding
- Inflammation Research Network and Snyder Institute for Chronic Diseases, Department of Physiology & Pharmacology (V.K.P.V, M.S., K.M., M.M., S.A.H., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary AB, Canada; Alberta Children's Hospital Research Institute and Department of Chemistry, University of Calgary AB, Canada (E.G., A.J.F., D.D.); Departments of Pharmacology and Medical Education, Weill Cornell Medicine in Qatar, Al-Rayyan, Doha, Qatar (I. M., D. A-M., H.D., C.R.T.) and Bioinformatics (M.F.), Jamia Millia Islamia (Central University), Jaima Nagar, Okhla New Delhi, India
| | - Chris R Triggle
- Inflammation Research Network and Snyder Institute for Chronic Diseases, Department of Physiology & Pharmacology (V.K.P.V, M.S., K.M., M.M., S.A.H., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary AB, Canada; Alberta Children's Hospital Research Institute and Department of Chemistry, University of Calgary AB, Canada (E.G., A.J.F., D.D.); Departments of Pharmacology and Medical Education, Weill Cornell Medicine in Qatar, Al-Rayyan, Doha, Qatar (I. M., D. A-M., H.D., C.R.T.) and Bioinformatics (M.F.), Jamia Millia Islamia (Central University), Jaima Nagar, Okhla New Delhi, India
| | - Morley D Hollenberg
- Inflammation Research Network and Snyder Institute for Chronic Diseases, Department of Physiology & Pharmacology (V.K.P.V, M.S., K.M., M.M., S.A.H., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary AB, Canada; Alberta Children's Hospital Research Institute and Department of Chemistry, University of Calgary AB, Canada (E.G., A.J.F., D.D.); Departments of Pharmacology and Medical Education, Weill Cornell Medicine in Qatar, Al-Rayyan, Doha, Qatar (I. M., D. A-M., H.D., C.R.T.) and Bioinformatics (M.F.), Jamia Millia Islamia (Central University), Jaima Nagar, Okhla New Delhi, India
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Pulakazhi Venu VK, Alston L, Iftinca M, Tsai YC, Stephens M, Warriyar K V V, Rehal S, Hudson G, Szczepanski H, von der Weid PY, Altier C, Hirota SA. Nr4A1 modulates inflammation-associated intestinal fibrosis and dampens fibrogenic signaling in myofibroblasts. Am J Physiol Gastrointest Liver Physiol 2021; 321:G280-G297. [PMID: 34288735 DOI: 10.1152/ajpgi.00338.2019] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Intestinal fibrosis is a common complication of the inflammatory bowel diseases (IBDs), contributing to tissue stiffening and luminal narrowing. Human nuclear receptor 4A 1 (NR4A1) was previously reported to regulate mesenchymal cell function and dampen fibrogenic signaling. NR4A1 gene variants are associated with IBD risk, and it has been shown to regulate intestinal inflammation. Here, we tested the hypothesis that NR4A1 acts as a negative regulator of intestinal fibrosis through regulating myofibroblast function. Using the SAMP1/YitFc mouse, we tested whether two pharmacological agents known to enhance NR4A1 signaling, cytosporone B (Csn-B) or 6-mercaptopurine (6-MP), could reduce fibrosis. We also used the dextran sulfate sodium (DSS) model of colitis and assessed the magnitude of colonic fibrosis in mouse nuclear receptor 4A 1 (Nr4a1-/-) and their wild-type littermates (Nr4a1+/+). Lastly, intestinal myofibroblasts isolated from Nr4a1-/- and Nr4a1+/+ mice or primary human intestinal myofibroblasts were stimulated with transforming growth factor-β1 (TGF-β1), in the presence or absence of Csn-B or 6-MP, and proliferation and ECM gene expression assessed. Csn-B or 6-MP treatment significantly reduced ileal thickness, collagen, and overall ECM content in SAMP1/YitFc mice. This was associated with a reduction in proliferative markers within the mesenchymal compartment. Nr4a1-/- mice exposed to DSS exhibited increased colonic thickening and ECM content. Nr4a1-/- myofibroblasts displayed enhanced TGF-β1-induced proliferation. Furthermore, Csn-B or 6-MP treatment was antiproliferative in Nr4a1+/+ but not Nr4a1-/- cells. Lastly, activating NR4A1 in human myofibroblasts reduced TGF-β1-induced collagen deposition and fibrosis-related gene expression. Our data suggest that NR4A1 can attenuate fibrotic processes in intestinal myofibroblasts and could provide a valuable clinical target to treat inflammation-associated intestinal fibrosis.NEW & NOTEWORTHY Fibrosis and increased muscle thickening contribute to stricture formation and intestinal obstruction, a complication that occurs in 30%-50% of patients with CD within 10 yr of disease onset. More than 50% of those who undergo surgery to remove the obstructed bowel will experience stricture recurrence. To date, there are no drug-based approaches approved to treat intestinal strictures. In the current submission, we identify NR4A1 as a novel target to treat inflammation-associated intestinal fibrosis.
