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1
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Ng MY, Hagen T. A strategy for liver selective NRF2 induction via cytochrome P450-activated prodrugs with low activity in hypoxia. J Biol Chem 2025; 301:108487. [PMID: 40209947 PMCID: PMC12145549 DOI: 10.1016/j.jbc.2025.108487] [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: 12/25/2024] [Revised: 03/19/2025] [Accepted: 04/01/2025] [Indexed: 04/12/2025] Open
Abstract
Activation of the transcription factor nuclear factor-erythroid 2-related factor 2 (NRF2) has been shown to be a promising therapeutic approach in the treatment of hepatosteatosis. NRF2 is believed to exert beneficial effects by upregulating cellular oxidative defense mechanisms and inhibiting inflammation. However, a major concern associated with long-term treatment with NRF2 activators are drug side effects, including the promotion of tumorigenesis. Many NRF2 activators function by forming cysteine adducts with KEAP1, which normally mediates the ubiquitination and degradation of NRF2. In this study, we identified NRF2 activator prodrugs of 4-methylcatechol and tert-butylhydroquinone. These prodrugs are converted into their active metabolites in a liver selective, cytochrome P450-dependent manner and function by inhibiting KEAP1, resulting in NRF2 activation. Unexpectedly, we also found that a number of NRF2-activating compounds, including 4-methylcatechol and tert-butylhydroquinone, show a markedly lower activity under hypoxic conditions than normoxia. Our findings suggest that the lower activity of these NRF2 inducers is a consequence of less potent cysteine adduct formation with KEAP1. The lower activity of NRF2 inducing compounds in hypoxia may limit tumor promoting effects of NRF2 induction. Our study provides an important proof of concept that it is possible to selectively activate NRF2 in the liver for the treatment of hepatosteatosis while avoiding tumorigenic effects as well as side effects of NRF2 activation in other tissues.
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Affiliation(s)
- Mei Ying Ng
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Thilo Hagen
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
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2
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Hashimoto H, Okazaki T, Honkura Y, Ren Y, Ngamsnae P, Hisaoka T, Koshiba Y, Suzuki J, Ebihara S, Katori Y. Nrf2 Deficiency Exacerbates the Decline in Swallowing and Respiratory Muscle Mass and Function in Mice with Aspiration Pneumonia. Int J Mol Sci 2024; 25:11829. [PMID: 39519380 PMCID: PMC11546094 DOI: 10.3390/ijms252111829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 10/29/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024] Open
Abstract
Aspiration pneumonia exacerbates swallowing and respiratory muscle atrophy. It induces respiratory muscle atrophy through three steps: proinflammatory cytokine production, caspase-3 and calpain, and then ubiquitin-proteasome activations. In addition, autophagy induces swallowing muscle atrophy. Nrf2 is the central detoxifying and antioxidant gene whose function in aspiration pneumonia is unclear. We explored the role of Nrf2 in aspiration pneumonia by examining swallowing and respiratory muscle mass and function using wild-type and Nrf2-knockout mice. Pepsin and lipopolysaccharide aspiration challenges caused aspiration pneumonia. The swallowing (digastric muscles) and respiratory (diaphragm) muscles were isolated. Quantitative RT-PCR and Western blotting were used to assess their proteolysis cascade. Pathological and videofluoroscopic examinations evaluated atrophy and swallowing function, respectively. Nrf2-knockouts showed exacerbated aspiration pneumonia compared with wild-types. Nrf2-knockouts exhibited more persistent and intense proinflammatory cytokine elevation than wild-types. In both mice, the challenge activated calpains and caspase-3 in the diaphragm but not in the digastric muscles. The digastric muscles showed extended autophagy activation in Nrf2-knockouts compared to wild-types. The diaphragms exhibited autophagy activation only in Nrf2-knockouts. Nrf2-knockouts showed worsened muscle atrophies and swallowing function compared with wild-types. Thus, activation of Nrf2 may alleviate inflammation, muscle atrophy, and function in aspiration pneumonia, a major health problem for the aging population, and may become a therapeutic target.
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Affiliation(s)
- Hikaru Hashimoto
- Department of Otolaryngology-Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; (H.H.)
| | - Tatsuma Okazaki
- Department of Rehabilitation Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan (S.E.)
- Center for Dysphagia of Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
| | - Yohei Honkura
- Department of Otolaryngology-Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; (H.H.)
- Center for Dysphagia of Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
| | - Yuzhuo Ren
- Department of Rehabilitation Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan (S.E.)
| | - Peerada Ngamsnae
- Department of Rehabilitation Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan (S.E.)
| | - Takuma Hisaoka
- Department of Otolaryngology-Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; (H.H.)
- Center for Dysphagia of Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
| | - Yasutoshi Koshiba
- Department of Otolaryngology-Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; (H.H.)
- Center for Dysphagia of Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
| | - Jun Suzuki
- Department of Otolaryngology-Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; (H.H.)
- Center for Dysphagia of Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
| | - Satoru Ebihara
- Department of Rehabilitation Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan (S.E.)
- Center for Dysphagia of Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
| | - Yukio Katori
- Department of Otolaryngology-Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; (H.H.)
- Center for Dysphagia of Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
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3
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Kostyuk AI, Rapota DD, Morozova KI, Fedotova AA, Jappy D, Semyanov AV, Belousov VV, Brazhe NA, Bilan DS. Modern optical approaches in redox biology: Genetically encoded sensors and Raman spectroscopy. Free Radic Biol Med 2024; 217:68-115. [PMID: 38508405 DOI: 10.1016/j.freeradbiomed.2024.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 02/10/2024] [Accepted: 03/13/2024] [Indexed: 03/22/2024]
Abstract
The objective of the current review is to summarize the current state of optical methods in redox biology. It consists of two parts, the first is dedicated to genetically encoded fluorescent indicators and the second to Raman spectroscopy. In the first part, we provide a detailed classification of the currently available redox biosensors based on their target analytes. We thoroughly discuss the main architecture types of these proteins, the underlying engineering strategies for their development, the biochemical properties of existing tools and their advantages and disadvantages from a practical point of view. Particular attention is paid to fluorescence lifetime imaging microscopy as a possible readout technique, since it is less prone to certain artifacts than traditional intensiometric measurements. In the second part, the characteristic Raman peaks of the most important redox intermediates are listed, and examples of how this knowledge can be implemented in biological studies are given. This part covers such fields as estimation of the redox states and concentrations of Fe-S clusters, cytochromes, other heme-containing proteins, oxidative derivatives of thiols, lipids, and nucleotides. Finally, we touch on the issue of multiparameter imaging, in which biosensors are combined with other visualization methods for simultaneous assessment of several cellular parameters.
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Affiliation(s)
- Alexander I Kostyuk
- M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia; Pirogov Russian National Research Medical University, 117997, Moscow, Russia
| | - Diana D Rapota
- M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia
| | - Kseniia I Morozova
- Faculty of Biology, M.V. Lomonosov Moscow State University, Moscow, 119234, Russia
| | - Anna A Fedotova
- M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia; Faculty of Biology, M.V. Lomonosov Moscow State University, Moscow, 119234, Russia
| | - David Jappy
- Federal Center of Brain Research and Neurotechnologies, Federal Medical Biological Agency, Moscow, 117997, Russia
| | - Alexey V Semyanov
- M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia; Faculty of Biology, M.V. Lomonosov Moscow State University, Moscow, 119234, Russia; Sechenov First Moscow State Medical University, Moscow, 119435, Russia; College of Medicine, Jiaxing University, Jiaxing, Zhejiang Province, 314001, China
| | - Vsevolod V Belousov
- M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia; Pirogov Russian National Research Medical University, 117997, Moscow, Russia; Federal Center of Brain Research and Neurotechnologies, Federal Medical Biological Agency, Moscow, 117997, Russia; Life Improvement by Future Technologies (LIFT) Center, Skolkovo, Moscow, 143025, Russia
| | - Nadezda A Brazhe
- M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia; Faculty of Biology, M.V. Lomonosov Moscow State University, Moscow, 119234, Russia.
| | - Dmitry S Bilan
- M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia; Pirogov Russian National Research Medical University, 117997, Moscow, Russia.
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4
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Yang L, Chen Y, He S, Yu D. The crucial role of NRF2 in erythropoiesis and anemia: Mechanisms and therapeutic opportunities. Arch Biochem Biophys 2024; 754:109948. [PMID: 38452967 DOI: 10.1016/j.abb.2024.109948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 02/25/2024] [Accepted: 02/27/2024] [Indexed: 03/09/2024]
Abstract
The nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor crucial in cellular defense against oxidative and electrophilic stresses. Recent research has highlighted the significance of NRF2 in normal erythropoiesis and anemia. NRF2 regulates genes involved in vital aspects of erythroid development, including hemoglobin catabolism, inflammation, and iron homeostasis in erythrocytes. Disrupted NRF2 activity has been implicated in various pathologies involving abnormal erythropoiesis. In this review, we summarize the progress made in understanding the mechanisms of NRF2 activation in erythropoiesis and explore the roles of NRF2 in various types of anemia. This review also discusses the potential of targeting NRF2 as a new therapeutic approach to treat anemia.
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Affiliation(s)
- Lei Yang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China
| | - Yong Chen
- Department of Oncology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, 225003, China
| | - Sheng He
- Guangxi Key Laboratory of Birth Defects Research and Prevention, Guangxi Key Laboratory of Reproductive Health and Birth Defects Prevention, Guangxi Zhuang Autonomous Region Women and Children Care Hospital, Nanning, Guangxi, 530000, China
| | - Duonan Yu
- Department of Hematology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610000, China; Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Yangzhou University, Yangzhou, 225009, China; Guangxi Key Laboratory of Birth Defects Research and Prevention, Guangxi Key Laboratory of Reproductive Health and Birth Defects Prevention, Guangxi Zhuang Autonomous Region Women and Children Care Hospital, Nanning, Guangxi, 530000, China.
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5
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Yang ML, Lin CL, Chen YC, Lu IA, Su BH, Chen YH, Liu KT, Wu CL, Shiau AL. Prothymosin α accelerates dengue virus-induced thrombocytopenia. iScience 2024; 27:108422. [PMID: 38213625 PMCID: PMC10783621 DOI: 10.1016/j.isci.2023.108422] [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: 03/07/2023] [Revised: 08/31/2023] [Accepted: 11/07/2023] [Indexed: 01/13/2024] Open
Abstract
Thrombocytopenia is the hallmark finding in dengue virus (DENV) infection. Prothymosin α (ProT) has both intracellular and extracellular functions involved in cell cycle progression, cell differentiation, gene regulation, oxidative stress response, and immunomodulation. In this study, we found that ProT levels were elevated in dengue patient sera as well as DENV-infected megakaryoblasts and their culture supernatants. ProT transgenic mice had reduced platelet counts with prolonged bleeding times. Upon treatment with DENV plus anti-CD41 antibody, they exhibited severe skin hemorrhage. Furthermore, overexpression of ProT suppressed megakaryocyte differentiation. Infection with DENV inhibited miR-126 expression, upregulated DNA (cytosine-5)-methyltransferase 1 (DNMT1), downregulated GATA-1, and increased ProT expression. Upregulation of ProT led to Nrf2 activation and reduced reactive oxygen species production, thereby suppressing megakaryopoiesis. We report the pathophysiological role of ProT in DENV infection and propose an involvement of the miR-126-DNMT1-GATA-1-ProT-Nrf2 signaling axis in DENV-induced thrombocytopenia.
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Affiliation(s)
- Mei-Lin Yang
- Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chia-Ling Lin
- Department of Pediatrics, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
| | - Yi-Cheng Chen
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - I-An Lu
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Bing-Hua Su
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yen-Hsu Chen
- Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- School of Medicine, Graduate Institute of Medicine, Sepsis Research Center, Center of Tropical Medicine and Infectious Diseases, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan
- Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Kuan-Ting Liu
- Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chao-Liang Wu
- Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Ai-Li Shiau
- Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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6
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Pfefferlé M, Vallelian F. Transcription Factor NRF2 in Shaping Myeloid Cell Differentiation and Function. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1459:159-195. [PMID: 39017844 DOI: 10.1007/978-3-031-62731-6_8] [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: 07/18/2024]
Abstract
NFE2-related factor 2 (NRF2) is a master transcription factor (TF) that coordinates key cellular homeostatic processes including antioxidative responses, autophagy, proteostasis, and metabolism. The emerging evidence underscores its significant role in modulating inflammatory and immune processes. This chapter delves into the role of NRF2 in myeloid cell differentiation and function and its implication in myeloid cell-driven diseases. In macrophages, NRF2 modulates cytokine production, phagocytosis, pathogen clearance, and metabolic adaptations. In dendritic cells (DCs), it affects maturation, cytokine production, and antigen presentation capabilities, while in neutrophils, NRF2 is involved in activation, migration, cytokine production, and NETosis. The discussion extends to how NRF2's regulatory actions pertain to a wide array of diseases, such as sepsis, various infectious diseases, cancer, wound healing, atherosclerosis, hemolytic conditions, pulmonary disorders, hemorrhagic events, and autoimmune diseases. The activation of NRF2 typically reduces inflammation, thereby modifying disease outcomes. This highlights the therapeutic potential of NRF2 modulation in treating myeloid cell-driven pathologies.
