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Stojanovic M, Kalanj-Bognar S. Toll-like receptors as a missing link in Notch signaling cascade during neurodevelopment. Front Mol Neurosci 2024; 17:1465023. [PMID: 39664114 PMCID: PMC11631889 DOI: 10.3389/fnmol.2024.1465023] [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: 07/15/2024] [Accepted: 11/01/2024] [Indexed: 12/13/2024] Open
Abstract
Neurodevelopment encompasses a complex series of molecular events occuring at defined time points distinguishable by the specific genetic readout and active protein machinery. Due to immense intricacy of intertwined molecular pathways, extracting and describing all the components of a single pathway is a demanding task. In other words, there is always a risk of leaving potential transient molecular partners unnoticed while investigating signaling cascades with core functions-and the very neglected ones could be the turning point in understanding the context and regulation of the signaling events. For example, signaling pathways of Notch and Toll-like receptors (TLRs) have been so far unrelated in the vast body of knowledge about neurodevelopment, however evidence from available literature points to their remarkable overlap in influence on identical molecular processes and reveals their potential functional links. Based on data demonstrating Notch and TLR structural engagement and functions during neurodevelopment, along with our description of novel molecular binding models, here we hypothesize that TLR proteins act as likely crucial components in the Notch signaling cascade. We advocate for the hypothesized role of TLRs in Notch signaling by: elaborating components and features of their pathways; reviewing their effects on fates of neural progenitor cells during neurodevelopment; proposing molecular and functional aspects of the hypothesis, along with venues for testing it. Finally, we discuss substantial indications of environmental influence on the proposed Notch-TLR system and its impact on neurodevelopmental outcomes.
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Affiliation(s)
- Mario Stojanovic
- Laboratory for Neurochemistry and Molecular Neurobiology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia
- Laboratory for Cell Biology and Signalling, Department for Molecular Biology, Institute Ruđer Bošković, Zagreb, Croatia
| | - Svjetlana Kalanj-Bognar
- Laboratory for Neurochemistry and Molecular Neurobiology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia
- Department for Chemistry and Biochemistry, School of Medicine, University of Zagreb, Zagreb, Croatia
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2
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Zhang X, Xu Z, Chen Q, Zhou Z. Notch signaling regulates pulmonary fibrosis. Front Cell Dev Biol 2024; 12:1450038. [PMID: 39450276 PMCID: PMC11499121 DOI: 10.3389/fcell.2024.1450038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 09/23/2024] [Indexed: 10/26/2024] Open
Abstract
Pulmonary fibrosis is a progressive interstitial lung disease associated with aging. The pathogenesis of pulmonary fibrosis remains unclear, however, alveolar epithelial cell injury, myofibroblast activation, and extracellular matrix (ECM) accumulation are recognized as key contributors. Moreover, recent studies have implicated cellular senescence, endothelial-mesenchymal transition (EndMT), and epigenetic modifications in the pathogenesis of fibrotic diseases. Various signaling pathways regulate pulmonary fibrosis, including the TGF-β, Notch, Wnt, Hedgehog, and mTOR pathways. Among these, the TGF-β pathway is extensively studied, while the Notch pathway has emerged as a recent research focus. The Notch pathway influences the fibrotic process by modulating immune cell differentiation (e.g., macrophages, lymphocytes), inhibiting autophagy, and promoting interstitial transformation. Consequently, inhibiting Notch signaling represents a promising approach to mitigating pulmonary fibrosis. In this review, we discuss the role of Notch signaling pathway in pulmonary fibrosis, aiming to offer insights for future therapeutic investigations.
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Affiliation(s)
| | - Zhihao Xu
- Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, China
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3
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Halasa M, Uosef A, Ubelaker HV, Subuddhi A, Mysore KR, Kubiak JZ, Ghobrial RM, Wosik J, Kloc M. Gadolinium retention effect on macrophages - a potential cause of MRI contrast agent Dotarem toxicity. Cell Tissue Res 2024; 397:51-60. [PMID: 38625373 DOI: 10.1007/s00441-024-03885-8] [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: 11/13/2023] [Accepted: 03/04/2024] [Indexed: 04/17/2024]
Abstract
Gadolinium is a component of the MRI contrast agent Dotarem. Although Dotarem is the least toxic among MRI contrasts used, gadolinium present in Dotarem accumulates for many years in various organs and tissues exerting toxic effects. We showed previously that gadolinium remains in macrophages for at least 7 days after exposure to Dotarem. However, very little is known about the effect of gadolinium retention on the immune cells such as macrophages. We studied the effect of 1-day and 7-day retention of gadolinium on various functions and molecular pathways of macrophages. Gadolinium retention for 7 days decreased macrophage adhesion and motility and dysregulated the expression of adhesion and fibrotic pathway-related proteins such as Notch1 and its ligand Jagged1, adhesion/migration-related proteins PAK1 and Shp1, immune response-related transcription factors Smad3 and TCF19, and chemokines CXCL10 and CXCL13, and dysregulated the mRNA expression of fibrosis-related genes involved in extracellular matrix (ECM) synthesis, such as Col6a1, Fibronectin, MMP9, and MMP12. It also completely (below a level of detection) shut down the transcription of anti-inflammatory M2 macrophage polarization marker the Arg-1. Such changes, if they occur in MRI patients, can be potentially detrimental to the patient's immune system and immune response-related processes.
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Affiliation(s)
- Marta Halasa
- Transplant Immunology, The Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX, 77030, USA
- Department of Surgery, The Houston Methodist Hospital, 6670 Bertner Ave., Houston, TX, 77030, USA
| | - Ahmed Uosef
- Transplant Immunology, The Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX, 77030, USA
- Department of Surgery, The Houston Methodist Hospital, 6670 Bertner Ave., Houston, TX, 77030, USA
| | - Henry V Ubelaker
- Transplant Immunology, The Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX, 77030, USA
- Department of Surgery, The Houston Methodist Hospital, 6670 Bertner Ave., Houston, TX, 77030, USA
| | - Arijita Subuddhi
- Transplant Immunology, The Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX, 77030, USA
- Tuberculosis Research Advancement Center (TRAC), Emory Vaccine Center, Emory National Primate Research Center, Atlanta, GA, USA
| | - Krupa R Mysore
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
| | - Jacek Z Kubiak
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine - National Research Institute (WIM-PIB), Szaserow 128, 04-141, Warsaw, Poland
- Dynamics and Mechanics of Epithelia Group, Institute of Genetics and Development of Rennes, CNRS, UMR 6290, Faculty of Medicine, University of Rennes, 35043, Rennes, France
| | - Rafik M Ghobrial
- Transplant Immunology, The Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX, 77030, USA
- Department of Surgery, The Houston Methodist Hospital, 6670 Bertner Ave., Houston, TX, 77030, USA
| | - Jarek Wosik
- Electrical and Computer Engineering Department, University of Houston, Houston Science Center Building, Room 324, 4302 University Drive, Houston, TX, 77204, USA.
- Texas Center for Superconductivity, University of Houston, Houston Science Center Building, Room 324, 4302 University Drive, Houston, TX, 77204, USA.
| | - Malgorzata Kloc
- Transplant Immunology, The Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX, 77030, USA.
- Department of Surgery, The Houston Methodist Hospital, 6670 Bertner Ave., Houston, TX, 77030, USA.
- MD Anderson Cancer Center, Department of Genetics, The University of Texas, Houston, TX, USA.
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Sachan N, Sharma V, Mutsuddi M, Mukherjee A. Notch signalling: multifaceted role in development and disease. FEBS J 2024; 291:3030-3059. [PMID: 37166442 DOI: 10.1111/febs.16815] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 02/08/2023] [Accepted: 05/10/2023] [Indexed: 05/12/2023]
Abstract
Notch pathway is an evolutionarily conserved signalling system that operates to influence an astonishing array of cell fate decisions in different developmental contexts. Notch signalling plays important roles in many developmental processes, making it difficult to name a tissue or a developing organ that does not depend on Notch function at one stage or another. Thus, dysregulation of Notch signalling is associated with many developmental defects and various pathological conditions, including cancer. Although many recent advances have been made to reveal different aspects of the Notch signalling mechanism and its intricate regulation, there are still many unanswered questions related to how the Notch signalling pathway functions in so many developmental events. The same pathway can be deployed in numerous cellular contexts to play varied and critical roles in an organism's development and this is only possible because of the complex regulatory mechanisms of the pathway. In this review, we provide an overview of the mechanism and regulation of the Notch signalling pathway along with its multifaceted functions in different aspects of development and disease.
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Affiliation(s)
- Nalani Sachan
- Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, India
- Department of Cell Biology, NYU Grossman School of Medicine, New York, NY, USA
| | - Vartika Sharma
- Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Mousumi Mutsuddi
- Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Ashim Mukherjee
- Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, India
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Liu L, Li F, Zhang L, Cheng Y, Wu L, Tie R, Jiang X, Gao W, Liu B, Wei Y, Chang P, Xu J, Zhao H, Zhang L. Cysteine and glycine-rich protein 2 is crucial for maintaining the malignant phenotypes of gliomas through its action on Notch signalling cascade. Toxicol Appl Pharmacol 2024; 487:116969. [PMID: 38744347 DOI: 10.1016/j.taap.2024.116969] [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: 03/10/2024] [Revised: 05/08/2024] [Accepted: 05/09/2024] [Indexed: 05/16/2024]
Abstract
Cysteine and glycine-rich protein 2 (CSRP2) is expressed differently in numerous cancers and plays a key role in carcinogenesis. However, the role of CSRP2 in glioma is unknown. This study sought to determine the expression profile and clinical significance of CSRP2 in glioma and explore its biological functions and mechanisms via lentivirus-mediated CSRP2 silencing experiments. Increased CSRP2 was frequently observed in gliomas, which was associated with clinicopathological characteristics and an unfavourable prognosis. Decreasing CSRP2 led to the suppression of malignant proliferation, metastasis and stemness in glioma cells while causing hypersensitivity to chemotherapeutic drugs. Mechanistic investigations revealed that CSRP2 plays a role in mediating the Notch signalling cascade. Silencing CSRP2 decreased the levels of Notch1, cleaved Notch1, HES1 and HEY1, suppressing the Notch signalling cascade. Reactivation of Notch markedly diminished the tumour-inhibiting effects of CSRP2 silencing on the malignant phenotypes of glioma cells. Notably, CSRP2-silencing glioma cells exhibited reduced potential in the formation of xenografts in nude mice in vivo, which was associated with an impaired Notch signalling cascade. These results showed that CSRP2 is overexpressed in glioma and has a crucial role in sustaining the malignant phenotypes of glioma, suggesting that targeting CSRP2 could be a promising strategy for glioma treatment.
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Affiliation(s)
- Lingtong Liu
- Department of Neurosurgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, No.32 West Second Section First Ring Road, Chengdu 610072, China
| | - Fei Li
- Department of Neurosurgery, Second Affiliated Hospital of Xi'an Medical University, No. 167 Fangdong Street, Xi'an 710038, China
| | - Lingxue Zhang
- Department of Neurosurgery, Second Affiliated Hospital of Xi'an Medical University, No. 167 Fangdong Street, Xi'an 710038, China
| | - Yingying Cheng
- Department of Neurosurgery, Second Affiliated Hospital of Xi'an Medical University, No. 167 Fangdong Street, Xi'an 710038, China
| | - Lin Wu
- Central Laboratory, Second Affiliated Hospital of Xi'an Medical University, No. 167 Fangdong Street, Xi'an 710038, China
| | - Ru Tie
- Central Laboratory, Second Affiliated Hospital of Xi'an Medical University, No. 167 Fangdong Street, Xi'an 710038, China
| | - Xiaobing Jiang
- Department of Neurosurgery, Second Affiliated Hospital of Xi'an Medical University, No. 167 Fangdong Street, Xi'an 710038, China
| | - Wenwen Gao
- Department of Neurosurgery, Second Affiliated Hospital of Xi'an Medical University, No. 167 Fangdong Street, Xi'an 710038, China
| | - Bochuan Liu
- Department of Neurosurgery, Second Affiliated Hospital of Xi'an Medical University, No. 167 Fangdong Street, Xi'an 710038, China
| | - Yao Wei
- Department of Neurosurgery, Second Affiliated Hospital of Xi'an Medical University, No. 167 Fangdong Street, Xi'an 710038, China
| | - Pan Chang
- Central Laboratory, Second Affiliated Hospital of Xi'an Medical University, No. 167 Fangdong Street, Xi'an 710038, China
| | - Jun Xu
- Department of Neurosurgery, Xi'an Daxing Hospital, No. 353 Laodong North Road, Lianhu District, Xi'an 710016, China
| | - Haikang Zhao
- Department of Neurosurgery, Second Affiliated Hospital of Xi'an Medical University, No. 167 Fangdong Street, Xi'an 710038, China.
| | - Liang Zhang
- Department of Neurosurgery, Second Affiliated Hospital of Xi'an Medical University, No. 167 Fangdong Street, Xi'an 710038, China; Department of Neurosurgery, Xi'an Daxing Hospital, No. 353 Laodong North Road, Lianhu District, Xi'an 710016, China; Northwest University, No. 1 Xuefu Street, Guodu Education and Technology Industrial Zone, Chang'an District, Xi'an 710127, China.