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Affiliation(s)
- Vivek Krishna Pulakazhi Venu
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Disease, University of Calgary, Calgary, Alberta, Canada
| | - Laurie Alston
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Disease, University of Calgary, Calgary, Alberta, Canada
| | - Mircea Iftinca
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Disease, University of Calgary, Calgary, Alberta, Canada
| | - Yi-Cheng Tsai
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Disease, University of Calgary, Calgary, Alberta, Canada
| | - Matthew Stephens
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Disease, University of Calgary, Calgary, Alberta, Canada
| | - Vineetha Warriyar K V
- Faculty of Kinesiology, Sport Injury Prevention Research Centre, University of Calgary, Calgary, Alberta, Canada
| | - Sonia Rehal
- Department of Advanced Diagnostics, University Health Network, Toronto, Ontario, Canada
| | - Grace Hudson
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Disease, University of Calgary, Calgary, Alberta, Canada
| | - Holly Szczepanski
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Disease, University of Calgary, Calgary, Alberta, Canada
| | - Pierre-Yves von der Weid
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Disease, University of Calgary, Calgary, Alberta, Canada
| | - Christophe Altier
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Disease, University of Calgary, Calgary, Alberta, Canada.,Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
| | - Simon A Hirota
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Department of Immunology, Microbiology & Infectious Diseases, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Disease, University of Calgary, Calgary, Alberta, Canada.,Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
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27
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Zhang H, Geng N, Sun L, Che X, Xiao Q, Tao Z, Chen L, Lyu Y, Shao Q, Pu J. Nuclear Receptor Nur77 Protects Against Abdominal Aortic Aneurysm by Ameliorating Inflammation Via Suppressing LOX-1. J Am Heart Assoc 2021; 10:e021707. [PMID: 34325521 PMCID: PMC8475661 DOI: 10.1161/jaha.121.021707] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Background Abdominal aortic aneurysm (AAA) is a life-threatening vascular disorder characterized by chronic inflammation of the aortic wall, which lacks effective pharmacotherapeutic remedies and has an extremely high mortality. Nuclear receptor NR4A1 (Nur77) functions in various chronic inflammatory diseases. However, the influence of Nur77 on AAA has remained unclear. Herein, we sought to determine the effects of Nur77 on the development of AAA. Methods and Results We observed that Nur77 expression decreased significantly in human and mice AAA lesions. Deletion of Nur77 accelerated the development of AAA in mice, as evidenced by increased AAA incidence, abdominal aortic diameters, elastin fragmentation, and collagen content. Consistent with genetic manipulation, pharmacological activation of Nur77 by celastrol showed beneficial effects against AAA. Microscopic and molecular analyses indicated that the detrimental effects of Nur77 deficiency were associated with aggravated macrophage infiltration in AAA lesions and increased pro-inflammatory cytokines secretion and matrix metalloproteinase (MMP-9) expression. Bioinformatics analyses further revealed that LOX-1 was upregulated by Nur77 deficiency and consequently increased the expression of cytokines and MMP-9. Moreover, rescue experiments verified that LOX-1 notably aggravated inflammatory response, an effect that was blunted by Nur77. Conclusions This study firstly demonstrated a crucial role of Nur77 in the formation of AAA by targeting LOX-1, which implicated Nur77 might be a potential therapeutic target for AAA.