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Affiliation(s)
- Marc Pfefferlé
- Department of Internal Medicine, Spital Limmattal, Schlieren, Switzerland
| | - Florence Vallelian
- Department of Internal Medicine, University of Zurich and University Hospital of Zurich, Zurich, Switzerland.
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Guo X, Cheng C, Wang L, Li D, Fan R, Wei X. Polystyrene nanoplastics induce haematotoxicity with cell oxeiptosis and senescence involved in C57BL/6J mice. ENVIRONMENTAL TOXICOLOGY 2023; 38:2487-2498. [PMID: 37466197 DOI: 10.1002/tox.23886] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 06/07/2023] [Accepted: 06/29/2023] [Indexed: 07/20/2023]
Abstract
Nanoplastics (NPs) has become a worrying serious environmental problem. However, the toxicological effects and mechanisms of NPs on hematopoiesis are still unknown. To this end, male C57BL/6J mice were directly exposed to the serial concentration gradient of polystyrene NPs (PSNPs, 0, 30, 60, and 120 μg d), respectively, for 42 days by intragastric administration. Results show that PSNPs were clearly visible in bone tissues, meanwhile, induced the count of major blood indicators (WBC, RBC, and LYM) decreased. H&E staining displayed that exposed to PSNPs can cause hematopoietic damage of BM and extramedullary hematopoiesis in spleen. Flow cytometry result show that the proportion of LSK represented a dose-dependent significantly decreased after PSNPs exposure. Further research found that PSNPs can cause the systemic oxidative stress occurs manifested as MDA accumulated. In addition, as the dose of PSNPs increased, the fluorescence intensity of Keap1 and p53 in femur sections gradually increased, meanwhile, the expression of cell oxeiptosis signal pathway Keap1/PGAM5/AIFM1 and the cell senescence signal pathway p53/p21 was all increased, markedly. Overall, our study demonstrated that PSNPs exposure caused oxidative stress, potentially resulting in cell oxeiptosis and senescence to develop haematotoxicity in C57BL/6J mice.
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Affiliation(s)
- Xiaoli Guo
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Cheng Cheng
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Lin Wang
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Dongbei Li
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Ruihua Fan
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Xudong Wei
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
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8
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Scicchitano S, Faniello MC, Mesuraca M. Zinc Finger 521 Modulates the Nrf2-Notch Signaling Pathway in Human Ovarian Carcinoma. Int J Mol Sci 2023; 24:14755. [PMID: 37834202 PMCID: PMC10572470 DOI: 10.3390/ijms241914755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 09/21/2023] [Accepted: 09/27/2023] [Indexed: 10/15/2023] Open
Abstract
The human zinc finger protein 521 (ZNF521) is a co-transcriptional factor with multiple recognized regulatory functions in a range of normal, cancer and stem cell compartments. ZNF521 regulates proliferation, progression and CSC (cancer stem cell) compartments in human ovarian cancer (hOC), which is a very aggressive and late-diagnosed female tumor. Two other important regulators of hOC are the NRF2 and NOTCH signaling pathways. In the present paper, the mRNA and protein levels of ZNF521 were correlated with those of the NRF2-NOTCH signaling components in two different hOC cell lines and in a public dataset of 381 hOC patients. The data show that high levels of ZNF521 significantly increase NRF2-NOTCH signaling expression; conversely, the silencing of ZNF521 impairs NRF2-NOTCH signaling. This experimental work shows that, in hOC, different levels of ZNF521 modulate the NRF2-NOTCH signaling pathway and also influences hOC CSC properties.
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Affiliation(s)
- Stefania Scicchitano
- Research Center of Biochemistry and Advanced Molecular Biology, Department of Experimental and Clinical Medicine, “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy;
| | - Maria Concetta Faniello
- Research Center of Biochemistry and Advanced Molecular Biology, Department of Experimental and Clinical Medicine, “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy;
| | - Maria Mesuraca
- Laboratory of Molecular Haematopoiesis and Stem Cell Biology, Department of Experimental and Clinical Medicine, University Magna Græcia, 88100 Catanzaro, Italy
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9
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Mas G, Man N, Nakata Y, Martinez-Caja C, Karl D, Beckedorff F, Tamiro F, Chen C, Duffort S, Itonaga H, Mookhtiar AK, Kunkalla K, Valencia AM, Collings CK, Kadoch C, Vega F, Kogan SC, Shiekhattar R, Morey L, Bilbao D, Nimer SD. The SWI/SNF chromatin-remodeling subunit DPF2 facilitates NRF2-dependent antiinflammatory and antioxidant gene expression. J Clin Invest 2023; 133:e158419. [PMID: 37200093 PMCID: PMC10313367 DOI: 10.1172/jci158419] [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: 01/12/2022] [Accepted: 05/16/2023] [Indexed: 05/20/2023] Open
Abstract
During emergency hematopoiesis, hematopoietic stem cells (HSCs) rapidly proliferate to produce myeloid and lymphoid effector cells, a response that is critical against infection or tissue injury. If unresolved, this process leads to sustained inflammation, which can cause life-threatening diseases and cancer. Here, we identify a role of double PHD fingers 2 (DPF2) in modulating inflammation. DPF2 is a defining subunit of the hematopoiesis-specific BAF (SWI/SNF) chromatin-remodeling complex, and it is mutated in multiple cancers and neurological disorders. We uncovered that hematopoiesis-specific Dpf2-KO mice developed leukopenia, severe anemia, and lethal systemic inflammation characterized by histiocytic and fibrotic tissue infiltration resembling a clinical hyperinflammatory state. Dpf2 loss impaired the polarization of macrophages responsible for tissue repair, induced the unrestrained activation of Th cells, and generated an emergency-like state of HSC hyperproliferation and myeloid cell-biased differentiation. Mechanistically, Dpf2 deficiency resulted in the loss of the BAF catalytic subunit BRG1 from nuclear factor erythroid 2-like 2-controlled (NRF2-controlled) enhancers, impairing the antioxidant and antiinflammatory transcriptional response needed to modulate inflammation. Finally, pharmacological reactivation of NRF2 suppressed the inflammation-mediated phenotypes and lethality of Dpf2Δ/Δ mice. Our work establishes an essential role of the DPF2-BAF complex in licensing NRF2-dependent gene expression in HSCs and immune effector cells to prevent chronic inflammation.
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Affiliation(s)
- Gloria Mas
- Sylvester Comprehensive Cancer Center and
| | - Na Man
- Sylvester Comprehensive Cancer Center and
| | - Yuichiro Nakata
- Sylvester Comprehensive Cancer Center and
- Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA
| | | | | | - Felipe Beckedorff
- Sylvester Comprehensive Cancer Center and
- Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA
| | | | - Chuan Chen
- Sylvester Comprehensive Cancer Center and
| | | | | | | | | | - Alfredo M. Valencia
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
- Chemical Biology Program, Harvard University, Cambridge, Massachusetts, USA
| | - Clayton K. Collings
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Cigall Kadoch
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Francisco Vega
- Sylvester Comprehensive Cancer Center and
- Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Scott C. Kogan
- Helen Diller Family Comprehensive Cancer Center and
- Department of Laboratory Medicine, UCSF, San Francisco, California, USA
| | - Ramin Shiekhattar
- Sylvester Comprehensive Cancer Center and
- Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Lluis Morey
- Sylvester Comprehensive Cancer Center and
- Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Daniel Bilbao
- Sylvester Comprehensive Cancer Center and
- Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Stephen D. Nimer
- Sylvester Comprehensive Cancer Center and
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
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10
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Chavez JS, Rabe JL, Niño KE, Wells HH, Gessner RL, Mills TS, Hernandez G, Pietras EM. PU.1 is required to restrain myelopoiesis during chronic inflammatory stress. Front Cell Dev Biol 2023; 11:1204160. [PMID: 37497478 PMCID: PMC10368259 DOI: 10.3389/fcell.2023.1204160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 06/19/2023] [Indexed: 07/28/2023] Open
Abstract
Chronic inflammation is a common feature of aging and numerous diseases such as diabetes, obesity, and autoimmune syndromes and has been linked to the development of hematological malignancy. Blood-forming hematopoietic stem cells (HSC) can contribute to these diseases via the production of tissue-damaging myeloid cells and/or the acquisition of mutations in epigenetic and transcriptional regulators that initiate evolution toward leukemogenesis. We previously showed that the myeloid "master regulator" transcription factor PU.1 is robustly induced in HSC by pro-inflammatory cytokines such as interleukin (IL)-1β and limits their proliferative activity. Here, we used a PU.1-deficient mouse model to investigate the broader role of PU.1 in regulating hematopoietic activity in response to chronic inflammatory challenges. We found that PU.1 is critical in restraining inflammatory myelopoiesis via suppression of cell cycle and self-renewal gene programs in myeloid-biased multipotent progenitor (MPP) cells. Our data show that while PU.1 functions as a key driver of myeloid differentiation, it plays an equally critical role in tailoring hematopoietic responses to inflammatory stimuli while limiting expansion and self-renewal gene expression in MPPs. These data identify PU.1 as a key regulator of "emergency" myelopoiesis relevant to inflammatory disease and leukemogenesis.
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Affiliation(s)
- James S. Chavez
- Division of Hematology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Jennifer L. Rabe
- Division of Hematology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Katia E. Niño
- Division of Hematology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Harrison H. Wells
- Division of Hematology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Rachel L. Gessner
- Division of Hematology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Taylor S. Mills
- Division of Hematology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Giovanny Hernandez
- Division of Hematology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Eric M. Pietras
- Division of Hematology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
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11
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Wang Y, Jin X, Li M, Gao J, Zhao X, Ma J, Shi C, He B, Hu L, Shi J, Liu G, Qu G, Zheng Y, Jiang G. PM 2.5 Increases Systemic Inflammatory Cells and Associated Disease Risks by Inducing NRF2-Dependent Myeloid-Biased Hematopoiesis in Adult Male Mice. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2023; 57:7924-7937. [PMID: 37184982 DOI: 10.1021/acs.est.2c09024] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/17/2023]
Abstract
Although PM2.5 (fine particles with aerodynamic diameter <2.5 μm) exposure shows the potential to impact normal hematopoiesis, the detailed alterations in systemic hematopoiesis and the underlying mechanisms remain unclear. For hematopoiesis under steady-state or stress conditions, nuclear factor erythroid 2-related factor 2 (NRF2) is essential for regulating hematopoietic processes to maintain blood homeostasis. Herein, we characterized changes in the populations of hematopoietic stem progenitor cells and committed hematopoietic progenitors in the lungs and bone marrow (BM) of wild-type and Nrf2-/- C57BL/6J male mice. PM2.5-induced NRF2-dependent biased hematopoiesis toward myeloid lineage in the lungs and BM generates excessive numbers of various inflammatory immune cells, including neutrophils, monocytes, and platelets. The increased population of these immune cells in the lungs, BM, and peripheral blood has been associated with observed pulmonary fibrosis and high disease risks in an NRF2-dependent manner. Therefore, although NRF2 is a protective factor against stressors, upon PM2.5 exposure, NRF2 is involved in stress myelopoiesis and enhanced PM2.5 toxicity in pulmonary injury, even leading to systemic inflammation.