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Kacker S, Parsad V, Singh N, Hordiichuk D, Alvarez S, Gohar M, Kacker A, Rai SK. Planar Cell Polarity Signaling: Coordinated Crosstalk for Cell Orientation. J Dev Biol 2024; 12:12. [PMID: 38804432 PMCID: PMC11130840 DOI: 10.3390/jdb12020012] [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: 01/28/2024] [Revised: 04/08/2024] [Accepted: 04/13/2024] [Indexed: 05/29/2024] Open
Abstract
The planar cell polarity (PCP) system is essential for positioning cells in 3D networks to establish the proper morphogenesis, structure, and function of organs during embryonic development. The PCP system uses inter- and intracellular feedback interactions between components of the core PCP, characterized by coordinated planar polarization and asymmetric distribution of cell populations inside the cells. PCP signaling connects the anterior-posterior to left-right embryonic plane polarity through the polarization of cilia in the Kupffer's vesicle/node in vertebrates. Experimental investigations on various genetic ablation-based models demonstrated the functions of PCP in planar polarization and associated genetic disorders. This review paper aims to provide a comprehensive overview of PCP signaling history, core components of the PCP signaling pathway, molecular mechanisms underlying PCP signaling, interactions with other signaling pathways, and the role of PCP in organ and embryonic development. Moreover, we will delve into the negative feedback regulation of PCP to maintain polarity, human genetic disorders associated with PCP defects, as well as challenges associated with PCP.
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Affiliation(s)
- Sandeep Kacker
- Department of Pharmacology, Medical University of the Americas, Charlestown KN 1102, Saint Kitts and Nevis;
| | - Varuneshwar Parsad
- Department of Human Body Structure and Function, Medical University of the Americas, Charlestown KN 1102, Saint Kitts and Nevis; (V.P.); (D.H.)
| | - Naveen Singh
- Department of Cerll and Molecular Biology, Medical University of the Americas, Charlestown KN 1102, Saint Kitts and Nevis; (N.S.); (S.A.); (M.G.)
| | - Daria Hordiichuk
- Department of Human Body Structure and Function, Medical University of the Americas, Charlestown KN 1102, Saint Kitts and Nevis; (V.P.); (D.H.)
| | - Stacy Alvarez
- Department of Cerll and Molecular Biology, Medical University of the Americas, Charlestown KN 1102, Saint Kitts and Nevis; (N.S.); (S.A.); (M.G.)
| | - Mahnoor Gohar
- Department of Cerll and Molecular Biology, Medical University of the Americas, Charlestown KN 1102, Saint Kitts and Nevis; (N.S.); (S.A.); (M.G.)
| | - Anshu Kacker
- Department of Histology and Human Physiology, Medical University of the Americas, Charlestown KN 1102, Saint Kitts and Nevis;
| | - Sunil Kumar Rai
- Department of Cerll and Molecular Biology, Medical University of the Americas, Charlestown KN 1102, Saint Kitts and Nevis; (N.S.); (S.A.); (M.G.)
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Wang S, Gu S, Chen J, Yuan Z, Liang P, Cui H. Mechanism of Notch Signaling Pathway in Malignant Progression of Glioblastoma and Targeted Therapy. Biomolecules 2024; 14:480. [PMID: 38672496 PMCID: PMC11048644 DOI: 10.3390/biom14040480] [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: 01/26/2024] [Revised: 04/04/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
Glioblastoma multiforme (GBM) is the most aggressive form of glioma and the most common primary tumor of the central nervous system. Despite significant advances in clinical management strategies and diagnostic techniques for GBM in recent years, it remains a fatal disease. The current standard of care includes surgery, radiation, and chemotherapy, but the five-year survival rate for patients is less than 5%. The search for a more precise diagnosis and earlier intervention remains a critical and urgent challenge in clinical practice. The Notch signaling pathway is a critical signaling system that has been extensively studied in the malignant progression of glioblastoma. This highly conserved signaling cascade is central to a variety of biological processes, including growth, proliferation, self-renewal, migration, apoptosis, and metabolism. In GBM, accumulating data suggest that the Notch signaling pathway is hyperactive and contributes to GBM initiation, progression, and treatment resistance. This review summarizes the biological functions and molecular mechanisms of the Notch signaling pathway in GBM, as well as some clinical advances targeting the Notch signaling pathway in cancer and glioblastoma, highlighting its potential as a focus for novel therapeutic strategies.
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Affiliation(s)
- Shenghao Wang
- Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China;
| | - Sikuan Gu
- State Key Laboratory of Resource Insects, Southwest University, Chongqing 400716, China; (S.G.); (J.C.); (Z.Y.)
| | - Junfan Chen
- State Key Laboratory of Resource Insects, Southwest University, Chongqing 400716, China; (S.G.); (J.C.); (Z.Y.)
| | - Zhiqiang Yuan
- State Key Laboratory of Resource Insects, Southwest University, Chongqing 400716, China; (S.G.); (J.C.); (Z.Y.)
| | - Ping Liang
- Department of Neurosurgery, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
| | - Hongjuan Cui
- Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China;
- State Key Laboratory of Resource Insects, Southwest University, Chongqing 400716, China; (S.G.); (J.C.); (Z.Y.)
- Department of Neurosurgery, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
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Lin N, Chi H, Guo Q, Liu Z, Ni L. Notch Signaling Inhibition Alleviates Allergies Caused by Antarctic Krill Tropomyosin through Improving Th1/Th2 Imbalance and Modulating Gut Microbiota. Foods 2024; 13:1144. [PMID: 38672818 PMCID: PMC11048830 DOI: 10.3390/foods13081144] [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: 01/29/2024] [Revised: 02/19/2024] [Accepted: 04/05/2024] [Indexed: 04/28/2024] Open
Abstract
Antarctic krill tropomyosin (AkTM) has been shown in mice to cause IgE-mediated food allergy. The objective of this work was to investigate the role of Notch signaling in AkTM-sensitized mice, as well as to determine the changes in gut microbiota composition and short-chain fatty acids (SCFAs) in the allergic mice. An AkTM-induced food allergy mouse model was built and N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) was used as an γ-secretase inhibitor to inhibit the activation of Notch signaling. Food allergy indices, some key transcription factors, histologic alterations in the small intestine, and changes in gut microbiota composition were examined. The results showed that DAPT inhibited Notch signaling, which reduced AkTM-specific IgE, suppressed mast cell degranulation, decreased IL-4 but increased IFN-γ production, and alleviated allergic symptoms. Quantitative real-time PCR and Western blotting analyses revealed that expressions of Hes-1, Gata3, and IL-4 were down-regulated after DAPT treatment, accompanied by increases in T-bet and IFN-γ, indicating that Notch signaling was active in AkTM-sensitized mice and blocking it could reverse the Th1/Th2 imbalance. Expressions of key transcription factors revealed that Notch signaling could promote Th2 cell differentiation in sensitized mice. Furthermore, 16S rRNA sequencing results revealed that AkTM could alter the diversity and composition of gut microbiota in mice, leading to increases in inflammation-inducing bacteria such as Enterococcus and Escherichia-Shigella. Correlation analysis indicated that reduced SCFA concentrations in AkTM-allergic mice may be related to decreases in certain SCFA-producing bacteria, such as Clostridia_UCG-014. The changes in gut microbiota and SCFAs could be partially restored by DAPT treatment. Our findings showed that inhibiting Notch signaling could alleviate AkTM-induced food allergy by correcting Th1/Th2 imbalance and modulating the gut microbiota.
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Affiliation(s)
- Na Lin
- East China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shanghai 200090, China; (N.L.); (Q.G.); (L.N.)
| | - Hai Chi
- East China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shanghai 200090, China; (N.L.); (Q.G.); (L.N.)
- College of Food Science and Engineering, Dalian Ocean University, Dalian 116023, China
| | - Quanyou Guo
- East China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shanghai 200090, China; (N.L.); (Q.G.); (L.N.)
| | - Zhidong Liu
- East China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shanghai 200090, China; (N.L.); (Q.G.); (L.N.)
| | - Ling Ni
- East China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shanghai 200090, China; (N.L.); (Q.G.); (L.N.)
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Bashir S, Cai CL, Marcelino M, Aranda JV, Beharry KD. Comparison of Glutathione Nanoparticles, CoEnzyme Q10, and Fish Oil for Prevention of Oxygen-Induced Retinopathy in Neonatal Rats. Pharmaceuticals (Basel) 2024; 17:381. [PMID: 38543167 PMCID: PMC10975314 DOI: 10.3390/ph17030381] [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: 01/22/2024] [Revised: 03/06/2024] [Accepted: 03/12/2024] [Indexed: 04/01/2024] Open
Abstract
Notch ligands and receptors are important for cell specification and angiogenesis, but their role in oxygen-induced retinopathy (OIR) is not well studied. Delta-like ligand (DLL)-4/Notch inhibits angiogenesis, while Jagged-1/Notch promotes angiogenesis. We tested the hypothesis that early supplementation with antioxidants and/or fish oil curtails severe OIR by inducing DLL-4/Notch and reducing Jagged-1/Notch. Newborn rats were exposed to brief intermittent hypoxia (IH) during hyperoxia, during which they received daily oral supplements of (1) fish oil, (2) coenzyme Q10 (CoQ10) in olive oil (OO), (3) glutathione nanoparticles (nGSH), (4) fish oil + CoQ10, or (5) OO (controls) from birth (P0) to P14. At P14, the pups were placed in room air (RA) until P21, with no further treatment. Oxidative stress, apoptosis, ocular histopathology, and Notch signaling were assessed. Neonatal IH resulted in severe retinal damage consistent with retinopathy of prematurity (ROP). Retinal damage was associated with induced oxidative stress and Jagged-1/Notch signaling, as well as reduced DLL-4/Notch signaling. All treatments reversed these outcomes, but nGSH produced the most beneficial outcomes. Severe OIR promoted the induction of Jagged-1/Notch and curtailed DLL-4/Notch, which was an effect that could be reversed with nGSH supplementation. These findings may indicate a potential alternate pathway for ROP treatment and/or prevention.
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Affiliation(s)
- Sidra Bashir
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York Downstate Health Sciences University, Brooklyn, NY 11203, USA; (S.B.); (C.L.C.); (J.V.A.)
| | - Charles L. Cai
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York Downstate Health Sciences University, Brooklyn, NY 11203, USA; (S.B.); (C.L.C.); (J.V.A.)
| | - Matthew Marcelino
- Medical School, State University of New York Downstate Health Sciences University, Brooklyn, NY 11203, USA;
| | - Jacob V. Aranda
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York Downstate Health Sciences University, Brooklyn, NY 11203, USA; (S.B.); (C.L.C.); (J.V.A.)
- Department of Ophthalmology, State University of New York Downstate Health Sciences University, Brooklyn, NY 11203, USA
- SUNY Eye Institute, Brooklyn, NY 11203, USA
| | - Kay D. Beharry
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York Downstate Health Sciences University, Brooklyn, NY 11203, USA; (S.B.); (C.L.C.); (J.V.A.)
- Department of Ophthalmology, State University of New York Downstate Health Sciences University, Brooklyn, NY 11203, USA
- SUNY Eye Institute, Brooklyn, NY 11203, USA
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Involvement of the Notch signaling system in alveolar bone resorption. JAPANESE DENTAL SCIENCE REVIEW 2023; 59:38-47. [PMID: 36880060 PMCID: PMC9985033 DOI: 10.1016/j.jdsr.2023.02.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 02/05/2023] [Accepted: 02/16/2023] [Indexed: 03/05/2023] Open
Abstract
The Notch pathway is an evolutionarily preserved signaling pathway involved in a variety of vital cell functions. Additionally, it is one of the key regulators of inflammation, and controls the differentiation and function of different cells. Moreover, it was found to be involved in skeletal development and bone remodeling process. This review provides an overview of the involvement of the Notch signaling pathway in the pathogenesis of alveolar bone resorption in different forms of pathological conditions such as apical periodontitis, periodontal disease, and peri-implantitis. In vitro and in vivo evidence have confirmed the involvement of Notch signaling in alveolar bone homeostasis. Nonetheless, Notch signaling system, along with complex network of different biomolecules are involved in pathological process of bone resorption in apical periodontitis, periodontitis, and peri-implantitis. In this regard, there is a substantial interest to control the activity of this pathway in the treatment of disorders associated with its dysregulation. This review provides knowledge on Notch signaling and outlines its functions in alveolar bone homeostasis and alveolar bone resorption. Further investigations are needed to determine whether inhibition of the Notch signaling pathways might be beneficial and safe as a novel approach in the treatment of these pathological conditions.
