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Rostami A, Palomer X, Pizarro-Delgado J, Peña L, Zamora M, Montori-Grau M, Barroso E, Valenzuela-Alcaraz B, Crispi F, Salvador JM, García R, Hurlé MA, Nistal F, Vázquez-Carrera M. GADD45A suppression contributes to cardiac remodeling by promoting inflammation, fibrosis and hypertrophy. Cell Mol Life Sci 2025; 82:189. [PMID: 40301189 PMCID: PMC12040809 DOI: 10.1007/s00018-025-05704-x] [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: 01/07/2025] [Revised: 04/03/2025] [Accepted: 04/07/2025] [Indexed: 05/01/2025]
Abstract
The growth arrest and DNA damage inducible 45A (GADD45A) is a multifaceted protein associated with stress signaling and cellular injury. Aside its well-established tumor suppressor activity, recent studies point to additional roles for GADD45A, including the regulation of catabolic and anabolic pathways, or the prevention of inflammation, fibrosis, and oxidative stress in some tissues and organs. However, little is known about its function in cardiac disease. In this study, we aimed to evaluate the role of GADD45A in the heart by using mice with constitutive and systemic deletion of Gadd45a, and cardiac cells of human origin. Gadd45a suppression in knockout mice triggered cardiac fibrosis, inflammation, and apoptosis, and these changes correlated with an hyperactivation of the pro-inflammatory and pro-fibrotic transcription factors activator protein-1 (AP-1), nuclear factor-κB (NF-κB), and signal transducer and activator of transcription 3 (STAT3). Deletion of Gadd45a also resulted in substantial cardiac hypertrophy, which negatively impacted cardiac morphology and function in knockout mice. Consistent with this, GADD45A overexpression in human AC16 cardiomyocytes partially prevented the inflammatory and fibrotic responses induced by tumor necrosis factor-α (TNF-α). Overall, data presented in this study highlight an important role for GADD45A in the heart, since it may prevent inflammation, fibrosis, and apoptosis, and, by this means, preserve cardiac function and performance. Since fibrosis and inflammation are crucial in the progression of cardiac hypertrophy and subsequent heart failure, these results suggest that promoting the activity of this protein might be a promising therapeutic strategy to slow down the progression of these deleterious diseases.
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Affiliation(s)
- Adel Rostami
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, 08028, España
- Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, 08028, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, 28029, Spain
- Pediatric Research Institute, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950, Spain
| | - Xavier Palomer
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, 08028, España.
- Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, 08028, Spain.
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, 28029, Spain.
- Pediatric Research Institute, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950, Spain.
| | - Javier Pizarro-Delgado
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, 08028, España
- Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, 08028, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, 28029, Spain
- Pediatric Research Institute, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950, Spain
| | - Lucía Peña
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, 08028, España
- Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, 08028, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, 28029, Spain
- Pediatric Research Institute, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950, Spain
| | - Mònica Zamora
- BCNatal - Fetal Medicine Research Center (Hospital Clínic and Hospital Sant Joan de Déu), University of Barcelona, Barcelona, 08028, Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, 08036, Spain
| | - Marta Montori-Grau
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, 08028, España
- Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, 08028, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, 28029, Spain
- Pediatric Research Institute, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950, Spain
| | - Emma Barroso
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, 08028, España
- Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, 08028, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, 28029, Spain
- Pediatric Research Institute, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950, Spain
| | - Brenda Valenzuela-Alcaraz
- BCNatal - Fetal Medicine Research Center (Hospital Clínic and Hospital Sant Joan de Déu), University of Barcelona, Barcelona, 08028, Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, 08036, Spain
| | - Fàtima Crispi
- BCNatal - Fetal Medicine Research Center (Hospital Clínic and Hospital Sant Joan de Déu), University of Barcelona, Barcelona, 08028, Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, 08036, Spain
- Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Madrid, 28029, Spain
| | - Jesús M Salvador
- Department of Immunology and Oncology, National Center for Biotechnology/CSIC, Madrid, 28049, Spain
| | - Raquel García
- Departamento de Fisiología y Farmacología, Facultad de Medicina, Universidad de Cantabria, Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - María A Hurlé
- Departamento de Fisiología y Farmacología, Facultad de Medicina, Universidad de Cantabria, Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - Francisco Nistal
- Servicio de Cirugía Cardiovascular, Departamento de Ciencias Médicas y Quirúrgicas, Facultad de Medicina, Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Marqués de Valdecilla (IDIVAL), Universidad de Cantabria, Santander, Spain
- Spanish Biomedical Research Center in Cardiovascular Diseases (CIBERCV), Instituto de Salud Carlos III, Santander, Spain
| | - Manuel Vázquez-Carrera
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, 08028, España.
- Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, 08028, Spain.
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, 28029, Spain.
- Pediatric Research Institute, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950, Spain.
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Qi T, Qin H, Yu F, Zhou Z, Chen Y, Liu P, Zeng H, Weng J. XLOC_015548 Mitigates Skeletal Muscle Atrophy via the Gadd45g/MEK/ERK Pathway and Redox Regulation. FRONT BIOSCI-LANDMRK 2025; 30:36233. [PMID: 40302339 DOI: 10.31083/fbl36233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Revised: 03/09/2025] [Accepted: 03/12/2025] [Indexed: 05/02/2025]
Abstract
BACKGROUND Skeletal muscle atrophy is a common musculoskeletal disorder that significantly reduces patient quality of life. Long non-coding RNA (lncRNA) XLOC_015548 has been identified as a pivotal regulator of C2C12 myoblast proliferation and differentiation. However, its role in mitigating denervation-induced muscle atrophy and the underlying mechanisms remain unclear. METHODS We employed lentiviral-mediated stable expression of XLOC_015548 in C2C12 myoblasts and skeletal muscle-specific XLOC_015548-edited mouse models to investigate the function of this lncRNA. Muscle atrophy models were established in vitro by glucocorticoid-induced atrophy with dexamethasone (DEX) and in vivo by sciatic nerve transection-induced denervation. The MEK inhibitor U0126 was used to assess the role of the growth arrest and DNA damage-inducible 45 gamma/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (Gadd45g/MEK/ERK) signaling pathway. RESULTS Overexpression of XLOC_015548 significantly activated the MEK/ERK signaling pathway (p < 0.05) by downregulating Gadd45g expression (p < 0.05) and promoting its cytoplasmic localization, thereby enhancing cell proliferation and myotube formation. Furthermore, XLOC_015548 reduced the level of reactive oxygen species (ROS) (p < 0.01), stabilized the mitochondrial membrane potential, and alleviated DEX-induced oxidative stress. These protective effects were partially reversed by U0126, confirming the involvement of the MEK/ERK pathway. Skeletal muscle-specific overexpression of XLOC_015548 in vivo significantly reduced denervation-induced muscle atrophy (q < 0.05) and increased the muscle fiber cross-sectional area. CONCLUSION XLOC_015548 plays a critical role in promoting myogenic differentiation and protecting against muscle atrophy by regulating Gadd45g expression, activating the MEK/ERK signaling pathway, and reducing oxidative stress. These findings underscore the therapeutic potential of XLOC_015548 in skeletal muscle atrophy, and provide a foundation for lncRNA-based treatment strategies.
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Affiliation(s)
- Tiantian Qi
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, 518036 Shenzhen, Guangdong, China
| | - Haotian Qin
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, 518036 Shenzhen, Guangdong, China
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, 518036 Shenzhen, Guangdong, China
- Shenzhen Key Laboratory of Orthopaedic Diseases and Biomaterials Research, 518036 Shenzhen, Guangdong, China
| | - Fei Yu
- Department of Spine Surgery, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, 518035 Shenzhen, Guangdong, China
| | - Zimeng Zhou
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, 518036 Shenzhen, Guangdong, China
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, 518036 Shenzhen, Guangdong, China
- Shenzhen Key Laboratory of Orthopaedic Diseases and Biomaterials Research, 518036 Shenzhen, Guangdong, China
| | - Yingqi Chen
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, 518036 Shenzhen, Guangdong, China
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, 518036 Shenzhen, Guangdong, China
- Shenzhen Key Laboratory of Orthopaedic Diseases and Biomaterials Research, 518036 Shenzhen, Guangdong, China
| | - Peng Liu
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, 518036 Shenzhen, Guangdong, China
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, 518036 Shenzhen, Guangdong, China
- Shenzhen Key Laboratory of Orthopaedic Diseases and Biomaterials Research, 518036 Shenzhen, Guangdong, China
| | - Hui Zeng
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, 518036 Shenzhen, Guangdong, China
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, 518036 Shenzhen, Guangdong, China
- Shenzhen Key Laboratory of Orthopaedic Diseases and Biomaterials Research, 518036 Shenzhen, Guangdong, China
- Department of Orthopedic Trauma, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, 518035 Shenzhen, Guangdong, China
| | - Jian Weng
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, 518036 Shenzhen, Guangdong, China
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, 518036 Shenzhen, Guangdong, China
- Shenzhen Key Laboratory of Orthopaedic Diseases and Biomaterials Research, 518036 Shenzhen, Guangdong, China
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Liu W, Zhang X, Liu J, Pu L, Ai L, Xu H, Wang G, Wang D, Song X, Zhang Y, Zhang L, Gao J, Cheng X, Wang X, Tong J, Xie X, Dong F, Zhang Y, Zhu P, Chen Z, Wu P, Shi L. An erythroid-biased FOS hi hematopoietic multipotent progenitor subpopulation contributes to adaptation to chronic hypoxia. Cell Stem Cell 2025:S1934-5909(25)00100-6. [PMID: 40220764 DOI: 10.1016/j.stem.2025.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 02/24/2025] [Accepted: 03/18/2025] [Indexed: 04/14/2025]
Abstract
Hypoxia imposes notable stress on organisms and even causes tissue damage; however, the cellular and molecular mechanisms underlying hypoxic adaptation and maladaptation are elusive. Here, we performed single-cell RNA sequencing to analyze hematopoietic stem and progenitor cells (HSPCs) and erythroid cells in a mouse model of high-altitude polycythemia (HAPC) mimicking long-term high-altitude hypoxia exposure. We identified a distinct erythroid-biased multipotent progenitor subset, FOShi MPP, characterized by a unique responsiveness to interferon (IFN) signaling, which expands under hypoxia conditions. This subset rapidly responds to hypoxia during re-ascent by sustaining low methylation of erythroid-priming genes, suggesting a memory function in HSPCs for faster acclimatization. Additionally, erythroid cells in HAPC mice had active metabolic and autophagic activity, as well as abundant CD47 expression that prevented the phagocytosis of erythrocytes. Finally, CD47 blockade and/or IFNα treatments alleviated erythrocytosis in HAPC mice. These approaches might constitute promising therapeutic strategies for HAPC.
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Affiliation(s)
- Weili Liu
- Department of Environmental Medicine, Tianjin Institute of Environmental and Operational Medicine, Academy of Military Medical Sciences, Tianjin 300050, China.
| | - Xiaoru Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - Jinhua Liu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - Lingling Pu
- Department of Environmental Medicine, Tianjin Institute of Environmental and Operational Medicine, Academy of Military Medical Sciences, Tianjin 300050, China
| | - Lanlan Ai
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - Hongbao Xu
- Department of Environmental Medicine, Tianjin Institute of Environmental and Operational Medicine, Academy of Military Medical Sciences, Tianjin 300050, China
| | - Guangrui Wang
- Department of Environmental Medicine, Tianjin Institute of Environmental and Operational Medicine, Academy of Military Medical Sciences, Tianjin 300050, China
| | - Ding Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - Xiaona Song
- Department of Environmental Medicine, Tianjin Institute of Environmental and Operational Medicine, Academy of Military Medical Sciences, Tianjin 300050, China
| | - Yingnan Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - Ling Zhang
- Department of Environmental Medicine, Tianjin Institute of Environmental and Operational Medicine, Academy of Military Medical Sciences, Tianjin 300050, China
| | - Jie Gao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - Xiaoling Cheng
- Department of Environmental Medicine, Tianjin Institute of Environmental and Operational Medicine, Academy of Military Medical Sciences, Tianjin 300050, China
| | - Xinxing Wang
- Department of Environmental Medicine, Tianjin Institute of Environmental and Operational Medicine, Academy of Military Medical Sciences, Tianjin 300050, China
| | - Jingyuan Tong
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - Xiaowei Xie
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - Fang Dong
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - Yingchi Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - Ping Zhu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
| | - Zhaoli Chen
- Department of Environmental Medicine, Tianjin Institute of Environmental and Operational Medicine, Academy of Military Medical Sciences, Tianjin 300050, China.
| | - Peng Wu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
| | - Lihong Shi
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China; Tianjin Institute of Health Science, Tianjin 300020, China.
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Ma Y, Li Y, Yin Z, Huang JJ, Ye Z, Chen X, Du J, Huang Z. Gadd45γ alleviates collagen-induced arthritis by increasing IL-10 level and suppressing JNK activity. Int Immunopharmacol 2025; 151:114329. [PMID: 40007379 DOI: 10.1016/j.intimp.2025.114329] [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: 10/07/2024] [Revised: 02/06/2025] [Accepted: 02/14/2025] [Indexed: 02/27/2025]
Abstract
It has been shown that Gadd45β alleviated K/BxN serum-induced arthritis, but in collagen-induced arthritis (CIA), it exacerbated joint inflammatory response, clinical signs, and symptoms. So far, the function of Gadd45γ in arthritis remains to be explored. This study aimed to investigate the role and immune regulatory mechanism of Gadd45γ in arthritis by intra-articular injection of a lentiviral vector encoding the Gadd45γ gene (LV-Gadd45γ) or lentiviral vectors (LV). The experiments showed that CIA increased the level of Gadd45γ, overexpression of Gadd45γ inhibited the symptoms and articular destruction of CIA, reduced the pro-inflammatory cytokine IL-1β, IL-6, and matrix metalloproteinases-13 (MMP-13), and increased the anti-inflammatory cytokine IL-10. In turn, high levels of IL-10 elevated Gadd45γ in CIA mice, human rheumatoid synovial fibroblasts (HRSF), and RAW cell lines. Furthermore, the increasing expression of Gadd45γ dramatically raised IL-10 and diminished the phosphorylation of c-Jun N-terminal kinase (JNK) in CIA mice and HRSF. Mechanistic analysis showed that the attenuating effect of Gadd45γ on CIA may be attributed to the mutual enhancement of the expression of Gadd45γ and IL-10 and the inhibition of JNK activity through downregulating IL-1β and IL-6. The results indicate that Gadd45γ can act as an inflammatory suppressor and joint damage attenuator in CIA mice. Increased IL-10 levels through a positive feedback circuit between Gadd45γ and IL-10 and the inhibitory effect of Gadd45γ on JNK activity endows this protein with the ability to inhibit CIA.
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Affiliation(s)
- Yanmei Ma
- Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen 518040, China; Department of Immunology, Biological Therapy Institute, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Health Science Center, Shenzhen University, Shenzhen 518060, China; Joint Research Laboratory for Rheumatology of Shenzhen University Health Science Center and Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen 518060, China
| | - Yanqun Li
- Department of Immunology, Biological Therapy Institute, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Health Science Center, Shenzhen University, Shenzhen 518060, China
| | - Zhihua Yin
- Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen 518040, China; Joint Research Laboratory for Rheumatology of Shenzhen University Health Science Center and Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen 518060, China
| | - Jennifer Jin Huang
- Department of Chemistry and Biochemistry, University of Oklahoma, 101 Stephenson Parkway Norman, OK 73019-5251, USA
| | - Zhizhong Ye
- Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen 518040, China; Joint Research Laboratory for Rheumatology of Shenzhen University Health Science Center and Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen 518060, China
| | - Xinpeng Chen
- Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen 518040, China; Joint Research Laboratory for Rheumatology of Shenzhen University Health Science Center and Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen 518060, China.
| | - Jing Du
- Department of Laboratory Medicine, Peking University Shenzhen Hospital, Shenzhen, China.
| | - Zhong Huang
- Department of Immunology, Biological Therapy Institute, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Health Science Center, Shenzhen University, Shenzhen 518060, China; Joint Research Laboratory for Rheumatology of Shenzhen University Health Science Center and Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen 518060, China.
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Zhang Y, Qin L, Liu J. Bioinformatics and machine learning approaches to explore key biomarkers in muscle aging linked to adipogenesis. BMC Musculoskelet Disord 2025; 26:285. [PMID: 40121419 PMCID: PMC11929359 DOI: 10.1186/s12891-025-08528-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 03/12/2025] [Indexed: 03/25/2025] Open
Abstract
Adipogenesis is intricately linked to the onset and progression of muscle aging; however, the relevant biomarkers remain unclear. This study sought to identify key genes associated with adipogenesis in the context of muscle aging. Firstly, gene expression profiles from biopsies of the vastus lateralis muscle in both young and elderly population were retrieved from the GEO database. After intersecting with the results of differential gene analysis, weighted gene co-expression network analysis, and sets of adipogenesis-related genes, 29 adipogenesis-related differential expressed genes (ARDEGs) were selected. Connectivity Map (cMAP) analysis identified tamsulosin, fraxidin, and alaproclate as key target compounds. In further, using three machine learning algorithms and the friends analysis, four hub ARDEGs, ESRRA, RXRG, GADD45A, and CEBPB were identified and verified in vivo aged mice muscles. Immune infiltration analysis showed a strong link between several immune cells and hub ARDEGs. In all, these findings suggested that ESRRA, RXRG, GADD45A, and CEBPB could serve as adipogenesis related biomarkers in muscle aging.