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Affiliation(s)
- Yuanyuan Wang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xiaoting Jin
- School of Public Health, Qingdao University, Qingdao 266071, China
| | - Min Li
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- Research Center for Analytical Sciences, Department of Chemistry, College of Sciences, Northeastern University, Shenyang 110819, China
| | - Jie Gao
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- School of Environmental, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310000, China
| | - Xingchen Zhao
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Juan Ma
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Chunzhen Shi
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- College of Ecology and Environment, Beijing Technology and Business University, Beijing 100048, China
| | - Bin He
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- School of Environmental, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310000, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ligang Hu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- School of Environmental, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310000, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
- Institute of Environment and Health, Jianghan University, Wuhan 430056, China
| | - Jianbo Shi
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- School of Environmental, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310000, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
- Institute of Environment and Health, Jianghan University, Wuhan 430056, China
| | - Guoliang Liu
- Department of Pulmonary and Critical Care Medicine, National Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China
- Institute of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, Chinese Academy of Medical Sciences, Beijing 100029, China
| | - Guangbo Qu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- School of Environmental, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310000, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
- Institute of Environment and Health, Jianghan University, Wuhan 430056, China
| | - Yuxin Zheng
- School of Public Health, Qingdao University, Qingdao 266071, China
| | - Guibin Jiang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- School of Environmental, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310000, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
- Institute of Environment and Health, Jianghan University, Wuhan 430056, China
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12
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Pant A, Dasgupta D, Tripathi A, Pyaram K. Beyond Antioxidation: Keap1-Nrf2 in the Development and Effector Functions of Adaptive Immune Cells. Immunohorizons 2023; 7:288-298. [PMID: 37099275 PMCID: PMC10579846 DOI: 10.4049/immunohorizons.2200061] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 04/05/2023] [Indexed: 04/27/2023] Open
Abstract
Ubiquitously expressed in mammalian cells, the Kelch-like ECH-associated protein 1 (Keap1)-NF erythroid 2-related factor 2 (Nrf2) complex forms the evolutionarily conserved antioxidation system to tackle oxidative stress caused by reactive oxygen species. Reactive oxygen species, generated as byproducts of cellular metabolism, were identified as essential second messengers for T cell signaling, activation, and effector responses. Apart from its traditional role as an antioxidant, a growing body of evidence indicates that Nrf2, tightly regulated by Keap1, modulates immune responses and regulates cellular metabolism. Newer functions of Keap1 and Nrf2 in immune cell activation and function, as well as their role in inflammatory diseases such as sepsis, inflammatory bowel disease, and multiple sclerosis, are emerging. In this review, we highlight recent findings about the influence of Keap1 and Nrf2 in the development and effector functions of adaptive immune cells, that is, T cells and B cells, and discuss the knowledge gaps in our understanding. We also summarize the research potential and targetability of Nrf2 for treating immune pathologies.
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Affiliation(s)
- Anil Pant
- Department of Veterinary Pathobiology, School of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX
| | - Debolina Dasgupta
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS
| | - Aprajita Tripathi
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS
| | - Kalyani Pyaram
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS
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13
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Yagishita Y, Chartoumpekis DV, Kensler TW, Wakabayashi N. NRF2 and the Moirai: Life and Death Decisions on Cell Fates. Antioxid Redox Signal 2023; 38:684-708. [PMID: 36509429 PMCID: PMC10025849 DOI: 10.1089/ars.2022.0200] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Significance: The transcription factor NRF2 (NF-E2-related factor 2) plays an important role as a master regulator of the cellular defense system by activating transcriptional programs of NRF2 target genes encoding multiple enzymes related to cellular redox balance and xenobiotic detoxication. Comprehensive transcriptional analyses continue to reveal an ever-broadening range of NRF2 target genes, demonstrating the sophistication and diversification of NRF2 biological signatures beyond its canonical cytoprotective roles. Recent Advances: Accumulating evidence indicates that NRF2 has a strong association with the regulation of cell fates by influencing key processes of cellular transitions in the three major phases of the life cycle of the cell (i.e., cell birth, cell differentiation, and cell death). The molecular integration of NRF2 signaling into this regulatory program occurs through a wide range of NRF2 target genes encompassing canonical functions and those manipulating cell fate pathways. Critical Issues: A singular focus on NRF2 signaling for dissecting its actions limits in-depth understanding of its intersection with the molecular machinery of cell fate determinations. Compensatory responses of downstream pathways governed by NRF2 executed by a variety of transcription factors and multifactorial signaling crosstalk require further exploration. Future Directions: Further investigations using optimized in vivo models and active engagement of overarching approaches to probe the interplay of widespread pathways are needed to study the properties and capabilities of NRF2 signaling as a part of a large network within the cell fate regulatory domain. Antioxid. Redox Signal. 38, 684-708.
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Affiliation(s)
- Yoko Yagishita
- Translational Research Program, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Dionysios V Chartoumpekis
- Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital, Lausanne, Switzerland
| | - Thomas W Kensler
- Translational Research Program, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Nobunao Wakabayashi
- Translational Research Program, Fred Hutchinson Cancer Center, Seattle, Washington, USA
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14
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Hirose W, Horiuchi M, Li D, Motoike IN, Zhang L, Nishi H, Taniyama Y, Kamei T, Suzuki M, Kinoshita K, Katsuoka F, Taguchi K, Yamamoto M. Selective Elimination of NRF2-Activated Cells by Competition With Neighboring Cells in the Esophageal Epithelium. Cell Mol Gastroenterol Hepatol 2022; 15:153-178. [PMID: 36115578 PMCID: PMC9672893 DOI: 10.1016/j.jcmgh.2022.09.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 09/08/2022] [Accepted: 09/08/2022] [Indexed: 12/29/2022]
Abstract
BACKGROUND & AIMS NF-E2-related factor 2 (NRF2) is a transcription factor that regulates cytoprotective gene expression in response to oxidative and electrophilic stresses. NRF2 activity is mainly controlled by Kelch-like ECH-associated protein 1 (KEAP1). Constitutive NRF2 activation by NRF2 mutations or KEAP1 dysfunction results in a poor prognosis for esophageal squamous cell carcinoma (ESCC) through the activation of cytoprotective functions. However, the detailed contributions of NRF2 to ESCC initiation or promotion have not been clarified. Here, we investigated the fate of NRF2-activated cells in the esophageal epithelium. METHODS We generated tamoxifen-inducible, squamous epithelium-specific Keap1 conditional knockout (Keap1-cKO) mice in which NRF2 was inducibly activated in a subset of cells at the adult stage. Histologic, quantitative reverse-transcription polymerase chain reaction, single-cell RNA-sequencing, and carcinogen experiments were conducted to analyze the Keap1-cKO esophagus. RESULTS KEAP1-deleted/NRF2-activated cells and cells with normal NRF2 expression (KEAP1-normal cells) coexisted in the Keap1-cKO esophageal epithelium in approximately equal numbers, and NRF2-activated cells formed dysplastic lesions. NRF2-activated cells exhibited weaker attachment to the basement membrane and gradually disappeared from the epithelium. In contrast, neighboring KEAP1-normal cells exhibited accelerated proliferation and started dominating the epithelium but accumulated DNA damage that triggered carcinogenesis upon carcinogen exposure. CONCLUSIONS Constitutive NRF2 activation promotes the selective elimination of epithelial cells via cell competition, but this competition induces DNA damage in neighboring KEAP1-normal cells, which predisposes them to chemical-induced ESCC.
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Affiliation(s)
- Wataru Hirose
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan,Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Makoto Horiuchi
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan,Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Donghan Li
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Ikuko N. Motoike
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan,Graduate School of Information Sciences, Tohoku University, Sendai, Japan
| | - Lin Zhang
- Graduate School of Information Sciences, Tohoku University, Sendai, Japan
| | - Hafumi Nishi
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan,Graduate School of Information Sciences, Tohoku University, Sendai, Japan
| | - Yusuke Taniyama
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takashi Kamei
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mikiko Suzuki
- Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kengo Kinoshita
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan,Graduate School of Information Sciences, Tohoku University, Sendai, Japan,Advanced Research Center for Innovations in Next Generation Medicine (INGEM), Tohoku University, Sendai, Japan
| | - Fumiki Katsuoka
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan,Advanced Research Center for Innovations in Next Generation Medicine (INGEM), Tohoku University, Sendai, Japan
| | - Keiko Taguchi
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan,Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan,Advanced Research Center for Innovations in Next Generation Medicine (INGEM), Tohoku University, Sendai, Japan
| | - Masayuki Yamamoto
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan; Advanced Research Center for Innovations in Next Generation Medicine (INGEM), Tohoku University, Sendai, Japan.
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15
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Chen H, Zhong K, Zhang Y, Xie L, Chen P. Bisphenol A Interferes with Redox Balance and the Nrf2 Signaling Pathway in Xenopus tropicalis during Embryonic Development. Animals (Basel) 2022; 12:ani12070937. [PMID: 35405925 PMCID: PMC8996838 DOI: 10.3390/ani12070937] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 04/05/2022] [Accepted: 04/05/2022] [Indexed: 11/30/2022] Open
Abstract
Simple Summary Toxicological studies of the effects of BPA on tropical clawed frog (Xenopus tropicalis) early embryos show that temporary exposure to BPA during early embryonic development can result in dramatic teratogenesis, DNA damage, and abnormal gene expression. The overall results of this study provide valuable insights for a more holistic assessment of the environmental risks related to BPA in aquatic ecosystems. Abstract Bisphenol A (BPA), an environmental estrogen, is widely used and largely released into the hydrosphere, thus inducing adverse effects in aquatic organisms. Here, Xenopus tropicalis was used as an animal model to investigate the oxidative effects of BPA on early embryonic development. BPA exposure prevalently caused development delay and shortened body length. Furthermore, BPA exposure significantly increased the levels of reactive oxygen species (ROS) and DNA damage in embryos. Thus, the details of BPA interference with antioxidant regulatory pathways during frog early embryonic development should be further explored.
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Affiliation(s)
- Hongjun Chen
- College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China; (H.C.); (K.Z.); (Y.Z.)
| | - Keke Zhong
- College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China; (H.C.); (K.Z.); (Y.Z.)
| | - Yongpu Zhang
- College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China; (H.C.); (K.Z.); (Y.Z.)
| | - Lei Xie
- College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China; (H.C.); (K.Z.); (Y.Z.)
- Correspondence: (L.X.); (P.C.)
| | - Peichao Chen
- College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China; (H.C.); (K.Z.); (Y.Z.)
- Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Harvard Medical School, Massachusetts General Hospital, Harvard University, Boston, MA 02114, USA
- Correspondence: (L.X.); (P.C.)
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16
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Zhao M, Murakami S, Matsumaru D, Kawauchi T, Nabeshima YI, Motohashi H. NRF2 Pathway Activation Attenuates Aging-Related Renal Phenotypes due to α-Klotho Deficiency. J Biochem 2022; 171:579-589. [DOI: 10.1093/jb/mvac014] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Accepted: 02/03/2022] [Indexed: 11/13/2022] Open
Abstract
Summary
Oxidative stress is one of the major causes of the age-related functional decline in cells and tissues. The KEAP1-NRF2 system plays a central role in the regulation of redox balance, and NRF2 activation exerts antiaging effects by controlling oxidative stress in aged tissues. α-Klotho was identified as an aging suppressor protein based on the premature aging phenotypes of its mutant mice, and its expression is known to gradually decrease during aging. Because α-Klotho has been shown to possess antioxidant function, aging-related phenotypes of α-Klotho mutant mice seem to be attributable to increased oxidative stress at least in part. To examine whether NRF2 activation antagonizes aging-related phenotypes caused by α-Klotho deficiency, we crossed α-Klotho-deficient (Kl–/–) mice with a Keap1-knockdown background, in which the NRF2 pathway is constitutively activated in the whole body. NRF2 pathway activation in Kl–/– mice extended the lifespan and dramatically improved aging-related renal phenotypes. With elevated expression of antioxidant genes accompanied by an oxidative stress decrease, the antioxidant effects of NRF2 seem to make a major contribution to the attenuation of aging-related renal phenotypes of Kl–/– mice. Thus, NRF2 is expected to exert an antiaging function by partly compensating for the functional decline of α-Klotho during physiological aging.