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Platonova N, Lazzari E, Colombo M, Falleni M, Tosi D, Giannandrea D, Citro V, Casati L, Ronchetti D, Bolli N, Neri A, Torricelli F, Crews LA, Jamieson CHM, Chiaramonte R. The Potential of JAG Ligands as Therapeutic Targets and Predictive Biomarkers in Multiple Myeloma. Int J Mol Sci 2023; 24:14558. [PMID: 37834003 PMCID: PMC10572399 DOI: 10.3390/ijms241914558] [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: 07/28/2023] [Revised: 09/03/2023] [Accepted: 09/20/2023] [Indexed: 10/15/2023] Open
Abstract
The NOTCH ligands JAG1 and JAG2 have been correlated in vitro with multiple myeloma (MM) cell proliferation, drug resistance, self-renewal and a pathological crosstalk with the tumor microenvironment resulting in angiogenesis and osteoclastogenesis. These findings suggest that a therapeutic approach targeting JAG ligands might be helpful for the care of MM patients and lead us to explore the role of JAG1 and JAG2 in a MM in vivo model and primary patient samples. JAG1 and JAG2 protein expression represents a common feature in MM cell lines; therefore, we assessed their function through JAG1/2 conditional silencing in a MM xenograft model. We observed that JAG1 and JAG2 showed potential as therapeutic targets in MM, as their silencing resulted in a reduction in the tumor burden. Moreover, JAG1 and JAG2 protein expression in MM patients was positively correlated with the presence of MM cells in patients' bone marrow biopsies. Finally, taking advantage of the Multiple Myeloma Research Foundation (MMRF) CoMMpass global dataset, we showed that JAG2 gene expression level was a predictive biomarker associated with patients' overall survival and progression-free survival, independently from other main molecular or clinical features. Overall, these results strengthened the rationale for the development of a JAG1/2-tailored approach and the use of JAG2 as a predictive biomarker in MM.
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Affiliation(s)
- Natalia Platonova
- Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy; (N.P.); (E.L.); (M.C.); (M.F.); (D.T.); (D.G.); (V.C.); (L.C.)
| | - Elisa Lazzari
- Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy; (N.P.); (E.L.); (M.C.); (M.F.); (D.T.); (D.G.); (V.C.); (L.C.)
- Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center, University of California, La Jolla, CA 92093, USA; (L.A.C.); (C.H.M.J.)
- UC San Diego Sanford, Stem Cell Institute, La Jolla, CA 92037, USA
| | - Michela Colombo
- Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy; (N.P.); (E.L.); (M.C.); (M.F.); (D.T.); (D.G.); (V.C.); (L.C.)
| | - Monica Falleni
- Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy; (N.P.); (E.L.); (M.C.); (M.F.); (D.T.); (D.G.); (V.C.); (L.C.)
- Unit of Pathology A.O. San Paolo, Via A. Di Rudinì 8, 20142 Milan, Italy
| | - Delfina Tosi
- Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy; (N.P.); (E.L.); (M.C.); (M.F.); (D.T.); (D.G.); (V.C.); (L.C.)
- Unit of Pathology A.O. San Paolo, Via A. Di Rudinì 8, 20142 Milan, Italy
| | - Domenica Giannandrea
- Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy; (N.P.); (E.L.); (M.C.); (M.F.); (D.T.); (D.G.); (V.C.); (L.C.)
| | - Valentina Citro
- Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy; (N.P.); (E.L.); (M.C.); (M.F.); (D.T.); (D.G.); (V.C.); (L.C.)
| | - Lavinia Casati
- Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy; (N.P.); (E.L.); (M.C.); (M.F.); (D.T.); (D.G.); (V.C.); (L.C.)
| | - Domenica Ronchetti
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, 20122 Milan, Italy; (D.R.); (N.B.)
| | - Niccolò Bolli
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, 20122 Milan, Italy; (D.R.); (N.B.)
- Hematology, Fondazione Cà Granda IRCCS Policlinico, 20122 Milan, Italy
| | - Antonino Neri
- Scientific Directorate, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Federica Torricelli
- Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Leslie A. Crews
- Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center, University of California, La Jolla, CA 92093, USA; (L.A.C.); (C.H.M.J.)
| | - Catriona H. M. Jamieson
- Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center, University of California, La Jolla, CA 92093, USA; (L.A.C.); (C.H.M.J.)
- UC San Diego Sanford, Stem Cell Institute, La Jolla, CA 92037, USA
| | - Raffaella Chiaramonte
- Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy; (N.P.); (E.L.); (M.C.); (M.F.); (D.T.); (D.G.); (V.C.); (L.C.)
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12
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Sen P, Ghosh SS. The Intricate Notch Signaling Dynamics in Therapeutic Realms of Cancer. ACS Pharmacol Transl Sci 2023; 6:651-670. [PMID: 37200816 PMCID: PMC10186364 DOI: 10.1021/acsptsci.2c00239] [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: 11/29/2022] [Indexed: 05/20/2023]
Abstract
The Notch pathway is remarkably simple without the interventions of secondary messengers. It possesses a unique receptor-ligand interaction that imparts signaling upon cleavage of the receptor followed by the nuclear localization of its cleaved intracellular domain. It is found that the transcriptional regulator of the Notch pathway lies at the intersection of multiple signaling pathways that enhance the aggressiveness of cancer. The preclinical and clinical evidence supports the pro-oncogenic function of Notch signaling in various tumor subtypes. Owing to its oncogenic role, the Notch signaling pathway assists in enhanced tumorigenesis by facilitating angiogenesis, drug resistance, epithelial to mesenchymal transition, etc., which is also attributed to the poor outcome in patients. Therefore, it is extremely vital to discover a suitable inhibitor to downregulate the signal-transducing ability of Notch. The Notch inhibitory agents, such as receptor decoys, protease (ADAM and γ-secretase) inhibitors, and monoclonal/bispecific antibodies, are being investigated as candidate therapeutic agents. Studies conducted by our group exemplify the promising results in ablating tumorigenic aggressiveness by inhibiting the constituents of the Notch pathway. This review deals with the detailed mechanism of the Notch pathways and their implications in various malignancies. It also bestows us with the recent therapeutic advances concerning Notch signaling in the context of monotherapy and combination therapy.
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Affiliation(s)
- Plaboni Sen
- Department
of Biosciences and Bioengineering, Indian
Institute of Technology Guwahati, Guwahati 781039, Assam, India
| | - Siddhartha Sankar Ghosh
- Department
of Biosciences and Bioengineering, Indian
Institute of Technology Guwahati, Guwahati 781039, Assam, India
- Centre
for Nanotechnology, Indian Institute of
Technology Guwahati, Guwahati 781039, Assam, India
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13
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Shtukmaster S, Huber K. The role of the Notch signalling pathway in regulating the balance between neuronal and nonneuronal cells in sympathetic ganglia and the adrenal gland. PLoS One 2023; 18:e0281486. [PMID: 36795650 PMCID: PMC9934399 DOI: 10.1371/journal.pone.0281486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 01/24/2023] [Indexed: 02/17/2023] Open
Abstract
Sympathetic neurons and endocrine chromaffin cells of the adrenal medulla are catecholaminergic cells that derive from the neural crest. According to the classic model, they develop from a common sympathoadrenal (SA) progenitor that has the ability to differentiate into both sympathetic neurons and chromaffin cells depending on signals provided by their final environment. Our previous data revealed that a single premigratory neural crest cell can give rise to both sympathetic neurons and chromaffin cells, indicating that the fate decision between these cell types occurs after delamination. A more recent study demonstrated that at least half of chromaffin cells arise from a later contribution by Schwann cell precursors. Since Notch signalling is known to be implicated in the regulation of cell fate decisions, we investigated the early role of Notch signalling in regulating the development of neuronal and non-neuronal SA cells within sympathetic ganglia and the adrenal gland. To this end, we implemented both gain and loss of function approaches. Electroporation of premigratory neural crest cells with plasmids encoding Notch inhibitors revealed an elevation in the number of SA cells expressing the catecholaminergic enzyme tyrosine-hydroxylase, with a concomitant reduction in the number of cells expressing the glial marker P0 in both sympathetic ganglia and adrenal gland. As expected, gain of Notch function had the opposite effect. Numbers of neuronal and non-neuronal SA cells were affected differently by Notch inhibition depending on the time of its onset. Together our data show that Notch signalling can regulate the ratio of glial cells, neuronal SA cells and nonneuronal SA cells in both sympathetic ganglia and the adrenal gland.
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Affiliation(s)
- Stella Shtukmaster
- Department of Anatomy Institute for Anatomy and Cell Biology, University of Marburg, Marburg, Hessen, Germany
- * E-mail:
| | - Katrin Huber
- Department of Medicine, University of Fribourg, Fribourg, Switzerland
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14
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Dong CX, Malecki C, Robertson E, Hambly B, Jeremy R. Molecular Mechanisms in Genetic Aortopathy-Signaling Pathways and Potential Interventions. Int J Mol Sci 2023; 24:ijms24021795. [PMID: 36675309 PMCID: PMC9865322 DOI: 10.3390/ijms24021795] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/02/2023] [Accepted: 01/11/2023] [Indexed: 01/18/2023] Open
Abstract
Thoracic aortic disease affects people of all ages and the majority of those aged <60 years have an underlying genetic cause. There is presently no effective medical therapy for thoracic aneurysm and surgery remains the principal intervention. Unlike abdominal aortic aneurysm, for which the inflammatory/atherosclerotic pathogenesis is well established, the mechanism of thoracic aneurysm is less understood. This paper examines the key cell signaling systems responsible for the growth and development of the aorta, homeostasis of endothelial and vascular smooth muscle cells and interactions between pathways. The evidence supporting a role for individual signaling pathways in pathogenesis of thoracic aortic aneurysm is examined and potential novel therapeutic approaches are reviewed. Several key signaling pathways, notably TGF-β, WNT, NOTCH, PI3K/AKT and ANGII contribute to growth, proliferation, cell phenotype and survival for both vascular smooth muscle and endothelial cells. There is crosstalk between pathways, and between vascular smooth muscle and endothelial cells, with both synergistic and antagonistic interactions. A common feature of the activation of each is response to injury or abnormal cell stress. Considerable experimental evidence supports a contribution of each of these pathways to aneurysm formation. Although human information is less, there is sufficient data to implicate each pathway in the pathogenesis of human thoracic aneurysm. As some pathways i.e., WNT and NOTCH, play key roles in tissue growth and organogenesis in early life, it is possible that dysregulation of these pathways results in an abnormal aortic architecture even in infancy, thereby setting the stage for aneurysm development in later life. Given the fine tuning of these signaling systems, functional polymorphisms in key signaling elements may set up a future risk of thoracic aneurysm. Multiple novel therapeutic agents have been developed, targeting cell signaling pathways, predominantly in cancer medicine. Future investigations addressing cell specific targeting, reduced toxicity and also less intense treatment effects may hold promise for effective new medical treatments of thoracic aortic aneurysm.
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Affiliation(s)
- Charlotte Xue Dong
- Faculty of Health and Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia
| | - Cassandra Malecki
- Faculty of Health and Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia
- The Baird Institute, Camperdown, NSW 2042, Australia
| | - Elizabeth Robertson
- Faculty of Health and Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia
| | - Brett Hambly
- Faculty of Health and Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia
| | - Richmond Jeremy
- Faculty of Health and Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia
- The Baird Institute, Camperdown, NSW 2042, Australia
- Correspondence:
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15
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Zamfirescu AM, Yatsenko AS, Shcherbata HR. Notch signaling sculpts the stem cell niche. Front Cell Dev Biol 2022; 10:1027222. [PMID: 36605720 PMCID: PMC9810114 DOI: 10.3389/fcell.2022.1027222] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 12/02/2022] [Indexed: 12/24/2022] Open
Abstract
Adult stem cells depend on their niches for regulatory signaling that controls their maintenance, division, and their progeny differentiation. While communication between various types of stem cells and their niches is becoming clearer, the process of stem cell niche establishment is still not very well understood. Model genetic organisms provide simplified systems to address various complex questions, for example, how is a stem cell niche formed? What signaling cascades induce the stem cell niche formation? Are the mechanisms of stem cell niche formation conserved? Notch signaling is an evolutionarily conserved pathway first identified in fruit flies, crucial in fate acquisition and spatiotemporal patterning. While the core logic behind its activity is fairly simple and requires direct cell-cell interaction, it reaches an astonishing complexity and versatility by combining its different modes of action. Subtleties such as equivalency between communicating cells, their physical distance, receptor and ligand processing, and endocytosis can have an effect on the way the events unfold, and this review explores some important general mechanisms of action, later on focusing on its involvement in stem cell niche formation. First, looking at invertebrates, we will examine how Notch signaling induces the formation of germline stem cell niche in male and female Drosophila. In the developing testis, a group of somatic gonadal precursor cells receive Delta signals from the gut, activating Notch signaling and sealing their fate as niche cells even before larval hatching. Meanwhile, the ovarian germline stem cell niche is built later during late larval stages and requires a two-step process that involves terminal filament formation and cap cell specification. Intriguingly, double security mechanisms of Notch signaling activation coordinated by the soma or the germline control both steps to ensure the robustness of niche assembly. Second, in the vast domains of mammalian cellular signaling, there is an emerging picture of Notch being an active player in a variety of tissues in health and disease. Notch involvement has been shown in stem cell niche establishment in multiple organs, including the brain, muscle, and intestine, where the stem cell niches are essential for the maintenance of adult stem cells. But adult stem cells are not the only cells looking for a home. Cancer stem cells use Notch signaling at specific stages to gain an advantage over endogenous tissue and overpower it, at the same time acquiring migratory and invasive abilities to claim new tissues (e.g., bone) as their territory. Moreover, in vitro models such as organoids reveal similar Notch employment when it comes to the developing stem cell niches. Therefore, a better understanding of the processes regulating stem cell niche assembly is key for the fields of stem cell biology and regenerative medicines.