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Affiliation(s)
- Yumin Zhang
- Division of Geriatric Endocrinology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
| | - Li Qin
- Division of Geriatric Endocrinology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Juan Liu
- Division of Geriatric Endocrinology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
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Herrera-Sánchez MP, Rodríguez-Hernández R, Rondón-Barragán IS. Comparative Transcriptome Analysis of Hens' Livers in Conventional Cage vs. Cage-Free Egg Production Systems. Vet Med Int 2025; 2025:3041254. [PMID: 40160973 PMCID: PMC11952924 DOI: 10.1155/vmi/3041254] [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: 10/31/2024] [Accepted: 02/22/2025] [Indexed: 04/02/2025] Open
Abstract
Different conditions of production systems including stocking density, thermal conditions, and behavior restriction can have a significant detrimental effect on the health and performance of laying hens. The conventional cage system is one of the systems that have been reported to cause stress problems in birds, due to social and behavioral stress. Emerging technologies have facilitated a deeper understanding of animal responses to various scenarios and can be an additional tool to conventional ones to assess animal welfare, where transcriptomic analysis has the potential to show the genetic changes that occur in response to stress. According to this, the aim of this work was to characterize the liver transcriptome of hens housed under two egg production systems (conventional cage and cage-free). Liver tissue from Hy-Line Brown hens housed in conventional cage (n = 3) and cage-free (n = 3) production systems at week 80 of age was processed using the Illumina platform to identify differentially expressed genes with a padj < 0.05. Regarding the differentially expressed genes, 138 genes were found, of which 81 were upregulated and 57 downregulated. Some of the genes of interest were TENM2, GRIN2C, and ACACB, which would indicate greater fat synthesis in the liver of caged hens. The enriched KEGG pathways were DNA replication and the cell cycle. In conclusion, it was identified that the cage production system may influence DNA replication and the cell cycle since the genes related to these terms were found suppressed, which would indicate cellular instability.
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Affiliation(s)
- María Paula Herrera-Sánchez
- Poultry Research Group, Laboratory of Immunology and Molecular Biology, Faculty of Veterinary Medicine and Zootechnics, Universidad del Tolima, Altos de Santa Helena, Ibagué 730006299, Tolima, Colombia
- Immunobiology and Pathogenesis Research Group, Laboratory of Immunology and Molecular Biology, Faculty of Veterinary Medicine and Zootechnics, Universidad del Tolima, Altos de Santa Helena, Ibagué 730006299, Tolima, Colombia
| | - Roy Rodríguez-Hernández
- Poultry Research Group, Laboratory of Immunology and Molecular Biology, Faculty of Veterinary Medicine and Zootechnics, Universidad del Tolima, Altos de Santa Helena, Ibagué 730006299, Tolima, Colombia
| | - Iang Schroniltgen Rondón-Barragán
- Poultry Research Group, Laboratory of Immunology and Molecular Biology, Faculty of Veterinary Medicine and Zootechnics, Universidad del Tolima, Altos de Santa Helena, Ibagué 730006299, Tolima, Colombia
- Immunobiology and Pathogenesis Research Group, Laboratory of Immunology and Molecular Biology, Faculty of Veterinary Medicine and Zootechnics, Universidad del Tolima, Altos de Santa Helena, Ibagué 730006299, Tolima, Colombia
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7
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Li XQ, Zhang JX, Li L, Wu QY, Ruan XZ, Chen PP, Ma KL. Deficiency of Growth Arrest and DNA Damage-Inducible 45 α -R-Loop Pathway and Kidney Injury in Diabetic Nephropathy. J Am Soc Nephrol 2025:00001751-990000000-00588. [PMID: 40100277 DOI: 10.1681/asn.0000000681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 03/12/2025] [Indexed: 03/20/2025] Open
Abstract
Background Diabetic nephropathy is a primary cause of kidney failure. Persistent hyperglycemia causes metabolic perturbations epigenetically dysregulating gene expression in kidney cells, thereby leading to diabetic nephropathy pathogenesis. On analyzing the Gene Expression Omnibus database by using machine learning algorithms, our preliminary results demonstrated that growth arrest and DNA damage–inducible 45α (GADD45α) might serve as key regulators in diabetic nephropathy. Furthermore, emerging evidence has shown that R-loops, the three-stranded DNA–RNA structures, are crucial to gene expression during diabetic nephropathy. Therefore, this study aimed to investigate the role of GADD45α in diabetic nephropathy by modulating epigenetic alterations through interaction with R-loops. Methods A diabetic mouse model was established by injecting streptozotocin intraperitoneally into mice. Kidney histology and biochemical markers were analyzed in wild-type, GADD45α knockout, and renal tubule–specific GADD45α-overexpressing mice. The GADD45α lentivirus was used to induce the overexpression of GADD45α in human kidney-2 (a proximal tubular epithelial cell line) cells, while high-glucose treatment was applied to verify the mechanisms in vitro. Results GADD45α expression was reduced in kidneys of diabetic nephropathy, correlating with kidney dysfunction. GADD45α knockout worsened kidney injuries, while overexpression mitigated them. Mechanistically, GADD45α interacted with R-loops on the six-transmembrane epithelial antigen of the prostate 4 (STEAP4) promoter, recruiting ten eleven translocation 1 to activate STEAP4 transcription. Deficiency in the GADD45α-R-loop pathway exacerbated mitochondrial injury, disrupted lipid metabolism, and increased oxidative stress in diabetic nephropathy. Conclusions Deficiency of GADD45α exacerbates diabetic nephropathy by interacting with R-loops and inhibiting STEAP4 promoter demethylation. Targeting the GADD45α-R-loop pathway offers therapeutic potential against diabetic nephropathy.
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Affiliation(s)
- Xue Qi Li
- Institute of Nephrology, Zhong da Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Jia Xiu Zhang
- Institute of Nephrology, Zhong da Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Liang Li
- Institute of Nephrology, Zhong da Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Qin Yi Wu
- Institute of Nephrology, Zhong da Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Xiong Zhong Ruan
- Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- John Moorhead Research Laboratory, Centre for Nephrology, University College London Medical School, Royal Free Campus, University College London, London, United Kingdom
| | - Pei Pei Chen
- Department of Nephrology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Kun Ling Ma
- Institute of Nephrology, Zhong da Hospital, School of Medicine, Southeast University, Nanjing, China
- Department of Nephrology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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8
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Zhang C, Jiang S, Storey KB, Zhang W. Better Transcriptomic Stability and Broader Transcriptomic Thermal Response Range Drive the Greater Thermal Tolerance in a Global Invasive Turtle Relative to Native Turtle. Integr Zool 2025. [PMID: 39910901 DOI: 10.1111/1749-4877.12959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 12/09/2024] [Accepted: 01/16/2025] [Indexed: 02/07/2025]
Abstract
Greater thermal tolerance of invasive species benefits their survival and spread under extreme climate events, especially under global warming. Revealing the mechanisms underlying the interspecific differences in thermal tolerance between invasive and native species can help understand the invasion process and predict potential invaders. Here, we link the changes in global transcriptomics and antioxidant defense at multiple temperatures with the differences in thermal limits in the juveniles of a successful globally invasive turtle, Trachemys scripta elegans, and a native turtle in China, Mauremys reevesii. The two species show different thermal tolerances and have co-existed in habitats with the risk of overheating. The majority of the transcriptional response to thermal stress is conserved in the two turtle species, including protein folding or DNA damage responses activated under relatively moderate thermal stress and regulation of the cell cycle and apoptosis during severe thermal stress. Greater thermal tolerance of T. scripta elegans can be associated with a more stable global transcriptome during thermal stress, except for necessary stress responses, and a broader thermal range of continuous up-regulation of the core mechanisms promoting survival under thermal stress, mainly protein folding and negative regulation of apoptosis. Under extreme hot conditions, the opposite change trends of genes involved in survival mechanisms during thermal stress between invasive and native turtles can be due to differences in energy turnover. The present study provides insights into the mechanisms of physiological differences between invasive and native species given global transcriptional changes and helps understand successful invasion and predict potential invasive species.
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Affiliation(s)
- Changyi Zhang
- Research Center of Herpetology, College of Life Science, Nanjing Normal University, Nanjing, China
| | - Shufen Jiang
- Research Center of Herpetology, College of Life Science, Nanjing Normal University, Nanjing, China
| | - Kenneth B Storey
- Institute of Biochemistry and Department of Biology, Carleton University, Ottawa, Ontario, Canada
| | - Wenyi Zhang
- Research Center of Herpetology, College of Life Science, Nanjing Normal University, Nanjing, China
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9
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Naponelli V, Piscazzi A, Mangieri D. Cellular and Molecular Mechanisms Modulated by Genistein in Cancer. Int J Mol Sci 2025; 26:1114. [PMID: 39940882 PMCID: PMC11818640 DOI: 10.3390/ijms26031114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/21/2025] [Accepted: 01/23/2025] [Indexed: 02/16/2025] Open
Abstract
Genistein (4',5,7-trihydroxyisoflavone) is a phytoestrogen belonging to a subclass of natural flavonoids that exhibits a wide range of pharmacological functions, including antioxidant and anti-inflammatory properties. These characteristics make genistein a valuable phytochemical compound for the prevention and/or treatment of cancer. Genistein effectively inhibits tumor growth and dissemination by modulating key cellular mechanisms. This includes the suppression of angiogenesis, the inhibition of epithelial-mesenchymal transition, and the regulation of cancer stem cell proliferation. These effects are mediated through pivotal signaling pathways such as JAK/STAT, PI3K/Akt/mTOR, MAPK/ERK, NF-κB, and Wnt/β-catenin. Moreover, genistein interferes with the function of specific cyclin/CDK complexes and modulates the activation of Bcl-2/Bax and caspases, playing a critical role in halting tumor cell division and promoting apoptosis. The aim of this review is to discuss in detail the key cellular and molecular mechanisms underlying the pleiotropic anticancer effects of this flavonoid.
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Affiliation(s)
- Valeria Naponelli
- Department of Medicine and Surgery, University of Parma, Plesso Biotecnologico Integrato, Via Volturno 39, 43126 Parma, Italy
| | - Annamaria Piscazzi
- Department of Clinical and Experimental Medicine, University of Foggia, Via Pinto 1, 71122 Foggia, Italy
| | - Domenica Mangieri
- Department of Clinical and Experimental Medicine, University of Foggia, Via Pinto 1, 71122 Foggia, Italy
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10
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Javid N, Abdoli S, Shahbazi M. Rational strategies for designing next-generation oncolytic viruses based on transcriptome analysis of tumor cells infected with oncolytic herpes simplex virus-1. Front Oncol 2025; 14:1469511. [PMID: 39850819 PMCID: PMC11754274 DOI: 10.3389/fonc.2024.1469511] [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: 07/23/2024] [Accepted: 12/09/2024] [Indexed: 01/25/2025] Open
Abstract
Introduction Oncolytic herpes simplex viruses (oHSVs) are a type of biotherapeutic utilized in cancer therapy due to their ability to selectively infect and destroy tumor cells without harming healthy cells. We sought to investigate the functional genomic response and altered metabolic pathways of human cancer cells to oHSV-1 infection and to elucidate the influence of these responses on the relationship between the virus and the cancer cells. Methods Two datasets containing gene expression profiles of tumor cells infected with oHSV-1 (G207) and non-infected cells from the Gene Expression Omnibus (GEO) database were processed and normalized using the R software. Common differentially expressed genes between datasets were selected to identify hub genes and were further analyzed. Subsequently, the expression of hub genes was verified by real-time polymerase chain reaction (qRT-PCR) in MDA-MB-231 (a breast cancer cell line) infected with oHSV-1 and non-infected cells. Results The results of our data analysis indicated notable disparities in the genes associated with the proteasome pathway between infected and non-infected cells. Our ontology analysis revealed that the proteasome-mediated ubiquitin-dependent protein catabolic process was a significant biological process, with a p-value of 5.8E-21. Additionally, extracellular exosomes and protein binding were identified as significant cellular components and molecular functions, respectively. Common hub genes with degree and maximum neighborhood component (MNC) methods, including PSMD2, PSMD4, PSMA2, PSMD14, PSMD11, PSMC3, PSMC2, PSMD8, and PSMA4, were also identified. Analysis of gene expression by qRT-PCR and differential gene expression revealed that GADD45g genes can be effective genes in the proliferation of oncolytic HSV-1 virus. Conclusion The transcriptome changes in tumor cells infected by oHSV-1 may be utilized to predict oncolytic efficacy and provide rational strategies for designing next-generation oncolytic viruses.
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Affiliation(s)
- Naeme Javid
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Shahriyar Abdoli
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Majid Shahbazi
- Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
- AryaTina Gene (ATG) Biopharmaceutical Company Gorgan, Gorgan, Iran
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11
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Dermitzakis I, Kyriakoudi SA, Chatzianagnosti S, Chatzi D, Vakirlis E, Meditskou S, Manthou ME, Theotokis P. Epigenetics in Skin Homeostasis and Ageing. EPIGENOMES 2025; 9:3. [PMID: 39846570 PMCID: PMC11755608 DOI: 10.3390/epigenomes9010003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 12/19/2024] [Accepted: 12/31/2024] [Indexed: 01/24/2025] Open
Abstract
The skin, the largest organ of the human body, plays numerous essential roles, including protection against environmental hazards and the regulation of body temperature. The processes of skin homeostasis and ageing are complex and influenced by many factors, with epigenetic mechanisms being particularly significant. Epigenetics refers to the regulation of gene expression without altering the underlying DNA sequence. The dynamic nature of the skin, characterized by constant cellular turnover and responsiveness to environmental stimuli, requires precise gene activity control. This control is largely mediated by epigenetic modifications such as DNA methylation, histone modification, and regulation by non-coding RNAs. The present review endeavours to provide a comprehensive exploration and elucidation of the role of epigenetic mechanisms in regulating skin homeostasis and ageing. By integrating our current knowledge of epigenetic modifications with the latest advancements in dermatological research, we can gain a deeper comprehension of the complex regulatory networks that govern skin biology. Understanding these mechanisms also presents promising avenues for therapeutic interventions aimed at improving skin health and mitigating age-related skin conditions.
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Affiliation(s)
- Iasonas Dermitzakis
- Department of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (S.A.K.); (S.C.); (D.C.); (S.M.); (M.E.M.); (P.T.)
| | - Stella Aikaterini Kyriakoudi
- Department of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (S.A.K.); (S.C.); (D.C.); (S.M.); (M.E.M.); (P.T.)
| | - Sofia Chatzianagnosti
- Department of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (S.A.K.); (S.C.); (D.C.); (S.M.); (M.E.M.); (P.T.)
| | - Despoina Chatzi
- Department of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (S.A.K.); (S.C.); (D.C.); (S.M.); (M.E.M.); (P.T.)
| | - Efstratios Vakirlis
- First Department of Dermatology and Venereology, School of Medicine, Aristotle University of Thessaloniki, 54643 Thessaloniki, Greece;
| | - Soultana Meditskou
- Department of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (S.A.K.); (S.C.); (D.C.); (S.M.); (M.E.M.); (P.T.)
| | - Maria Eleni Manthou
- Department of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (S.A.K.); (S.C.); (D.C.); (S.M.); (M.E.M.); (P.T.)
| | - Paschalis Theotokis
- Department of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (S.A.K.); (S.C.); (D.C.); (S.M.); (M.E.M.); (P.T.)
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12
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Kawataki S, Kubota Y, Katayama K, Imoto S, Takekawa M. GADD45β-MTK1 signaling axis mediates oncogenic stress-induced activation of the p38 and JNK pathways. Cancer Sci 2025; 116:128-142. [PMID: 39526327 PMCID: PMC11711059 DOI: 10.1111/cas.16389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 10/22/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024] Open
Abstract
The ERK pathway governs essential biological processes such as cell proliferation and survival, and its hyperactivation by various oncogenes ultimately drives carcinogenesis. However, normal mammalian cells typically recognize aberrant ERK signaling as oncogenic stress and respond by inducing cell cycle arrest or apoptosis through activation of the p38 and JNK pathways. Despite the critical role of this response in preventing carcinogenesis, the precise molecular mechanisms underlying oncogene-induced, ERK-dependent activation of p38/JNK and its tumor-suppressive effects remain unclear. Here, we demonstrate that MAP three kinase 1 (MTK1), a stress-responsive MAPKKK, serves as a key mediator of p38/JNK activation induced by oncogenic ERK signaling. Mechanistically, aberrant ERK signaling induces sustained expression of the transcription factor early growth response protein 1 (EGR1), which promotes the production of the MTK1 activator GADD45β, leading to persistent activation of MTK1-p38/JNK signaling. Gene knockout and transcriptome analyses revealed that this GADD45β/MTK1-mediated cross-talk between the ERK and p38/JNK pathways preferentially upregulates a specific set of genes involved in apoptosis and the immune response. Notably, the expression of EGR1, GADD45β, and MTK1 is frequently downregulated in many cancers with high ERK activity, resulting in the disruption of the tumor-suppressive ERK-p38/JNK cross-talk. Restoring GADD45β expression in cancer cells reactivates p38/JNK signaling and suppresses tumorigenesis. Our findings delineate a molecular mechanism by which normal cells sense and respond to oncogenic stress to prevent abnormal growth, and highlight the significance of its dysregulation in cancer.
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Affiliation(s)
- Saeko Kawataki
- Division of Cell Signaling and Molecular Medicine, Institute of Medical ScienceThe University of TokyoTokyoJapan
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier SciencesThe University of TokyoChibaJapan
| | - Yuji Kubota
- Division of Cell Signaling and Molecular Medicine, Institute of Medical ScienceThe University of TokyoTokyoJapan
| | - Kotoe Katayama
- Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical ScienceThe University of TokyoTokyoJapan
| | - Seiya Imoto
- Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical ScienceThe University of TokyoTokyoJapan
- Division of Health Medical Intelligence, Human Genome Center, Institute of Medical ScienceThe University of TokyoTokyoJapan
| | - Mutsuhiro Takekawa
- Division of Cell Signaling and Molecular Medicine, Institute of Medical ScienceThe University of TokyoTokyoJapan
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier SciencesThe University of TokyoChibaJapan
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13
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El Khaled El Faraj R, Chakraborty S, Zhou M, Sobol M, Thiele D, Shatford-Adams LM, Correa Cassal M, Kaster AK, Dietrich S, Levkin PA, Popova AA. Drug-Induced Differential Gene Expression Analysis on Nanoliter Droplet Microarrays: Enabling Tool for Functional Precision Oncology. Adv Healthc Mater 2025; 14:e2401820. [PMID: 39444094 DOI: 10.1002/adhm.202401820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 10/01/2024] [Indexed: 10/25/2024]
Abstract
Drug-induced differential gene expression analysis (DGEA) is essential for uncovering the molecular basis of cell phenotypic changes and understanding individual tumor responses to anticancer drugs. Performing high throughput DGEA is challenging due to the high cost and labor-intensive multi-step sample preparation protocols. In particular, performing drug-induced DGEA on cancer cells derived from patient biopsies is even more challenging due to the scarcity of available cells. A novel, miniaturized, nanoliter-scale method for drug-induced DGEA is introduced, enabling high-throughput and parallel analysis of patient-derived cell drug responses, overcoming the limitations and laborious nature of traditional protocols. The method is based on the Droplet Microarray (DMA), a microscope glass slide with hydrophilic spots on a superhydrophobic background, facilitating droplet formation for cell testing. DMA allows microscopy-based phenotypic analysis, cDNA extraction, and DGEA. The procedure includes cell lysis for mRNA isolation and cDNA conversion followed by droplet pooling for qPCR analysis. In this study, the drug-induced DGEA protocol on the DMA platform is demonstrated using patient-derived chronic lymphocytic leukemia (CLL) cells. This methodology is critical for DGEA with limited cell numbers and promise for applications in functional precision oncology. This method enables molecular profiling of patient-derived samples after drug treatment, crucial for understanding individual tumor responses to anticancer drugs.