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Affiliation(s)
- Mingyue Zhao
- Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan
| | - Shohei Murakami
- Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan
| | - Daisuke Matsumaru
- Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan
| | - Takeshi Kawauchi
- Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe 650-0047, Japan
| | - Yo-ichi Nabeshima
- Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe 650-0047, Japan
| | - Hozumi Motohashi
- Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan
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17
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Picerno A, Stasi A, Franzin R, Curci C, di Bari I, Gesualdo L, Sallustio F. Why stem/progenitor cells lose their regenerative potential. World J Stem Cells 2021; 13:1714-1732. [PMID: 34909119 PMCID: PMC8641024 DOI: 10.4252/wjsc.v13.i11.1714] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/26/2021] [Accepted: 10/31/2021] [Indexed: 02/06/2023] Open
Abstract
Nowadays, it is clear that adult stem cells, also called as tissue stem cells, play a central role to repair and maintain the tissue in which they reside by their self-renewal ability and capacity of differentiating into distinct and specialized cells. As stem cells age, their renewal ability declines and their capacity to maintain organ homeostasis and regeneration is impaired. From a molecular perspective, these changes in stem cells properties can be due to several types of cell intrinsic injury and DNA aberrant alteration (i.e epigenomic profile) as well as changes in the tissue microenviroment, both into the niche and by systemic circulating factors. Strikingly, it has been suggested that aging-induced deterioration of stem cell functions may play a key role in the pathophysiology of the various aging-associated disorders. Therefore, understanding how resident stem cell age and affects near and distant tissues is fundamental. Here, we examine the current knowledge about aging mechanisms in several kinds of adult stem cells under physiological and pathological conditions and the principal aging-related changes in number, function and phenotype that determine the loss of tissue renewal properties. Furthermore, we examine the possible cell rejuvenation strategies. Stem cell rejuvenation may reverse the aging phenotype and the discovery of effective methods for inducing and differentiating pluripotent stem cells for cell replacement therapies could open up new possibilities for treating age-related diseases.
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Affiliation(s)
- Angela Picerno
- Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari 70124, Italy
| | - Alessandra Stasi
- Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari 70124, Italy
| | - Rossana Franzin
- Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari 70124, Italy
| | - Claudia Curci
- Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari 70124, Italy
| | - Ighli di Bari
- Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari 70124, Italy
| | - Loreto Gesualdo
- Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari 70124, Italy
| | - Fabio Sallustio
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari 70124, Italy
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18
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Ding Y, Li Y, Zhao Z, Cliff Zhang Q, Liu F. The chromatin-remodeling enzyme Smarca5 regulates erythrocyte aggregation via Keap1-Nrf2 signaling. eLife 2021; 10:72557. [PMID: 34698638 PMCID: PMC8594921 DOI: 10.7554/elife.72557] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 10/23/2021] [Indexed: 12/30/2022] Open
Abstract
Although thrombosis has been extensively studied using various animal models, our understanding of the underlying mechanism remains elusive. Here, using zebrafish model, we demonstrated that smarca5-deficient red blood cells (RBCs) formed blood clots in the caudal vein plexus. We further used the anti-thrombosis drugs to treat smarca5zko1049a embryos and found that a thrombin inhibitor, argatroban, partially prevented blood clot formation in smarca5zko1049a. To explore the regulatory mechanism of smarca5 in RBC homeostasis, we profiled the chromatin accessibility landscape and transcriptome features in RBCs from smarca5zko1049a and their siblings and found that both the chromatin accessibility at the keap1a promoter and expression of keap1a were decreased. Keap1 is a suppressor protein of Nrf2, which is a major regulator of oxidative responses. We further identified that the expression of hmox1a, a downstream target of Keap1-Nrf2 signaling pathway, was markedly increased upon smarca5 deletion. Importantly, overexpression of keap1a or knockdown of hmox1a partially rescued the blood clot formation, suggesting that the disrupted Keap1-Nrf2 signaling is responsible for the RBC aggregation in smarca5 mutants. Together, our study using zebrafish smarca5 mutants characterizes a novel role for smarca5 in RBC aggregation, which may provide a new venous thrombosis animal model to support drug screening and pre-clinical therapeutic assessments to treat thrombosis.
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Affiliation(s)
- Yanyan Ding
- The Max-Planck Center for Tissue Stem Cell Research and Regenerative Medicine, Bioland Laboratory, Guangzhou, China.,State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Yuzhe Li
- MOE Key Laboratory of Bioinformatics, Beijing Advanced Innovation Center for Structural Biology & Frontier Research Center for Biological Structure, Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China.,Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Ziqian Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Qiangfeng Cliff Zhang
- MOE Key Laboratory of Bioinformatics, Beijing Advanced Innovation Center for Structural Biology & Frontier Research Center for Biological Structure, Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China.,Tsinghua-Peking Center for Life Sciences, Beijing, China
| | - Feng Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
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19
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Sinha S, Pereira-Reis J, Guerra A, Rivella S, Duarte D. The Role of Iron in Benign and Malignant Hematopoiesis. Antioxid Redox Signal 2021; 35:415-432. [PMID: 33231101 PMCID: PMC8328043 DOI: 10.1089/ars.2020.8155] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 10/26/2020] [Accepted: 11/20/2020] [Indexed: 12/21/2022]
Abstract
Significance: Iron is an essential element required for sustaining a normal healthy life. However, an excess amount of iron in the bloodstream and tissue generates toxic hydroxyl radicals through Fenton reactions. Henceforth, a balance in iron concentration is extremely important to maintain cellular homeostasis in both normal hematopoiesis and erythropoiesis. Iron deficiency or iron overload can impact hematopoiesis and is associated with many hematological diseases. Recent Advances: The mechanisms of action of key iron regulators such as erythroferrone and the discovery of new drugs, such as ACE-536/luspatercept, are of potential interest to treat hematological disorders, such as β-thalassemia. New therapies targeting inflammation-induced ineffective erythropoiesis are also in progress. Furthermore, emerging evidences support differential interactions between iron and its cellular antioxidant responses of hematopoietic and neighboring stromal cells. Both iron and its systemic regulator, such as hepcidin, play a significant role in regulating erythropoiesis. Critical Issues: Significant pre-clinical studies are on the way and new drugs targeting iron metabolism have been recently approved or are undergoing clinical trials to treat pathological conditions with impaired erythropoiesis such as myelodysplastic syndromes or β-thalassemia. Future Directions: Future studies should explore how iron regulates hematopoiesis in both benign and malignant conditions. Antioxid. Redox Signal. 35, 415-432.
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Affiliation(s)
- Sayantani Sinha
- Division of Hematology, Department of Pediatrics, The Children's Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania, USA
| | - Joana Pereira-Reis
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal
| | - Amaliris Guerra
- Division of Hematology, Department of Pediatrics, The Children's Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania, USA
| | - Stefano Rivella
- Division of Hematology, Department of Pediatrics, The Children's Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania, USA
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Cell and Molecular Biology Affinity Group (CAMB), University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania, USA
- Penn Center for Musculoskeletal Disorders, The Children's Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania, USA
| | - Delfim Duarte
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal
- Department of Onco-Hematology, Instituto Português de Oncologia (IPO), Porto, Portugal
- Unit of Biochemistry, Department of Biomedicine, Faculdade de Medicina da Universidade do Porto (FMUP), Porto, Portugal
- Porto Comprehensive Cancer Center (P.CCC), Porto, Portugal
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20
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Ludikhuize MC, Rodríguez Colman MJ. Metabolic Regulation of Stem Cells and Differentiation: A Forkhead Box O Transcription Factor Perspective. Antioxid Redox Signal 2021; 34:1004-1024. [PMID: 32847377 DOI: 10.1089/ars.2020.8126] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Significance: Stem cell activation and differentiation occur along changes in cellular metabolism. Metabolic transitions translate into changes in redox balance, cell signaling, and epigenetics, thereby regulating these processes. Metabolic transitions are key regulators of cell fate and exemplify the moonlighting nature of many metabolic enzymes and their associated metabolites. Recent Advances: Forkhead box O transcription factors (FOXOs) are bona fide regulators of cellular homeostasis. FOXOs are multitasking proteins able to regulate cell cycle, cellular metabolism, and redox state. Recent and ongoing research poses FOXOs as key factors in stem cell maintenance and differentiation in several tissues. Critical Issues: The multitasking nature of FOXOs and their tissue-specific expression patterns hinders to disclose a possible conserved mechanism of regulation of stem cell maintenance and differentiation. Moreover, cellular metabolism, cell signaling, and epigenetics establish complex regulatory interactions, which challenge the establishment of the causal/temporal nature of metabolic changes and stem cell activation and differentiation. Future Directions: The development of single-cell technologies and in vitro models able to reproduce the dynamics of stem cell differentiation are actively contributing to define the role of metabolism in this process. This knowledge is key to understanding and designing therapies for those pathologies where the balance between proliferation and differentiation is lost. Importantly, metabolic interventions could be applied to optimize stem cell cultures meant for therapeutical applications, such as transplantations, to treat autoimmune and degenerative disorders. Antioxid. Redox Signal. 34, 1004-1024.
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Affiliation(s)
- Marlies Corine Ludikhuize
- Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| | - María José Rodríguez Colman
- Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
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21
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Examination of Novel Immunomodulatory Effects of L-Sulforaphane. Nutrients 2021; 13:nu13020602. [PMID: 33673203 PMCID: PMC7917832 DOI: 10.3390/nu13020602] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 02/10/2021] [Accepted: 02/10/2021] [Indexed: 01/08/2023] Open
Abstract
The dietary isothiocyanate L-sulforaphane (LSF), derived from cruciferous vegetables, is reported to have several beneficial biological properties, including anti-inflammatory and immunomodulatory effects. However, there is limited data on how LSF modulates these effects in human immune cells. The present study was designed to investigate the immunomodulatory effects of LSF (10 µM and 50 µM) on peripheral blood mononuclear cell (PBMC) populations and cytokine secretion in healthy adult volunteers (n = 14), in the presence or absence of bacterial (lipopolysaccharide) and viral (imiquimod) toll-like receptor (TLRs) stimulations. Here, we found that LSF reduced pro-inflammatory cytokines interleukin (IL)-6, IL-1β, and chemokines monocyte chemoattractant protein (MCP)-1 irrespective of TLR stimulations. This result was associated with LSF significantly reducing the proportion of natural killer (NK) cells and monocytes while increasing the proportions of dendritic cells (DCs), T cells and B cells. We found a novel effect of LSF in relation to reducing cluster of differentiation (CD) 14+ monocytes while simultaneously increasing monocyte-derived DCs (moDCs: lineage-Human Leukocyte Antigen-DR isotype (HLA-DR)+CD11blow-high CD11chigh). LSF was also shown to induce a 3.9-fold increase in the antioxidant response element (ARE) activity in a human monocyte cell line (THP-1). Our results provide important insights into the immunomodulatory effects of LSF, showing in human PBMCs an ability to drive differentiation of monocytes towards an immature monocyte-derived dendritic cell phenotype with potentially important biological functions. These findings provide insights into the potential role of LSF as a novel immunomodulatory drug candidate and supports the need for further preclinical and phase I clinical studies.
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22
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Sekine H, Motohashi H. Roles of CNC Transcription Factors NRF1 and NRF2 in Cancer. Cancers (Basel) 2021; 13:cancers13030541. [PMID: 33535386 PMCID: PMC7867063 DOI: 10.3390/cancers13030541] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 01/27/2021] [Indexed: 12/30/2022] Open
Abstract
Simple Summary Although NRF1 (nuclear factor erythroid 2-like 1; NFE2L1) and NRF2 (nuclear factor erythroid 2-like 2; NFE2L2) belong to the CNC (cap‘n’collar) transcription factor family and share DNA recognition elements, their functions in vivo are substantially different. In cancer cells, while NRF2 confers therapeutic resistance via increasing antioxidant capacity and modulating glucose and glutamine metabolism, NRF1 confers therapeutic resistance via triggering proteasome bounce back response. Proteasome inhibition activates NRF1, and NRF1, in turn, activates the proteasome by inducing the transcriptional activation of proteasome subunit genes. One of the oncometabolites, UDP-GlcNAc (uridine diphosphate N-acetylglucosamine), has been found to be a key to the NRF1-mediated proteasome bounce back response. In this review, we introduce the roles of NRF1 in the cancer malignancy in comparison with NRF2. Abstract Cancer cells exhibit unique metabolic features and take advantage of them to enhance their survival and proliferation. While the activation of NRF2 (nuclear factor erythroid 2-like 2; NFE2L2), a CNC (cap‘n’collar) family transcription factor, is effective for the prevention and alleviation of various diseases, NRF2 contributes to cancer malignancy by promoting aggressive tumorigenesis and conferring therapeutic resistance. NRF2-mediated metabolic reprogramming and increased antioxidant capacity underlie the malignant behaviors of NRF2-activated cancer cells. Another member of the CNC family, NRF1, plays a key role in the therapeutic resistance of cancers. Since NRF1 maintains proteasome activity by inducing proteasome subunit genes in response to proteasome inhibitors, NRF1 protects cancer cells from proteotoxicity induced by anticancer proteasome inhibitors. An important metabolite that activates NRF1 is UDP-GlcNAc (uridine diphosphate N-acetylglucosamine), which is abundantly generated in many cancer cells from glucose and glutamine via the hexosamine pathway. Thus, the metabolic signatures of cancer cells are closely related to the oncogenic and tumor-promoting functions of CNC family members. In this review, we provide a brief overview of NRF2-mediated cancer malignancy and elaborate on NRF1-mediated drug resistance affected by an oncometabolite UDP-GlcNAc.