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Affiliation(s)
- Hengyuan Zhang
- Department of Cardiology Renji HospitalSchool of Medicine, Shanghai Jiao Tong University Shanghai China
| | - Na Geng
- Department of Cardiology Renji HospitalSchool of Medicine, Shanghai Jiao Tong University Shanghai China
| | - Lingyue Sun
- Department of Cardiology Renji HospitalSchool of Medicine, Shanghai Jiao Tong University Shanghai China
| | - Xinyu Che
- Department of Cardiology Renji HospitalSchool of Medicine, Shanghai Jiao Tong University Shanghai China
| | - Qingqing Xiao
- Department of Cardiology Renji HospitalSchool of Medicine, Shanghai Jiao Tong University Shanghai China
| | - Zhenyu Tao
- Department of Cardiology Renji HospitalSchool of Medicine, Shanghai Jiao Tong University Shanghai China
| | - Long Chen
- Department of Cardiology Renji HospitalSchool of Medicine, Shanghai Jiao Tong University Shanghai China
| | - Yuyan Lyu
- Department of Cardiology Renji HospitalSchool of Medicine, Shanghai Jiao Tong University Shanghai China
| | - Qin Shao
- Department of Cardiology Renji HospitalSchool of Medicine, Shanghai Jiao Tong University Shanghai China
| | - Jun Pu
- Department of Cardiology Renji HospitalSchool of Medicine, Shanghai Jiao Tong University Shanghai China
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NR4A1 Regulates Tamoxifen Resistance by Suppressing ERK Signaling in ER-Positive Breast Cancer. Cells 2021; 10:cells10071633. [PMID: 34209871 PMCID: PMC8307977 DOI: 10.3390/cells10071633] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 06/18/2021] [Accepted: 06/28/2021] [Indexed: 11/18/2022] Open
Abstract
Endocrine therapy is used to treat estrogen receptor (ER)-positive breast cancer. Tamoxifen is effective against this cancer subtype. Nonetheless, approximately 30% of patients treated with tamoxifen acquire resistance, resulting in therapeutic challenges. NR4A1 plays key roles in processes associated with carcinogenesis, apoptosis, DNA repair, proliferation, and inflammation. However, the role of NR4A1 in tamoxifen-resistant ER-positive breast cancer has not yet been elucidated. Here, we propose that NR4A1 is a promising target to overcome tamoxifen resistance. NR4A1 gene expression was downregulated in tamoxifen-resistant MCF7 (TamR) cells compared to that in MCF7 cells. Kaplan-Meier plots were used to identify high NR4A1 expression correlated with increased survival rates in patients with ER-positive breast cancer following tamoxifen treatment. Gain and loss of function experiments showed that NR4A1 restores sensitivity to tamoxifen by regulating cell proliferation, migration, invasion, and apoptosis. NR4A1 localized to the cytoplasm enhanced the expression of apoptotic factors. In silico and in vitro analyses revealed that NR4A1 enhanced responsiveness to tamoxifen by suppressing ERK signaling in ER-positive breast cancer, suggesting that the NR4A1/ERK signaling axis modulates tamoxifen resistance. These results indicate that NR4A1 could be a potential therapeutic target to overcome tamoxifen resistance in ER-positive breast cancer.
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NR4A1 Regulates Tamoxifen Resistance by Suppressing ERK Signaling in ER-Positive Breast Cancer. Cells 2021. [PMID: 34209871 DOI: 10.3390/cells10071633/s1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2023] Open
Abstract
Endocrine therapy is used to treat estrogen receptor (ER)-positive breast cancer. Tamoxifen is effective against this cancer subtype. Nonetheless, approximately 30% of patients treated with tamoxifen acquire resistance, resulting in therapeutic challenges. NR4A1 plays key roles in processes associated with carcinogenesis, apoptosis, DNA repair, proliferation, and inflammation. However, the role of NR4A1 in tamoxifen-resistant ER-positive breast cancer has not yet been elucidated. Here, we propose that NR4A1 is a promising target to overcome tamoxifen resistance. NR4A1 gene expression was downregulated in tamoxifen-resistant MCF7 (TamR) cells compared to that in MCF7 cells. Kaplan-Meier plots were used to identify high NR4A1 expression correlated with increased survival rates in patients with ER-positive breast cancer following tamoxifen treatment. Gain and loss of function experiments showed that NR4A1 restores sensitivity to tamoxifen by regulating cell proliferation, migration, invasion, and apoptosis. NR4A1 localized to the cytoplasm enhanced the expression of apoptotic factors. In silico and in vitro analyses revealed that NR4A1 enhanced responsiveness to tamoxifen by suppressing ERK signaling in ER-positive breast cancer, suggesting that the NR4A1/ERK signaling axis modulates tamoxifen resistance. These results indicate that NR4A1 could be a potential therapeutic target to overcome tamoxifen resistance in ER-positive breast cancer.