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Affiliation(s)
- Razan El Khaled El Faraj
- Institute of Biological and Chemical Systems-Functional Molecular Systems, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany
| | - Shraddha Chakraborty
- Institute of Biological and Chemical Systems-Functional Molecular Systems, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi, 110016, India
| | - Meijun Zhou
- Institute of Biological and Chemical Systems-Functional Molecular Systems, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany
| | - Morgan Sobol
- Institute for Biological Interfaces 5, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany
| | - David Thiele
- Institute for Biological Interfaces 5, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany
| | | | - Maximiano Correa Cassal
- Institute for Biological Interfaces 5, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany
| | - Anne-Kristin Kaster
- Institute for Biological Interfaces 5, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany
| | - Sascha Dietrich
- Department for Hematology, Immunology and Clinical Oncology, Heinrich-Heine-University Düsseldorf, 40225, Düsseldorf, Germany
| | - Pavel A Levkin
- Institute of Biological and Chemical Systems-Functional Molecular Systems, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany
| | - Anna A Popova
- Institute of Biological and Chemical Systems-Functional Molecular Systems, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany
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14
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Wells C, Pogribna M, Sharmah A, Paredes A, Word B, Patri AK, Lyn-Cook B, Hammons G. Exposure to a Titanium Dioxide Product Alters DNA Methylation in Human Cells. NANOMATERIALS (BASEL, SWITZERLAND) 2024; 14:2037. [PMID: 39728572 DOI: 10.3390/nano14242037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 12/02/2024] [Accepted: 12/09/2024] [Indexed: 12/28/2024]
Abstract
The safety of titanium dioxide (TiO2), widely used in foods and personal care products, has been of ongoing concern. Significant toxicity of TiO2 has been reported, suggesting a risk to human health. To evaluate its potential epigenotoxicity, the effect of exposure to a TiO2 product to which humans could be exposed on DNA methylation, a primary epigenetic mechanism, was investigated using two human cell lines (Caco-2 (colorectal) and HepG2 (liver)) relevant to human exposure. Global methylation was determined by enzyme-linked immunosorbent assay-based immunochemical analysis. Gene promoter methylation was evaluated using EpiTect Methyl II Signature PCR System Array technology. Expression of DNA methyltransferases, MBD2, and URHF1 was quantified by qRT-PCR. A decrease in global DNA methylation was observed in both cell lines. Across the cell lines, seven genes (BNIP3, DNAJC15, GADD45G, GDF15, INSIG1, SCARA3, and TP53) were identified in which promoters were methylated. Changes in promoter methylation were associated with gene expression. Results also revealed aberrant expression of regulatory genes, DNA methyltransferases, MBD2, and UHRF1. Findings from the study clearly demonstrate the impact of TiO2 exposure on DNA methylation in two cell types, supporting the potential involvement of this epigenetic mechanism in its biological responses. Hence, epigenetic studies are critical for complete assessment of potential risk from exposure.
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Affiliation(s)
- Carlos Wells
- Division of Biochemical Toxicity, FDA/National Center for Toxicological Research, Jefferson, AR 72079, USA
| | - Marta Pogribna
- Division of Biochemical Toxicity, FDA/National Center for Toxicological Research, Jefferson, AR 72079, USA
| | - Arjun Sharmah
- Division of Nanotechology Core, FDA/National Center for Toxicological Research, Jefferson, AR 72079, USA
| | - Angel Paredes
- Division of Nanotechology Core, FDA/National Center for Toxicological Research, Jefferson, AR 72079, USA
| | - Beverly Word
- Division of Biochemical Toxicity, FDA/National Center for Toxicological Research, Jefferson, AR 72079, USA
| | - Anil K Patri
- Division of Nanotechology Core, FDA/National Center for Toxicological Research, Jefferson, AR 72079, USA
| | - Beverly Lyn-Cook
- Division of Biochemical Toxicity, FDA/National Center for Toxicological Research, Jefferson, AR 72079, USA
| | - George Hammons
- Division of Biochemical Toxicity, FDA/National Center for Toxicological Research, Jefferson, AR 72079, USA
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15
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Bellver-Sanchis A, Ávila-López PA, Tic I, Valle-García D, Ribalta-Vilella M, Labrador L, Banerjee DR, Guerrero A, Casadesus G, Poulard C, Pallàs M, Griñán-Ferré C. Neuroprotective effects of G9a inhibition through modulation of peroxisome-proliferator activator receptor gamma-dependent pathways by miR-128. Neural Regen Res 2024; 19:2532-2542. [PMID: 38526289 PMCID: PMC11090428 DOI: 10.4103/1673-5374.393102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 12/17/2023] [Accepted: 12/28/2023] [Indexed: 03/26/2024] Open
Abstract
JOURNAL/nrgr/04.03/01300535-202419110-00033/figure1/v/2024-03-08T184507Z/r/image-tiff Dysregulation of G9a, a histone-lysine N-methyltransferase, has been observed in Alzheimer's disease and has been correlated with increased levels of chronic inflammation and oxidative stress. Likewise, microRNAs are involved in many biological processes and diseases playing a key role in pathogenesis, especially in multifactorial diseases such as Alzheimer's disease. Therefore, our aim has been to provide partial insights into the interconnection between G9a, microRNAs, oxidative stress, and neuroinflammation. To better understand the biology of G9a, we compared the global microRNA expression between senescence-accelerated mouse-prone 8 (SAMP8) control mice and SAMP8 treated with G9a inhibitor UNC0642. We found a downregulation of miR-128 after a G9a inhibition treatment, which interestingly binds to the 3' untranslated region (3'-UTR) of peroxisome-proliferator activator receptor γ (PPARG) mRNA. Accordingly, Pparg gene expression levels were higher in the SAMP8 group treated with G9a inhibitor than in the SAMP8 control group. We also observed modulation of oxidative stress responses might be mainly driven Pparg after G9a inhibitor. To confirm these antioxidant effects, we treated primary neuron cell cultures with hydrogen peroxide as an oxidative insult. In this setting, treatment with G9a inhibitor increases both cell survival and antioxidant enzymes. Moreover, up-regulation of PPARγ by G9a inhibitor could also increase the expression of genes involved in DNA damage responses and apoptosis. In addition, we also described that the PPARγ/AMPK axis partially explains the regulation of autophagy markers expression. Finally, PPARγ/GADD45α potentially contributes to enhancing synaptic plasticity and neurogenesis after G9a inhibition. Altogether, we propose that pharmacological inhibition of G9a leads to a neuroprotective effect that could be due, at least in part, by the modulation of PPARγ-dependent pathways by miR-128.
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Affiliation(s)
- Aina Bellver-Sanchis
- Department of Pharmacology and Therapeutic Chemistry, Institut de Neurociències-Universitat de Barcelona, Barcelona, Spain
| | - Pedro A. Ávila-López
- Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Iva Tic
- Department of Pharmacology and Therapeutic Chemistry, Institut de Neurociències-Universitat de Barcelona, Barcelona, Spain
| | - David Valle-García
- Institute of Biotechnology, National Autonomous University of Mexico, Cuernavaca, Mexico
| | - Marta Ribalta-Vilella
- Department of Pharmacology and Therapeutic Chemistry, Institut de Neurociències-Universitat de Barcelona, Barcelona, Spain
| | - Luis Labrador
- Department of Pharmacology and Therapeutics, Health Science Center-University of Florida, Gainesville, FL, USA
| | - Deb Ranjan Banerjee
- Department of Chemistry, National Institute of Technology Durgapur, M G Avenue, Durgapur, West Bengal, India
| | - Ana Guerrero
- Department of Pharmacology and Therapeutic Chemistry, Institut de Neurociències-Universitat de Barcelona, Barcelona, Spain
| | - Gemma Casadesus
- Department of Pharmacology and Therapeutics, Health Science Center-University of Florida, Gainesville, FL, USA
| | - Coralie Poulard
- Cancer Research Cancer Lyon, Université de Lyon, Lyon, France
- Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France
- CNRS UMR5286, Centre de Recherche en Cancérlogie de Lyon, Lyon, France
| | - Mercè Pallàs
- Department of Pharmacology and Therapeutic Chemistry, Institut de Neurociències-Universitat de Barcelona, Barcelona, Spain
- Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
| | - Christian Griñán-Ferré
- Department of Pharmacology and Therapeutic Chemistry, Institut de Neurociències-Universitat de Barcelona, Barcelona, Spain
- Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
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Cheng-Mei W, Luo G, Liu P, Ren W, Yang S. Potential Biomarkers in Myocardial Fibrosis: A Bioinformatic Analysis. Arq Bras Cardiol 2024; 121:e20230674. [PMID: 39699450 DOI: 10.36660/abc.20230674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 08/26/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Myocardial fibrosis (MF) occurs throughout the onset and progression of cardiovascular disease, and early diagnosis of MF is beneficial for improving cardiac function, but there is a lack of research on early biomarkers of MF. OBJECTIVES Utilizing bioinformatics techniques, we identified potential biomarkers for MF. METHODS Datasets related to MF were sourced from the GEO database. After processing the data, differentially expressed genes were screened. Differentially expressed genes were enriched, and subsequently, protein-protein interaction (PPI) was performed to analyze the differential genes. The associated miRNAs and transcription factors were predicted for these core genes. Finally, ROC validation was performed on the core genes to determine their specificity and sensitivity as potential biomarkers. The level of significance adopted was 5% (p < 0.05). RESULTS A total of 91 differentially expressed genes were identified, and PPI analysis yielded 31 central genes. Enrichment analysis showed that apoptosis, collagen, extracellular matrix, cell adhesion, and inflammation were involved in MF. One hundred and forty-two potential miRNAs were identified. the transcription factors JUN, NF-κB1, SP1, RELA, serum response factor (SRF), and STAT3 were enriched in most of the core targets. Ultimately, IL11, GADD45B, GDF5, NOX4, IGFBP3, ACTC1, MYOZ2, and ITGB8 had higher diagnostic accuracy and sensitivity in predicting MF based on ROC curve analysis. CONCLUSION Eight genes, IL11, GADD45B, GDF5, NOX4, IGFBP3, ACTC1, MYOZ2, and ITGB8, can serve as candidate biomarkers for MF. Processes such as cellular apoptosis, collagen protein synthesis, extracellular matrix formation, cellular adhesion, and inflammation are implicated in the development of MF.
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Affiliation(s)
- Wang Cheng-Mei
- Beibei Traditional Chinese Medicine Hospital, Chongqing - China
| | - Gang Luo
- The Affiliated Hospital of Traditional Chinese Medicine of Southwest Medical University, Luzhou, Sichuan - China
| | - Ping Liu
- The Affiliated Hospital of Traditional Chinese Medicine of Southwest Medical University, Luzhou, Sichuan - China
| | - Wei Ren
- The Affiliated Hospital of Traditional Chinese Medicine of Southwest Medical University, Luzhou, Sichuan - China
| | - Sijin Yang
- The Affiliated Hospital of Traditional Chinese Medicine of Southwest Medical University, Luzhou, Sichuan - China
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Althobaiti NA, Al-Abbas NS, Alsharif I, Albalawi AE, Almars AI, Basabrain AA, Jafer A, Ellatif SA, Bauthman NM, Almohaimeed HM, Soliman MH. Gadd45A-mediated autophagy regulation and its impact on Alzheimer's disease pathogenesis: Deciphering the molecular Nexus. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167353. [PMID: 39004381 DOI: 10.1016/j.bbadis.2024.167353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 06/18/2024] [Accepted: 07/08/2024] [Indexed: 07/16/2024]
Abstract
BACKGROUND The growth arrest and DNA damage-inducible 45 (Gadd45) gene has been implicated in various central nervous system (CNS) functions, both normal and pathological, including aging, memory, and neurodegenerative diseases. In this study, we examined whether Gadd45A deletion triggers pathways associated with neurodegenerative diseases including Alzheimer's disease (AD). METHODS Utilizing transcriptome data from AD-associated hippocampus samples, we identified Gadd45A as a pivotal regulator of autophagy. Comprehensive analyses, including Gene Ontology enrichment and protein-protein interaction network assessments, highlighted Cdkn1A as a significant downstream target of Gadd45A. Experimental validation confirmed Gadd45A's role in modulating Cdkn1A expression and autophagy levels in hippocampal cells. We also examined the effects of autophagy on hippocampal functions and proinflammatory cytokine secretion. Additionally, a murine model was employed to validate the importance of Gadd45A in neuroinflammation and AD pathology. RESULTS Our study identified 20 autophagy regulatory factors associated with AD, with Gadd45A emerging as a critical regulator. Experimental findings demonstrated that Gadd45A influences hippocampal cell fate by reducing Cdkn1A expression and suppressing autophagic activity. Comparisons between wild-type (WT) and Gadd45A knockout (Gadd45A-/-) mice revealed that Gadd45A-/- mice exhibited significant cognitive impairments, including deficits in working and spatial memory, increased Tau hyperphosphorylation, and elevated levels of kinases involved in Tau phosphorylation in the hippocampus. Additionally, Gadd45A-/- mice showed significant increases in pro-inflammatory cytokines and decreases autophagy markers in the brain. Neurotrophin levels and dendritic spine length were also reduced in Gadd45A-/- mice, likely contributing to the observed cognitive deficits. CONCLUSIONS These findings support the direct involvement of the Gadd45A gene in AD pathogenesis, and enhancing the expression of Gadd45A may represent a promising therapeutic strategy for the treatment of AD.
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Affiliation(s)
- Norah A Althobaiti
- Biology Department, College of Science and Humanities, Shaqra University, Saudi Arabia
| | - Nouf S Al-Abbas
- Department of Biology, Jamoum University College, Umm Al-Qura University, 21955 Makkah, Saudi Arabia
| | - Ifat Alsharif
- Department of Biology, Jamoum University College, Umm Al-Qura University, 21955 Makkah, Saudi Arabia
| | - Aishah E Albalawi
- Faculty of Science, Department of Biology, University of Tabuk, Tabuk 47913, Saudi Arabia
| | - Amany I Almars
- Department of Medial Laboratory Sciences, Faculty of Applied Medical Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Ammar A Basabrain
- Department of Medial Laboratory Sciences, Faculty of Applied Medical Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Hematology Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Ayman Jafer
- Department of Medial Laboratory Sciences, Faculty of Applied Medical Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Sawsan Abd Ellatif
- Bioprocess Development Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), City of Scientific Research and Technological Applications (SRTA-City), Alexandria 21934, Egypt
| | - Nuha M Bauthman
- Department of Obstetric & Gynecology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Hailah M Almohaimeed
- Department of Basic Science, College of Medicine, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Mona H Soliman
- Botany and Microbiology Department, Faculty of Science, Cairo University, Giza 12613, Egypt; Biology Department, Faculty of Science, Taibah University, Al-Sharm, Yanbu El-Bahr, Yanbu 46429, Saudi Arabia.
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18
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Hou Y, Hao H, Yuan Y, Zhang J, Liu Z, Nie Y, Zhang S, Yuan S, Yang M. Nifuratel Induces Triple-Negative Breast Cancer Cell G2/M Phase Block and Apoptosis by Regulating GADD45A. Pharmaceuticals (Basel) 2024; 17:1269. [PMID: 39458909 PMCID: PMC11510481 DOI: 10.3390/ph17101269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 09/18/2024] [Accepted: 09/20/2024] [Indexed: 10/28/2024] Open
Abstract
(1) Background: Nifuratel (NF113), derived from nitrofuran, has a specific anti-tumor effect. However, the potential mechanisms of NF113 in triple-negative breast cancer remain unknown. (2) Methods: In the study, CCK8 assay and colony formation assays were used to evaluate the inhibition effect of NF113 on cell proliferation. Apoptosis and cell cycle distribution were tested by flow cytometry. The mechanism of NF113's anti-tumor effect was predicted by transcriptome sequencing and verified by using PCR and Western blot experiments. Breast cancer organoids constructed from the patient-derived tumor xenograft model and the MDA-MB-468 xenograft mouse model were established to evaluate the effect of NF113. (3) Results: Our study showed that NF113 had an anti-tumor effect on triple-negative breast cancer both in vitro and in vivo. NF113 also induced apoptosis and G2/M phase arrest in triple-negative breast cancer cells. Our experimental data further verified that NF113 reduced GADD5A mRNA and protein expression, which were significantly upregulated in breast cancer, with downstream CDC25C and AKT phosphorylation changes. (4) Conclusions: Our data provided compelling evidence that NF113 inhibited breast cancer growth via upregulating GADD45A. Conclusion: NF113 was able to exert inhibitory effects on the proliferation of triple-negative breast cancer in vivo and in vitro, which may induce G2/M phase arrest via the GADD45A/CyclinB/CDK1 pathway and apoptosis via GADD45A/JNK/P38.