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Affiliation(s)
| | | | - Halyna R. Shcherbata
- Mount Desert Island Biological Laboratory, Bar Harbor, ME, United States,*Correspondence: Halyna R. Shcherbata,
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16
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Bai X, Wang S. Signaling pathway intervention in premature ovarian failure. Front Med (Lausanne) 2022; 9:999440. [PMID: 36507521 PMCID: PMC9733706 DOI: 10.3389/fmed.2022.999440] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 11/14/2022] [Indexed: 11/27/2022] Open
Abstract
Premature ovarian failure (POF) is a multifactorial disease that refers to the occurrence of secondary amenorrhea, estrogen decrease, and gonadotropin increase in women under the age of 40. The prevalence of POF is increasing year by year, and the existing instances can be categorized as primary or secondary cases. This disease has adverse effects on both the physiology and psychology of women. Hormone replacement therapy is the recommended treatment for POF, and a multidisciplinary strategy is required to enhance the quality of life of patients. According to recent studies, the primary mechanism of POF is the depletion of ovarian reserve function as a result of increased primordial follicular activation or primordial follicular insufficiency. Therefore, understanding the processes of primordial follicle activation and associated pathways and exploring effective interventions are important for the treatment of POF.
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17
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Li DY, Gao SJ, Sun J, Zhang LQ, Wu JY, Song FH, Liu DQ, Zhou YQ, Mei W. Notch signaling activation contributes to paclitaxel-induced neuropathic pain via activation of A1 astrocytes. Eur J Pharmacol 2022; 928:175130. [PMID: 35777441 DOI: 10.1016/j.ejphar.2022.175130] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 06/18/2022] [Accepted: 06/24/2022] [Indexed: 12/29/2022]
Abstract
Paclitaxel-induced neuropathic pain (PINP) is a progressive and refractory side effect of chemotherapy with few effective treatments at present. It is well-established that astrocytes activation contributes to the development of PINP. Recent reports showed astrocytes can be divided into A1 and A2 phenotypes. However, whether the transformation of astrocytes participates in PINP and the underlying mechanisms remain unknown. As Notch signaling pathway have shown to be involved in neuropathic pain, we aimed to investigate the relationship between Notch signaling pathway and A1 astrocytes in PINP. Herein we found that both A1 astrocytes and Notch signaling were markedly activated in the spinal cord of PINP rats and the downstream molecules of Notch signaling were colocalized with A1 astrocytes. DAPT (an inhibitor of Notch signaling) not only suppressed the mechanical allodynia of PINP rats, but also inhibited the activation of Notch signaling pathway and A1 astrocytes. Furthermore, Jagged1 (a ligand of Notch1 receptors) dose-dependently induced mechanical hyperalgesia in naïve rats and simultaneously led to Notch signaling activation and A1 astrocytes transformation, all of which were inhibited by DAPT. Taken together, these results demonstrate Notch signaling activation contributes to PINP via A1 astrocytes activation, which provides a promising therapeutic target for PINP.
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Affiliation(s)
- Dan-Yang Li
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Shao-Jie Gao
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jia Sun
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Long-Qing Zhang
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jia-Yi Wu
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Fan-He Song
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Dai-Qiang Liu
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Ya-Qun Zhou
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Wei Mei
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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18
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Wang Y, Xie W, Feng Y, Xu Z, He Y, Xiong Y, Chen L, Li X, Liu J, Liu G, Wu Q. Epithelial‑derived exosomes promote M2 macrophage polarization via Notch2/SOCS1 during mechanical ventilation. Int J Mol Med 2022; 50:96. [PMID: 35616134 PMCID: PMC9170191 DOI: 10.3892/ijmm.2022.5152] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 05/10/2022] [Indexed: 11/24/2022] Open
Abstract
Alveolar macrophages (AMs) play an essential role in ventilator-induced lung injury (VILI). Exosomes and their cargo, including microRNAs (miRNAs/miRs) serve as regulators of the intercellular communications between macrophages and epithelial cells (ECs), and are involved in maintaining homeostasis in lung tissue. The present study found that exosomes released by ECs subjected to cyclic stretching promoted M2 macrophage polarization. It was demonstrated that miR-21a-5p, upregulated in epithelial-derived exosomes, increased the percentage of M2 macrophages by suppressing the expression of Notch2 and the suppressor of cytokine signaling 1 (SOCS1). The overexpression of Notch2 decreased the percentage of M2 macrophages. However, these effects were reversed by the downregulation of SOCS1. The percentage of M2 macrophages was increased in both short-term high- and low-tidal-volume mechanical ventilation, and the administration of exosomes-derived from cyclically stretched ECs had the same function. However, the administration of miR-21a-5p antagomir decreased M2 macrophage activation induced by cyclically stretched ECs or ventilation. Thus, the present study demonstrates that the intercellular transferring of exosomes from ECs to AMs promotes M2 macrophage polarization. Exosomes may prove to be a novel treatment for VILI.
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Affiliation(s)
- Yanting Wang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Wanli Xie
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Yiqi Feng
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Zhenzhen Xu
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Yuyao He
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Yue Xiong
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Lu Chen
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Xia Li
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Jie Liu
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Guoyang Liu
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Qingping Wu
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
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19
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Notch signaling in malignant gliomas: supporting tumor growth and the vascular environment. Cancer Metastasis Rev 2022; 41:737-747. [PMID: 35624227 DOI: 10.1007/s10555-022-10041-7] [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: 02/13/2022] [Accepted: 05/18/2022] [Indexed: 11/02/2022]
Abstract
Glioblastoma is the most malignant form of glioma, which is the most commonly occurring tumor of the central nervous system. Notch signaling in glioblastoma is considered to be a marker of an undifferentiated tumor cell state, associated with tumor stem cells. Notch is also known for facilitating tumor dormancy escape, recurrence and progression after treatment. Studies in vitro suggest that reducing, removing or blocking the expression of this gene triggers tumor cell differentiation, which shifts the phenotype away from stemness status and consequently facilitates treatment. In contrast, in the vasculature, Notch appears to also function as an important receptor that defines mature non-leaking vessels, and increasing its expression promotes tumor normalization in models of cancer in vivo. Failures in clinical trials with Notch inhibitors are potentially related to their opposing effects on the tumor versus the tumor vasculature, which points to the need for a greater understanding of this signaling pathway.
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20
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Lin YW, Li XX, Fu FH, Liu B, Xing X, Qi R, Ma L. Notch1/Hes1‑PTEN/AKT/IL‑17A feedback loop regulates Th17 cell differentiation in mouse psoriasis‑like skin inflammation. Mol Med Rep 2022; 26:223. [PMID: 35582997 PMCID: PMC9175275 DOI: 10.3892/mmr.2022.12739] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 05/03/2022] [Indexed: 11/06/2022] Open
Abstract
IL‑17A, the effector cytokine of T helper (Th) 17 cells, plays a crucial role in the pathogenesis of psoriasis. The Notch1 and PI3K/AKT signaling pathways are implicated in Th17 cell differentiation and IL‑17A production. The present study aimed to evaluate the regulatory effect of the Notch1/hairy and enhancer of split 1 (Hes1)‑PTEN/AKT/IL‑17A feedback loop on Th17 cell differentiation via the PI3K/AKT inhibitor LY294002 in a mouse model of psoriasis. Mice were randomly divided into 3 groups: a control group, a model group [5% imiquimod (IMQ)‑induced group] and an intervention group (5% IMQ‑induced plus LY294002‑treated group). Skin structural characteristics were recorded and evaluated by hematoxylin and eosin staining. The weights of the spleens and inguinal lymph nodes were measured. Th17 cell percentage, as well as the mRNA and protein expression levels of Notch1, Notch1 intracellular domain (NICD1), Hes1, PTEN, AKT, phosphorylated (p)‑AKT, mTOR complex 1 (mTORC1), p‑mTORC1, S6 kinase (S6K)1, S6K2 and IL‑17A were detected in skin samples of the three experimental groups. Additionally, splenic mononuclear cells from model mice were treated by 10 and 50 µM LY294002 to further evaluate its regulatory effect on Notch1/Hes1‑PTEN/AKT/IL‑17A feedback loop. Increased Th17 cell percentage, increased expression of Notch1, NICD1, Hes1, AKT, p‑AKT, mTORC1, p‑mTORC1, S6K1, S6K2 and IL‑17A, and decreased PTEN levels were observed in model mice alongside marked psoriasis‑like skin inflammation, splenomegaly and lymphadenopathy. LY294002 treatment significantly alleviated the severity of psoriasis‑like skin inflammation in the intervention mice, attenuated the degree of epidermal hyperplasia and dermal inflammatory cell infiltration, and mitigated splenomegaly and lymphadenopathy. In addition, LY294002 treatment reversed the increased Th17 cell percentage, as well as the increased expression of Notch1, NICD1, Hes1, AKT, p‑AKT, mTORC1, p‑mTORC1, S6K1, S6K2 and IL‑17A, and the decreased expression of PTEN. In vitro study from 5% IMQ‑induced mouse splenic mononuclear cells presented that high dose of LY294002 exerted more obviously regulatory effect on Notch1/Hes1‑PTEN/AKT/IL‑17A feedback loop. The current findings suggested that the Notch1/Hes1‑PTEN/AKT/IL‑17A feedback loop regulates Th17 cell differentiation within the disease environment of psoriasis. Blocking the Notch1/Hes1‑PTEN/AKT/IL‑17A feedback loop may thus be a potential therapeutic method for management of psoriatic inflammation.
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Affiliation(s)
- Ya-Wen Lin
- Department of Dermatology, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China
| | - Xin-Xin Li
- Department of Dermatology, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China
| | - Fang-Hui Fu
- Department of Dermatology, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China
| | - Bin Liu
- Institute for Metabolic and Neuropsychiatric Disorders, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China
| | - Xiaoyun Xing
- Department of Dermatology, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China
| | - Ruiqun Qi
- Department of Dermatology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Lei Ma
- Department of Dermatology, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China
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21
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Endocytosis at the Crossroad of Polarity and Signaling Regulation: Learning from Drosophila melanogaster and Beyond. Int J Mol Sci 2022; 23:ijms23094684. [PMID: 35563080 PMCID: PMC9101507 DOI: 10.3390/ijms23094684] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 04/19/2022] [Accepted: 04/21/2022] [Indexed: 02/06/2023] Open
Abstract
Cellular trafficking through the endosomal–lysosomal system is essential for the transport of cargo proteins, receptors and lipids from the plasma membrane inside the cells and across membranous organelles. By acting as sorting stations, vesicle compartments direct the fate of their content for degradation, recycling to the membrane or transport to the trans-Golgi network. To effectively communicate with their neighbors, cells need to regulate their compartmentation and guide their signaling machineries to cortical membranes underlying these contact sites. Endosomal trafficking is indispensable for the polarized distribution of fate determinants, adaptors and junctional proteins. Conversely, endocytic machineries cooperate with polarity and scaffolding components to internalize receptors and target them to discrete membrane domains. Depending on the cell and tissue context, receptor endocytosis can terminate signaling responses but can also activate them within endosomes that act as signaling platforms. Therefore, cell homeostasis and responses to environmental cues rely on the dynamic cooperation of endosomal–lysosomal machineries with polarity and signaling cues. This review aims to address advances and emerging concepts on the cooperative regulation of endocytosis, polarity and signaling, primarily in Drosophila melanogaster and discuss some of the open questions across the different cell and tissue types that have not yet been fully explored.
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22
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Hughes AM, Kuek V, Kotecha RS, Cheung LC. The Bone Marrow Microenvironment in B-Cell Development and Malignancy. Cancers (Basel) 2022; 14:2089. [PMID: 35565219 PMCID: PMC9102980 DOI: 10.3390/cancers14092089] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/11/2022] [Accepted: 04/20/2022] [Indexed: 11/16/2022] Open
Abstract
B lymphopoiesis is characterized by progressive loss of multipotent potential in hematopoietic stem cells, followed by commitment to differentiate into B cells, which mediate the humoral response of the adaptive immune system. This process is tightly regulated by spatially distinct bone marrow niches where cells, including mesenchymal stem and progenitor cells, endothelial cells, osteoblasts, osteoclasts, and adipocytes, interact with B-cell progenitors to direct their proliferation and differentiation. Recently, the B-cell niche has been implicated in initiating and facilitating B-cell precursor acute lymphoblastic leukemia. Leukemic cells are also capable of remodeling the B-cell niche to promote their growth and survival and evade treatment. Here, we discuss the major cellular components of bone marrow niches for B lymphopoiesis and the role of the malignant B-cell niche in disease development, treatment resistance and relapse. Further understanding of the crosstalk between leukemic cells and bone marrow niche cells will enable development of additional therapeutic strategies that target the niches in order to hinder leukemia progression.
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Affiliation(s)
- Anastasia M. Hughes
- Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA 6009, Australia; (A.M.H.); (V.K.); (R.S.K.)