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Guebel DV, Torres NV, Acebes Á. Mapping the transcriptomic changes of endothelial compartment in human hippocampus across aging and mild cognitive impairment. Biol Open 2021; 10:bio057950. [PMID: 34184731 PMCID: PMC8181899 DOI: 10.1242/bio.057950] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 04/07/2021] [Indexed: 12/17/2022] Open
Abstract
Compromise of the vascular system has important consequences on cognitive abilities and neurodegeneration. The identification of the main molecular signatures present in the blood vessels of human hippocampus could provide the basis to understand and tackle these pathologies. As direct vascular experimentation in hippocampus is problematic, we achieved this information by computationally disaggregating publicly available whole microarrays data of human hippocampal homogenates. Three conditions were analyzed: 'Young Adults', 'Aged', and 'aged with Mild Cognitive Impairment' (MCI). The genes identified were contrasted against two independent data-sets. Here we show that the endothelial cells from the Younger Group appeared in an 'activated stage'. In turn, in the Aged Group, the endothelial cells showed a significant loss of response to shear stress, changes in cell adhesion molecules, increased inflammation, brain-insulin resistance, lipidic alterations, and changes in the extracellular matrix. Some specific changes in the MCI group were also detected. Noticeably, in this study the features arisen from the Aged Group (high tortuosity, increased bifurcations, and smooth muscle proliferation), pose the need for further experimental verification to discern between the occurrence of arteriogenesis and/or vascular remodeling by capillary arterialization. This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Daniel V. Guebel
- Program Agustín de Betancourt, Universidad de La Laguna, Tenerife 38200, Spain
- Department of Biochemistry, Cellular Biology and Genetics, Institute of Biomedical Technologies, Universidad de La Laguna, Tenerife 38200, Spain
| | - Néstor V. Torres
- Department of Biochemistry, Cellular Biology and Genetics, Institute of Biomedical Technologies, Universidad de La Laguna, Tenerife 38200, Spain
| | - Ángel Acebes
- Department of Basic Medical Sciences, Institute of Biomedical Technologies, University of La Laguna, Tenerife 38200, Spain
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Discovery of new chalone adamantyl arotinoids having RXRα-modulating and anticancer activities. Bioorg Chem 2021; 113:104961. [PMID: 34023650 DOI: 10.1016/j.bioorg.2021.104961] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 04/21/2021] [Accepted: 05/01/2021] [Indexed: 11/23/2022]
Abstract
In the present study, a new series of chalcone adamantly arotinoids (chalcone AdArs) derived from RAR antagonist MX781, are synthesized, characterized, and evaluated for the biological activities in vitro. The studies of antiproliferative activity and RXRα-binding affinity of target compounds result in the discovery of a lead candidate (WA15), which is a good RXRα binder (Kd = 2.89 × 10-6 M) with potent antiproliferative activity against human cancer cell lines (IC50 ≈ 10 μM) and low toxic to normal LO2 and MRC-5 cells (IC50 > 50 μM). Different from MX781, WA15 eliminates RARα antagonist activity but inhibits 9-cis-RA-induced RXRα transactivation activity in a dose-dependent manner. Compound WA15 is found to be a good apoptosis inducer in various cancer cells and promotes cell apoptosis in an RXRα-independent manner. Besides, WA15 shows the induction of proteasome-dependent RXRα degradation which might enhance the WA15-induced apoptosis. Finally, the immunoblotting indicates that WA15 can inhibit the TNFα-induced IKK activation and IκBα degradation, suggesting that the anticancer activity of WA15 might be related to the inhibition of IKK/NF-κB signal pathway.