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Affiliation(s)
- Yuhang Hou
- New Drug Screening and Pharmacodynamics Evaluation Center, National Key Laboratory for Multi-Target Natural Drugs, China Pharmaceutical University, Nanjing 210000, China (Y.Y.); (J.Z.); (Z.L.)
| | - Hongyun Hao
- New Drug Screening and Pharmacodynamics Evaluation Center, National Key Laboratory for Multi-Target Natural Drugs, China Pharmaceutical University, Nanjing 210000, China (Y.Y.); (J.Z.); (Z.L.)
| | - Yan Yuan
- New Drug Screening and Pharmacodynamics Evaluation Center, National Key Laboratory for Multi-Target Natural Drugs, China Pharmaceutical University, Nanjing 210000, China (Y.Y.); (J.Z.); (Z.L.)
| | - Jing Zhang
- New Drug Screening and Pharmacodynamics Evaluation Center, National Key Laboratory for Multi-Target Natural Drugs, China Pharmaceutical University, Nanjing 210000, China (Y.Y.); (J.Z.); (Z.L.)
| | - Zhengrui Liu
- New Drug Screening and Pharmacodynamics Evaluation Center, National Key Laboratory for Multi-Target Natural Drugs, China Pharmaceutical University, Nanjing 210000, China (Y.Y.); (J.Z.); (Z.L.)
| | - Yimin Nie
- Key Laboratory of Straw Comprehensive Utilization and Black Soil Conservation, Ministry of Education, College of Life Sciences, Jilin Agricultural University, Changchun 130118, China
| | - Shichang Zhang
- New Drug Screening and Pharmacodynamics Evaluation Center, National Key Laboratory for Multi-Target Natural Drugs, China Pharmaceutical University, Nanjing 210000, China (Y.Y.); (J.Z.); (Z.L.)
| | - Shengtao Yuan
- New Drug Screening and Pharmacodynamics Evaluation Center, National Key Laboratory for Multi-Target Natural Drugs, China Pharmaceutical University, Nanjing 210000, China (Y.Y.); (J.Z.); (Z.L.)
| | - Mei Yang
- New Drug Screening and Pharmacodynamics Evaluation Center, National Key Laboratory for Multi-Target Natural Drugs, China Pharmaceutical University, Nanjing 210000, China (Y.Y.); (J.Z.); (Z.L.)
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Nakano N, Tashiro E, Shimada T, Ebisawa M, Kojima S, Ayabe K, Yamamoto Y, Maeda S, Itoh F, Itoh S. Involvement of mitogen- and stress-activated protein kinase 1 in BMP-6-induced chondrocyte differentiation. J Biol Chem 2024; 300:107806. [PMID: 39307301 PMCID: PMC11541777 DOI: 10.1016/j.jbc.2024.107806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 08/27/2024] [Accepted: 09/13/2024] [Indexed: 10/27/2024] Open
Abstract
Bone morphogenetic proteins (BMPs) are involved in several cellular responsive actions, such as development, cell differentiation, and apoptosis, via their specific transmembrane receptors. In particular, BMPs promote the differentiation and maturation of bone and cartilage from mesenchymal stem cells. Based on comprehensive analyses performed with a large number of antibodies, mitogen- and stress-activated protein kinase (MSK)1 was found to be immediately phosphorylated in the mouse chondrocyte precursor cell line, ATDC5, upon BMP-6 stimulation. The overexpression and knockdown of MSK1 in ATDC5 cells also enhanced and suppressed BMP-6-induced chondrocyte differentiation, respectively. Similar to ATDC5 cells, an ex vivo organ culture system using mouse embryonic metatarsal bones also demonstrated that BMP-6-mediated MSK1 activation might play a role in chondrocyte differentiation. Using several inhibitors, the p38 kinase pathway was confirmed to be implicated in BMP-6-induced phosphorylation of MSK1. Furthermore, MSK1 mutants lacking kinase activities and those lacking serine/threonine residues targeted by p38 kinase severely impaired their ability to potentiate BMP-6-induced chondrogenic differentiation of ATDC5 cells. Interestingly, a loss-of-function study for Smad4 perturbed BMP-6-induced phosphorylation of p38 kinase to inhibit BMP-6-mediated chondrocyte differentiation via MSK1 activation. Overall, both Smad-dependent and independent pathways require BMP-6-induced chondrocyte differentiation via MSK1 activation in ATDC5 cells.
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Affiliation(s)
- Naoko Nakano
- Laboratory of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo, Japan
| | - Etsu Tashiro
- Laboratory of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo, Japan
| | - Takayuki Shimada
- Laboratory of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo, Japan
| | - Masayasu Ebisawa
- Laboratory of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo, Japan
| | - Sayaka Kojima
- Laboratory of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo, Japan
| | - Kaho Ayabe
- Laboratory of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo, Japan
| | - Yohei Yamamoto
- Laboratory of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo, Japan
| | - Shingo Maeda
- Department of Bone and Joint Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Kagoshima, Japan
| | - Fumiko Itoh
- Laboratory of Stem Cell Regulation, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan
| | - Susumu Itoh
- Laboratory of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo, Japan.
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20
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Palomer X, Salvador JM, Griñán-Ferré C, Barroso E, Pallàs M, Vázquez-Carrera M. GADD45A: With or without you. Med Res Rev 2024; 44:1375-1403. [PMID: 38264852 DOI: 10.1002/med.22015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 12/11/2023] [Accepted: 01/09/2024] [Indexed: 01/25/2024]
Abstract
The growth arrest and DNA damage inducible (GADD)45 family includes three small and ubiquitously distributed proteins (GADD45A, GADD45B, and GADD45G) that regulate numerous cellular processes associated with stress signaling and injury response. Here, we provide a comprehensive review of the current literature investigating GADD45A, the first discovered member of the family. We first depict how its levels are regulated by a myriad of genotoxic and non-genotoxic stressors, and through the combined action of intricate transcriptional, posttranscriptional, and even, posttranslational mechanisms. GADD45A is a recognized tumor suppressor and, for this reason, we next summarize its role in cancer, as well as the different mechanisms by which it regulates cell cycle, DNA repair, and apoptosis. Beyond these most well-known actions, GADD45A may also influence catabolic and anabolic pathways in the liver, adipose tissue and skeletal muscle, among others. Not surprisingly, GADD45A may trigger AMP-activated protein kinase activity, a master regulator of metabolism, and is known to act as a transcriptional coregulator of numerous nuclear receptors. GADD45A has also been reported to display a cytoprotective role by regulating inflammation, fibrosis and oxidative stress in several organs and tissues, and is regarded an important contributor for the development of heart failure. Overall data point to that GADD45A may play an important role in metabolic, neurodegenerative and cardiovascular diseases, and also autoimmune-related disorders. Thus, the potential mechanisms by which dysregulation of GADD45A activity may contribute to the progression of these diseases are also reviewed below.
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Affiliation(s)
- Xavier Palomer
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain
- Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain
- Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
| | - Jesús M Salvador
- Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain
| | - Christian Griñán-Ferré
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain
- Institut de Neurociències, Universitat de Barcelona (NeuroUB), Barcelona, Spain
- Spanish Biomedical Research Center in Neurodegenerative Diseases (CIBERNED)-Instituto de Salud Carlos III, Madrid, Spain
| | - Emma Barroso
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain
- Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain
- Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
| | - Mercè Pallàs
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain
- Institut de Neurociències, Universitat de Barcelona (NeuroUB), Barcelona, Spain
- Spanish Biomedical Research Center in Neurodegenerative Diseases (CIBERNED)-Instituto de Salud Carlos III, Madrid, Spain
| | - Manuel Vázquez-Carrera
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain
- Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain
- Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
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21
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Wydorski PJ, Zmijewska A, Franczak A. The Extremely-Low-Frequency Electromagnetic Field Affects Apoptosis and Oxidative-Stress-Related Genes and Proteins in the Porcine Endometrium-An In Vitro Study. Int J Mol Sci 2024; 25:6931. [PMID: 39000040 PMCID: PMC11241303 DOI: 10.3390/ijms25136931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 06/20/2024] [Accepted: 06/21/2024] [Indexed: 07/14/2024] Open
Abstract
Nowadays, the extremely-low-frequency electromagnetic field (ELF-EMF) is recognized as environmental pollution. The data indicate that the ELF-EMF may affect factors related to epigenetic regulation and alter important biological processes in the uterus. The impact of the ELF-EMF on apoptosis and oxidative-stress-related genes has not been documented in porcine endometrium. This raises the question of whether the exposure to the ELF-EMF can induce apoptosis and/or oxidative stress in the endometrium of pigs during the peri-implantation period. Porcine endometrial slices (100 ± 5 mg) collected (n = 5) during the peri-implantation period were treated in vitro with ELF-EMF at a frequency of 50 Hz and flux density of 8 × 104 mG for 2 h. To determine the effect of ELF-EMF on apoptosis and oxidative stress in the endometrium, CASP3, CASP7, CIDEB, GADD45G, NOS1, NOS2, NOS3, and TP53I3 mRNA transcript were analyzed using real-time PCR, and protein abundance of CASP3, CASP7 using Western blot, and eNOS using ELISA were determined. Moreover, CASP3/7 and NOS activity was analyzed using flow cytometry and colorimetry, respectively. The decreased CASP7 and increased NOS3 mRNA transcript and protein abundance in ELF-EMF-treated endometrium were observed. Moreover, CIDEB, GADD45G, and TP53I3 mRNA transcript abundance was increased. Only p ≤ 0.05 was considered a statistically significant difference. The documented alterations indicate the potential of the ELF-EMF to affect apoptosis and generate oxidative stress in the endometrium. The insight into observed consequences documents for the first time the fact that the ELF-EMF may influence endometrial cell proliferation, angiogenesis, and/or tissue receptivity during peri-implantation.
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Affiliation(s)
| | | | - Anita Franczak
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719 Olsztyn, Poland; (P.J.W.); (A.Z.)
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22
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Du D, Zhou M, Ju C, Yin J, Wang C, Xu X, Yang Y, Li Y, Cui L, Wang Z, Lei Y, Li H, He F, He J. METTL1-mediated tRNA m 7G methylation and translational dysfunction restricts breast cancer tumorigenesis by fueling cell cycle blockade. J Exp Clin Cancer Res 2024; 43:154. [PMID: 38822363 PMCID: PMC11140866 DOI: 10.1186/s13046-024-03076-x] [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: 03/18/2024] [Accepted: 05/20/2024] [Indexed: 06/03/2024] Open
Abstract
BACKGROUND RNA modifications of transfer RNAs (tRNAs) are critical for tRNA function. Growing evidence has revealed that tRNA modifications are related to various disease processes, including malignant tumors. However, the biological functions of methyltransferase-like 1 (METTL1)-regulated m7G tRNA modifications in breast cancer (BC) remain largely obscure. METHODS The biological role of METTL1 in BC progression were examined by cellular loss- and gain-of-function tests and xenograft models both in vitro and in vivo. To investigate the change of m7G tRNA modification and mRNA translation efficiency in BC, m7G-methylated tRNA immunoprecipitation sequencing (m7G tRNA MeRIP-seq), Ribosome profiling sequencing (Ribo-seq), and polysome-associated mRNA sequencing were performed. Rescue assays were conducted to decipher the underlying molecular mechanisms. RESULTS The tRNA m7G methyltransferase complex components METTL1 and WD repeat domain 4 (WDR4) were down-regulated in BC tissues at both the mRNA and protein levels. Functionally, METTL1 inhibited BC cell proliferation, and cell cycle progression, relying on its enzymatic activity. Mechanistically, METTL1 increased m7G levels of 19 tRNAs to modulate the translation of growth arrest and DNA damage 45 alpha (GADD45A) and retinoblastoma protein 1 (RB1) in a codon-dependent manner associated with m7G. Furthermore, in vivo experiments showed that overexpression of METTL1 enhanced the anti-tumor effectiveness of abemaciclib, a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor. CONCLUSION Our study uncovered the crucial tumor-suppressive role of METTL1-mediated tRNA m7G modification in BC by promoting the translation of GADD45A and RB1 mRNAs, selectively blocking the G2/M phase of the cell cycle. These findings also provided a promising strategy for improving the therapeutic benefits of CDK4/6 inhibitors in the treatment of BC patients.
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Affiliation(s)
- Dan Du
- Department of Medical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Mingxia Zhou
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Chenxi Ju
- Department of Medical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Jie Yin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Chang Wang
- Department of Medical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Xinyu Xu
- Department of Medical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yunqing Yang
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yun Li
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Le Cui
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Zhengyang Wang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yuqing Lei
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450008, China
| | - Hongle Li
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450008, China.
| | - Fucheng He
- Department of Medical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
| | - Jing He
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
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Chettiar V, Patel A, Chettiar SS, Jhala DD. Meta-analysis of endometrial transcriptome data reveals novel molecular targets for recurrent implantation failure. J Assist Reprod Genet 2024; 41:1417-1431. [PMID: 38456991 PMCID: PMC11143096 DOI: 10.1007/s10815-024-03077-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 02/27/2024] [Indexed: 03/09/2024] Open
Abstract
PURPOSE Gene expression analysis of the endometrium has been shown to be a useful approach for identifying the molecular signatures and pathways involved in recurrent implantation failure (RIF). Nevertheless, individual studies have limitations in terms of study design, methodology and analysis to detect minor changes in expression levels or identify novel gene signatures associated with RIF. METHOD To overcome this, we conducted an in silico meta-analysis of nine studies, the systematic collection and integration of gene expression data, utilizing rigorous selection criteria and statistical techniques to ensure the robustness of our findings. RESULTS Our meta-analysis successfully unveiled a meta-signature of 49 genes closely associated with RIF. Of these genes, 38 were upregulated and 11 downregulated in RIF patients' endometrium and believed to participate in key processes like cell differentiation, communication, and adhesion. GADD45A, IGF2, and LIF, known for their roles in implantation, were identified, along with lesser-studied genes like OPRK1, PSIP1, SMCHD1, and SOD2 related to female infertility. Many of these genes are involved in MAPK and PI3K-Akt pathways, indicating their role in inflammation. We also investigated to look for key miRNAs regulating these 49 dysregulated mRNAs as potential diagnostic biomarkers. Along with this, we went to associate protein-protein interactions of 49 genes, and we could recognize one cluster consisting of 11 genes (consisted of 22 nodes and 11 edges) with the highest score (p = 0.001). Finally, we validated some of the genes by qRT-PCR in our samples. CONCLUSION In summary, the meta-signature genes hold promise for improving RIF patient identification and facilitating the development of personalized treatment strategies, illuminating the multifaceted nature of this complex condition.
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Affiliation(s)
- Venkatlaxmi Chettiar
- Department of Life Sciences, School of Sciences, Gujarat University, Ahmedabad, Gujarat, India
| | - Alpesh Patel
- GeneXplore Diagnostics and Research Centre PVT. LTD., Ahmedabad, Gujarat, India
| | | | - Devendrasinh D Jhala
- Department of Zoology, School of Sciences, Gujarat University, Ahmedabad, Gujarat, India.
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24
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Jiang L, Wang Q, Jiang Y, Peng D, Zong K, Li S, Xie W, Zhang C, Li K, Wu Z, Huang Z. Identification of diagnostic gene signatures and molecular mechanisms for non-alcoholic fatty liver disease and Alzheimer's disease through machine learning algorithms. Clin Chim Acta 2024; 557:117892. [PMID: 38537674 DOI: 10.1016/j.cca.2024.117892] [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: 02/19/2024] [Revised: 03/23/2024] [Accepted: 03/24/2024] [Indexed: 04/13/2024]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) and Alzheimer's disease (AD) pose significant global health challenges. Recent studies have suggested a link between these diseases; however, the underlying mechanisms remain unclear. This study aimed to decode the shared molecular landscapes of NAFLD and AD using bioinformatic approaches. METHODS We analyzed three datasets for NAFLD and AD from the Gene Expression Omnibus (GEO). This study involved identifying differentially expressed genes (DEGs), using weighted gene co-expression network analysis (WGCNA), and using machine learning for biomarker discovery. The diagnostic biomarkers were validated using expression analysis, receiver operating characteristic (ROC) curves, and nomogram models. Furthermore, Gene Set Enrichment Analysis (GSEA) and CIBERSORT were used to investigate molecular pathways and immune cell distributions related to GADD45G and NUPR1. RESULTS This study identified 14 genes that are common to NAFLD and AD. Machine learning identified six biomarkers for NAFLD, four for AD, and two crucial shared biomarkers: GADD45G and NUPR1. Validation confirmed their expression patterns and robust predictive abilities. GSEA revealed the intricate roles of these biomarkers in disease-associated pathways. Immune cell profiling highlighted the importance of macrophages under these conditions. CONCLUSION This study highlights GADD45G and NUPR1 as key biomarkers for NAFLD and AD, and provides novel insights into their molecular connections. These findings revealed potential therapeutic targets, particularly in macrophage-mediated pathways, thus enriching our understanding of these complex diseases.
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Affiliation(s)
- Liqing Jiang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qian Wang
- Department of General Practice, Chengdu Seventh People's Hospital, Chengdu, China
| | - Yingsong Jiang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Dadi Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Kezhen Zong
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shan Li
- Department of Hepatobiliary Pancreatic Tumor Center, Chongqing University Cancer Hospital, Chongqing, China
| | - Wenyuan Xie
- Department of Hepatobiliary Pancreatic Tumor Center, Chongqing University Cancer Hospital, Chongqing, China
| | - Cheng Zhang
- Department of Hepatobiliary Pancreatic Tumor Center, Chongqing University Cancer Hospital, Chongqing, China
| | - Kaili Li
- Department of Hepatobiliary Pancreatic Tumor Center, Chongqing University Cancer Hospital, Chongqing, China
| | - Zhongjun Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Hepatobiliary Pancreatic Tumor Center, Chongqing University Cancer Hospital, Chongqing, China.
| | - Zuotian Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Hepatobiliary Pancreatic Tumor Center, Chongqing University Cancer Hospital, Chongqing, China.
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25
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Zhang P, You N, Ding Y, Zhu W, Wang N, Xie Y, Huang W, Ren Q, Qin T, Fu R, Zhang L, Xiao Z, Cheng T, Ma X. Gadd45g insufficiency drives the pathogenesis of myeloproliferative neoplasms. Nat Commun 2024; 15:2989. [PMID: 38582902 PMCID: PMC10998908 DOI: 10.1038/s41467-024-47297-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 03/22/2024] [Indexed: 04/08/2024] Open
Abstract
Despite the identification of driver mutations leading to the initiation of myeloproliferative neoplasms (MPNs), the molecular pathogenesis of MPNs remains incompletely understood. Here, we demonstrate that growth arrest and DNA damage inducible gamma (GADD45g) is expressed at significantly lower levels in patients with MPNs, and JAK2V617F mutation and histone deacetylation contribute to its reduced expression. Downregulation of GADD45g plays a tumor-promoting role in human MPN cells. Gadd45g insufficiency in the murine hematopoietic system alone leads to significantly enhanced growth and self-renewal capacity of myeloid-biased hematopoietic stem cells, and the development of phenotypes resembling MPNs. Mechanistically, the pathogenic role of GADD45g insufficiency is mediated through a cascade of activations of RAC2, PAK1 and PI3K-AKT signaling pathways. These data characterize GADD45g deficiency as a novel pathogenic factor in MPNs.