- Curtin Medical School, Curtin University, Perth, WA 6102, Australia
| | - Vincent Kuek
- Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA 6009, Australia; (A.M.H.); (V.K.); (R.S.K.)
- Curtin Medical School, Curtin University, Perth, WA 6102, Australia
- School of Biomedical Sciences, University of Western Australia, Perth, WA 6009, Australia
| | - Rishi S. Kotecha
- Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA 6009, Australia; (A.M.H.); (V.K.); (R.S.K.)
- Curtin Medical School, Curtin University, Perth, WA 6102, Australia
- School of Medicine, University of Western Australia, Perth, WA 6009, Australia
- Department of Clinical Haematology, Oncology, Blood and Marrow Transplantation, Perth Children’s Hospital, Perth, WA 6009, Australia
| | - Laurence C. Cheung
- Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA 6009, Australia; (A.M.H.); (V.K.); (R.S.K.)
- Curtin Medical School, Curtin University, Perth, WA 6102, Australia
- Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia
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23
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Sood C, Justis VT, Doyle SE, Siegrist SE. Notch signaling regulates neural stem cell quiescence entry and exit in Drosophila. Development 2022; 149:274416. [PMID: 35112131 PMCID: PMC8918809 DOI: 10.1242/dev.200275] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 01/13/2022] [Indexed: 12/18/2022]
Abstract
Stem cells enter and exit quiescence as part of normal developmental programs and to maintain tissue homeostasis in adulthood. Although it is clear that stem cell intrinsic and extrinsic cues, local and systemic, regulate quiescence, it remains unclear whether intrinsic and extrinsic cues coordinate to control quiescence and how cue coordination is achieved. Here, we report that Notch signaling coordinates neuroblast intrinsic temporal programs with extrinsic nutrient cues to regulate quiescence in Drosophila. When Notch activity is reduced, quiescence is delayed or altogether bypassed, with some neuroblasts dividing continuously during the embryonic-to-larval transition. During embryogenesis before quiescence, neuroblasts express Notch and the Notch ligand Delta. After division, Delta is partitioned to adjacent GMC daughters where it transactivates Notch in neuroblasts. Over time, in response to intrinsic temporal cues and increasing numbers of Delta-expressing daughters, neuroblast Notch activity increases, leading to cell cycle exit and consequently, attenuation of Notch pathway activity. Quiescent neuroblasts have low to no active Notch, which is required for exit from quiescence in response to nutrient cues. Thus, Notch signaling coordinates proliferation versus quiescence decisions.
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24
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Swaminathan B, Youn SW, Naiche LA, Du J, Villa SR, Metz JB, Feng H, Zhang C, Kopan R, Sims PA, Kitajewski JK. Endothelial Notch signaling directly regulates the small GTPase RND1 to facilitate Notch suppression of endothelial migration. Sci Rep 2022; 12:1655. [PMID: 35102202 PMCID: PMC8804000 DOI: 10.1038/s41598-022-05666-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 01/07/2022] [Indexed: 11/24/2022] Open
Abstract
To control sprouting angiogenesis, endothelial Notch signaling suppresses tip cell formation, migration, and proliferation while promoting barrier formation. Each of these responses may be regulated by distinct Notch-regulated effectors. Notch activity is highly dynamic in sprouting endothelial cells, while constitutive Notch signaling drives homeostatic endothelial polarization, indicating the need for both rapid and constitutive Notch targets. In contrast to previous screens that focus on genes regulated by constitutively active Notch, we characterized the dynamic response to Notch. We examined transcriptional changes from 1.5 to 6 h after Notch signal activation via ligand-specific or EGTA induction in cultured primary human endothelial cells and neonatal mouse brain. In each combination of endothelial type and Notch manipulation, transcriptomic analysis identified distinct but overlapping sets of rapidly regulated genes and revealed many novel Notch target genes. Among the novel Notch-regulated signaling pathways identified were effectors in GPCR signaling, notably, the constitutively active GTPase RND1. In endothelial cells, RND1 was shown to be a novel direct Notch transcriptional target and required for Notch control of sprouting angiogenesis, endothelial migration, and Ras activity. We conclude that RND1 is directly regulated by endothelial Notch signaling in a rapid fashion in order to suppress endothelial migration.
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Affiliation(s)
- Bhairavi Swaminathan
- Department of Physiology and Biophysics, University of Illinois Chicago, Chicago, IL, 60612, USA
| | - Seock-Won Youn
- Department of Physiology and Biophysics, University of Illinois Chicago, Chicago, IL, 60612, USA
| | - L A Naiche
- Department of Physiology and Biophysics, University of Illinois Chicago, Chicago, IL, 60612, USA
| | - Jing Du
- Department of Physiology and Biophysics, University of Illinois Chicago, Chicago, IL, 60612, USA
| | - Stephanie R Villa
- Department of Physiology and Biophysics, University of Illinois Chicago, Chicago, IL, 60612, USA
| | - Jordan B Metz
- Department of Systems Biology, Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, 10032, USA
| | - Huijuan Feng
- Department of Systems Biology, Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, 10032, USA
| | - Chaolin Zhang
- Department of Systems Biology, Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, 10032, USA
| | - Raphael Kopan
- Division of Developmental Biology, Department of Pediatrics, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Peter A Sims
- Department of Systems Biology, Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, 10032, USA
| | - Jan K Kitajewski
- Department of Physiology and Biophysics, University of Illinois Chicago, Chicago, IL, 60612, USA.
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25
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Eve M, Gandawijaya J, Yang L, Oguro-Ando A. Neuronal Cell Adhesion Molecules May Mediate Neuroinflammation in Autism Spectrum Disorder. Front Psychiatry 2022; 13:842755. [PMID: 35492721 PMCID: PMC9051034 DOI: 10.3389/fpsyt.2022.842755] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 02/15/2022] [Indexed: 12/15/2022] Open
Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by restrictive and repetitive behaviors, alongside deficits in social interaction and communication. The etiology of ASD is largely unknown but is strongly linked to genetic variants in neuronal cell adhesion molecules (CAMs), cell-surface proteins that have important roles in neurodevelopment. A combination of environmental and genetic factors are believed to contribute to ASD pathogenesis. Inflammation in ASD has been identified as one of these factors, demonstrated through the presence of proinflammatory cytokines, maternal immune activation, and activation of glial cells in ASD brains. Glial cells are the main source of cytokines within the brain and, therefore, their activity is vital in mediating inflammation in the central nervous system. However, it is unclear whether the aforementioned neuronal CAMs are involved in modulating neuroimmune signaling or glial behavior. This review aims to address the largely unexplored role that neuronal CAMs may play in mediating inflammatory cascades that underpin neuroinflammation in ASD, primarily focusing on the Notch, nuclear factor-κB (NF-κB), and mitogen-activated protein kinase (MAPK) cascades. We will also evaluate the available evidence on how neuronal CAMs may influence glial activity associated with inflammation. This is important when considering the impact of environmental factors and inflammatory responses on ASD development. In particular, neural CAM1 (NCAM1) can regulate NF-κB transcription in neurons, directly altering proinflammatory signaling. Additionally, NCAM1 and contactin-1 appear to mediate astrocyte and oligodendrocyte precursor proliferation which can alter the neuroimmune response. Importantly, although this review highlights the limited information available, there is evidence of a neuronal CAM regulatory role in inflammatory signaling. This warrants further investigation into the role other neuronal CAM family members may have in mediating inflammatory cascades and would advance our understanding of how neuroinflammation can contribute to ASD pathology.
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Affiliation(s)
- Madeline Eve
- University of Exeter Medical School, University of Exeter, Exeter, United Kingdom
| | - Josan Gandawijaya
- University of Exeter Medical School, University of Exeter, Exeter, United Kingdom
| | - Liming Yang
- University of Exeter Medical School, University of Exeter, Exeter, United Kingdom
| | - Asami Oguro-Ando
- University of Exeter Medical School, University of Exeter, Exeter, United Kingdom
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26
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Zhou H, Zhao W, Zheng Z, Aweya JJ, Zhang Y, Zhu J, Zhao Y, Chen X, Yao D. The Notch receptor-ligand Delta is involved in the immune response of Penaeus vannamei. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2021; 125:104147. [PMID: 34111502 DOI: 10.1016/j.dci.2021.104147] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 05/10/2021] [Accepted: 05/26/2021] [Indexed: 06/12/2023]
Abstract
In the Notch signaling pathway in vertebrates and invertebrates, the ligand Delta plays crucial roles in cell proliferation, differentiation, and immunity. Although the Notch signaling pathway has recently been implicated in the immune defense of Penaeus vannamei, the association of Delta with this immune response remains unclear. Here, we cloned and characterized the Delta homolog in P. vannamei (designated as PvDelta). PvDelta has a 2493 bp open reading frame (ORF) encoding a putative protein of 830 amino acids. Bioinformatics analysis revealed that PvDelta contains an N-terminal signal peptide, a conserved Notch ligand (MNNL) domain, a Delta/Serrate/Lag-2 segment, 9 epidermal growth factors segments, a transmembrane domain, and shares high homology with other Delta family members. Transcripts of PvDelta were detected in all shrimp tissues tested and were induced by Vibrio parahaemolyticus, white spot syndrome virus (WSSV), and lipopolysaccharide (LPS), indicating its involvement in shrimp immune response. Moreover, after PvDelta knockdown followed by LPS stimulation, the expression of Notch signaling pathway genes (i.e., PvNotch, PvCSL, and PvHey) was downregulated. Finally, shrimp depleted of PvDelta showed a lower survival rate in response to V. parahaemolyticus challenge. In sum, our data reveal that PvDelta is involved in the innate immunity of shrimp by positively modulating the Notch signaling pathway.
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Affiliation(s)
- Hui Zhou
- Department of Biology and Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou, 515063, China
| | - Weiling Zhao
- Department of Biology and Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou, 515063, China
| | - Zhihong Zheng
- Department of Biology and Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou, 515063, China
| | - Jude Juventus Aweya
- Department of Biology and Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou, 515063, China
| | - Yueling Zhang
- Department of Biology and Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou, 515063, China
| | - Jinghua Zhu
- Department of Biology and Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou, 515063, China
| | - Yongzhen Zhao
- Guangxi Academy of Fishery Sciences, Guangxi Key Laboratory of Aquatic Genetic Breeding and Healthy Aquaculture, Nanning, 530021, China
| | - Xiuli Chen
- Guangxi Academy of Fishery Sciences, Guangxi Key Laboratory of Aquatic Genetic Breeding and Healthy Aquaculture, Nanning, 530021, China
| | - Defu Yao
- Department of Biology and Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou, 515063, China.
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27
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Silva VR, Santos LDS, Dias RB, Quadros CA, Bezerra DP. Emerging agents that target signaling pathways to eradicate colorectal cancer stem cells. Cancer Commun (Lond) 2021; 41:1275-1313. [PMID: 34791817 PMCID: PMC8696218 DOI: 10.1002/cac2.12235] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/28/2021] [Accepted: 10/25/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) represents the third most commonly diagnosed cancer and the second leading cause of cancer death worldwide. The modern concept of cancer biology indicates that cancer is formed of a small population of cells called cancer stem cells (CSCs), which present both pluripotency and self-renewal properties. These cells are considered responsible for the progression of the disease, recurrence and tumor resistance. Interestingly, some cell signaling pathways participate in CRC survival, proliferation, and self-renewal properties, and most of them are dysregulated in CSCs, including the Wingless (Wnt)/β-catenin, Notch, Hedgehog, nuclear factor kappa B (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), peroxisome proliferator-activated receptor (PPAR), phosphatidyl-inositol-3-kinase/Akt/mechanistic target of rapamycin (PI3K/Akt/mTOR), and transforming growth factor-β (TGF-β)/Smad pathways. In this review, we summarize the strategies for eradicating CRC stem cells by modulating these dysregulated pathways, which will contribute to the study of potential therapeutic schemes, combining conventional drugs with CSC-targeting drugs, and allowing better cure rates in anti-CRC therapy.
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Affiliation(s)
- Valdenizia R Silva
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil
| | - Luciano de S Santos
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil
| | - Rosane B Dias
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil
| | - Claudio A Quadros
- São Rafael Hospital, Rede D'Or/São Luiz, Salvador, Bahia, 41253-190, Brazil.,Bahia State University, Salvador, Bahia, 41150-000, Brazil
| | - Daniel P Bezerra
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil
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28
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Eleftherianos I, Heryanto C, Bassal T, Zhang W, Tettamanti G, Mohamed A. Haemocyte-mediated immunity in insects: Cells, processes and associated components in the fight against pathogens and parasites. Immunology 2021; 164:401-432. [PMID: 34233014 PMCID: PMC8517599 DOI: 10.1111/imm.13390] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 06/28/2021] [Indexed: 12/27/2022] Open
Abstract
The host defence of insects includes a combination of cellular and humoral responses. The cellular arm of the insect innate immune system includes mechanisms that are directly mediated by haemocytes (e.g., phagocytosis, nodulation and encapsulation). In addition, melanization accompanying coagulation, clot formation and wound healing, nodulation and encapsulation processes leads to the formation of cytotoxic redox-cycling melanin precursors and reactive oxygen and nitrogen species. However, demarcation between cellular and humoral immune reactions as two distinct categories is not straightforward. This is because many humoral factors affect haemocyte functions and haemocytes themselves are an important source of many humoral molecules. There is also a considerable overlap between cellular and humoral immune functions that span from recognition of foreign intruders to clot formation. Here, we review these immune reactions starting with the cellular mechanisms that limit haemolymph loss and participate in wound healing and clot formation and advancing to cellular functions that are critical in restricting pathogen movement and replication. This information is important because it highlights that insect cellular immunity is controlled by a multilayered system, different components of which are activated by different pathogens or during the different stages of the infection.