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Affiliation(s)
- Hiroki Sekine
- Correspondence: ; Tel.: +81-22-717-8553; Fax: +81-22-717-8554
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23
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Zhu X, Xi C, Ward A, Takezaki M, Shi H, Peterson KR, Pace BS. NRF2 mediates γ-globin gene regulation through epigenetic modifications in a β-YAC transgenic mouse model. Exp Biol Med (Maywood) 2020; 245:1308-1318. [PMID: 32715783 DOI: 10.1177/1535370220945305] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
IMPACT STATEMENT Sickle cell disease is an inherited hemoglobin disorder that affects over 100,000 people in the United States causing high morbidity and early mortality. Although new treatments were recently approved by the FDA, only one drug Hydroxyurea induces fetal hemoglobin expression to inhibit sickle hemoglobin polymerization in red blood cells. Our laboratory previously demonstrated the ability of the NRF2 activator, dimethyl fumarate to induce fetal hemoglobin in the sickle cell mouse model. In this study, we investigated molecular mechanisms of γ-globin gene activation by NRF2. We observed the ability of NRF2 to modulate chromatin structure in the human β-like globin gene locus of β-YAC transgenic mice during development. Furthermore, an NRF2/TET3 interaction regulates γ-globin gene DNA methylation. These findings provide potential new molecular targets for small molecule drug developed for treating sickle cell disease.
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Affiliation(s)
- Xingguo Zhu
- Division of Hematology/Oncology, Department of Pediatrics, Augusta University, Augusta, GA 30912, USA.,Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
| | - Caixia Xi
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
| | - Alexander Ward
- Division of Hematology/Oncology, Department of Pediatrics, Augusta University, Augusta, GA 30912, USA
| | - Mayuko Takezaki
- Division of Hematology/Oncology, Department of Pediatrics, Augusta University, Augusta, GA 30912, USA
| | - Huidong Shi
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
| | - Kenneth R Peterson
- Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Betty S Pace
- Division of Hematology/Oncology, Department of Pediatrics, Augusta University, Augusta, GA 30912, USA.,Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.,Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA
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24
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Gbotosho OT, Kapetanaki MG, Ross M, Ghosh S, Weidert F, Bullock GC, Watkins S, Ofori-Acquah SF, Kato GJ. Nrf2 deficiency in mice attenuates erythropoietic stress-related macrophage hypercellularity. Exp Hematol 2020; 84:19-28.e4. [PMID: 32151553 PMCID: PMC7237317 DOI: 10.1016/j.exphem.2020.02.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 02/27/2020] [Accepted: 02/29/2020] [Indexed: 12/11/2022]
Abstract
Erythropoiesis in the bone marrow and spleen depends on intricate interactions between the resident macrophages and erythroblasts. Our study focuses on identifying the role of nuclear factor erythroid 2-related factor 2 (Nrf2) during recovery from stress erythropoiesis. To that end, we induced stress erythropoiesis in Nrf2+/+ and Nrf2-null mice and evaluated macrophage subsets known to support erythropoiesis and erythroid cell populations. Our results confirm macrophage and erythroid hypercellularity after acute blood loss. Importantly, Nrf2 depletion results in a marked numerical reduction of F4/80+/CD169+/CD11b+ macrophages, which is more prominent under the induction of stress erythropoiesis. The observed macrophage deficiency is concomitant to a significantly impaired erythroid response to acute stress erythropoiesis in both murine bone marrow and murine spleen. Additionally, peripheral blood reticulocyte count as a response to acute blood loss is delayed in Nrf2-deficient mice compared with age-matched controls (11.0 ± 0.6% vs. 14.8 ± 0.6%, p ≤ 0.001). Interestingly, we observe macrophage hypercellularity in conjunction with erythroid hyperplasia in the bone marrow during stress erythropoiesis in Nrf2+/+ controls, with both impaired in Nrf2-/- mice. We further confirm the finding of macrophage hypercellularity in another model of erythroid hyperplasia, the transgenic sickle cell mouse, characterized by hemolytic anemia and chronic stress erythropoiesis. Our results revealed the role of Nrf2 in stress erythropoiesis in the bone marrow and that macrophage hypercellularity occurs concurrently with erythroid expansion during stress erythropoiesis. Macrophage hypercellularity is a previously underappreciated feature of stress erythropoiesis in sickle cell disease and recovery from blood loss.
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Affiliation(s)
- Oluwabukola T Gbotosho
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA; Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Maria G Kapetanaki
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Mark Ross
- Center for Biologic Imaging, Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, PA
| | - Samit Ghosh
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA; Center for Translational and International Hematology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA
| | - Frances Weidert
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Grant C Bullock
- Division of Hematopathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Simon Watkins
- Center for Biologic Imaging, Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, PA
| | - Solomon F Ofori-Acquah
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA; Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA; Center for Translational and International Hematology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA; School of Biomedical and Allied Health Sciences, University of Ghana, Accra, Ghana
| | - Gregory J Kato
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA; Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA.
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25
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Wu WL, Papagiannakopoulos T. The Pleiotropic Role of the KEAP1/NRF2 Pathway in Cancer. ANNUAL REVIEW OF CANCER BIOLOGY 2020. [DOI: 10.1146/annurev-cancerbio-030518-055627] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The unregulated proliferative capacity of many tumors is dependent on dysfunctional nutrient utilization and ROS (reactive oxygen species) signaling to sustain a deranged metabolic state. Although it is clear that cancers broadly rely on these survival and signaling pathways, how they achieve these aims varies dramatically. Mutations in the KEAP1/NRF2 pathway represent a potent cancer adaptation to exploit native cytoprotective pathways that involve both nutrient metabolism and ROS regulation. Despite activating these advantageous processes, mutations within KEAP1/ NRF2 are not universally selected for across cancers and instead appear to interact with particular tumor driver mutations and tissues of origin. Here, we highlight the relationship between the KEAP1/NRF2 signaling axis and tumor biology with a focus on genetic mutation, metabolism, immune regulation, and treatment implications and opportunities. Understanding the dysregulation of KEAP1 and NRF2 provides not only insight into a commonly mutated tumor suppressor pathway but also a window into the factors dictating the development and evolution of many cancers.
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Affiliation(s)
- Warren L. Wu
- Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
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26
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Dai X, Yan X, Wintergerst KA, Cai L, Keller BB, Tan Y. Nrf2: Redox and Metabolic Regulator of Stem Cell State and Function. Trends Mol Med 2020; 26:185-200. [PMID: 31679988 DOI: 10.1016/j.molmed.2019.09.007] [Citation(s) in RCA: 136] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 09/09/2019] [Accepted: 09/17/2019] [Indexed: 02/08/2023]
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) is ubiquitously expressed in most eukaryotic cells and functions to induce a broad range of cellular defenses against exogenous and endogenous stresses, including oxidants, xenobiotics, and excessive nutrient/metabolite supply. Because the production and fate of stem cells are often modulated by cellular redox and metabolic homeostasis, important roles of Nrf2 have emerged in the regulation of stem cell quiescence, survival, self-renewal, proliferation, senescence, and differentiation. In a rapidly advancing field, this review summarizes Nrf2 signaling in the context of stem cell state and function and provides a rationale for Nrf2 as a therapeutic target in stem cell-based regenerative medicine.
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Affiliation(s)
- Xiaozhen Dai
- School of Biosciences and Technology, Chengdu Medical College, Chengdu, Sichuan, China
| | - Xiaoqing Yan
- Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Kupper A Wintergerst
- Division of Endocrinology, Department of Pediatrics, University of Louisville, Louisville, KY, USA; Wendy Novak Diabetes Center, Louisville, KY, USA; Pediatric Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY, USA
| | - Lu Cai
- Wendy Novak Diabetes Center, Louisville, KY, USA; Pediatric Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA
| | - Bradley B Keller
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA; Kosair Charities Pediatric Heart Research Program, Cardiovascular Innovation Institute, University of Louisville, Louisville, KY, USA.
| | - Yi Tan
- Wendy Novak Diabetes Center, Louisville, KY, USA; Pediatric Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA.
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27
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Al Ageeli E. Alterations of Mitochondria and Related Metabolic Pathways in Leukemia: A Narrative Review. SAUDI JOURNAL OF MEDICINE & MEDICAL SCIENCES 2019; 8:3-11. [PMID: 31929772 PMCID: PMC6945320 DOI: 10.4103/sjmms.sjmms_112_18] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 02/12/2019] [Accepted: 07/21/2019] [Indexed: 12/14/2022]
Abstract
Dysregulation of mitochondrial function often precedes malignant transformation of hematopoietic stem cells (HSCs). Mitochondria have a direct role in the maintenance of HSC functions. For example, D-2-hydroxyglutarate, generated due to the activity of mutated mitochondrial isocitrate dehydrogenase (IDH), has been implicated in the pathogenesis of leukemia. Furthermore, disturbances in the fatty acid breakdown and pyruvate oxidation are often seen in leukemic cells. These and other abnormalities expedite leukemogenesis and chemoresistance of leukemic cells. However, it needs to be elucidated whether these aberrations are the result or cause of leukemogenesis. Accordingly, for this review, a search was carried out in PubMed and Google Scholar databases until June 2019 to assess the relationship between metabolic pathways in altered mitochondria and leukemia development. In the present review, an overview of mitochondria-related mechanisms and their abnormalities in leukemia is presented, with mitochondrial pathways and factors, such as mitophagy, intermediary metabolism enzymes, oncometabolites and reactive oxygen species' generation, discussed as potential diagnostic and therapeutic targets in leukemia.
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Affiliation(s)
- Essam Al Ageeli
- Department of Medical Biochemistry (Medical Genetics), Faculty of Medicine, Jazan University, Jazan, Saudi Arabia
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28
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Wu S, Lu H, Bai Y. Nrf2 in cancers: A double-edged sword. Cancer Med 2019; 8:2252-2267. [PMID: 30929309 PMCID: PMC6536957 DOI: 10.1002/cam4.2101] [Citation(s) in RCA: 332] [Impact Index Per Article: 55.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 02/21/2019] [Accepted: 02/26/2019] [Indexed: 12/11/2022] Open
Abstract
The Nrf2/Keap1 pathway is an important signaling cascade responsible for the resistance of oxidative damage induced by exogenous chemicals. It maintains the redox homeostasis, exerts anti-inflammation and anticancer activity by regulating its multiple downstream cytoprotective genes, thereby plays a vital role in cell survival. Interestingly, in recent years, accumulating evidence suggests that Nrf2 has a contradictory role in cancers. Aberrant activation of Nrf2 is associated with poor prognosis. The constitutive activation of Nrf2 in various cancers induces pro-survival genes and promotes cancer cell proliferation by metabolic reprogramming, repression of cancer cell apoptosis, and enhancement of self-renewal capacity of cancer stem cells. More importantly, Nrf2 is proved to contribute to the chemoresistance and radioresistance of cancer cells as well as inflammation-induced carcinogenesis. A number of Nrf2 inhibitors discovered for cancer treatment were reviewed in this report. These provide a new strategy that targeting Nrf2 could be a promising therapeutic approach against cancer. This review aims to summarize the dual effects of Nrf2 in cancer, revealing its function both in cancer prevention and inhibition, to further discover novel anticancer treatment.