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Affiliation(s)
- Peiwen Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, 301600, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Na You
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, 301600, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Yiyi Ding
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, 301600, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Wenqi Zhu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, 301600, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Nan Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, 301600, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Yueqiao Xie
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, 301600, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Wanling Huang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, 301600, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Qian Ren
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, 301600, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Tiejun Qin
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, 301600, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Rongfeng Fu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, 301600, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Lei Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
- Tianjin Institutes of Health Science, Tianjin, 301600, China.
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China.
| | - Zhijian Xiao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
- Tianjin Institutes of Health Science, Tianjin, 301600, China.
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China.
| | - Tao Cheng
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
- Tianjin Institutes of Health Science, Tianjin, 301600, China.
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China.
- Department of Stem Cell and Regenerative Medicine, Peking Union Medical College, Tianjin, China.
| | - Xiaotong Ma
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
- Tianjin Institutes of Health Science, Tianjin, 301600, China.
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China.
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Wang KY, Wang KJ, Shen LL, Wang XH. The down-regulation of GADD45B leads to a conversion of cellular oxidative phosphorylation to glycolysis and promotes the progression of bladder cancer. Heliyon 2024; 10:e27427. [PMID: 38501008 PMCID: PMC10945183 DOI: 10.1016/j.heliyon.2024.e27427] [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: 05/15/2023] [Revised: 02/28/2024] [Accepted: 02/28/2024] [Indexed: 03/20/2024] Open
Abstract
Background The predominant feature of cancer cells during the process of carcinogenesis is the inclination towards glycolytic metabolism rather than mitochondrial oxidative phosphorylation. Nevertheless, there is a scarcity of research investigating the correlation between bladder cancer and mitochondrial energy metabolism. Methods A qPCR array comprising 90 genes associated with mitochondrial oxidative phosphorylation was employed to discern metabolic disparities between three sets of bladder cancer tissue and adjacent normal tissue. Wound healing and transwell assays were utilized to assess cell migration and invasion capabilities, respectively. Colony formation assays were conducted to ascertain the tumorigenic potential of the cells. The proliferative capacity of the cells was examined through in vitro CCK-8 assays. Additionally, nude mouse models were established to evaluate the impact of bladder tumor cells on in vivo proliferation. The Seahorse XFe96 Analyzer was utilized to quantify mitochondrial oxidative phosphorylation, while the levels of glucose-6-phosphate and pyruvate were assessed to evaluate glycolysis. Results Examination of qPCR array data demonstrated a noteworthy inhibition of mitochondrial oxidative phosphorylation in bladder cancer tissue, as evidenced by the down-regulation of a majority of genes associated with mitochondrial energy metabolism. Notably, GADD45B may potentially exert a significant influence on bladder cancer development, warranting further investigation. The down-regulation of GADD45B in bladder cancer cells resulted in impaired mitochondrial respiration and elevated levels of glycolysis, thereby enhancing cell migration and invasion. Conversely, up-regulation of GADD45B had the opposite effect. Furthermore, over-expression of GADD45B inhibited tumor proliferation and tumorigenesis in both in vitro and in vivo settings. Conclusion These findings from our study indicate that the down-regulation of GADD45B promotes the shift of cell mitochondrial oxidative phosphorylation towards glycolysis, thereby facilitating the progression of bladder cancer.
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Affiliation(s)
- Kai-yun Wang
- Department of Urology, the Affiliated People's Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Ke-jie Wang
- Department of Urology, the Affiliated People's Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Li-liang Shen
- Department of Urology, the Affiliated People's Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Xu-hui Wang
- Department of Urology, the Affiliated People's Hospital of Ningbo University, Ningbo, Zhejiang, China
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Segatto NV, Simões LD, Bender CB, Sousa FS, Oliveira TL, Paschoal JDF, Pacheco BS, Lopes I, Seixas FK, Qazi A, Thomas FM, Chaki S, Robertson N, Newsom J, Patel S, Rund LA, Jordan LR, Bolt C, Schachtschneider KM, Schook LB, Collares TV. Oncopig bladder cancer cells recapitulate human bladder cancer treatment responses in vitro. Front Oncol 2024; 14:1323422. [PMID: 38469237 PMCID: PMC10926022 DOI: 10.3389/fonc.2024.1323422] [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: 10/19/2023] [Accepted: 01/05/2024] [Indexed: 03/13/2024] Open
Abstract
Introduction Bladder cancer is a common neoplasia of the urinary tract that holds the highest cost of lifelong treatment per patient, highlighting the need for a continuous search for new therapies for the disease. Current bladder cancer models are either imperfect in their ability to translate results to clinical practice (mouse models), or rare and not inducible (canine models). Swine models are an attractive alternative to model the disease due to their similarities with humans on several levels. The Oncopig Cancer Model has been shown to develop tumors that closely resemble human tumors. However, urothelial carcinoma has not yet been studied in this platform. Methods We aimed to develop novel Oncopig bladder cancer cell line (BCCL) and investigate whether these urothelial swine cells mimic human bladder cancer cell line (5637 and T24) treatment-responses to cisplatin, doxorubicin, and gemcitabine in vitro. Results Results demonstrated consistent treatment responses between Oncopig and human cells in most concentrations tested (p>0.05). Overall, Oncopig cells were more predictive of T24 than 5637 cell therapeutic responses. Microarray analysis also demonstrated similar alterations in expression of apoptotic (GADD45B and TP53INP1) and cytoskeleton-related genes (ZMYM6 and RND1) following gemcitabine exposure between 5637 (human) and Oncopig BCCL cells, indicating apoptosis may be triggered through similar signaling pathways. Molecular docking results indicated that swine and humans had similar Dg values between the chemotherapeutics and their target proteins. Discussion Taken together, these results suggest the Oncopig could be an attractive animal to model urothelial carcinoma due to similarities in in vitro therapeutic responses compared to human cells.
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Affiliation(s)
- Natália V. Segatto
- Technology Development Center, Laboratory of Cancer Biotechnology, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Lucas D. Simões
- Technology Development Center, Laboratory of Cancer Biotechnology, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Camila B. Bender
- Technology Development Center, Laboratory of Cancer Biotechnology, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Fernanda S. Sousa
- Technology Development Center, Laboratory of Cancer Biotechnology, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Thais L. Oliveira
- Technology Development Center, Laboratory of Cancer Biotechnology, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Júlia D. F. Paschoal
- Technology Development Center, Laboratory of Cancer Biotechnology, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Bruna S. Pacheco
- Technology Development Center, Laboratory of Cancer Biotechnology, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Isadora Lopes
- Technology Development Center, Laboratory of Cancer Biotechnology, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Fabiana K. Seixas
- Technology Development Center, Laboratory of Cancer Biotechnology, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Aisha Qazi
- Department of Animal Sciences, University of Illinois, Urbana, IL, United States
| | - Faith M. Thomas
- Department of Animal Sciences, University of Illinois, Urbana, IL, United States
| | - Sulalita Chaki
- Department of Animal Sciences, University of Illinois, Urbana, IL, United States
| | | | | | - Shovik Patel
- Department of Animal Sciences, University of Illinois, Urbana, IL, United States
| | - Laurie A. Rund
- Department of Animal Sciences, University of Illinois, Urbana, IL, United States
| | - Luke R. Jordan
- Department of Animal Sciences, University of Illinois, Urbana, IL, United States
- Sus Clinicals Inc., Chicago, IL, United States
| | - Courtni Bolt
- Department of Animal Sciences, University of Illinois, Urbana, IL, United States
- Sus Clinicals Inc., Chicago, IL, United States
| | | | - Lawrence B. Schook
- Department of Animal Sciences, University of Illinois, Urbana, IL, United States
- Sus Clinicals Inc., Chicago, IL, United States
| | - Tiago V. Collares
- Technology Development Center, Laboratory of Cancer Biotechnology, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil
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Griñán-Ferré C, Jarne-Ferrer J, Bellver-Sanchis A, Ribalta-Vilella M, Barroso E, Salvador JM, Jurado-Aguilar J, Palomer X, Vázquez-Carrera M, Pallàs M. Deletion of Gadd45a Expression in Mice Leads to Cognitive and Synaptic Impairment Associated with Alzheimer's Disease Hallmarks. Int J Mol Sci 2024; 25:2595. [PMID: 38473843 DOI: 10.3390/ijms25052595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 02/10/2024] [Accepted: 02/18/2024] [Indexed: 03/14/2024] Open
Abstract
Gadd45 genes have been implicated in survival mechanisms, including apoptosis, autophagy, cell cycle arrest, and DNA repair, which are processes related to aging and life span. Here, we analyzed if the deletion of Gadd45a activates pathways involved in neurodegenerative disorders such as Alzheimer's Disease (AD). This study used wild-type (WT) and Gadd45a knockout (Gadd45a-/-) mice to evaluate AD progression. Behavioral tests showed that Gadd45a-/- mice presented lower working and spatial memory, pointing out an apparent cognitive impairment compared with WT animals, accompanied by an increase in Tau hyperphosphorylation and the levels of kinases involved in its phosphorylation in the hippocampus. Moreover, Gadd45a-/- animals significantly increased the brain's pro-inflammatory cytokines and modified autophagy markers. Notably, neurotrophins and the dendritic spine length of the neurons were reduced in Gadd45a-/- mice, which could contribute to the cognitive alterations observed in these animals. Overall, these findings demonstrate that the lack of the Gadd45a gene activates several pathways that exacerbate AD pathology, suggesting that promoting this protein's expression or function might be a promising therapeutic strategy to slow down AD progression.
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Affiliation(s)
- Christian Griñán-Ferré
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028 Barcelona, Spain
- Institute of Neurosciences of the University of Barcelona, University of Barcelona, 08035 Barcelona, Spain
- Spanish Biomedical Research Center in Neurodegenerative Diseases (CIBERNED)-National Institute of Health Carlos III, 28029 Madrid, Spain
| | - Júlia Jarne-Ferrer
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028 Barcelona, Spain
- Institute of Neurosciences of the University of Barcelona, University of Barcelona, 08035 Barcelona, Spain
| | - Aina Bellver-Sanchis
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028 Barcelona, Spain
- Institute of Neurosciences of the University of Barcelona, University of Barcelona, 08035 Barcelona, Spain
| | - Marta Ribalta-Vilella
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028 Barcelona, Spain
- Institute of Neurosciences of the University of Barcelona, University of Barcelona, 08035 Barcelona, Spain
| | - Emma Barroso
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028 Barcelona, Spain
- Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-National Institute of Health Carlos III, 28029 Madrid, Spain
- Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, Spain
| | - Jesús M Salvador
- Department of Immunology and Oncology, National Center for Biotechnology/CSIC, 28049 Madrid, Spain
| | - Javier Jurado-Aguilar
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028 Barcelona, Spain
- Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-National Institute of Health Carlos III, 28029 Madrid, Spain
- Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, Spain
| | - Xavier Palomer
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028 Barcelona, Spain
- Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-National Institute of Health Carlos III, 28029 Madrid, Spain
- Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, Spain
| | - Manuel Vázquez-Carrera
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028 Barcelona, Spain
- Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-National Institute of Health Carlos III, 28029 Madrid, Spain
- Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, Spain
| | - Mercè Pallàs
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028 Barcelona, Spain
- Institute of Neurosciences of the University of Barcelona, University of Barcelona, 08035 Barcelona, Spain
- Spanish Biomedical Research Center in Neurodegenerative Diseases (CIBERNED)-National Institute of Health Carlos III, 28029 Madrid, Spain
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Chen L, Yan J, Shi H, Zhang Z, Zhao Y, Zhao Y, Wang Y, Ou J. Intervention mechanism of marine-based chito-oligosaccharide on acute liver injury induced by AFB 1 in rats. BIORESOUR BIOPROCESS 2024; 11:13. [PMID: 38647922 PMCID: PMC10992386 DOI: 10.1186/s40643-023-00708-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 11/22/2023] [Indexed: 04/25/2024] Open
Abstract
Aflatoxin B1 (AFB1) is extremely hepatotoxic, a causative agent of liver cancer, and can cause symptoms of acute or chronic liver damage. Chito-oligosaccharides (COS), obtained from the degradation of chitosan derived from shrimp and crab shells, is a natural antioxidant substance and its antitumor properties have been widely studied, but less research has been done on the prevention of AFB1-induced acute liver injury. In this study, rats were acutely exposed to 1 mg/kg BW AFB1 and simultaneously gavaged with different doses of COS for 8 days. The results showed that COS attenuated the hepatic histopathological changes and reduced serum biochemical indices (ALT, AST, ALP, and TBIL) in rats. It significantly inhibited MDA content and promoted SOD and GSH-Px activity production. Moreover, it also improved hepatocyte apoptosis. Furthermore, AFB1-vs-HCOS differential genes were enriched with 622 GO entries, and 380 were Biological Processes, 170 were Molecular Functions, 72 were Cellular Components. Differentially expressed genes (DEGs) analyzed by KEGG enrichment were more enriched in pathways, such as metabolism, PPAR signaling pathway, and peroxisome. Q-PCR technique verified that Lama5, Egr1, Cyp2b1, and Gadd45g in DEGs were associated with oxidative stress damage and apoptosis. In conclusion, COS intervention reduces the effect of AFB1 on hepatic genes and thus reduces the changes in hepatic gene function.
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Affiliation(s)
- Lin Chen
- College of Food Sciences and Technology, Shanghai Ocean University, Shanghai, 201306, China
| | - Jiahui Yan
- College of Food Sciences and Technology, Shanghai Ocean University, Shanghai, 201306, China
| | - Huijun Shi
- College of Food Sciences and Technology, Shanghai Ocean University, Shanghai, 201306, China
| | - Zhaohuan Zhang
- College of Food Sciences and Technology, Shanghai Ocean University, Shanghai, 201306, China
- Shanghai Engineering Research Center of Aquatic Product Processing and Preservation, Shanghai, 201306, China
- Laboratory of Quality and Safety Risk Assessment for Aquatic Product on Storage and Preservation, Ministry of Agriculture and Rural Affairs, Shanghai, 201306, China
| | - YueLiang Zhao
- College of Food Sciences and Technology, Shanghai Ocean University, Shanghai, 201306, China
| | - Yong Zhao
- College of Food Sciences and Technology, Shanghai Ocean University, Shanghai, 201306, China
- Shanghai Engineering Research Center of Aquatic Product Processing and Preservation, Shanghai, 201306, China
- Laboratory of Quality and Safety Risk Assessment for Aquatic Product on Storage and Preservation, Ministry of Agriculture and Rural Affairs, Shanghai, 201306, China
| | - Yuan Wang
- Engineering Research Center of Modern Preparation Technology of TCM, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Jie Ou
- College of Food Sciences and Technology, Shanghai Ocean University, Shanghai, 201306, China.
- Shanghai Engineering Research Center of Aquatic Product Processing and Preservation, Shanghai, 201306, China.
- Laboratory of Quality and Safety Risk Assessment for Aquatic Product on Storage and Preservation, Ministry of Agriculture and Rural Affairs, Shanghai, 201306, China.
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30
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Martin-Folgar R, González-Caballero MC, Torres-Ruiz M, Cañas-Portilla AI, de Alba González M, Liste I, Morales M. Molecular effects of polystyrene nanoplastics on human neural stem cells. PLoS One 2024; 19:e0295816. [PMID: 38170698 PMCID: PMC10763972 DOI: 10.1371/journal.pone.0295816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 11/30/2023] [Indexed: 01/05/2024] Open
Abstract
Nanoplastics (NPs) have been found in many ecological environments (aquatic, terrestrial, air). Currently, there is great concern about the exposition and impact on animal health, including humans, because of the effects of ingestion and accumulation of these nanomaterials (NMs) in aquatic organisms and their incorporation into the food chain. NPs´ mechanisms of action on humans are currently unknown. In this study, we evaluated the altered molecular mechanisms on human neural stem cell line (hNS1) after 4 days of exposure to 30 nm polystyrene (PS) NPs (0.5, 2.5 and 10 μg/mL). Our results showed that NPs can induce oxidative stress, cellular stress, DNA damage, alterations in inflammatory response, and apoptosis, which could lead to tissue damage and neurodevelopmental diseases.
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Affiliation(s)
- Raquel Martin-Folgar
- Grupo de Biología y Toxicología Ambiental, Departamento de Física Matemática y de Fluidos, Facultad de Ciencias, UNED. Urbanización Monte Rozas, Las Rozas (Madrid), Spain
| | - Mª Carmen González-Caballero
- Environmental Toxicology Unit, Centro Nacional de Sanidad Ambiental (CNSA), Instituto de Salud Carlos III (ISCIII), Majadahonda (Madrid), Spain
| | - Mónica Torres-Ruiz
- Environmental Toxicology Unit, Centro Nacional de Sanidad Ambiental (CNSA), Instituto de Salud Carlos III (ISCIII), Majadahonda (Madrid), Spain
| | - Ana I. Cañas-Portilla
- Environmental Toxicology Unit, Centro Nacional de Sanidad Ambiental (CNSA), Instituto de Salud Carlos III (ISCIII), Majadahonda (Madrid), Spain
| | - Mercedes de Alba González
- Environmental Toxicology Unit, Centro Nacional de Sanidad Ambiental (CNSA), Instituto de Salud Carlos III (ISCIII), Majadahonda (Madrid), Spain
| | - Isabel Liste
- Environmental Toxicology Unit, Centro Nacional de Sanidad Ambiental (CNSA), Instituto de Salud Carlos III (ISCIII), Majadahonda (Madrid), Spain
| | - Mónica Morales
- Grupo de Biología y Toxicología Ambiental, Departamento de Física Matemática y de Fluidos, Facultad de Ciencias, UNED. Urbanización Monte Rozas, Las Rozas (Madrid), Spain
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31
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Huang W, Bates R, Zou X, Queen NJ, Mo X, Arnold WD, Ray A, Owendoff G, Cao L. Environmental Enrichment Improves Motor Function and Muscle Transcriptome of Aged Mice. Adv Biol (Weinh) 2024; 8:e2300148. [PMID: 37518850 PMCID: PMC10825065 DOI: 10.1002/adbi.202300148] [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: 04/14/2023] [Revised: 06/29/2023] [Indexed: 08/01/2023]
Abstract
Aging results in the progressive decline of muscle strength. Interventions to maintain muscle strength may mitigate the age-related loss of physical function, thus maximizing health span. The work on environmental enrichment (EE), an experimental paradigm recapitulating aspects of an active lifestyle, has revealed EE-induced metabolic benefits mediated by a brain-fat axis across the lifespan of mice. EE initiated at 18-month of age shows a trend toward an increased mean lifespan. While previous work described EE's influences on the aging dynamics of several central-peripheral processes, its influence on muscle remained understudied. Here, the impact of EE is investigated on motor function, neuromuscular physiology, and the skeletal muscle transcriptome. EE is initiated in 20-month-old mice for a five-month period. EE mice exhibit greater relative lean mass that is associated with improved mobility and hindlimb grip strength. Transcriptomic profiling of muscle tissue reveals an EE-associated enrichment of gene expression within several metabolic pathways related to oxidative phosphorylation and the TCA cycle. Many mitochondrial-related genes-several of which participate in the electron transport chain-are upregulated. Stress-responsive signaling pathways are downregulated because of EE. The results suggest that EE improves motor function-possibly through preservation of mitochondrial function-even late in life.