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Pandey SK, Paul A, Shteinfer-Kuzmine A, Zalk R, Bunz U, Shoshan-Barmatz V. SMAC/Diablo controls proliferation of cancer cells by regulating phosphatidylethanolamine synthesis. Mol Oncol 2021; 15:3037-3061. [PMID: 33794068 PMCID: PMC8564633 DOI: 10.1002/1878-0261.12959] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 01/26/2021] [Accepted: 03/31/2021] [Indexed: 01/13/2023] Open
Abstract
SMAC/Diablo, a pro-apoptotic protein, yet it is overexpressed in several cancer types. We have described a noncanonical function for SMAC/Diablo as a regulator of lipid synthesis during cancer cell proliferation and development. Here, we explore the molecular mechanism through which SMAC/Diablo regulates phospholipid synthesis. We showed that SMAC/Diablo directly interacts with mitochondrial phosphatidylserine decarboxylase (PSD) and inhibits its catalytic activity during synthesis of phosphatidylethanolamine (PE) from phosphatidylserine (PS). Unlike other phospholipids (PLs), PE is synthesized not only in the endoplasmic reticulum but also in mitochondria. As a result, PSD activity and mitochondrial PE levels were increased in the mitochondria of SMAC/Diablo-deficient cancer cells, with the total amount of cellular PLs and phosphatidylcholine (PC) being lower as compared to SMAC-expressing cancer cells. Moreover, in the absence of SMAC/Diablo, PSD inhibited cancer cell proliferation by catalysing the overproduction of mitochondrial PE and depleting the cellular levels of PC, PE and PS. Additionally, we demonstrated that both SMAC/Diablo and PSD colocalization in the nucleus resulted in increased levels of nuclear PE, that acts as a signalling molecule in regulating several nuclear activities. By using a peptide array composed of 768-peptides derived from 11 SMAC-interacting proteins, we identified six nuclear proteins ARNT, BIRC2, MAML2, NR4A1, BIRC5 and HTRA2 Five of them also interacted with PSD through motifs that are not involved in SMAC binding. Synthetic peptides carrying the PSD-interacting motifs of these proteins could bind purified PSD and inhibit the PSD catalytic activity. When targeted specifically to the mitochondria or the nucleus, these synthetic peptides inhibited cancer cell proliferation. To our knowledge, these are the first reported inhibitors of PSD acting also as inhibitors of cancer cell proliferation. Altogether, we demonstrated that phospholipid metabolism and PE synthesis regulated by the SMAC-PSD interaction are essential for cancer cell proliferation and may be potentially targeted for treating cancer.
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Affiliation(s)
- Swaroop Kumar Pandey
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.,National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Avijit Paul
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.,National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Anna Shteinfer-Kuzmine
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.,National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Ran Zalk
- Ilse Katz Institute for Nanoscale Science & Technology, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Uwe Bunz
- Organisch-Chemisches Institut, Ruprecht-Karls-Universität Heidelberg, Germany
| | - Varda Shoshan-Barmatz
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.,National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel
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Potent synthetic and endogenous ligands for the adopted orphan nuclear receptor Nurr1. Exp Mol Med 2021; 53:19-29. [PMID: 33479411 PMCID: PMC8080818 DOI: 10.1038/s12276-021-00555-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 10/19/2020] [Accepted: 11/05/2020] [Indexed: 01/30/2023] Open
Abstract
Until recently, Nurr1 (NR4A2) was known as an orphan nuclear receptor without a canonical ligand-binding domain, featuring instead a narrow and tight cavity for small molecular ligands to bind. In-depth characterization of its ligand-binding pocket revealed that it is highly dynamic, with its structural conformation changing more than twice on the microsecond-to-millisecond timescale. This observation suggests the possibility that certain ligands are able to squeeze into this narrow space, inducing a conformational change to create an accessible cavity. The cocrystallographic structure of Nurr1 bound to endogenous ligands such as prostaglandin E1/A1 and 5,6-dihydroxyindole contributed to clarifying the crucial roles of Nurr1 and opening new avenues for therapeutic interventions for neurodegenerative and/or inflammatory diseases related to Nurr1. This review introduces novel endogenous and synthetic Nurr1 agonists and discusses their potential effects in Nurr1-related diseases.