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Affiliation(s)
- Shijia Wu
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hong Lu
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yongheng Bai
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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29
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Abstract
SIGNIFICANCE Iron and oxygen are intimately linked: iron is an essential nutrient utilized as a cofactor in enzymes for oxygen transport, oxidative phosphorylation, and metabolite oxidation. However, excess labile iron facilitates the formation of oxygen-derived free radicals capable of damaging biomolecules. Therefore, biological utilization of iron is a tightly regulated process. The nuclear factor (erythroid-derived 2)-like 2 (NRF2) transcription factor, which can respond to oxidative and electrophilic stress, regulates several genes involved in iron metabolism. Recent Advances: The bulk of NRF2 transcription factor research has focused on its roles in detoxification and cancer prevention. Recent works have identified that several genes involved in heme synthesis, hemoglobin catabolism, iron storage, and iron export are under the control of NRF2. Constitutive NRF2 activation and subsequent deregulation of iron metabolism have been implicated in cancer development: NRF2-mediated upregulation of the iron storage protein ferritin or heme oxygenase 1 can lead to enhanced proliferation and therapy resistance. Of note, NRF2 activation and alterations to iron signaling in cancers may hinder efforts to induce the iron-dependent cell death process known as ferroptosis. CRITICAL ISSUES Despite growing recognition of NRF2 as a modulator of iron signaling, exactly how iron metabolism is altered due to NRF2 activation in normal physiology and in pathologic conditions remains imprecise; moreover, the roles of NRF2-mediated iron signaling changes in disease progression are only beginning to be uncovered. FUTURE DIRECTIONS Further studies are necessary to connect NRF2 activation with physiological and pathological changes to iron signaling and oxidative stress. Antioxid. Redox Signal. 00, 000-000.
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Affiliation(s)
- Michael John Kerins
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona , Tucson, Arizona
| | - Aikseng Ooi
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona , Tucson, Arizona
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30
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The effects of Nrf2 knockout on regulation of benzene-induced mouse hematotoxicity. Toxicol Appl Pharmacol 2018; 358:56-67. [DOI: 10.1016/j.taap.2018.09.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 09/02/2018] [Accepted: 09/04/2018] [Indexed: 01/29/2023]
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31
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Ohl K, Fragoulis A, Klemm P, Baumeister J, Klock W, Verjans E, Böll S, Möllmann J, Lehrke M, Costa I, Denecke B, Schippers A, Roth J, Wagner N, Wruck C, Tenbrock K. Nrf2 Is a Central Regulator of Metabolic Reprogramming of Myeloid-Derived Suppressor Cells in Steady State and Sepsis. Front Immunol 2018; 9:1552. [PMID: 30034396 PMCID: PMC6043652 DOI: 10.3389/fimmu.2018.01552] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Accepted: 06/22/2018] [Indexed: 12/18/2022] Open
Abstract
Arising in inflammatory conditions, myeloid-derived suppressor cells (MDSCs) are constantly confronted with intracellular and extracellular reactive oxygen species molecules and oxidative stress. Generating mice with a constitutive activation of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) we show a pivotal role of the antioxidant stress defense for development of these immune-modulatory cells. These mice are characterized by a massive increase of splenic CD11b+Gr-1+ cells, which exhibit typical suppressive characteristics of MDSCs. Whole transcriptome analysis revealed Nrf2-dependent activation of cell cycle and metabolic pathways, which resemble pathways in CD11b+Gr-1+ MDSCs expanded by in vivo LPS exposure. Constitutive Nrf2 activation thereby regulates activation and balance between glycolysis and mitochondrial metabolism and hence expansion of highly suppressive MDSCs, which mediate protection in LPS-induced sepsis. Our study establishes Nrf2 as key regulator of MDSCs and acquired tolerance against LPS-induced sepsis.
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Affiliation(s)
- Kim Ohl
- Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany
| | - Athanassios Fragoulis
- Department of Anatomy and Cell Biology, Medical Faculty, RWTH Aachen, Aachen, Germany.,Department of General Visceral and Transplantation Surgery, Molecular Tumor Biology, Medical Faculty, RWTH Aachen, Aachen, Germany
| | - Patricia Klemm
- Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany
| | - Julian Baumeister
- Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany
| | - Wiebke Klock
- Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany
| | - Eva Verjans
- Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany.,Institute of Pharmacology and Toxicology, RWTH Aachen, Aachen, Germany
| | - Svenja Böll
- Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany.,Institute of Pharmacology and Toxicology, RWTH Aachen, Aachen, Germany
| | - Julia Möllmann
- Department of Medicine I, Medical Faculty, RWTH Aachen, Aachen, Germany
| | - Michael Lehrke
- Department of Medicine I, Medical Faculty, RWTH Aachen, Aachen, Germany
| | - Ivan Costa
- Interdisciplinary Centre for Clinical Research (IZKF) Aachen, Medical Faculty, RWTH Aachen, Aachen, Germany
| | - Bernd Denecke
- Interdisciplinary Centre for Clinical Research (IZKF) Aachen, Medical Faculty, RWTH Aachen, Aachen, Germany
| | - Angela Schippers
- Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany
| | - Johannes Roth
- Institute of Immunology, University of Münster, Münster, Germany
| | - Norbert Wagner
- Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany
| | - Christoph Wruck
- Department of Anatomy and Cell Biology, Medical Faculty, RWTH Aachen, Aachen, Germany
| | - Klaus Tenbrock
- Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany
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Abstract
Stem cell aging is a process in which stem cells progressively lose their ability to self-renew or differentiate, succumb to senescence or apoptosis, and eventually become functionally depleted. Unresolved oxidative stress and concomitant oxidative damages of cellular macromolecules including nucleic acids, proteins, lipids, and carbohydrates have been recognized to contribute to stem cell aging. Excessive production of reactive oxygen species and insufficient cellular antioxidant reserves compromise cell repair and metabolic homeostasis, which serves as a mechanistic switch for a variety of aging-related pathways. Understanding the molecular trigger, regulation, and outcomes of those signaling networks is critical for developing novel therapies for aging-related diseases by targeting stem cell aging. Here we explore the key features of stem cell aging biology, with an emphasis on the roles of oxidative stress in the aging process at the molecular level. As a concept of cytoprotection of stem cells in transplantation, we also discuss how systematic enhancement of endogenous antioxidant capacity before or during graft into tissues can potentially raise the efficacy of clinical therapy. Finally, future directions for elucidating the control of oxidative stress and developing preventive/curative strategies against stem cell aging are discussed.
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Affiliation(s)
- Feng Chen
- 1 State Key Discipline of Infectious Diseases and Chemical Biology Laboratory for Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Yingxia Liu
- 1 State Key Discipline of Infectious Diseases and Chemical Biology Laboratory for Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Nai-Kei Wong
- 1 State Key Discipline of Infectious Diseases and Chemical Biology Laboratory for Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Jia Xiao
- 1 State Key Discipline of Infectious Diseases and Chemical Biology Laboratory for Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China.,2 Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China
| | - Kwok-Fai So
- 3 GMH Institute of CNS Regeneration, Guangdong Medical Key Laboratory of Brain Function and Diseases, Jinan University, Guangzhou, China
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Hamada S, Shimosegawa T, Taguchi K, Nabeshima T, Yamamoto M, Masamune A. Simultaneous K-ras activation and Keap1 deletion cause atrophy of pancreatic parenchyma. Am J Physiol Gastrointest Liver Physiol 2018; 314:G65-G74. [PMID: 28971839 DOI: 10.1152/ajpgi.00228.2017] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) system has a wide variety of effects in addition to the oxidative stress response, such as growth promotion and chemoresistance of cancer cells. Nrf2 is constitutively activated in most cancer cells. However, the activation of Nrf2 together with oncogenic mutations does not always result in cancer promotion. K-rasLSL-G12D/+:: p53LSL-R172H/+:: Pdx-1-Cre (KPC) mice are an established model of pancreatic cancer that specifically express mutants of both K-ras and p53 in the pancreas by using Pdx-1-Cre. We here generated Pdx-1-Cre::K-rasLSL-G12D/+:: Keap1fl/fl (KC::Keap1) and KPC:: Keap1fl/fl (KPC::Keap1) mice in which Nrf2 is constitutively activated by Keap1 deletion. KC::Keap1 and KPC::Keap1 mice started to die or showed obvious weakness at approximately around 40 days after birth. Histological examination revealed that KC::Keap1 and KPC::Keap1 mice did not develop pancreatic cancer but, instead, progressive atrophy of the pancreatic parenchyma. In these mice, amylase-positive acinar cells as well as insulin- and glucagon-positive islet cells were decreased and surrounded by fibrotic tissues. KC::Keap1 and KPC::Keap1 mice presented lower body weight and glucose levels than C::Keap1 mice, presumably resulting from pancreatic exocrine insufficiency. Histological changes were not obvious in C::Keap1 and PC::Keap1 mice. The presence of the p53 mutation did not affect the phenotypes in KC::Keap1 mice. Heterologous or homologous Nrf2 deletion ( Nrf2+/- or Nrf2-/-) rescued the pancreatic phenotypes, weight loss, and hypoglycemia in KC::Keap1 mice, suggesting that Nrf2 is a major downstream target of Keap1. In conclusion, simultaneous K-ras activation and Keap1 deletion caused progressive atrophy of the pancreatic parenchyma in mice. NEW & NOTEWORTHY Aberrant activation of the Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) system usually promotes carcinogenesis, and we assumed that simultaneous activation of K-ras and Nrf2 might promote pancreatic carcinogenesis. Conditional expression of mutant K-ras and Keap1 deletion did not result in pancreatic cancer development. Instead, these mice developed progressive loss of pancreatic parenchyma, accompanied by body weight loss and hypoglycemia, presumably because of pancreatic exocrine insufficiency. Nrf2 activation by Keap1 deletion concomitant with K-ras activation cause pancreatic atrophy.
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Affiliation(s)
- Shin Hamada
- Division of Gastroenterology, Tohoku University Graduate School of Medicine , Sendai , Japan
| | - Tooru Shimosegawa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine , Sendai , Japan
| | - Keiko Taguchi
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine , Sendai , Japan
| | - Tatsuhide Nabeshima
- Division of Gastroenterology, Tohoku University Graduate School of Medicine , Sendai , Japan
| | - Masayuki Yamamoto
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine , Sendai , Japan
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine , Sendai , Japan
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Han X, Zhang J, Xue X, Zhao Y, Lu L, Cui M, Miao W, Fan S. Theaflavin ameliorates ionizing radiation-induced hematopoietic injury via the NRF2 pathway. Free Radic Biol Med 2017; 113:59-70. [PMID: 28939421 DOI: 10.1016/j.freeradbiomed.2017.09.014] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 09/08/2017] [Accepted: 09/17/2017] [Indexed: 12/24/2022]
Abstract
It has been well established that reactive oxygen species (ROS) play a critical role in ionizing radiation (IR)-induced hematopoietic injury. Theaflavin (TF), a polyphenolic compound from black tea, has been implicated in the regulation of endogenous cellular antioxidant systems. However, it remains unclear whether TF could ameliorate IR-induced hematopoietic injury, particularly the hematopoietic stem cell (HSC) injury. In this study, we explored the potential role of TF in IR-induced HSC injury and the underlying mechanism in a total body irradiation (TBI) mouse model. Our results showed that TF improved survival of irradiated wild-type mice and ameliorated TBI-induced hematopoietic injury by attenuating myelosuppression and myeloid skewing, increasing HSC frequency, and promoting reconstitution of irradiated HSCs. Furthermore, TF inhibited TBI-induced HSC senescence. These effects of TF were associated with a decline in ROS levels and DNA damage in irradiated HSCs. TF reduced oxidative stress mainly by up-regulating nuclear factor erythroid 2-related factor 2 (NRF2) and its downstream targets in irradiated Lineage-c-kit+ positive cells. However, TF failed to improve the survival, to increase HSC frequency and to reduce ROS levels of HSCs in irradiated Nrf2-/- mice. These findings suggest that TF ameliorates IR-induced HSC injury via the NRF2 pathway. Therefore, TF has the potential to be used as a radioprotective agent to ameliorate IR-induced hematopoietic injury.
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Affiliation(s)
- Xiaodan Han
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin 300192, China.
| | - Junling Zhang
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin 300192, China.
| | - Xiaolei Xue
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin 300192, China
| | - Yu Zhao
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin 300192, China
| | - Lu Lu
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin 300192, China
| | - Ming Cui
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin 300192, China
| | - Weimin Miao
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300041,China
| | - Saijun Fan
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin 300192, China.