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Affiliation(s)
- Wei Huang
- Department of Cancer Biology & Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
- The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Rhiannon Bates
- The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Xunchang Zou
- Department of Cancer Biology & Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
- The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Nicholas J. Queen
- Department of Cancer Biology & Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
- The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Xiaokui Mo
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - W. David Arnold
- Department of Neurology, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
- Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Alissa Ray
- Department of Neurology, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Gregory Owendoff
- Department of Neurology, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Lei Cao
- Department of Cancer Biology & Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
- The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
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Deng H, Wang Y, Yin Y, Shu J, Zhang J, Shu X, Wu F, He J. Effects of matrix viscoelasticity on cell-matrix interaction, actin cytoskeleton organization, and apoptosis of osteosarcoma MG-63 cells. J Mater Chem B 2023; 12:222-232. [PMID: 38079114 DOI: 10.1039/d3tb02001k] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2023]
Abstract
Many recent reports have shown the effects of viscoelasticity of the extracellular matrix on the spreading, migration, proliferation, survival and cell-matrix interaction of mesenchymal stem cells and normal cells. However, the effect of matrix viscoelasticity on the behavior of tumor cells is still in the state of preliminary exploration. To this aim, we prepared a viscoelastic hydrogel matrix with a storage modulus of about 2 kPa and a loss modulus adjustable from 0 to 600 Pa, through adding linear alginate and regulating the compactness of a polyacrylamide covalent network. Overall, the addition of viscous components inhibited the apoptosis of osteosarcoma MG-63 cells, while it promoted their spreading and proliferation and in particular led to a well-developed cytoskeleton organization. However, with the increase of the viscous fraction, this trend was reversed, and the apoptosis of MG-63 cells gradually increased with gradually decreased spreading and proliferation, accompanied by a surprising manner change of the cytoskeleton from fusiform cells dominated by focal adhesion to dendritic cells dominated by pseudopodia. Besides the upregulation of MAPK, Ras, Rap1 and PI3K-Akt pathways commonly involved in mechanotransduction, the upregulation of the Wnt pathway and inhibited endoplasmic reticulum stress-mediated apoptosis were observed for the viscous matrix with a low loss modulus. The high viscosity matrix showed additional involvement of Hippo and NF-kappa B signaling pathways related to the cell-matrix interaction, with downregulation of the endoplasmic reticulum stress pathway and upregulation related to mitochondrial organization. Our study would provide insight into the effect of viscosity on fundamental behaviors of tumor cells and might have important implications in designing antitumor materials.
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Affiliation(s)
- Huan Deng
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, P. R. China.
| | - Yao Wang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, P. R. China.
| | - Yue Yin
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, P. R. China.
| | - Jun Shu
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, P. R. China.
| | - Junwei Zhang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, P. R. China.
| | - Xuedong Shu
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, P. R. China.
| | - Fang Wu
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, P. R. China.
| | - Jing He
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, P. R. China.
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Furman M, Sihotsky V, Virag M, Kopolovets I, Nemethova M, Mucha R. Quantitative analysis of selected genetic markers of induced brain stroke ischemic tolerance detected in human blood. Brain Res 2023; 1821:148590. [PMID: 37739332 DOI: 10.1016/j.brainres.2023.148590] [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: 06/20/2023] [Revised: 09/14/2023] [Accepted: 09/19/2023] [Indexed: 09/24/2023]
Abstract
A brain stroke is a serious disease and the second leading cause of death in the European Union. Carotid stenosis accounts for 15% of all ischemic cerebral strokes. However, there is currently no effective screening for carotid disease. Analysis of the DNA from peripheral blood is increasingly being used for several disease diagnoses. The potentially beneficial therapeutic method of inducing tissue tolerance to ischemia has so far been studied mainly in animal models. The aim of this study is to investigate changes in the gene expression of selected markers of brain ischemia during carotid endarterectomy, considered in this study as an activator of ischemic tolerance. During the carotid endarterectomy, there is a short-term occlusion of the internal carotid artery. Using the RT-qPCR method, we detected changes in the early identified gene markers of brain ischemia (ADM, CDKN1A, GADD45G, IL6, TM4SF1) in peripheral blood during sub lethal cerebral ischemia caused by carotid endarterectomy. Patients underwenting surgical procedure were divided into three groups: asymptomatic, symptomatic, and those who underwent carotid endarterectomy after an acute stroke. The results were compared to a negative/control group. Carotid endarterectomy had an impact on the expression of all monitored biomarkers. We observed statistically significant changes (p value 0.05-0.001) when comparing the groups among themselves, as well as the presence of ischemic tolerance of brain tissue to ischemic attacks. In conclusion, ADM, GADD45G, and TM4SF1 were affected in symptomatic patients, GADD45G and IL6 in acute patients, and CDKN1A and ADM in asymptomatic group after application of carotid endarterectomy.
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Affiliation(s)
- Marek Furman
- Institute of Neurobiology of Biomedical Research Center, Slovak Academy of Sciences, Soltesovej 4, 040 01 Kosice, Slovakia
| | - Vladimir Sihotsky
- Eastern Slovak Institute of Cardiovascular Diseases and Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Ondavska 8, 040 01 Kosice, Slovakia
| | - Michal Virag
- Eastern Slovak Institute of Cardiovascular Diseases and Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Ondavska 8, 040 01 Kosice, Slovakia
| | - Ivan Kopolovets
- Eastern Slovak Institute of Cardiovascular Diseases and Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Ondavska 8, 040 01 Kosice, Slovakia
| | - Miroslava Nemethova
- Institute of Neurobiology of Biomedical Research Center, Slovak Academy of Sciences, Soltesovej 4, 040 01 Kosice, Slovakia
| | - Rastislav Mucha
- Institute of Neurobiology of Biomedical Research Center, Slovak Academy of Sciences, Soltesovej 4, 040 01 Kosice, Slovakia.
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Chen L, Fang C, Yuan X, Liu M, Wu P, Zhong L, Chen Z. Has-miR-300-GADD45B promotes melanoma growth via cell cycle. Aging (Albany NY) 2023; 15:13920-13943. [PMID: 38070141 PMCID: PMC10756120 DOI: 10.18632/aging.205276] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 10/16/2023] [Indexed: 12/21/2023]
Abstract
Response to oncogenic factors like UV, GADD45 family in skin participates in scavenging ROS, DNA repair and cell cycle control. Because of this, the previous study of the chronic UVB injury model has found that hsa-miR-300 can conduct intercellular transport by exosomes and target regulation of GADD45B. Whether the hsa-miR-300-GADD45B still regulates tumor development by cell cycle pathway is unclear. Through transcriptomic analysis of primary (n=39) and metastatic (n=102) melanoma, it was confirmed that in metastatic samples, some of the 97 down-regulated genes participate in maintaining skin homeostasis while 42 up-regulated genes were enriched in cancer-related functions. Furthermore, CDKN1A, CDKN2A, CXCR4 and RAD51 in the melanoma pathway, were also differentially expressed between normal skin and melanoma. CDKN1A and CDKN2A were also found to be involved in TP53-dependent cell cycle regulation. In conclusion, it was speculated that CDKN1A, CDKN2A, TP53, GADD45B and hsa-miR-300 may have regulatory relationships. It was demonstrated that there is a bidirectional regulation between hsa-miR-300 and TP53. In addition, miR-300 can regulate CDKN1A by GADD45B/TP53 and promote melanoma growth by accelerating the cell cycle transition from G1/S to G2 phase.
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Affiliation(s)
- Long Chen
- Department of Burn Plastic and Cosmetology, Affiliated Fuling Hospital, Chongqing University, Chongqing 408099, China
- College of Bioengineering, Chongqing University, Chongqing 400000, China
- Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu 610500, Sichuan, China
- Non-Coding RNA and Drug Discovery Key Laboratory of Sichuan Province, Chengdu Medical College, Chengdu 610500, Sichuan, China
| | - Chenglong Fang
- Department of Rehabilitation, LinYi People’s Hospital, Linyi 276000, Shandong, China
| | - Xiaoxue Yuan
- College of Bioengineering, Chongqing University, Chongqing 400000, China
| | - Mengqi Liu
- College of Bioengineering, Chongqing University, Chongqing 400000, China
| | - Ping Wu
- Department of Burn Plastic and Cosmetology, Affiliated Fuling Hospital, Chongqing University, Chongqing 408099, China
| | - Li Zhong
- College of Bioengineering, Chongqing University, Chongqing 400000, China
| | - Zhiyong Chen
- Department of Burn Plastic and Cosmetology, Affiliated Fuling Hospital, Chongqing University, Chongqing 408099, China
- College of Bioengineering, Chongqing University, Chongqing 400000, China
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Misra G, Rajawat J, Pal R, Smith JC, Kumar A. Targeted inhibition of MASTL kinase activity induces apoptosis in breast cancer. Life Sci 2023; 334:122250. [PMID: 37931742 DOI: 10.1016/j.lfs.2023.122250] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 10/20/2023] [Accepted: 11/03/2023] [Indexed: 11/08/2023]
Abstract
Microtubule-associated serine/threonine kinase-like (MASTL) (or Greatwall kinase (GWL)) is an important cell cycle regulating kinase that regulates the G2-M transition. Uncontrolled MASTL activity is implicated in breast cancer progression. To date, very few inhibitors have been reported against this protein. Here, structure-based computational modeling indicates that the natural product flavopiridol (FLV) binds strongly to MASTL and these results are validated using molecular dynamics simulation studies. An in vitro kinase assay reveals an EC50 (effective concentration) value of FLV to be 82.1 nM and a better IC50 compared to the positive reference compound, staurosporine. FLV is found to inhibit MASTL kinase activity, arresting the cell growth in the G1 phase and inducing apoptosis in breast cancer cells. Consistent with these results differential gene expression obtained using RNA sequencing studies, and validated by RT PCR and immunoblot analysis, indicate that MASTL inhibition induces cell cycle arrest and apoptotic-related genes. Furthermore, metastasis- and inflammation-related genes are downregulated. Thus, the deregulation of MASTL signaling pathways on targeted inhibition of its kinase activity is revealed. This study lays a strong foundation for investigating FLV as a lead compound in breast cancer therapeutics.
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Affiliation(s)
- Gauri Misra
- National Institute of Biologicals (Ministry of Health and Family Welfare, Government of India), Noida 201309, India.
| | - Jyotika Rajawat
- Institute of Advanced Molecular Genetics & Infectious Diseases, ONGC, Centre for Advanced Studies, University of Lucknow, Lucknow 226 007, UP, India
| | - Rajesh Pal
- Precision Sarcoma Research Group, German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Jeremy C Smith
- Oak Ridge National Laboratory, Biosciences Division, UT/ORNL Center for Molecular Biophysics, Oak Ridge, TN, USA; Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, TN, USA
| | - Amit Kumar
- Department of Electrical and Electronic Engineering, University of Cagliari, Via Marengo 2, 09123 Cagliari, Italy
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Zhang L, Li N, Zhang X, Wu H, Yu S. Hexavalent chromium caused DNA damage repair and apoptosis via the PI3K/AKT/FOXO1 pathway triggered by oxidative stress in the lung of rat. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 267:115622. [PMID: 37890257 DOI: 10.1016/j.ecoenv.2023.115622] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 10/17/2023] [Accepted: 10/21/2023] [Indexed: 10/29/2023]
Abstract
Hexavalent chromium [Cr(VI)] is an occupational carcinogen that accumulates in the lungs and causes lung injury and even lung cancer. 36 SD male rats received inhalable intratracheal instillation of Cr(VI) (0.05, 0.25 mg Cr/kg) or the same volume (3 ml/kg) of normal saline weekly for 28 days (total 5 times). After 28 days of exposure, half of the rats in each group were sacrificed for investigation, and the rest stopped exposure and began to be self-repaired for two weeks. Histopathology analyses revealed that Cr(VI) induced slight dilatation and hemorrhage of perialveolar capillaries, pulmonary bronchodilation, and congestion with peripheral flaky-like necrosis accompanied by inflammatory cell infiltration, especially the 0.25 mg Cr/kg group. Cr(VI) exposure caused the increase of blood Cr, urinary Cr, MDA, urinary 8-hydroxy-2' -deoxyguanosine (8-OHdG), and the decrease of GSH and MDA, while two-week repair only reduced urinary Cr. Exposure to Cr(VI) significantly upregulated FOXO1 and downregulated p-AKT and p-FOXO1 for two weeks. PI3K in the 0.25 mg Cr/kg group was inhibited after two weeks of repair. Cr(VI) exposure mainly promoted GADD45a and CHK2 in the exposure group, promoted Bim, Bax/Bcl-2, and suppressed Bcl-2 and Bcl-xL in the repair group. These results demonstrate that Cr(VI) may induce DNA damage repair and apoptosis in the lung by activating the PI3K/AKT/FOXO1 pathway. Two-week repair may alleviate oxidative stress and DNA damage induced by Cr(VI) exposure but couldn't eliminate its effects. This study provides a new perspective for exploring the Cr(VI) induced lung cancer mechanism.
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Affiliation(s)
- Lixia Zhang
- Department of Scientific Research, Henan Medical College, Zhengzhou City, Henan Province 451191, China; School of Public Health, Zhengzhou University, Zhengzhou City, Henan Province 450001, China
| | - Ningning Li
- Department of Scientific Research, Henan Medical College, Zhengzhou City, Henan Province 451191, China
| | - Xiuzhi Zhang
- Department of Pathology, Henan Medical College, Zhengzhou City, Henan Province 451191, China
| | - Hui Wu
- Henan Institute for Occupational Medicine, Zhengzhou City, Henan Province 450052, China
| | - Shanfa Yu
- Department of Scientific Research, Henan Medical College, Zhengzhou City, Henan Province 451191, China.
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Tölle J, Koch A, Schlicht K, Finger D, Kaehler W, Höppner M, Graetz C, Dörfer C, Schulte DM, Fawzy El-Sayed K. Effect of Hyperbaric Oxygen and Inflammation on Human Gingival Mesenchymal Stem/Progenitor Cells. Cells 2023; 12:2479. [PMID: 37887323 PMCID: PMC10605813 DOI: 10.3390/cells12202479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 10/06/2023] [Accepted: 10/11/2023] [Indexed: 10/28/2023] Open
Abstract
The present study explores for the first time the effect of hyperbaric oxygen (HBO) on gingival mesenchymal stem cells' (G-MSCs) gene expression profile, intracellular pathway activation, pluripotency, and differentiation potential under an experimental inflammatory setup. G-MSCs were isolated from five healthy individuals (n = 5) and characterized. Single (24 h) or double (72 h) HBO stimulation (100% O2, 3 bar, 90 min) was performed under experimental inflammatory [IL-1β (1 ng/mL)/TNF-α (10 ng/mL)/IFN-γ (100 ng/mL)] and non-inflammatory micro-environment. Next Generation Sequencing and KEGG pathway enrichment analysis, G-MSCs' pluripotency gene expression, Wnt-/β-catenin pathway activation, proliferation, colony formation, and differentiation were investigated. G-MSCs demonstrated all mesenchymal stem/progenitor cells' characteristics. The beneficial effect of a single HBO stimulation was evident, with anti-inflammatory effects and induction of differentiation (TLL1, ID3, BHLHE40), proliferation/cell survival (BMF, ID3, TXNIP, PDK4, ABL2), migration (ABL2) and osteogenic differentiation (p < 0.05). A second HBO stimulation at 72 h had a detrimental effect, significantly increasing the inflammation-induced cellular stress and ROS accumulation through HMOX1, BHLHE40, and ARL4C amplification and pathway enrichment (p < 0.05). Results outline a positive short-term single HBO anti-inflammatory, regenerative, and differentiation stimulatory effect on G-MSCs. A second (72 h) stimulation is detrimental to the same properties. The current results could open new perspectives in the clinical application of short-termed HBO induction in G-MSCs-mediated periodontal reparative/regenerative mechanisms.
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Affiliation(s)
- Johannes Tölle
- Clinic for Conservative Dentistry and Periodontology, School of Dental Medicine, Christian-Albrechts-University, 24105 Kiel, Germany; (J.T.); (D.F.); (C.G.); (C.D.)
| | - Andreas Koch
- German Naval Medical Institute, 24119 Kiel, Germany; (A.K.); (W.K.)
| | - Kristina Schlicht
- Institute of Diabetes and Clinical Metabolic Research, University Hospital Schleswig-Holstein, 24105 Kiel, Germany; (K.S.); (D.M.S.)
| | - Dirk Finger
- Clinic for Conservative Dentistry and Periodontology, School of Dental Medicine, Christian-Albrechts-University, 24105 Kiel, Germany; (J.T.); (D.F.); (C.G.); (C.D.)
| | - Wataru Kaehler
- German Naval Medical Institute, 24119 Kiel, Germany; (A.K.); (W.K.)
| | - Marc Höppner
- Institute of Clinical Molecular Biology, School of Medicine, Christian-Albrechts-University, 24105 Kiel, Germany;
| | - Christian Graetz
- Clinic for Conservative Dentistry and Periodontology, School of Dental Medicine, Christian-Albrechts-University, 24105 Kiel, Germany; (J.T.); (D.F.); (C.G.); (C.D.)
| | - Christof Dörfer
- Clinic for Conservative Dentistry and Periodontology, School of Dental Medicine, Christian-Albrechts-University, 24105 Kiel, Germany; (J.T.); (D.F.); (C.G.); (C.D.)
| | - Dominik M. Schulte
- Institute of Diabetes and Clinical Metabolic Research, University Hospital Schleswig-Holstein, 24105 Kiel, Germany; (K.S.); (D.M.S.)