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Affiliation(s)
- Ioannis Eleftherianos
- Infection and Innate Immunity LaboratoryDepartment of Biological SciencesInstitute for Biomedical SciencesThe George Washington UniversityWashingtonDCUSA
| | - Christa Heryanto
- Infection and Innate Immunity LaboratoryDepartment of Biological SciencesInstitute for Biomedical SciencesThe George Washington UniversityWashingtonDCUSA
| | - Taha Bassal
- Department of EntomologyFaculty of ScienceCairo UniversityGizaEgypt
| | - Wei Zhang
- State Key Laboratory Breeding Base of Green Pesticide and Agricultural BioengineeringKey Laboratory of Green Pesticide and Agricultural BioengineeringMinistry of EducationGuizhou UniversityGuiyangChina
| | - Gianluca Tettamanti
- Department of Biotechnology and Life SciencesUniversity of InsubriaVareseItaly
- BAT Center‐Interuniversity Center for Studies on Bioinspired Agro‐Environmental TechnologyUniversity of Napoli Federico IINapoliItaly
| | - Amr Mohamed
- Department of EntomologyFaculty of ScienceCairo UniversityGizaEgypt
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29
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Marelli F, Rurale G, Persani L. From Endoderm to Progenitors: An Update on the Early Steps of Thyroid Morphogenesis in the Zebrafish. Front Endocrinol (Lausanne) 2021; 12:664557. [PMID: 34149617 PMCID: PMC8213386 DOI: 10.3389/fendo.2021.664557] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 05/14/2021] [Indexed: 12/24/2022] Open
Abstract
The mechanisms underlying thyroid gland development have a central interest in biology and this review is aimed to provide an update on the recent advancements on the early steps of thyroid differentiation that were obtained in the zebrafish, because this teleost fish revealed to be a suitable organism to study the early developmental stages. Physiologically, the thyroid precursors fate is delineated by the appearance among the endoderm cells of the foregut of a restricted cell population expressing specific transcription factors, including pax2a, nkx2.4b, and hhex. The committed thyroid primordium first appears as a thickening of the pharyngeal floor of the anterior endoderm, that subsequently detaches from the floor and migrates to its final location where it gives rise to the thyroid hormone-producing follicles. At variance with mammalian models, thyroid precursor differentiation in zebrafish occurs early during the developmental process before the dislocation to the eutopic positioning of thyroid follicles. Several pathways have been implicated in these early events and nowadays there is evidence of a complex crosstalk between intrinsic (coming from the endoderm and thyroid precursors) and extrinsic factors (coming from surrounding tissues, as the cardiac mesoderm) whose organization in time and space is probably required for the proper thyroid development. In particular, Notch, Shh, Fgf, Bmp, and Wnt signaling seems to be required for the commitment of endodermal cells to a thyroid fate at specific developmental windows of zebrafish embryo. Here, we summarize the recent findings produced in the various zebrafish experimental models with the aim to define a comprehensive picture of such complicated puzzle.
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Affiliation(s)
- Federica Marelli
- Dipartimento di Malattie Endocrine e del Metabolismo, IRCCS Istituto Auxologico Italiano IRCCS, Milan, Italy
- Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano - LITA, Segrate, Italy
| | - Giuditta Rurale
- Dipartimento di Malattie Endocrine e del Metabolismo, IRCCS Istituto Auxologico Italiano IRCCS, Milan, Italy
| | - Luca Persani
- Dipartimento di Malattie Endocrine e del Metabolismo, IRCCS Istituto Auxologico Italiano IRCCS, Milan, Italy
- Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano - LITA, Segrate, Italy
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30
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Guo S, Quan S, Zou S. Roles of the Notch Signaling Pathway in Ovarian Functioning. Reprod Sci 2021; 28:2770-2778. [PMID: 34008156 DOI: 10.1007/s43032-021-00610-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 05/05/2021] [Indexed: 11/30/2022]
Abstract
The Notch signaling pathway regulates cell invasion, adhesion, proliferation, apoptosis, and differentiation via cell-to-cell interactions and plays important physiological roles in the ovary. This review summarizes current knowledge about the Notch signaling pathway in relation to ovarian functions and reveals the potential underlying mechanisms. We conducted an in-depth review of relevant literature to determine the current status of research into the Notch signaling pathway in relation to ovarian functioning and reveal potential underlying mechanisms. The activation of different Notch receptors promotes the formation of primordial follicles and proliferation of granulosa cells and inhibits steroid secretion. Abnormal regulation of the Notch signaling pathway or direct mutations might lead to over-activation or under-activation of the receptors, resulting in Notch upregulation or downregulation. It can also disrupt the normal physiological functions of the ovary. The lncRNA HOTAIR and growth hormones improved premature ovarian failure (POF) and promoted follicle maturation in a mouse model of POF by upregulating Notch1 expression. They also stimulated the Notch1 signaling pathway, increased the level of plasma estradiol, and decreased the level of plasma follicle-stimulating hormone. Thus, Notch1 could serve as a novel therapeutic target for POF. Several studies have reported multiple roles of Notch in regulating female primordial follicle formation and follicle maturation. Direct mutations in Notch-related molecules or abnormal gene regulation in the signaling pathway can lead to ovarian dysfunction. However, the underlying mechanisms are not fully understood.
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Affiliation(s)
- Shuhan Guo
- Department of Obstetrics and Gynecology, Reproductive Medicine Center, Nanfang Hospital/The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Song Quan
- Department of Obstetrics and Gynecology, Reproductive Medicine Center, Nanfang Hospital/The First School of Clinical Medicine, Southern Medical University, Guangzhou, China.
| | - Siyi Zou
- Department of Obstetrics and Gynecology, Reproductive Medicine Center, Nanfang Hospital/The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
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31
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Chen J, Li J, Chen J, Cheng W, Lin J, Ke L, Liu G, Bai X, Zhang P. Treatment of collagen-induced arthritis rat model by using Notch signalling inhibitor. J Orthop Translat 2021; 28:100-107. [PMID: 33816113 PMCID: PMC7995347 DOI: 10.1016/j.jot.2021.01.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 11/22/2020] [Accepted: 01/15/2021] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND The Notch signalling pathway has been reported to play a key role in rheumatoid arthritis (RA) development. Thus, inhibition of the activation of this signalling pathway may be a promising approach to the treatment of RA. In this study, the Notch signalling inhibitor LY411575, which can inhibit both Notch1 and Notch3, was used for the treatment of collagen-induced arthritis (CIA) rats. METHODS Wistar rats were immunised with bovine type II collagen (CII) to establish rats CIA model. The inhibitory effects of LY411575 on Notch1 intracellular domain (N1ICD) and Notch3 intracellular domain (N3ICD) protein was verified by western blot (WB) in vitro. CIA rats were treated with different doses of LY411575 for 15 and 28 days, respectively. Methotrexate and sodium carboxymethyl cellulose (CMC-Na) were used as positive and negative (vehicle) control respectively. Destruction of the rat ankle joint and the bone loss on the periarticular side were evaluated by micro-computed tomography (Micro-CT). In addition, destruction of the ankle articular cartilage and the osteoclast numbers were determined by histology. Expression of N1ICD and N3ICD in the ankle joint was detected by immunohistochemistry. RESULTS LY411575 could significantly inhibit the expression of N1ICD and N3ICD in vitro. Micro-CT test showed that the ankle joint destruction significantly improved after treatment with LY411575 (5 mg/kg and 10 mg/kg, respectively). The bone quality in the LY411575 (5 mg/kg and 10 mg/kg, respectively) groups were improved compared with the vehicle group. Histological analysis showed that LY411575 (5 mg/kg and 10 mg/kg, respectively) treatment reduced the severity of ankle joint inflammation in CIA rats (including ankle joint destruction, pannus formation, and cartilage damage) and reduced the expression of N1ICD and N3ICD in CIA rats ankle joints significantly. CONCLUSION The inhibitor of Notch signalling LY411575 is an effective treatment for CIA. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE Our study provides new evidence to support the potential clinical application of Notch signalling pathway inhibitor LY411575 as a drug candidate for the treatment of RA.
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Affiliation(s)
- Jianhai Chen
- Center for Translational Medicine Research and Development, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jian Li
- Center for Translational Medicine Research and Development, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jinqing Chen
- Research Laboratory for Biomedical Optics and Molecular Imaging, Shenzhen Key Laboratory for Molecular Imaging, Guangdong Provincial Key Laboratory of Biomedical Optical Imaging Technology, CAS Key Laboratory of Health Informatics, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Wenxiang Cheng
- Center for Translational Medicine Research and Development, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China
| | - Jietao Lin
- Center for Translational Medicine Research and Development, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Liqing Ke
- Center for Translational Medicine Research and Development, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China
| | - Gang Liu
- Shenzhen Hospital, University of Chinese Academy of Sciences, China
| | - Xueling Bai
- Center for Translational Medicine Research and Development, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China
| | - Peng Zhang
- Center for Translational Medicine Research and Development, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Shenzhen Engineering Research Center for Medical Bioactive Materials, China
- Shenzhen Hospital, University of Chinese Academy of Sciences, China
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Distant activation of Notch signaling induces stem cell niche assembly. PLoS Genet 2021; 17:e1009489. [PMID: 33780456 PMCID: PMC8031783 DOI: 10.1371/journal.pgen.1009489] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 04/08/2021] [Accepted: 03/15/2021] [Indexed: 11/26/2022] Open
Abstract
Here we show that multiple modes of Notch signaling activation specify the complexity of spatial cellular interactions necessary for stem cell niche assembly. In particular, we studied the formation of the germline stem cell niche in Drosophila ovaries, which is a two-step process whereby terminal filaments are formed first. Then, terminal filaments signal to the adjacent cap cell precursors, resulting in Notch signaling activation, which is necessary for the lifelong acquisition of stem cell niche cell fate. The genetic data suggest that in order to initiate the process of stem cell niche assembly, Notch signaling is activated among non-equipotent cells via distant induction, where germline Delta is delivered to somatic cells located several diameters away via cellular projections generated by primordial germ cells. At the same time, to ensure the robustness of niche formation, terminal filament cell fate can also be induced by somatic Delta via cis- or trans-inhibition. This exemplifies a double security mechanism that guarantees that the germline stem cell niche is formed, since it is indispensable for the adjacent germline precursor cells to acquire and maintain stemness necessary for successful reproduction. These findings contribute to our understanding of the formation of stem cell niches in their natural environment, which is important for stem cell biology and regenerative medicine. Adult organs often contain a stem cell niche that maintains stem cells necessary for the replenishment of different types of terminally differentiated cells that are continuously lost. This study reveals that various modes of Notch signaling activation induce the formation of the germline stem cell niche in Drosophila. We show for the first time that even among non-equipotent cells, Notch signaling can be trans-activated via distant induction mode, where the ligand Delta is delivered via cellular protrusions to the somatic stem cell niche precursors located several cell diameters away. Moreover, there is a second security mechanism controlled by the soma that additionally ensures that the stem cell niche is formed. In the stem cell niche precursors, Notch signaling can be locally inhibited by the somatic Delta. While Notch signaling trans-inhibition has been proposed via mathematical modelling, our findings show that a group of cells that have high Delta can be seen in a living organism, confirming that this mode of Notch signaling inhibition by trans-Delta exists in vivo. This work provides significant advances in the understanding of Notch signaling and the stem cell niche formation, which is important for the fields of stem cell biology and regenerative medicine.
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Dutta D, Sharma V, Mutsuddi M, Mukherjee A. Regulation of Notch signaling by E3 ubiquitin ligases. FEBS J 2021; 289:937-954. [PMID: 33644958 DOI: 10.1111/febs.15792] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 02/07/2021] [Accepted: 02/25/2021] [Indexed: 12/11/2022]
Abstract
Notch signaling is an evolutionarily conserved pathway that is widely used for multiple cellular events during development. Activation of the Notch pathway occurs when the ligand from a neighboring cell binds to the Notch receptor and induces cleavage of the intracellular domain of Notch, which further translocates into the nucleus to activate its downstream genes. The involvement of the Notch pathway in diverse biological events is possible due to the complexity in its regulation. In order to maintain tight spatiotemporal regulation, the Notch receptor, as well as its ligand, undergoes a series of physical and biochemical modifications that, in turn, helps in proper maintenance and fine-tuning of the signaling outcome. Ubiquitination is the post-translational addition of a ubiquitin molecule to a substrate protein, and the process is regulated by E3 ubiquitin ligases. The present review describes the involvement of different E3 ubiquitin ligases that play an important role in the regulation and maintenance of proper Notch signaling and how perturbation in ubiquitination results in abnormal Notch signaling leading to a number of human diseases.