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NRF2 Activation Impairs Quiescence and Bone Marrow Reconstitution Capacity of Hematopoietic Stem Cells. Mol Cell Biol 2017; 37:MCB.00086-17. [PMID: 28674188 DOI: 10.1128/mcb.00086-17] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Accepted: 06/27/2017] [Indexed: 12/12/2022] Open
Abstract
Tissue stem cells are maintained in quiescence under physiological conditions but proliferate and differentiate to replenish mature cells under stressed conditions. The KEAP1-NRF2 system plays an essential role in stress response and cytoprotection against redox disturbance. To clarify the role of the KEAP1-NRF2 system in tissue stem cells, we focused on hematopoiesis in this study and used Keap1-deficient mice to examine the effects of persistent activation of NRF2 on long-term hematopoietic stem cells (LT-HSCs). We found that persistent activation of NRF2 due to Keap1 deficiency did not change the number of LT-HSCs but reduced their quiescence in steady-state hematopoiesis. During hematopoietic regeneration after bone marrow (BM) transplantation, persistent activation of NRF2 reduced the BM reconstitution capacity of LT-HSCs, suggesting that NRF2 reduces the quiescence of LT-HSCs and promotes their differentiation, leading to eventual exhaustion. Transient activation of NRF2 by an electrophilic reagent also promotes the entry of LT-HSCs into the cell cycle. Taken together, our findings show that NRF2 drives the cell cycle entry and differentiation of LT-HSCs at the expense of their quiescence and maintenance, an effect that appears to be beneficial for prompt recovery from blood loss. We propose that the appropriate control of NRF2 activity by KEAP1 is essential for maintaining HSCs and guarantees their stress-induced regenerative response.
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36
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Wu X, Yang B, Hu Y, Sun R, Wang H, Fu J, Hou Y, Pi J, Xu Y. NRF2 Is a Potential Modulator of Hyperresistance to Arsenic Toxicity in Stem-Like Keratinocytes. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:7417694. [PMID: 29081891 PMCID: PMC5610874 DOI: 10.1155/2017/7417694] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Revised: 07/07/2017] [Accepted: 08/01/2017] [Indexed: 12/26/2022]
Abstract
Arsenic is a well-known human carcinogen. Stem cells are indicated to be involved in arsenic carcinogenesis and have a survival selection advantage during arsenic exposure with underlying mechanisms undefined. In the present study, we demonstrated that CD34high-enriched cells derived from HaCaT human keratinocytes showed stem-like phenotypes. These cells were more resistant to arsenic toxicity and had higher arsenic efflux ability than their mature compartments. The master transcription factor in antioxidant defense, nuclear factor erythroid 2-related factor 2 (NRF2) with its downstream genes, was highly expressed in CD34high-enriched cells. Stable knockdown of NRF2 abolished the hyperresistance to arsenic toxicity and holoclone-forming ability of CD34high-enriched cells. Our results suggest that skin epithelial stem/progenitor cells are more resistant to arsenic toxicity than mature cells, which is associated with the high innate expression of NRF2 in skin epithelial stem/progenitor cells.
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Affiliation(s)
- Xiafang Wu
- Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, Liaoning, China
| | - Bei Yang
- Department of Histology and Embryology, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning, China
| | - Yuxin Hu
- Experimental Teaching Center, School of Public Health, China Medical University, Shenyang, Liaoning, China
| | - Ru Sun
- Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, Liaoning, China
| | - Huihui Wang
- Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, Liaoning, China
| | - Jingqi Fu
- Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, Liaoning, China
| | - Yongyong Hou
- Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, Liaoning, China
| | - Jingbo Pi
- Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, Liaoning, China
- Experimental Teaching Center, School of Public Health, China Medical University, Shenyang, Liaoning, China
| | - Yuanyuan Xu
- Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, Liaoning, China
- Experimental Teaching Center, School of Public Health, China Medical University, Shenyang, Liaoning, China
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37
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Suzuki T, Yamamoto M. Stress-sensing mechanisms and the physiological roles of the Keap1-Nrf2 system during cellular stress. J Biol Chem 2017; 292:16817-16824. [PMID: 28842501 DOI: 10.1074/jbc.r117.800169] [Citation(s) in RCA: 321] [Impact Index Per Article: 40.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Transcription factor Nrf2 (NF-E2-related factor 2) is a master regulator of cellular responses against environmental stresses. Nrf2 induces the expression of detoxification and antioxidant enzymes and suppresses the induction of pro-inflammatory cytokine genes. Keap1 (Kelch-like ECH-associated protein 1) is an adaptor subunit of Cullin 3-based E3 ubiquitin ligase. Keap1 regulates the activity of Nrf2 and acts as a sensor for oxidative and electrophilic stresses. In this review, we discuss the molecular mechanisms by which the Keap1-Nrf2 system senses and regulates the cellular response to environmental stresses. In particular, we focus on the multiple stress-sensing mechanisms of Keap1 and novel regulatory functions of Nrf2.
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Affiliation(s)
- Takafumi Suzuki
- From the Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Masayuki Yamamoto
- From the Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
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38
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Suzuki T, Seki S, Hiramoto K, Naganuma E, Kobayashi EH, Yamaoka A, Baird L, Takahashi N, Sato H, Yamamoto M. Hyperactivation of Nrf2 in early tubular development induces nephrogenic diabetes insipidus. Nat Commun 2017; 8:14577. [PMID: 28233855 PMCID: PMC5333130 DOI: 10.1038/ncomms14577] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 01/13/2017] [Indexed: 12/27/2022] Open
Abstract
NF-E2-related factor-2 (Nrf2) regulates cellular responses to oxidative and electrophilic stress. Loss of Keap1 increases Nrf2 protein levels, and Keap1-null mice die of oesophageal hyperkeratosis because of Nrf2 hyperactivation. Here we show that deletion of oesophageal Nrf2 in Keap1-null mice allows survival until adulthood, but the animals develop polyuria with low osmolality and bilateral hydronephrosis. This phenotype is caused by defects in water reabsorption that are the result of reduced aquaporin 2 levels in the kidney. Renal tubular deletion of Keap1 promotes nephrogenic diabetes insipidus features, confirming that Nrf2 activation in developing tubular cells causes a water reabsorption defect. These findings suggest that Nrf2 activity should be tightly controlled during development in order to maintain renal homeostasis. In addition, tissue-specific ablation of Nrf2 in Keap1-null mice might create useful animal models to uncover novel physiological functions of Nrf2.
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Affiliation(s)
- Takafumi Suzuki
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Shiori Seki
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Keiichiro Hiramoto
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Eriko Naganuma
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Eri H Kobayashi
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Ayaka Yamaoka
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Liam Baird
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Nobuyuki Takahashi
- Department of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences Sendai, 980-8578, Japan
| | - Hiroshi Sato
- Department of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences Sendai, 980-8578, Japan
| | - Masayuki Yamamoto
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.,Tohoku Medical-Megabank Organization, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
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Kubben N, Zhang W, Wang L, Voss TC, Yang J, Qu J, Liu GH, Misteli T. Repression of the Antioxidant NRF2 Pathway in Premature Aging. Cell 2016; 165:1361-1374. [PMID: 27259148 DOI: 10.1016/j.cell.2016.05.017] [Citation(s) in RCA: 374] [Impact Index Per Article: 41.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 02/04/2016] [Accepted: 04/25/2016] [Indexed: 12/23/2022]
Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is a rare, invariably fatal premature aging disorder. The disease is caused by constitutive production of progerin, a mutant form of the nuclear architectural protein lamin A, leading, through unknown mechanisms, to diverse morphological, epigenetic, and genomic damage and to mesenchymal stem cell (MSC) attrition in vivo. Using a high-throughput siRNA screen, we identify the NRF2 antioxidant pathway as a driver mechanism in HGPS. Progerin sequesters NRF2 and thereby causes its subnuclear mislocalization, resulting in impaired NRF2 transcriptional activity and consequently increased chronic oxidative stress. Suppressed NRF2 activity or increased oxidative stress is sufficient to recapitulate HGPS aging defects, whereas reactivation of NRF2 activity in HGPS patient cells reverses progerin-associated nuclear aging defects and restores in vivo viability of MSCs in an animal model. These findings identify repression of the NRF2-mediated antioxidative response as a key contributor to the premature aging phenotype.
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Affiliation(s)
- Nard Kubben
- National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Weiqi Zhang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; FSU-CAS Innovation Institute, Foshan University, Foshan, Guangdong 528000, China
| | - Lixia Wang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ty C Voss
- High-Throughput Imaging Facility, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jiping Yang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jing Qu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Guang-Hui Liu
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; FSU-CAS Innovation Institute, Foshan University, Foshan, Guangdong 528000, China; Beijing Institute for Brain Disorders, Beijing 100069, China; University of Chinese Academy of Sciences, Beijing 100049, China.
| | - Tom Misteli
- National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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40
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Intracellular cholesterol transport proteins: roles in health and disease. Clin Sci (Lond) 2016; 130:1843-59. [DOI: 10.1042/cs20160339] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 07/12/2016] [Indexed: 12/13/2022]
Abstract
Effective cholesterol homoeostasis is essential in maintaining cellular function, and this is achieved by a network of lipid-responsive nuclear transcription factors, and enzymes, receptors and transporters subject to post-transcriptional and post-translational regulation, whereas loss of these elegant, tightly regulated homoeostatic responses is integral to disease pathologies. Recent data suggest that sterol-binding sensors, exchangers and transporters contribute to regulation of cellular cholesterol homoeostasis and that genetic overexpression or deletion, or mutations, in a number of these proteins are linked with diseases, including atherosclerosis, dyslipidaemia, diabetes, congenital lipoid adrenal hyperplasia, cancer, autosomal dominant hearing loss and male infertility. This review focuses on current evidence exploring the function of members of the ‘START’ (steroidogenic acute regulatory protein-related lipid transfer) and ‘ORP’ (oxysterol-binding protein-related proteins) families of sterol-binding proteins in sterol homoeostasis in eukaryotic cells, and the evidence that they represent valid therapeutic targets to alleviate human disease.
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41
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Activation of Nrf2-ARE signaling mitigates cyclophosphamide-induced myelosuppression. Toxicol Lett 2016; 262:17-26. [PMID: 27633142 DOI: 10.1016/j.toxlet.2016.09.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Revised: 09/06/2016] [Accepted: 09/11/2016] [Indexed: 11/21/2022]
Abstract
Myelosuppression is the most common dose-limiting adverse effect of chemotherapies. In the present study, we investigated the involvement of nuclear erythroid 2-related factor 2 (Nrf2) in cyclophosphamide-induced myelosuppression in mice, and evaluated the potential of activating Nrf2 signaling as a preventive strategy. The whole blood from Nrf2-/- mice exhibited decreased antioxidant capacities, while the bone marrow cells, peripheral blood mononuclear cells and granulocytes from Nrf2-/- mice were more susceptible to acrolein-induced cytotoxicity than those from wild type mice. Single dosage of cyclophosphamide induced significantly severer acute myelosuppression in Nrf2-/- mice than in wild type mice. Furthermore, Nrf2-/- mice exhibited greater loss of peripheral blood nucleated cells and recovered slower from myelosuppression nadir upon multiple consecutive dosages of cyclophosphamide than wild type mice did. This was accompanied with decreased antioxidant and detoxifying gene expressions and impaired colony formation ability of Nrf2-/- bone marrow cells. More importantly, activation of Nrf2 signaling by CDDO-Me significantly alleviated cyclophosphamide-induced myelosuppression, while this alleviation was diminished in Nrf2-/- mice. In conclusion, the present study shows that Nrf2 plays a protective role in cyclophosphamide-induced myelosuppression and activation of Nrf2 is a promising strategy to prevent or treat chemotherapy-induced myelosuppression.
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Chen X, Yan L, Guo Z, Chen Z, Chen Y, Li M, Huang C, Zhang X, Chen L. Adipose-derived mesenchymal stem cells promote the survival of fat grafts via crosstalk between the Nrf2 and TLR4 pathways. Cell Death Dis 2016; 7:e2369. [PMID: 27607584 PMCID: PMC5059864 DOI: 10.1038/cddis.2016.261] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Revised: 07/12/2016] [Accepted: 07/25/2016] [Indexed: 12/13/2022]
Abstract
Autologous fat grafting is an effective reconstructive surgery technique; however, its success is limited by inconsistent graft retention and an environment characterized by high oxidative stress and inflammation. Adipose-derived stem cells (ADSCs) increase the survival of fat grafts, although the underlying mechanisms remain unclear. Here, TLR4−/− and Nrf2−/− mice were used to explore the effects of oxidative stress and inflammation on the viability and function of ADSCs in vitro and in vivo. Enrichment of fat grafts with ADSCs inhibited inflammatory cytokine production, enhanced growth factor levels, increased fat graft survival, downregulated NADPH oxidase (NOX)1 and 4 expression, increased vascularization and reduced ROS production in a manner dependent on toll-like receptor (TLR)-4 and nuclear factor erythroid 2-related factor 2 (Nrf2) expression. Immunohistochemical analysis showed that exposure to hypoxia enhanced ADSC growth and promoted the differentiation of ADSCs into vascular endothelial cells. Hypoxia-induced inflammatory cytokine, growth factor and NOX1/4 upregulation, as well as increased ROS production and apoptosis in ADSCs were dependent on TLR4 and Nrf2, which also modulated the effect of ADSCs on promoting endothelial progenitor cell migration and angiogenesis. Western blot analyses showed that the effects of hypoxia on ADSCs were regulated by crosstalk between Nrf2 antioxidant responses and NF-κB- and TLR4-mediated inflammatory responses. Taken together, our results indicate that ADSCs can increase the survival of fat transplants through the modulation of inflammatory and oxidative responses via Nrf2 and TLR4, suggesting potential strategies to improve the use of ADSCs for cell therapy.