- Division of Endocrinology, Diabetes and Clinical Nutrition, Department of Internal Medicine I, University Hospital Schleswig-Holstein, 24105 Kiel, Germany
| | - Karim Fawzy El-Sayed
- Clinic for Conservative Dentistry and Periodontology, School of Dental Medicine, Christian-Albrechts-University, 24105 Kiel, Germany; (J.T.); (D.F.); (C.G.); (C.D.)
- Oral Medicine and Periodontology Department, Faculty of Dentistry, Cairo University, Cairo 12613, Egypt
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Zeng LP, Qin YQ, Lu XM, Feng ZB, Fang XL. Identify GADD45G as a potential target of 4-methoxydalbergione in treatment of liver cancer: bioinformatics analysis and in vivo experiment. World J Surg Oncol 2023; 21:324. [PMID: 37833694 PMCID: PMC10571512 DOI: 10.1186/s12957-023-03214-3] [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: 04/10/2023] [Accepted: 10/03/2023] [Indexed: 10/15/2023] Open
Abstract
BACKGROUND The growth arrest and DNA damage-inducible gene gamma (GADD45G), an important member of GADD45 family, has been connected to the development of certain human cancers. Our previous studies have confirmed that GADD45G expression could be upregulated by 4-methoxydalbergione (4MOD) in liver cancer cells, but its potential pathological role in hepatocellular carcinoma (HCC) has not been fully understood. This study aimed to determine potential role of GADD45G in HCC, and the effects of 4-methoxydalbergione (4MOD) on the regulation of GADD45G expression in vivo were also analyzed. METHODS Publicly available data and in-house immunohistochemistry (IHC) experiments were utilized to explore the expression profiles and clinical significance of GADD45G in HCC samples. Functional enrichment analysis based on GADD45G co-expression genes was used to excavate the molecular mechanism of GADD45G in HCC. We also conducted in vivo experiment on BALB/c nude mice to excavate the inhibitory effect of 4MOD on HCC and to evaluate the differences in the expression of GADD45G in xenograft tissues between the 4MOD-treated and untreated groups. RESULTS GADD45G displayed significant low expression in HCC tissues. Downregulated expression of GADD45G was positively correlated with some high risk factors in HCC patients and predicted worse prognosis of HCC patients. There was a close association of GADD45G mRNA expression and immune cells, including neutrophils, NK cells, CD8 T cells, and macrophages. Co-expressed genes of GADD45G were involved in several pathways including cell cycle, carbon metabolism, and peroxisome. 4MOD could significantly suppress the growth of HCC in vivo, and this inhibitory effect was dependent on the upregulation of GADD45G expression. CONCLUSION GADD45G expression can be used as a new clinical biomarker for HCC and GADD45G may be a potential target for the anti-cancer effect of 4MOD in liver cancer.
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Affiliation(s)
- Li-Ping Zeng
- Department of Pathology, Hunan University of Medicine, 492 Jinxinan RD, Huaihua, Hunan, 418000, People's Republic of China
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong RD, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China
| | - Yu-Qi Qin
- Department of Pathology, Jiangbin Hospital of Guangxi Zhuang Autonomous Region, 85 Hedi RD, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China
| | - Xiao-Min Lu
- Department of Pathology, Hunan University of Medicine, 492 Jinxinan RD, Huaihua, Hunan, 418000, People's Republic of China
| | - Zhen-Bo Feng
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong RD, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China.
| | - Xian-Lei Fang
- Department of Pathology, Hunan University of Medicine, 492 Jinxinan RD, Huaihua, Hunan, 418000, People's Republic of China.
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Robinson KS, Toh GA, Firdaus MJ, Tham KC, Rozario P, Lim CK, Toh YX, Lau ZH, Binder SC, Mayer J, Bonnard C, Schmidt FI, Common JE, Zhong FL. Diphtheria toxin activates ribotoxic stress and NLRP1 inflammasome-driven pyroptosis. J Exp Med 2023; 220:e20230105. [PMID: 37642997 PMCID: PMC10465786 DOI: 10.1084/jem.20230105] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 06/01/2023] [Accepted: 07/14/2023] [Indexed: 08/31/2023] Open
Abstract
The ZAKα-driven ribotoxic stress response (RSR) is activated by ribosome stalling and/or collisions. Recent work demonstrates that RSR also plays a role in innate immunity by activating the human NLRP1 inflammasome. Here, we report that ZAKα and NLRP1 sense bacterial exotoxins that target ribosome elongation factors. One such toxin, diphtheria toxin (DT), the causative agent for human diphtheria, triggers RSR-dependent inflammasome activation in primary human keratinocytes. This process requires iron-mediated DT production in the bacteria, as well as diphthamide synthesis and ZAKα/p38-driven NLRP1 phosphorylation in host cells. NLRP1 deletion abrogates IL-1β and IL-18 secretion by DT-intoxicated keratinocytes, while ZAKα deletion or inhibition additionally limits both pyroptotic and inflammasome-independent non-pyroptotic cell death. Consequently, pharmacologic inhibition of ZAKα is more effective than caspase-1 inhibition at protecting the epidermal barrier in a 3D skin model of cutaneous diphtheria. In summary, these findings implicate ZAKα-driven RSR and the NLRP1 inflammasome in antibacterial immunity and might explain certain aspects of diphtheria pathogenesis.
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Affiliation(s)
- Kim Samirah Robinson
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
- The A*STAR Skin Research Labs, Singapore, Singapore
| | - Gee Ann Toh
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | | | | | - Pritisha Rozario
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Chrissie K. Lim
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore
| | - Ying Xiu Toh
- The A*STAR Skin Research Labs, Singapore, Singapore
| | - Zhi Heng Lau
- The A*STAR Skin Research Labs, Singapore, Singapore
| | | | - Jacob Mayer
- Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany
| | | | - Florian I. Schmidt
- Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany
| | | | - Franklin L. Zhong
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
- Skin Research Institute of Singapore, Singapore, Singapore
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40
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Zhang L, Shen L, Huang Y, Cui S, Zhao Q, Zhang C, Zhuang S, Jiang G. Embryonic Exposure to UV-328 Impairs the Cell Cycle in Zebrafish ( Danio rerio) by Inhibiting the p38 MAPK/p53/Gadd45a Signaling Pathway. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2023. [PMID: 37384941 DOI: 10.1021/acs.est.3c02842] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/01/2023]
Abstract
The benzotriazole UV stabilizer UV-328 is well known for its potent antioxidative properties; however, there are concerns about how it may affect signaling nodes and lead to negative consequences. This study identified the key signaling cascades involved in oxidative stress in zebrafish (Danio rerio) larvae and evaluated the cell cycle arrests and associated developmental alternations. Exposure to UV-328 at 0.25, 0.50, 1.00, 2.00, and 4.00 μg/L downregulated gene expression associated with oxidative stress (cat, gpx, gst, and sod) and apoptosis (caspase-3, caspase-6, caspase-8, and caspase-9) at 3 days postfertilization (dpf). The transcriptome aberration in zebrafish with disrupted p38 mitogen-activated protein kinase (MAPK) cascades was validated based on decreased mRNA expressions of p38 MAPK (0.36-fold), p53 (0.33-fold), and growth arrest and DNA damage-inducible protein 45 α (Gadd45a) (0.52-fold) after a 3- and 14-day exposure alongside a correspondingly decreased protein expression. The percentage of cells in the Gap 1 (G1) phase increased from 69.60% to a maximum of 77.07% (p < 0.05) in the 3 dpf embryos. UV-328 inhibited the p38 MAPK/p53/Gadd45a regulatory circuit but promoted G1 phase cell cycle arrest, abnormally accelerating the embryo hatching and heart rate. This study provided mechanistic insights that enrich the risk profiles of UV-328.
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Affiliation(s)
- Liang Zhang
- Key Laboratory of Environment Remediation and Ecological Health, Ministry of Education, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China
- Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
| | - Lilai Shen
- Key Laboratory of Environment Remediation and Ecological Health, Ministry of Education, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China
| | - Yizhou Huang
- Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
| | - Shixuan Cui
- Key Laboratory of Environment Remediation and Ecological Health, Ministry of Education, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China
| | - Qiming Zhao
- Key Laboratory of Environment Remediation and Ecological Health, Ministry of Education, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China
| | - Chunlong Zhang
- Department of Environmental Sciences, University of Houston-Clear Lake, 2700 Bay Area Boulevard, Houston, Texas 77058, United States
| | - Shulin Zhuang
- Key Laboratory of Environment Remediation and Ecological Health, Ministry of Education, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China
- Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
| | - Guibin Jiang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
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Wang X, Hao Y, Chen J, Ding P, Lv X, Zhou D, Li L, Li L, Xu Y, Zhu Y, Zhang W, Chen L, Liao T, He X, Ji QH, Hu W. Nuclear complement C3b promotes paclitaxel resistance by assembling the SIN3A/HDAC1/2 complex in non-small cell lung cancer. Cell Death Dis 2023; 14:351. [PMID: 37291119 PMCID: PMC10250389 DOI: 10.1038/s41419-023-05869-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 04/12/2023] [Accepted: 05/31/2023] [Indexed: 06/10/2023]
Abstract
In addition to the classical role as a serum effector system of innate immunity, accumulating evidence suggests that intracellular complement components have indispensable functions in immune defense, T cell homeostasis, and tumor cell proliferation and metastasis. Here, we revealed that complement component 3 (C3) is remarkably upregulated in paclitaxel (PTX)-resistant non-small cell lung cancer (NSCLC) cells and that knockdown of C3 promoted PTX-induced cell apoptosis, sensitizing resistant cells to PTX therapy. Ectopic C3 decreased PTX-induced apoptosis and induced resistance to PTX treatment in original NSCLC cells. Interestingly, C3b, the activated fragment of C3, was found to translocate into the nucleus and physically associate with the HDAC1/2-containing SIN3A complex to repress the expression of GADD45A, which plays an important role in cell growth inhibition and apoptosis induction. Importantly, C3 downregulated GADD45A by enhancing the binding of the SIN3A complex with the promoter of GADD45A, thus decreasing the H3Ac level to compress chromatin around the GADD45A locus. Subsequently, ectopic GADD45A promoted PTX-induced cell apoptosis, sensitizing resistant cells to PTX therapy, and insufficiency of GADD45A in original cancer cells induced resistance to PTX treatment. These findings identify a previously unknown nucleus location and oncogenic property for C3 in chemotherapy and provide a potential therapeutic opportunity to overcome PTX resistance.
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Affiliation(s)
- Xiaochao Wang
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yan Hao
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Jianfeng Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 East Dongfeng Road, Guangzhou, Guangdong, 510060, China
| | - Peipei Ding
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Xinyue Lv
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Danlei Zhou
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Ling Li
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Luying Li
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yanqing Xu
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yumeng Zhu
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Wei Zhang
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Lu Chen
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Tian Liao
- Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Xianghuo He
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Qing-Hai Ji
- Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Weiguo Hu
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
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Sang N, Zhong X, Gou K, Liu H, Xu J, Zhou Y, Zhou X, Liu Y, Chen Z, Zhou Y, Li Y, Tao L, Su N, Zhou L, Qiu J, Yang X, Zuo Z, Fu L, Zhang J, Li D, Li C, Sun Q, Lei J, Li R, Yang S, Cen X, Zhao Y. Pharmacological inhibition of LSD1 suppresses growth of hepatocellular carcinoma by inducing GADD45B. MedComm (Beijing) 2023; 4:e269. [PMID: 37250145 PMCID: PMC10209615 DOI: 10.1002/mco2.269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 03/29/2023] [Accepted: 04/05/2023] [Indexed: 05/31/2023] Open
Abstract
Lysine-specific histone demethylase 1 (LSD1) is an attractive target for malignancies therapy. Nevertheless, its role in hepatocellular carcinoma (HCC) progression and the potential of its inhibitor in HCC therapy remains unclear. Here, we show that LSD1 overexpression in human HCC tissues is associated with HCC progression and poor patient survival. ZY0511, a highly selective and potent inhibitor of LSD1, suppressed human HCC cell proliferation in vitro and tumor growth in cell-derived and patient-derived HCC xenograft models in vivo. Mechanistically, ZY0511 induced mRNA expression of growth arrest and DNA damage-inducible gene 45beta (GADD45B) by inducing histone H3 at lysine 4 (H3K4) methylation at the promoter of GADD45B, a novel target gene of LSD1. In human HCC tissues, LSD1 level was correlated with a decreased level of GADD45B, which was associated with HCC progression and predicted poor patient survival. Moreover, co-administration of ZY0511 and DTP3, which specifically enhanced the pro-apoptotic effect of GADD45B, effectively inhibited HCC cell proliferation both in vitro and in vivo. Collectively, our study revealed the potential value of LSD1 as a promising target of HCC therapy. ZY0511 is a promising candidate for HCC therapy through upregulating GADD45B, thereby providing a novel combinatorial strategy for treating HCC.
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Affiliation(s)
- Na Sang
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China Hospital, West China Medical School, Sichuan UniversityChengduChina
- Department of Radiation OncologyRadiation Oncology Key Laboratory of Sichuan ProvinceSichuan Clinical Research Center for CancerSichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of ChinaChengduChina
| | - Xi Zhong
- Department of PharmacologyKey Laboratory of Drug Targeting and Drug Delivery System of the Education MinistrySichuan Engineering Laboratory for Plant‐Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengduChina
| | - Kun Gou
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China Hospital, West China Medical School, Sichuan UniversityChengduChina
| | - Huan Liu
- Department of PharmacologyKey Laboratory of Drug Targeting and Drug Delivery System of the Education MinistrySichuan Engineering Laboratory for Plant‐Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengduChina
- National Chengdu Center for Safety Evaluation of DrugsState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduChina
| | - Jing Xu
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China Hospital, West China Medical School, Sichuan UniversityChengduChina
| | - Yang Zhou
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China Hospital, West China Medical School, Sichuan UniversityChengduChina
| | - Xia Zhou
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China Hospital, West China Medical School, Sichuan UniversityChengduChina
| | - Yuanzhi Liu
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China Hospital, West China Medical School, Sichuan UniversityChengduChina
| | - Zhiqian Chen
- Department of PharmacologyKey Laboratory of Drug Targeting and Drug Delivery System of the Education MinistrySichuan Engineering Laboratory for Plant‐Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengduChina
| | - Yue Zhou
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China Hospital, West China Medical School, Sichuan UniversityChengduChina
| | - Yan Li
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China Hospital, West China Medical School, Sichuan UniversityChengduChina
| | - Lei Tao
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China Hospital, West China Medical School, Sichuan UniversityChengduChina
| | - Na Su
- Department of PharmacyWest China Hospital, West China Medical School, Sichuan UniversityChengduChina
| | - Lingyun Zhou
- Center of Infectious DiseasesWest China HospitalSichuan UniversityChengduChina
| | - Jiahao Qiu
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China Hospital, West China Medical School, Sichuan UniversityChengduChina
| | - Xinyu Yang
- Department of PharmacologyKey Laboratory of Drug Targeting and Drug Delivery System of the Education MinistrySichuan Engineering Laboratory for Plant‐Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengduChina
| | - Zeping Zuo
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China Hospital, West China Medical School, Sichuan UniversityChengduChina
| | - Li Fu
- Core Facility CenterWest China HospitalSichuan UniversityChengduChina
| | - Jingyao Zhang
- Core Facility CenterWest China HospitalSichuan UniversityChengduChina
| | - Dan Li
- Core Facility CenterWest China HospitalSichuan UniversityChengduChina
| | - Cong Li
- Core Facility CenterWest China HospitalSichuan UniversityChengduChina
| | - Qingxiang Sun
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China Hospital, West China Medical School, Sichuan UniversityChengduChina
| | - Jian Lei
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China Hospital, West China Medical School, Sichuan UniversityChengduChina
| | - Rui Li
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China Hospital, West China Medical School, Sichuan UniversityChengduChina
| | - Shengyong Yang
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China Hospital, West China Medical School, Sichuan UniversityChengduChina
| | - Xiaobo Cen
- National Chengdu Center for Safety Evaluation of DrugsState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduChina
| | - Yinglan Zhao
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China Hospital, West China Medical School, Sichuan UniversityChengduChina
- Department of PharmacologyKey Laboratory of Drug Targeting and Drug Delivery System of the Education MinistrySichuan Engineering Laboratory for Plant‐Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengduChina
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Luan W, Wright AL, Brown-Wright H, Le S, San Gil R, Madrid San Martin L, Ling K, Jafar-Nejad P, Rigo F, Walker AK. Early activation of cellular stress and death pathways caused by cytoplasmic TDP-43 in the rNLS8 mouse model of ALS and FTD. Mol Psychiatry 2023; 28:2445-2461. [PMID: 37012334 PMCID: PMC10611572 DOI: 10.1038/s41380-023-02036-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 03/02/2023] [Accepted: 03/14/2023] [Indexed: 04/05/2023]
Abstract
TAR DNA binding protein 43 (TDP-43) pathology is a key feature of over 95% of amyotrophic lateral sclerosis (ALS) and nearly half of frontotemporal dementia (FTD) cases. The pathogenic mechanisms of TDP-43 dysfunction are poorly understood, however, activation of cell stress pathways may contribute to pathogenesis. We, therefore, sought to identify which cell stress components are critical for driving disease onset and neurodegeneration in ALS and FTD. We studied the rNLS8 transgenic mouse model, which expresses human TDP-43 with a genetically-ablated nuclear localisation sequence within neurons of the brain and spinal cord resulting in cytoplasmic TDP-43 pathology and progressive motor dysfunction. Amongst numerous cell stress-related biological pathways profiled using qPCR arrays, several critical integrated stress response (ISR) effectors, including CCAAT/enhancer-binding homologous protein (Chop/Ddit3) and activating transcription factor 4 (Atf4), were upregulated in the cortex of rNLS8 mice prior to disease onset. This was accompanied by early up-regulation of anti-apoptotic gene Bcl2 and diverse pro-apoptotic genes including BH3-interacting domain death agonist (Bid). However, pro-apoptotic signalling predominated after onset of motor phenotypes. Notably, pro-apoptotic cleaved caspase-3 protein was elevated in the cortex of rNLS8 mice at later disease stages, suggesting that downstream activation of apoptosis drives neurodegeneration following failure of early protective responses. Unexpectedly, suppression of Chop in the brain and spinal cord using antisense oligonucleotide-mediated silencing had no effect on overall TDP-43 pathology or disease phenotypes in rNLS8 mice. Cytoplasmic TDP-43 accumulation therefore causes very early activation of ISR and both anti- and pro-apoptotic signalling that switches to predominant pro-apoptotic activation later in disease. These findings suggest that precise temporal modulation of cell stress and death pathways may be beneficial to protect against neurodegeneration in ALS and FTD.