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Sadeghi MB, Nakhaee A, Saravani R. The effect of NR4A3-rs12686676 and XBP1-rs2269577 polymorphisms on type 2 diabetes mellitus susceptibility in an Iranian population: Case-control study. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Chen L, Fan F, Wu L, Zhao Y. The nuclear receptor 4A family members: mediators in human disease and autophagy. Cell Mol Biol Lett 2020; 25:48. [PMID: 33292165 PMCID: PMC7640683 DOI: 10.1186/s11658-020-00241-w] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 10/26/2020] [Indexed: 12/17/2022] Open
Abstract
The Nuclear receptor 4A (NR4A) subfamily, which belongs to the nuclear receptor (NR) superfamily, has three members: NR4A1 (Nur77), NR4A2 (Nurr1) and NR4A3 (Nor1). They are gene regulators with broad involvement in various signaling pathways and human disease responses, including autophagy. Here, we provide a concise overview of the current understanding of the role of the NR4A subfamily members in human diseases and review the research into their regulation of cell autophagy. A deeper understanding of these mechanisms has potential to improve drug development processes and disease therapy.
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Affiliation(s)
- Liqun Chen
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, 350108, China.
- Institute of Apply Genomics, Fuzhou University, Fuzhou, 350108, China.
| | - Fengtian Fan
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, 350108, China
- Institute of Apply Genomics, Fuzhou University, Fuzhou, 350108, China
| | - Lingjuan Wu
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, 350108, China
- Institute of Apply Genomics, Fuzhou University, Fuzhou, 350108, China
| | - Yiyi Zhao
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, 350108, China
- Institute of Apply Genomics, Fuzhou University, Fuzhou, 350108, China
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Jiang L, Dai S, Li J, Liang X, Qu L, Chen X, Guo M, Chen Z, Chen L, Wei H, Chen Y. Structural basis of binding of homodimers of the nuclear receptor NR4A2 to selective Nur-responsive DNA elements. J Biol Chem 2019; 294:19795-19803. [PMID: 31723028 PMCID: PMC6926456 DOI: 10.1074/jbc.ra119.010730] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 11/11/2019] [Indexed: 01/07/2023] Open
Abstract
Proteins of nuclear receptor subfamily 4 group A (NR4A), including NR4A1/NGFI-B, NR4A2/Nurr1, and NR4A3/NOR-1, are nuclear transcription factors that play important roles in metabolism, apoptosis, and proliferation. NR4A proteins recognize DNA response elements as monomers or dimers to regulate the transcription of a variety of genes involved in multiple biological processes. In this study, we determined two crystal structures of the NR4A2 DNA-binding domain (NR4A2-DBD) bound to two Nur-responsive elements: an inverted repeat and an everted repeat at 2.6-2.8 Å resolution. The structures revealed that two NR4A2-DBD molecules bind independently to the everted repeat, whereas two other NR4A2-DBD molecules form a novel dimer interface on the inverted repeat. Moreover, substitution of the interfacial residue valine 298 to lysine as well as mutation of DNA bases involved in the interactions abolished the dimerization. Overall, our structural, biochemical, and bioinformatics analyses provide a molecular basis for the binding of the NR4A2 protein dimers to NurREs and advance our understanding of the dimerization specificity of nuclear receptors.