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Affiliation(s)
- Xiaosong Chen
- Department of Plastic Surgery, The Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian 350001, China.,Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, Fujian 350000, China
| | - Liu Yan
- Department of Plastic Surgery, The Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian 350001, China.,Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, Fujian 350000, China
| | - Zhihui Guo
- Department of Plastic Surgery, The Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian 350001, China
| | - Zhaohong Chen
- Department of Burns Surgery, The Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian 350001, China
| | - Ying Chen
- Department of Plastic Surgery, The Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian 350001, China.,Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, Fujian 350000, China
| | - Ming Li
- Department of Plastic Surgery, The Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian 350001, China
| | - Chushan Huang
- Department of Plastic Surgery, The Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian 350001, China
| | - Xiaoping Zhang
- Institution of Interventional and Vascular surgery, Tongji Univerity, No 301 Middle Yan Chang Road, Shanghai 200072, China
| | - Liangwan Chen
- Department of Cardiac Surgery, The Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian 350001, China
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Small Maf proteins (MafF, MafG, MafK): History, structure and function. Gene 2016; 586:197-205. [PMID: 27058431 DOI: 10.1016/j.gene.2016.03.058] [Citation(s) in RCA: 181] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Revised: 03/11/2016] [Accepted: 03/30/2016] [Indexed: 12/12/2022]
Abstract
The small Maf proteins (sMafs) are basic region leucine zipper (bZIP)-type transcription factors. The basic region of the Maf family is unique among the bZIP factors, and it contributes to the distinct DNA-binding mode of this class of proteins. MafF, MafG and MafK are the three vertebrate sMafs, and no functional differences have been observed among them in terms of their bZIP structures. sMafs form homodimers by themselves, and they form heterodimers with cap 'n' collar (CNC) proteins (p45 NF-E2, Nrf1, Nrf2, and Nrf3) and also with Bach proteins (Bach1 and Bach2). Because CNC and Bach proteins cannot bind to DNA as monomers, sMafs are indispensable partners that are required by CNC and Bach proteins to exert their functions. sMafs lack the transcriptional activation domain; hence, their homodimers act as transcriptional repressors. In contrast, sMafs participate in transcriptional activation or repression depending on their heterodimeric partner molecules and context. Mouse genetic analyses have revealed that various biological pathways are under the regulation of CNC-sMaf heterodimers. In this review, we summarize the history and current progress of sMaf studies in relation to their partners.
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Redox Modulating NRF2: A Potential Mediator of Cancer Stem Cell Resistance. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2016:2428153. [PMID: 26682001 PMCID: PMC4670665 DOI: 10.1155/2016/2428153] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Accepted: 07/27/2015] [Indexed: 12/17/2022]
Abstract
Tumors contain a distinct small subpopulation of cells that possess stem cell-like characteristics. These cells have been called cancer stem cells (CSCs) and are thought to be responsible for anticancer drug resistance and tumor relapse after therapy. Emerging evidence indicates that CSCs share many properties, such as self-renewal and quiescence, with normal stem cells. In particular, CSCs and normal stem cells retain low levels of reactive oxygen species (ROS), which can contribute to stem cell maintenance and resistance to stressful tumor environments. Current literatures demonstrate that the activation of ataxia telangiectasia mutated (ATM) and forkhead box O3 (FoxO3) is associated with the maintenance of low ROS levels in normal stem cells such as hematopoietic stem cells. However, the importance of ROS signaling in CSC biology remains poorly understood. Recent studies demonstrate that nuclear factor-erythroid 2-related factor 2 (NRF2), a master regulator of the cellular antioxidant defense system, is involved in the maintenance of quiescence, survival, and stress resistance of CSCs. Here, we review the recent findings on the roles of NRF2 in maintenance of the redox state and multidrug resistance in CSCs, focusing on how NRF2-mediated ROS modulation influences the growth and resistance of CSCs.
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Wakabayashi N, Chartoumpekis DV, Kensler TW. Crosstalk between Nrf2 and Notch signaling. Free Radic Biol Med 2015; 88:158-167. [PMID: 26003520 PMCID: PMC4628857 DOI: 10.1016/j.freeradbiomed.2015.05.017] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Revised: 05/08/2015] [Accepted: 05/12/2015] [Indexed: 12/17/2022]
Abstract
The transcription factor Nrf2 (nuclear factor, erythroid derived 2, like 2) belongs to the CNC-bZip protein family, forming a transcriptosome with its direct heterodimer partner, sMaf, and co-factors such as CBP/p300. Nrf2 binds to one or more AREs (antioxidant response elements) that are located in the gene regulatory regions of the hundreds of Nrf2 target genes. The AREs are key enhancers that are activated in response to endogenous or exogenous stresses to maintain cellular and tissue homeostasis. Data emanating from gene expression microarray analyses comparing Nrf2-disrupted and wild-type mouse embryonic fibroblasts (MEF) showed that expression of Notch1 and Notch-signaling-related genes were decreased in Nrf2-disrupted cells. This observation triggered our research on Nrf2-Notch crosstalk. A functional ARE has been identified upstream of the Notch1 major transcription start site. Furthermore, an Rbpjκ binding site is conserved on the promoters of Nrf2 among animal species. Notch1 is one of the transmembrane Notch family receptors that drive Notch signaling, together with the Rbpjκ transcription factor. After canonically accepting ligands such as Jags and Deltas, the receptor undergoes cleavage to yield the Notch intracellular domain, which translocates to the nucleus. Recent studies using conditional knockout mice indicate that Notch1 as well as Notch2 plays an important role postnatally in liver development and in maintenance of hepatic function. In this review, we summarize current understanding of the role of reciprocal transcriptional regulation between Nrf2 and Notch in adult liver from studies using Nrf2, Keap1, and Notch1 genetically engineered mice.
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Affiliation(s)
- Nobunao Wakabayashi
- Department of Pharmacology & Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| | - Dionysios V Chartoumpekis
- Department of Pharmacology & Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Thomas W Kensler
- Department of Pharmacology & Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Environmental Health Science, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
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Murakami S, Motohashi H. Roles of Nrf2 in cell proliferation and differentiation. Free Radic Biol Med 2015; 88:168-178. [PMID: 26119783 DOI: 10.1016/j.freeradbiomed.2015.06.030] [Citation(s) in RCA: 183] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Revised: 06/18/2015] [Accepted: 06/22/2015] [Indexed: 02/07/2023]
Abstract
The Keap1-Nrf2 system plays pivotal roles in defense mechanisms by regulating cellular redox homeostasis. Nrf2 is an inducible transcription factor that activates a battery of genes encoding antioxidant proteins and phase II enzymes in response to oxidative stress and electrophilic xenobiotics. The activity of Nrf2 is regulated by Keap1, which promotes the ubiquitination and subsequent degradation of Nrf2 under normal conditions and releases the inhibited Nrf2 activity upon exposure to the stresses. Though an impressive contribution of the Keap1-Nrf2 system to the protection from exogenous and endogenous electrophilic insults has been well established, a line of evidence has suggested that the Keap1-Nrf2 system has various novel functions, particularly in cell proliferation and differentiation. Because the proliferation and differentiation of diverse cell types are often influenced and modulated by the cellular redox balance, Nrf2 has been considered to control these cellular processes by regulating the cellular levels of reactive oxygen species (ROS). In addition, analyses of the genome-wide distribution of Nrf2 have identified new sets of Nrf2 target genes whose products are involved in cell proliferation and differentiation but not necessarily in the regulation of oxidative stress. Considering the most characteristic features of Nrf2 as an inducible transcription factor, a newly emerged concept proposes that the Keap1-Nrf2 system translates environmental stresses into regulatory network signals in cell fate determination. In this review, we introduce the contribution of Nrf2 to lineage-specific differentiation, maintenance and differentiation of stem cells, and proliferation of normal and cancer cells, and we discuss how the response to fluctuating environments modulates cell behavior through the Keap1-Nrf2 system.
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Affiliation(s)
- Shohei Murakami
- Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Hozumi Motohashi
- Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
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Demasi M, Simões V, Bonatto D. Cross-talk between redox regulation and the ubiquitin-proteasome system in mammalian cell differentiation. Biochim Biophys Acta Gen Subj 2014; 1850:1594-606. [PMID: 25450485 DOI: 10.1016/j.bbagen.2014.10.031] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Revised: 10/24/2014] [Accepted: 10/28/2014] [Indexed: 12/15/2022]
Abstract
BACKGROUND Embryogenesis and stem cell differentiation are complex and orchestrated signaling processes. Reactive oxygen species (ROS) act as essential signal transducers in cellular differentiation, as has been shown through recent discoveries. On the other hand, the ubiquitin-proteasome system (UPS) has long been known to play an important role in all cellular regulated processes, including differentiation. SCOPE OF REVIEW In the present review, we focus on findings that highlight the interplay between redox signaling and the UPS regarding cell differentiation. Through systems biology analyses, we highlight major routes during cardiomyocyte differentiation based on redox signaling and UPS modulation. MAJOR CONCLUSION Oxygen availability and redox signaling are fundamental regulators of cell fate upon differentiation. The UPS plays an important role in the maintenance of pluripotency and the triggering of differentiation. GENERAL SIGNIFICANCE Cellular differentiation has been a matter of intense investigation mainly because of its potential therapeutic applications. Understanding regulatory mechanisms underlying cell differentiation is an important issue. Correspondingly, the role of UPS and regulation of redox processes have been emerged as essential factors to control the fate of cells upon differentiation. This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation.
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Affiliation(s)
- Marilene Demasi
- Laboratory of Biochemistry and Biophysics, Instituto Butantan, São Paulo, SP, Brazil.
| | - Vanessa Simões
- Department of Genetics and Evolutive Biology, IB, Universidade de São Paulo, São Paulo, Brazil
| | - Diego Bonatto
- Center of Biotechnology, Universidade Federal do Rio Grande do Sul., Porto Alegre, RS, Brazil.
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Abstract
Keap1-Nrf2 system plays a central role in the stress response. While Keap1 ubiquitinates Nrf2 for degradation under unstressed conditions, this Keap1 activity is abrogated in response to oxidative or electrophilic stresses, leading to Nrf2 stabilization and coordinated activation of cytoprotective genes. We recently found that nuclear accumulation of Nrf2 is significantly increased by simultaneous deletion of Pten and Keap1, resulting in the stronger activation of Nrf2 target genes. To clarify the impact of the cross talk between the Keap1-Nrf2 and Pten-phosphatidylinositide 3-kinase-Akt pathways on the liver pathophysiology, in this study we have conducted closer analysis of liver-specific Pten::Keap1 double-mutant mice (Pten::Keap1-Alb mice). The Pten::Keap1-Alb mice were lethal by 1 month after birth and displayed severe hepatomegaly with abnormal expansion of ductal structures comprising cholangiocytes in a Nrf2-dependent manner. Long-term observation of Pten::Keap1-Alb::Nrf2(+/-) mice revealed that the Nrf2-heterozygous mice survived beyond 1 month but developed polycystic liver fibrosis by 6 months. Gsk3 directing the Keap1-independent degradation of Nrf2 was heavily phosphorylated and consequently inactivated by the double deletion of Pten and Keap1 genes. Thus, liver-specific disruption of Keap1 and Pten augments Nrf2 activity through inactivation of Keap1-dependent and -independent degradation of Nrf2 and establishes the Nrf2-dependent molecular network promoting the hepatomegaly and cholangiocyte expansion.
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