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Affiliation(s)
- Wei Luan
- Neurodegeneration Pathobiology Laboratory, Queensland Brain Institute, University of Queensland, St Lucia, QLD, Australia
| | - Amanda L Wright
- Neurodegeneration Pathobiology Laboratory, Queensland Brain Institute, University of Queensland, St Lucia, QLD, Australia
- Centre for Motor Neuron Disease Research, Macquarie Medical School, Macquarie University, Sydney, NSW, Australia
| | - Heledd Brown-Wright
- Neurodegeneration Pathobiology Laboratory, Queensland Brain Institute, University of Queensland, St Lucia, QLD, Australia
| | - Sheng Le
- Centre for Motor Neuron Disease Research, Macquarie Medical School, Macquarie University, Sydney, NSW, Australia
| | - Rebecca San Gil
- Neurodegeneration Pathobiology Laboratory, Queensland Brain Institute, University of Queensland, St Lucia, QLD, Australia
| | - Lidia Madrid San Martin
- Neurodegeneration Pathobiology Laboratory, Queensland Brain Institute, University of Queensland, St Lucia, QLD, Australia
| | - Karen Ling
- Ionis Pharmaceuticals, Carlsbad, CA, 90201, USA
| | | | - Frank Rigo
- Ionis Pharmaceuticals, Carlsbad, CA, 90201, USA
| | - Adam K Walker
- Neurodegeneration Pathobiology Laboratory, Queensland Brain Institute, University of Queensland, St Lucia, QLD, Australia.
- Centre for Motor Neuron Disease Research, Macquarie Medical School, Macquarie University, Sydney, NSW, Australia.
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Chen L, Hua J, He X. Genetic analysis of cuproptosis subtypes and immunological features in severe influenza. Microb Pathog 2023; 180:106162. [PMID: 37207785 DOI: 10.1016/j.micpath.2023.106162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/15/2023] [Accepted: 05/17/2023] [Indexed: 05/21/2023]
Abstract
The mechanisms regulating cuproptosis in severe influenza are still unknown. We aimed to identify the molecular subtypes of cuproptosis and immunological characteristics associated with severe influenza in patients requiring invasive mechanical ventilation (IMV). The expression of cuproptosis modulatory factors and immunological characteristics of these patients were analyzed using the public datasets (GSE101702, GSE21802, and GSE111368) from the Gene Expression Omnibus (GEO). Seven cuproptotic-associated genes (ATP7B, ATP7A, FDX1, LIAS, DLD, MTF1, DBT) related to active immune responses were identified in patients suffering from severe and non-severe influenza and two cuproptosis-associated molecular subtypes were discovered in severe influenza patients. Singe-set gene set expression analysis (SsGSEA) indicated that compared with subtype 2, subtype 1 was characterized by reduced adaptive cellular immune responses and increased neutrophil activation. Gene set variation assessment revealed that cluster-specific differentially expressed genes (DEGs) in subtype 1 were involved in autophagy, apoptosis, oxidative phosphorylation, and T cell, immune, and inflammatory responses, amongst others. The random forest (RF) model revealed the most differentiating efficiency with relatively small residual and root mean square error and an increased area under the curve value (AUC = 0.857). Lastly, a five-gene-based RF model (CD247, GADD45A, KIF1B, LIN7A, HLA_DPA1) was established, which showed satisfactory efficiency in the test datasets GSE111368 (AUC = 0.819). Nomogram calibration and decision curve analysis demonstrated its accuracy for the prediction of severe influenza. This study suggests that cuproptosis might be associated with the immunopathology of severe influenza. Additionally, an efficient model for the prediction of cuproptosis subtypes was developed which will contribute to the prevention and treatment of severe influenza patients needing IMV.
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Affiliation(s)
- Liang Chen
- Department of Infectious Diseases, Nanjing Lishui People's Hospital, Zhongda Hospital Lishui Branch, Southeast University, Nanjing, China.
| | - Jie Hua
- Department of Gastroenterology, Liyang People's Hospital, Liyang Branch Hospital of Jiangsu Province Hospital, Nanjing, China
| | - Xiaopu He
- Department of Geriatric Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Haonan L, Zehang S, Jiacong H, Zhenxing W, Shengli Z, Bailing C, Zhuning C, Haoran K. Interleukin-23 mediates the reduction of GADD45a expression to attenuate oxidative stress-induced cellular senescence in human fibroblasts. Mech Ageing Dev 2023; 212:111808. [PMID: 37030535 DOI: 10.1016/j.mad.2023.111808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 03/06/2023] [Accepted: 04/04/2023] [Indexed: 04/09/2023]
Abstract
The interleukin-23 (IL-23) plays a key role in various inflammatory diseases, such as spondyloarthritis, by acting on target cells through the IL-23/IL-17 pathway. Recent studies have suggested that IL-23 can also directly affect fibroblasts. Senescent fibroblasts are implicated in many physiological and pathological processes, including those related to inflammatory diseases. However, it remains unclear whether IL-23 can influence fibroblast senescence and contribute to pathogenesis. In our study, we investigated the effects of IL-23 on oxidative stress-induced senescence in human fibroblasts, using the H2O2-induced senescence model, and found that IL-23 pre-treatment significantly attenuated senescence in these cells. RNA-seq and in vitro experiments indicate that IL-23 may act by regulating GADD45a expression and the p38/MAPK pathway. Furthermore, we confirmed that IL-23 inhibits oxidative stress-induced up-regulation of GADD45a expression and subsequent activation of the p38/MAPK pathway through GADD45a knockdown and overexpression experiments. Our study is the first to demonstrate that IL-23 can effectively suppress the senescence of fibroblasts induced by oxidative stress, by inhibiting the H2O2-triggered induction of GADD45a and subsequent activation of the p38/MAPK pathway. These findings have significant implications for understanding the role of IL-23 in immune-inflammatory diseases and may provide a new avenue for the diagnosis and treatment of these conditions.
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Chen Y, Wu X, Liu X, Lai J, Gong Q. Comparative transcriptome analysis provides insights into the TDG supersaturation stress response of Schizothorax davidi. Comp Biochem Physiol C Toxicol Pharmacol 2023; 269:109618. [PMID: 37004899 DOI: 10.1016/j.cbpc.2023.109618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 03/23/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023]
Abstract
In the dam discharge season, the supersaturation of total dissolved gas (TDG) in the downstream channel can seriously affect the survival of aquatic organisms. However, few studies have revealed the mechanism by which TDG supersaturation affects the physiology of fish thus far. The present study was conducted to study the mechanism of the effect of TDG supersaturation on Schizothorax davidi, a species that is very sensitive to gas bubble disease. S. davidi was exposed to 116 % TDG supersaturation stress for 24 h. Serum biochemical tests showed that the aspartate aminotransferase and alanine aminotransferase levels after TDG supersaturation exposure were significantly decreased compared to those in the control group, while superoxide dismutase activity was significantly increased. RNA-Seq of gill tissues identified 1890 differentially expressed genes (DEGs), which consisted of 862 upregulated genes and 1028 downregulated genes, in the TDG supersaturation group vs. the control group. Pathway enrichment analysis revealed that the cell cycle, apoptosis and immune signaling pathways were affected by TDG stress. The results of this study may contribute to our understanding of the underlying molecular mechanism of environmental stress in fish.
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Affiliation(s)
- Yeyu Chen
- The Fishery Institute of the Sichuan Academy of Agricultural Sciences, Chengdu 611730, China
| | - Xiaoyun Wu
- The Fishery Institute of the Sichuan Academy of Agricultural Sciences, Chengdu 611730, China
| | - Xiaoqing Liu
- Key Laboratory of Fluid and Power Machinery, Ministry of Education, Xihua University, Chengdu 610039, China
| | - Jiansheng Lai
- The Fishery Institute of the Sichuan Academy of Agricultural Sciences, Chengdu 611730, China
| | - Quan Gong
- The Fishery Institute of the Sichuan Academy of Agricultural Sciences, Chengdu 611730, China.
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Ahrweiler-Sawaryn MC, Biswas A, Frias C, Frias J, Wilke NL, Wilke N, Berkessel A, Prokop A. Novel gold(I) complexes induce apoptosis in leukemia cells via the ROS-induced mitochondrial pathway with an upregulation of Harakiri and overcome multi drug resistances in leukemia and lymphoma cells and sensitize drug resistant tumor cells to apoptosis in vitro. Biomed Pharmacother 2023; 161:114507. [PMID: 36958194 DOI: 10.1016/j.biopha.2023.114507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 03/02/2023] [Accepted: 03/07/2023] [Indexed: 03/25/2023] Open
Abstract
Gold complexes could be promising for tumor therapy because of their cytotoxic and cytostatic properties. We present novel gold(I) complexes and clarify whether they also show antitumor activity by studying apoptosis induction in different tumor cell lines in vitro, comparing the compounds on resistant cells and analyzing the mechanism of action. We particularly highlight one gold complex that shows cytostatic and cytotoxic effects on leukemia and lymphoma cells already in the nanomolar range, induces apoptosis via the intrinsic signaling pathway, and plays a role in the production of reactive oxygen species. Furthermore, not only did we demonstrate a large number of resistance overcomes on resistant cell lines, but some of these cell lines were significantly more sensitive to the new gold compound. Our results show promising properties for the gold compound as anti-tumor drug and suggest that it can subvert resistance mechanisms and thus targets resistant cells for killing.
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Affiliation(s)
- Marie-C Ahrweiler-Sawaryn
- Department of Pediatric Hematology/Oncology, Helios Clinic Schwerin, Wismarsche Straße 393-397, 19055 Schwerin, Germany; Department of Pediatric Hematology/Oncology, Children's Hospital Cologne, Amsterdamer Straße 59, 50735 Cologne, Germany.
| | - Animesh Biswas
- Department of Chemistry, Organic Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne, Germany
| | - Corazon Frias
- Department of Pediatric Hematology/Oncology, Helios Clinic Schwerin, Wismarsche Straße 393-397, 19055 Schwerin, Germany; Department of Pediatric Hematology/Oncology, Children's Hospital Cologne, Amsterdamer Straße 59, 50735 Cologne, Germany
| | - Jerico Frias
- Department of Pediatric Hematology/Oncology, Helios Clinic Schwerin, Wismarsche Straße 393-397, 19055 Schwerin, Germany; Department of Pediatric Hematology/Oncology, Children's Hospital Cologne, Amsterdamer Straße 59, 50735 Cologne, Germany
| | - Nicola L Wilke
- Department of Pediatric Hematology/Oncology, Helios Clinic Schwerin, Wismarsche Straße 393-397, 19055 Schwerin, Germany; Department of Pediatric Hematology/Oncology, Children's Hospital Cologne, Amsterdamer Straße 59, 50735 Cologne, Germany
| | - Nathalie Wilke
- Department of Pediatric Hematology/Oncology, Helios Clinic Schwerin, Wismarsche Straße 393-397, 19055 Schwerin, Germany; Department of Pediatric Hematology/Oncology, Children's Hospital Cologne, Amsterdamer Straße 59, 50735 Cologne, Germany
| | - Albrecht Berkessel
- Department of Chemistry, Organic Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne, Germany
| | - Aram Prokop
- Department of Pediatric Hematology/Oncology, Helios Clinic Schwerin, Wismarsche Straße 393-397, 19055 Schwerin, Germany; Department of Pediatric Hematology/Oncology, Children's Hospital Cologne, Amsterdamer Straße 59, 50735 Cologne, Germany; Department of Research, Medical School Hamburg (MSH), University of Applied Sciences and Medical University, Am Kaiserkai 1, 20457, Germany
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Anerillas C, Altés G, Gorospe M. MAPKs in the early steps of senescence implemEMTation. Front Cell Dev Biol 2023; 11:1083401. [PMID: 37009481 PMCID: PMC10060890 DOI: 10.3389/fcell.2023.1083401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Accepted: 03/03/2023] [Indexed: 03/18/2023] Open
Abstract
Evidence is accumulating that the earliest stages of the DNA damage response can direct cells toward senescence instead of other cell fates. In particular, tightly regulated signaling through Mitogen-Activated Protein Kinases (MAPKs) in early senescence can lead to a sustained pro-survival program and suppress a pro-apoptotic program. Importantly, an epithelial-to-mesenchymal Transition (EMT)-like program appears essential for preventing apoptosis and favoring senescence following DNA damage. In this review, we discuss how MAPKs might influence EMT features to promote a senescent phenotype that increases cell survival at the detriment of tissue function.
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Qi P, Huang M, Li T. Identification of potential biomarkers and therapeutic targets for posttraumatic acute respiratory distress syndrome. BMC Med Genomics 2023; 16:54. [PMID: 36918848 PMCID: PMC10012314 DOI: 10.1186/s12920-023-01482-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 03/08/2023] [Indexed: 03/16/2023] Open
Abstract
BACKGROUND Despite improved supportive care, posttraumatic acute respiratory distress syndrome (ARDS) mortality has improved very little in recent years. Additionally, ARDS diagnosis is delayed or missed in many patients. We analyzed co-differentially expressed genes (co-DEGs) to explore the relationships between severe trauma and ARDS to reveal potential biomarkers and therapeutic targets for posttraumatic ARDS. METHODS Two gene expression datasets (GSE64711 and GSE76293) were downloaded from the Gene Expression Omnibus. The GSE64711 dataset included a subset of 244 severely injured trauma patients and 21 healthy controls. GSE76293 specimens were collected from 12 patients with ARDS who were recruited from trauma intensive care units and 11 age- and sex-matched healthy volunteers. Trauma DEGs and ARDS DEGs were identified using the two datasets. Subsequently, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein-protein interaction network analyses were performed to elucidate the molecular functions of the DEGs. Then, hub genes of the co-DEGs were identified. Finally, to explore whether posttraumatic ARDS and septic ARDS are common targets, we included a third dataset (GSE100159) for corresponding verification. RESULTS 90 genes were upregulated and 48 genes were downregulated in the two datasets and were therefore named co-DEGs. These co-DEGs were significantly involved in multiple inflammation-, immunity- and neutrophil activation-related biological processes. Ten co-upregulated hub genes (GAPDH, MMP8, HGF, MAPK14, LCN2, CD163, ENO1, CD44, ARG1 and GADD45A) and five co-downregulated hub genes (HERC5, IFIT2, IFIT3, RSAD2 and IFIT1) may be considered potential biomarkers and therapeutic targets for posttraumatic ARDS. Through the verification of the third dataset, posttraumatic ARDS may have its own unique targets worthy of further exploration. CONCLUSION This exploratory analysis supports a relationship between trauma and ARDS pathophysiology, specifically in relationship to the identified hub genes. These data may serve as potential biomarkers and therapeutic targets for posttraumatic ARDS.
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Affiliation(s)
- Peng Qi
- Department of Emergency, First Medical Center of Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China
| | - Mengjie Huang
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China
| | - Tanshi Li
- Department of Emergency, First Medical Center of Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China.
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Ren J, Hu Z, Li Q, Gu S, Lan F, Wang X, Li J, Li J, Shao L, Yang N, Sun C. Temperature-induced embryonic diapause in chickens is mediated by PKC-NF-κB-IRF1 signaling. BMC Biol 2023; 21:52. [PMID: 36882743 PMCID: PMC9993608 DOI: 10.1186/s12915-023-01550-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 02/22/2023] [Indexed: 03/09/2023] Open
Abstract
BACKGROUND Embryonic diapause (dormancy) is a state of temporary arrest of embryonic development that is triggered by unfavorable conditions and serves as an evolutionary strategy to ensure reproductive survival. Unlike maternally-controlled embryonic diapause in mammals, chicken embryonic diapause is critically dependent on the environmental temperature. However, the molecular control of diapause in avian species remains largely uncharacterized. In this study, we evaluated the dynamic transcriptomic and phosphoproteomic profiles of chicken embryos in pre-diapause, diapause, and reactivated states. RESULTS Our data demonstrated a characteristic gene expression pattern in effects on cell survival-associated and stress response signaling pathways. Unlike mammalian diapause, mTOR signaling is not responsible for chicken diapause. However, cold stress responsive genes, such as IRF1, were identified as key regulators of diapause. Further in vitro investigation showed that cold stress-induced transcription of IRF1 was dependent on the PKC-NF-κB signaling pathway, providing a mechanism for proliferation arrest during diapause. Consistently, in vivo overexpression of IRF1 in diapause embryos blocked reactivation after restoration of developmental temperatures. CONCLUSIONS We concluded that embryonic diapause in chicken is characterized by proliferation arrest, which is the same with other spices. However, chicken embryonic diapause is strictly correlated with the cold stress signal and mediated by PKC-NF-κB-IRF1 signaling, which distinguish chicken diapause from the mTOR based diapause in mammals.
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Affiliation(s)
- Junxiao Ren
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Zhengzheng Hu
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Quanlin Li
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Shuang Gu
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Fangren Lan
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Xiqiong Wang
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Jianbo Li
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Junying Li
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Liwa Shao
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Ning Yang
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China.
| | - Congjiao Sun
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China.
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