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Affiliation(s)
- Debdeep Dutta
- Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Vartika Sharma
- Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Mousumi Mutsuddi
- Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Ashim Mukherjee
- Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, India
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Anusewicz D, Orzechowska M, Bednarek AK. Notch Signaling Pathway in Cancer-Review with Bioinformatic Analysis. Cancers (Basel) 2021; 13:cancers13040768. [PMID: 33673145 PMCID: PMC7918426 DOI: 10.3390/cancers13040768] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/26/2021] [Accepted: 02/08/2021] [Indexed: 01/19/2023] Open
Abstract
Simple Summary The Notch signaling pathway, which controls multiple cell differentiation processes during the embryonic stage and adult life, is associated with carcinogenesis and disease progression. The aim of the present study was to highlight cancer heterogeneity with respect to the Notch pathway. Our analysis concerns the effects of the Notch signaling at different levels, including core components and downstream target genes. We also demonstrate overall and disease-free survival results, pointing out the characteristics of particular Notch components. Depending on tissue context, Notch members can be either oncogenic or suppressive. We observed different expression profile core components and target genes that could be associated with distinct survival of patients. Advances in our understanding of the Notch signaling in cancer are very promising for the development of new treatment strategies for the benefit of patients. Abstract Notch signaling is an evolutionarily conserved pathway regulating normal embryonic development and homeostasis in a wide variety of tissues. It is also critically involved in carcinogenesis, as well as cancer progression. Activation of the Notch pathway members can be either oncogenic or suppressive, depending on tissue context. The present study is a comprehensive overview, extended with a bioinformatics analysis of TCGA cohorts, including breast, bladder, cervical, colon, kidney, lung, ovary, prostate and rectum carcinomas. We performed global expression profiling of the Notch pathway core components and downstream targets. For this purpose, we implemented the Uniform Manifold Approximation and Projection algorithm to reduce the dimensions. Furthermore, we determined the optimal cutpoint using Evaluate Cutpoint software to established disease-free and overall survival with respect to particular Notch members. Our results demonstrated separation between tumors and their corresponding normal tissue, as well as between tumors in general. The differentiation of the Notch pathway, at its various stages, in terms of expression and survival resulted in distinct profiles of biological processes such as proliferation, adhesion, apoptosis and epithelial to mesenchymal transition. In conclusion, whether oncogenic or suppressive, Notch signaling is proven to be associated with various types of malignancies, and thus may be of interest as a potential therapeutic target.
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Structure, function, and pathology of protein O-glucosyltransferases. Cell Death Dis 2021; 12:71. [PMID: 33436558 PMCID: PMC7803782 DOI: 10.1038/s41419-020-03314-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 12/02/2020] [Accepted: 12/03/2020] [Indexed: 01/29/2023]
Abstract
Protein O-glucosylation is a crucial form of O-glycosylation, which involves glucose (Glc) addition to a serine residue within a consensus sequence of epidermal growth factor epidermal growth factor (EGF)-like repeats found in several proteins, including Notch. Glc provides stability to EGF-like repeats, is required for S2 cleavage of Notch, and serves to regulate the trafficking of Notch, crumbs2, and Eyes shut proteins to the cell surface. Genetic and biochemical studies have shown a link between aberrant protein O-glucosylation and human diseases. The main players of protein O-glucosylation, protein O-glucosyltransferases (POGLUTs), use uridine diphosphate (UDP)-Glc as a substrate to modify EGF repeats and reside in the endoplasmic reticulum via C-terminal KDEL-like signals. In addition to O-glucosylation activity, POGLUTs can also perform protein O-xylosylation function, i.e., adding xylose (Xyl) from UDP-Xyl; however, both activities rely on residues of EGF repeats, active-site conformations of POGLUTs and sugar substrate concentrations in the ER. Impaired expression of POGLUTs has been associated with initiation and progression of human diseases such as limb-girdle muscular dystrophy, Dowling-Degos disease 4, acute myeloid leukemia, and hepatocytes and pancreatic dysfunction. POGLUTs have been found to alter the expression of cyclin-dependent kinase inhibitors (CDKIs), by affecting Notch or transforming growth factor-β1 signaling, and cause cell proliferation inhibition or induction depending on the particular cell types, which characterizes POGLUT's cell-dependent dual role. Except for a few downstream elements, the precise mechanisms whereby aberrant protein O-glucosylation causes diseases are largely unknown, leaving behind many questions that need to be addressed. This systemic review comprehensively covers literature to understand the O-glucosyltransferases with a focus on POGLUT1 structure and function, and their role in health and diseases. Moreover, this study also raises unanswered issues for future research in cancer biology, cell communications, muscular diseases, etc.
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Orzechowska M, Anusewicz D, Bednarek AK. Functional Gene Expression Differentiation of the Notch Signaling Pathway in Female Reproductive Tract Tissues-A Comprehensive Review With Analysis. Front Cell Dev Biol 2021; 8:592616. [PMID: 33384996 PMCID: PMC7770115 DOI: 10.3389/fcell.2020.592616] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 11/11/2020] [Indexed: 12/13/2022] Open
Abstract
The Notch pathway involves evolutionarily conserved signaling regulating the development of the female tract organs such as breast, ovary, cervix, and uterine endometrium. A great number of studies revealed Notch aberrancies in association with their carcinogenesis and disease progression, the management of which is still challenging. The present study is a comprehensive review of the available literature on Notch signaling during the normal development and carcinogenesis of the female tract organs. The review has been enriched with our analyses of the TCGA data including breast, cervical, ovarian, and endometrial carcinomas concerning the effects of Notch signaling at two levels: the core components and downstream effectors, hence filling the lack of global overview of Notch-driven carcinogenesis and disease progression. Phenotype heterogeneity regarding Notch signaling was projected in two uniform manifold approximation and projection algorithm dimensions, preceded by the principal component analysis step reducing the data burden. Additionally, overall and disease-free survival analyses were performed with the optimal cutpoint determination by Evaluate Cutpoints software to establish the character of particular Notch components in tumorigenesis. In addition to the review, we demonstrated separate models of the examined cancers of the Notch pathway and its targets, although expression profiles of all normal tissues were much more similar to each other than to its cancerous compartments. Such Notch-driven cancerous differentiation resulted in a case of opposite association with DFS and OS. As a consequence, target genes also show very distinct profiles including genes associated with cell proliferation and differentiation, energy metabolism, or the EMT. In conclusion, the observed Notch associations with the female tract malignancies resulted from differential expression of target genes. This may influence a future analysis to search for new therapeutic targets based on specific Notch pathway profiles.
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Affiliation(s)
| | - Dorota Anusewicz
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz, Poland
| | - Andrzej K Bednarek
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz, Poland
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Zhang L, Evans A, von Ruhland C, Draman MS, Edkins S, Vincent AE, Berlinguer-Palmini R, Rees DA, Haridas AS, Morris D, Tee AR, Ludgate M, Turnbull DM, Karpe F, Dayan CM. Distinctive Features of Orbital Adipose Tissue (OAT) in Graves' Orbitopathy. Int J Mol Sci 2020; 21:E9145. [PMID: 33266331 PMCID: PMC7730568 DOI: 10.3390/ijms21239145] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/20/2020] [Accepted: 11/28/2020] [Indexed: 12/12/2022] Open
Abstract
Depot specific expansion of orbital-adipose-tissue (OAT) in Graves' Orbitopathy (GO) is associated with lipid metabolism signaling defects. We hypothesize that the unique adipocyte biology of OAT facilitates its expansion in GO. A comprehensive comparison of OAT and white-adipose-tissue (WAT) was performed by light/electron-microscopy, lipidomic and transcriptional analysis using ex vivo WAT, healthy OAT (OAT-H) and OAT from GO (OAT-GO). OAT-H/OAT-GO have a single lipid-vacuole and low mitochondrial number. Lower lipolytic activity and smaller adipocytes of OAT-H/OAT-GO, accompanied by similar essential linoleic fatty acid (FA) and (low) FA synthesis to WAT, revealed a hyperplastic OAT expansion through external FA-uptake via abundant SLC27A6 (FA-transporter) expression. Mitochondrial dysfunction of OAT in GO was apparent, as evidenced by the increased mRNA expression of uncoupling protein 1 (UCP1) and mitofusin-2 (MFN2) in OAT-GO compared to OAT-H. Transcriptional profiles of OAT-H revealed high expression of Iroquois homeobox-family (IRX-3&5), and low expression in HOX-family/TBX5 (essential for WAT/BAT (brown-adipose-tissue)/BRITE (BRown-in-whITE) development). We demonstrated unique features of OAT not presented in either WAT or BAT/BRITE. This study reveals that the pathologically enhanced FA-uptake driven hyperplastic expansion of OAT in GO is associated with a depot specific mechanism (the SLC27A6 FA-transporter) and mitochondrial dysfunction. We uncovered that OAT functions as a distinctive fat depot, providing novel insights into adipocyte biology and the pathological development of OAT expansion in GO.
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Affiliation(s)
- Lei Zhang
- School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK; (A.E.); (C.v.R.); (M.S.D.); (S.E.); (D.A.R.); (A.R.T.); (M.L.); (C.M.D.)
| | - Anna Evans
- School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK; (A.E.); (C.v.R.); (M.S.D.); (S.E.); (D.A.R.); (A.R.T.); (M.L.); (C.M.D.)
| | - Chris von Ruhland
- School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK; (A.E.); (C.v.R.); (M.S.D.); (S.E.); (D.A.R.); (A.R.T.); (M.L.); (C.M.D.)
| | - Mohd Shazli Draman
- School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK; (A.E.); (C.v.R.); (M.S.D.); (S.E.); (D.A.R.); (A.R.T.); (M.L.); (C.M.D.)
| | - Sarah Edkins
- School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK; (A.E.); (C.v.R.); (M.S.D.); (S.E.); (D.A.R.); (A.R.T.); (M.L.); (C.M.D.)
| | - Amy E. Vincent
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle NE2 4HH, UK; (A.E.V.); (D.M.T.)
| | | | - D. Aled Rees
- School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK; (A.E.); (C.v.R.); (M.S.D.); (S.E.); (D.A.R.); (A.R.T.); (M.L.); (C.M.D.)
| | - Anjana S Haridas
- Department of Ophthalmology, Cardiff & Vale University Health Board, Cardiff CF14 4XW, UK; (A.S.H.); (D.M.)
| | - Dan Morris
- Department of Ophthalmology, Cardiff & Vale University Health Board, Cardiff CF14 4XW, UK; (A.S.H.); (D.M.)
| | - Andrew R. Tee
- School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK; (A.E.); (C.v.R.); (M.S.D.); (S.E.); (D.A.R.); (A.R.T.); (M.L.); (C.M.D.)
| | - Marian Ludgate
- School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK; (A.E.); (C.v.R.); (M.S.D.); (S.E.); (D.A.R.); (A.R.T.); (M.L.); (C.M.D.)
| | - Doug M. Turnbull
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle NE2 4HH, UK; (A.E.V.); (D.M.T.)
| | - Fredrik Karpe
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK;
- NIHR Oxford Biomedical Research Center, OUH Foundation Trust, Oxford OX4 2PG, UK
| | - Colin M. Dayan
- School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK; (A.E.); (C.v.R.); (M.S.D.); (S.E.); (D.A.R.); (A.R.T.); (M.L.); (C.M.D.)
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Gratton R, Tricarico PM, d’Adamo AP, Bianco AM, Moura R, Agrelli A, Brandão L, Zupin L, Crovella S. Notch Signaling Regulation in Autoinflammatory Diseases. Int J Mol Sci 2020; 21:E8847. [PMID: 33238371 PMCID: PMC7700323 DOI: 10.3390/ijms21228847] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 11/13/2020] [Accepted: 11/21/2020] [Indexed: 12/22/2022] Open
Abstract
Notch pathway is a highly conserved intracellular signaling route that modulates a vast variety of cellular processes including proliferation, differentiation, migration, cell fate and death. Recently, the presence of a strict crosstalk between Notch signaling and inflammation has been described, although the precise molecular mechanisms underlying this interplay have not yet been fully unravelled. Disruptions in Notch cascade, due both to direct mutations and/or to an altered regulation in the core components of Notch signaling, might lead to hypo- or hyperactivation of Notch target genes and signaling molecules, ultimately contributing to the onset of autoinflammatory diseases. To date, alterations in Notch signaling have been reported as associated with three autoinflammatory disorders, therefore, suggesting a possible role of Notch in the pathogenesis of the following diseases: hidradenitis suppurativa (HS), Behçet disease (BD), and giant cell arteritis (GCA). In this review, we aim at better characterizing the interplay between Notch and autoinflammatory diseases, trying to identify the role of this signaling route in the context of these disorders.
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Affiliation(s)
- Rossella Gratton
- Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, 34137 Trieste, Italy; (R.G.); (A.P.d.); (A.M.B.); (R.M.); (L.B.); (L.Z.)
| | - Paola Maura Tricarico
- Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, 34137 Trieste, Italy; (R.G.); (A.P.d.); (A.M.B.); (R.M.); (L.B.); (L.Z.)
| | - Adamo Pio d’Adamo
- Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, 34137 Trieste, Italy; (R.G.); (A.P.d.); (A.M.B.); (R.M.); (L.B.); (L.Z.)