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Affiliation(s)
- Longying Jiang
- Department of Oncology, Laboratory of Structural Biology, NHC Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Shuyan Dai
- Department of Oncology, Laboratory of Structural Biology, NHC Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Jun Li
- Department of Oncology, Laboratory of Structural Biology, NHC Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Xujun Liang
- Department of Oncology, Laboratory of Structural Biology, NHC Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Lingzhi Qu
- Department of Oncology, Laboratory of Structural Biology, NHC Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Xiaojuan Chen
- Department of Oncology, Laboratory of Structural Biology, NHC Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Ming Guo
- Department of Oncology, Laboratory of Structural Biology, NHC Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Zhuchu Chen
- Department of Oncology, Laboratory of Structural Biology, NHC Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Lin Chen
- Department of Oncology, Laboratory of Structural Biology, NHC Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China,Molecular and Computational Biology Program, Departments of Biological Sciences and Chemistry, University of Southern California, Los Angeles, California 90089
| | - Hudie Wei
- Department of Oncology, Laboratory of Structural Biology, NHC Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China, To whom correspondence may be addressed. Tel.:
86-731-84327542; Fax:
86-731-84327542; E-mail:
| | - Yongheng Chen
- Department of Oncology, Laboratory of Structural Biology, NHC Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China, To whom correspondence may be addressed. Tel.:
86-731-84327542; Fax:
86-731-84327542; E-mail:
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Function of Nr4a Orphan Nuclear Receptors in Proliferation, Apoptosis and Fuel Utilization Across Tissues. Cells 2019; 8:cells8111373. [PMID: 31683815 PMCID: PMC6912296 DOI: 10.3390/cells8111373] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 10/24/2019] [Accepted: 10/30/2019] [Indexed: 12/21/2022] Open
Abstract
The Nr4a family of nuclear hormone receptors is composed of three members-Nr4a1/Nur77, Nr4a2/Nurr1 and Nr4a3/Nor1. While currently defined as ligandless, these transcription factors have been shown to regulate varied processes across a host of tissues. Of particular interest, the Nr4a family impinge, in a tissue dependent fashion, on cellular proliferation, apoptosis and fuel utilization. The regulation of these processes occurs through both nuclear and non-genomic pathways. The purpose of this review is to provide a balanced perspective of the tissue specific and Nr4a family member specific, effects on cellular proliferation, apoptosis and fuel utilization.
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Göl MF, Erdoğan FF, Bayramov KK, Mehmetbeyoğlu E, Özkul Y. Assessment of genes involved in behavior, learning, memory, and synaptic plasticity following status epilepticus in rats. Epilepsy Behav 2019; 98:101-109. [PMID: 31326869 DOI: 10.1016/j.yebeh.2019.06.023] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 06/09/2019] [Accepted: 06/11/2019] [Indexed: 02/05/2023]
Abstract
OBJECTIVE In this study, it was aimed to evaluate cognitive and behavioral changes after status epilepticus (SE) induced by pentylenetetrazole in immature rats via Morris water maze and open-field area tests and to assess alterations in expression of 84 key genes involved in synaptic plasticity after SE. METHOD The study was conducted on 30 immature rats (12-days old). The rats were assigned into groups as control and experiment (SE) groups. The SE was induced by pentylenetetrazole in 12-days old rats. In addition, experiment group was divided into two groups as mature (n = 8) and immature SE (n = 8) subgroups. Again, the control group was divided into two groups as mature (n = 7) and immature control (n = 7) subgroups. Hippocampal tissue samples were prepared, and expression of 84 key genes involved in synaptic plasticity was assessed in Genome and Stem Cell Center of Erciyes University before behavioral tests in immature rats (22-days old) and after open-filed area and Morris water maze tests in mature rats (72-days old) in both experiment and control groups. RESULTS No significant difference was detected in behavioral tests assessing spatial memory and learning among groups. Significant differences were detected, ARC (activity-regulated cytoskeleton-associated protein), BDNF (brain-derived neurotrophic factor), MAPK1 (mitogen-activated protein kinase 1), NR4A1 (nuclear receptor subfamily 4 group A member 1), PPP3CA (protein phosphatase 3 catalytic subunit alpha), RGS2 (regulator of G protein signaling 2), and TNF (tumor necrosis factor) gene expressions between control and experiment groups in immature rats whereas in ADCY8 (adenylate cyclase 8), BDNF (brain-derived neurotrophic factor), EGR4 (early growth response 4), and KIF17 (kinesin family member 17) gene expressions between control and experiment groups in mature rats. DISCUSSION In this study, differences detected in gene expressions of synaptic plasticity after SE indicate in which steps of synaptic plasticity may be problematic in epileptogenesis. The gene expressions in this study may be considered as potential biomarkers; however, epileptogenesis is a dynamic process and cannot be explained through a single mechanism. Future studies on epileptogenesis and studies specifically designed to evaluate genes detected in our study will further elucidate synaptic plasticity in epilepsy and epileptogenesis.
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Affiliation(s)
- Mehmet Fatih Göl
- Department of Neurology, Kayseri City Hospital, Kayseri, Turkey.
| | - Füsun Ferda Erdoğan
- Department of Neurology, Erciyes University Faculty of Medicine, Kayseri, Turkey
| | | | | | - Yusuf Özkul
- Department of Medical Genetics, Erciyes University Faculty of Medicine, Kayseri, Turkey
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