- Department of Medical Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy
| | - Anna Monica Bianco
- Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, 34137 Trieste, Italy; (R.G.); (A.P.d.); (A.M.B.); (R.M.); (L.B.); (L.Z.)
| | - Ronald Moura
- Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, 34137 Trieste, Italy; (R.G.); (A.P.d.); (A.M.B.); (R.M.); (L.B.); (L.Z.)
| | - Almerinda Agrelli
- Department of Pathology, Federal University of Pernambuco, Recife 50670-901, Brazil;
| | - Lucas Brandão
- Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, 34137 Trieste, Italy; (R.G.); (A.P.d.); (A.M.B.); (R.M.); (L.B.); (L.Z.)
| | - Luisa Zupin
- Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, 34137 Trieste, Italy; (R.G.); (A.P.d.); (A.M.B.); (R.M.); (L.B.); (L.Z.)
| | - Sergio Crovella
- Department of Biological and Environmental Sciences, College of Arts and Sciences, University of Qatar, Doha 2713, Qatar;
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Yang E, Shen J. The roles and functions of Paneth cells in Crohn's disease: A critical review. Cell Prolif 2020; 54:e12958. [PMID: 33174662 PMCID: PMC7791172 DOI: 10.1111/cpr.12958] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 10/15/2020] [Accepted: 10/24/2020] [Indexed: 12/13/2022] Open
Abstract
Paneth cells (PCs) are located at the base of small intestinal crypts and secrete the α‐defensins, human α‐defensin 5 (HD‐5) and human α‐defensin 6 (HD‐6) in response to bacterial, cholinergic and other stimuli. The α‐defensins are broad‐spectrum microbicides that play critical roles in controlling gut microbiota and maintaining intestinal homeostasis. Inflammatory bowel disease, including ulcerative colitis and Crohn's disease (CD), is a complicated autoimmune disorder. The pathogenesis of CD involves genetic factors, environmental factors and microflora. Surprisingly, with regard to genetic factors, many susceptible genes and pathogenic pathways of CD, including nucleotide‐binding oligomerization domain 2 (NOD2), autophagy‐related 16‐like 1 (ATG16L1), immunity‐related guanosine triphosphatase family M (IRGM), wingless‐related integration site (Wnt), leucine‐rich repeat kinase 2 (LRRK2), histone deacetylases (HDACs), caspase‐8 (Casp8) and X‐box‐binding protein‐1 (XBP1), are relevant to PCs. As the underlying mechanisms are being unravelled, PCs are identified as the central element of CD pathogenesis, integrating factors among microbiota, intestinal epithelial barrier dysfunction and the immune system. In the present review, we demonstrate how these genes and pathways regulate CD pathogenesis via their action on PCs and what treatment modalities can be applied to deal with these PC‐mediated pathogenic processes.
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Affiliation(s)
- Erpeng Yang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Renji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China
| | - Jun Shen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Renji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China
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Chen H, Xiao H, Gan H, Zhang L, Wang L, Li S, Wang D, Li T, Zhai X, Zhao J. Hypoxia-inducible Factor 2α Exerts Neuroprotective Effects by Promoting Angiogenesis via the VEGF/Notch Pathway after Intracerebral Hemorrhage Injury in Rats. Neuroscience 2020; 448:206-218. [PMID: 32736070 DOI: 10.1016/j.neuroscience.2020.07.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 06/15/2020] [Accepted: 07/06/2020] [Indexed: 10/23/2022]
Abstract
Angiogenesis after intracerebral hemorrhage (ICH) injury can effectively alleviate brain damage and improve neurological function. Hypoxia-inducible factor 2α (HIF-2α) is an important angiogenic regulator and exhibits protective effects in several neurological diseases; however, its role in ICH has not yet been reported. Hence, in the present study, we explored whether HIF-2α reduces ICH injury by promoting angiogenesis. In addition, we explored the role of the vascular endothelial growth factor (VEGF)/Notch pathway in HIF-2α-mediated angiogenesis. We injected 50 μL of autologous blood taken from the femoral artery into the right striatum of healthy male adult Sprague-Dawley rats to create an autologous-blood-induced rat model of ICH. Lentiviral vectors were injected to both overexpress and knock down HIF-2α expression. VEGF receptor 2 (VEGFR2) and Notch-specific inhibitors were injected intraperitoneally to block VEGFR2- and Notch-mediated signaling after lentiviral injections. Our data showed that HIF-2α overexpression reduced neurological-damage scores and brain-water content, suggesting it had a protective effect on ICH injury. In addition, overexpression of HIF-2α promoted angiogenesis, increased focal cerebral blood flow (CBF), and reduced neuronal damage, whereas HIF-2α knockdown resulted in the opposite effects. Furthermore, we found that HIF-2α-mediated angiogenesis was blocked by a Notch-specific inhibitor. Likewise, the HIF-2α-mediated increase in phospho-VEGFR-2, cleaved-Notch1 and Notch1 expression was reversed via a VEGFR2-specific inhibitor. Taken together, our results indicate that HIF-2α promotes angiogenesis via the VEGF/Notch pathway to attenuate ICH injury. Moreover, our findings may contribute to the development of a novel strategy for alleviating ICH injury via HIF-2α-mediated upregulation of angiogenesis.
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Affiliation(s)
- Hui Chen
- Department of Neurosurgery, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Han Xiao
- Department of Neurosurgery, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Hui Gan
- Department of Neurosurgery, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Li Zhang
- Department of Neurosurgery, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Lu Wang
- Department of Neurosurgery, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Siyu Li
- Department of Cardiology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Difei Wang
- Department of Neurosurgery, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Tiegang Li
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Meteria Medica, Peking Union Medical College and Chinese Academy of Sciences, Beijing 100050, China
| | - Xuan Zhai
- Department of Neurosurgery, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing 400010, China.
| | - Jing Zhao
- Department of Pathophysiology, Chongqing Medical University, Chongqing 400016, China; Institute of Neuroscience, Chongqing Medical University, Chongqing 400016, China.
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Vriend J, Rastegar M. Ubiquitin ligases and medulloblastoma: genetic markers of the four consensus subgroups identified through transcriptome datasets. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165839. [PMID: 32445667 DOI: 10.1016/j.bbadis.2020.165839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 04/23/2020] [Accepted: 05/13/2020] [Indexed: 01/05/2023]
Abstract
The ubiquitin proteasome system regulates key cellular processes in normal and in cancer cells. Herein, we review published data on the role of ubiquitin ligases in the four major subgroups of medulloblastoma (MB). While conventional literature serves as an initial source of information on cellular pathways in MB, large publicly available datasets of gene expression can be used to add information not previously identified in the literature. By analysing the publicly available Cavalli dataset, we show that increased expression of ZNRF3 characterizes the WNT subgroup of MB. The ZNRF3 gene codes for an E3 ligase associated with WNT receptors. Loss of a copy of chromosome 6 in a subtype of the WNT group was associated with decreased expression of the gene encoding the E3 ligase RNF146. While the E3 ligase SMURF regulates SHH receptors, increased expression of the gene encoding the Cullin Ring E3 adaptor PPP2R2C was statistically a better genetic marker of the SHH group. Genes whose expression was statistically strongly related to Group 3 included the E3 ligase gene TRIM58, and the gene for the E3 ligase adaptor, PPP2R2B. Group 4 MB was associated with expression of genes encoding several E3 ligases and E3 ligase adaptors involved in ribosome biogenesis. Increased expression of the genes encoding the E3 ligase adaptors and transcription repressors ZBTB18 and ZBTB38 were also noted in subgroup 4. These data suggest that several E3 ligases and their adaptors should be investigated as therapeutic targets for subgroup specific MB brain tumors.
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Affiliation(s)
- Jerry Vriend
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
| | - Mojgan Rastegar
- Department of Biochemistry and Medical Genetics and Regenerative Medicine Program, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada
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Rodríguez-Cano MM, González-Gómez MJ, Sánchez-Solana B, Monsalve EM, Díaz-Guerra MJM, Laborda J, Nueda ML, Baladrón V. NOTCH Receptors and DLK Proteins Enhance Brown Adipogenesis in Mesenchymal C3H10T1/2 Cells. Cells 2020; 9:cells9092032. [PMID: 32899774 PMCID: PMC7565505 DOI: 10.3390/cells9092032] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 08/27/2020] [Accepted: 09/03/2020] [Indexed: 12/26/2022] Open
Abstract
The NOTCH family of receptors and ligands is involved in numerous cell differentiation processes, including adipogenesis. We recently showed that overexpression of each of the four NOTCH receptors in 3T3-L1 preadipocytes enhances adipogenesis and modulates the acquisition of the mature adipocyte phenotype. We also revealed that DLK proteins modulate the adipogenesis of 3T3-L1 preadipocytes and mesenchymal C3H10T1/2 cells in an opposite way, despite their function as non-canonical inhibitory ligands of NOTCH receptors. In this work, we used multipotent C3H10T1/2 cells as an adipogenic model. We used standard adipogenic procedures and analyzed different parameters by using quantitative-polymerase chain reaction (qPCR), quantitative reverse transcription-polymerase chain reaction (qRT-PCR), luciferase, Western blot, and metabolic assays. We revealed that C3H10T1/2 multipotent cells show higher levels of NOTCH receptors expression and activity and lower Dlk gene expression levels than 3T3-L1 preadipocytes. We found that the overexpression of NOTCH receptors enhanced C3H10T1/2 adipogenesis levels, and the overexpression of NOTCH receptors and DLK (DELTA-like homolog) proteins modulated the conversion of cells towards a brown-like adipocyte phenotype. These and our prior results with 3T3-L1 preadipocytes strengthen the idea that, depending on the cellular context, a precise and highly regulated level of global NOTCH signaling is necessary to allow adipogenesis and determine the mature adipocyte phenotype.
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Affiliation(s)
- María-Milagros Rodríguez-Cano
- Departamento de Química Inorgánica, Laboratorio de Bioquímica y Biología Molecular, Facultad de Farmacia/CRIB/Unidad de Biomedicina, Orgánica y Bioquímica, Universidad de Castilla-La Mancha/CSIC, C/Almansa 14, 02008 Albacete, Spain; (M.-M.R.-C.); (M.-J.G.-G.)
| | - María-Julia González-Gómez
- Departamento de Química Inorgánica, Laboratorio de Bioquímica y Biología Molecular, Facultad de Farmacia/CRIB/Unidad de Biomedicina, Orgánica y Bioquímica, Universidad de Castilla-La Mancha/CSIC, C/Almansa 14, 02008 Albacete, Spain; (M.-M.R.-C.); (M.-J.G.-G.)
| | - Beatriz Sánchez-Solana
- National Institutes of Health, Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA;
| | - Eva-María Monsalve
- Departamento de Química Inorgánica, Laboratorio de Bioquímica y Biología Molecular, Facultad de Medicina de Albacete/CRIB/Unidad de Biomedicina, Orgánica y Bioquímica, Universidad de Castilla-La Mancha/CSIC, C/Almansa 14, 02008 Albacete, Spain; (E.-M.M.); (M.-J.M.D.-G.)
| | - María-José M. Díaz-Guerra
- Departamento de Química Inorgánica, Laboratorio de Bioquímica y Biología Molecular, Facultad de Medicina de Albacete/CRIB/Unidad de Biomedicina, Orgánica y Bioquímica, Universidad de Castilla-La Mancha/CSIC, C/Almansa 14, 02008 Albacete, Spain; (E.-M.M.); (M.-J.M.D.-G.)
| | - Jorge Laborda
- Departamento de Química Inorgánica, Laboratorio de Bioquímica y Biología Molecular, Facultad de Farmacia/CRIB/Unidad de Biomedicina, Orgánica y Bioquímica, Universidad de Castilla-La Mancha/CSIC, C/Almansa 14, 02008 Albacete, Spain; (M.-M.R.-C.); (M.-J.G.-G.)
- Correspondence: (J.L.); (M.-L.N.); (V.B.); Tel.: +34-967-599-200 (ext. 2926) (V.B.); Fax: +34-967-599-327 (V.B.)
| | - María-Luisa Nueda
- Departamento de Química Inorgánica, Laboratorio de Bioquímica y Biología Molecular, Facultad de Farmacia/CRIB/Unidad de Biomedicina, Orgánica y Bioquímica, Universidad de Castilla-La Mancha/CSIC, C/Almansa 14, 02008 Albacete, Spain; (M.-M.R.-C.); (M.-J.G.-G.)
- Correspondence: (J.L.); (M.-L.N.); (V.B.); Tel.: +34-967-599-200 (ext. 2926) (V.B.); Fax: +34-967-599-327 (V.B.)
| | - Victoriano Baladrón
- Departamento de Química Inorgánica, Laboratorio de Bioquímica y Biología Molecular, Facultad de Medicina de Albacete/CRIB/Unidad de Biomedicina, Orgánica y Bioquímica, Universidad de Castilla-La Mancha/CSIC, C/Almansa 14, 02008 Albacete, Spain; (E.-M.M.); (M.-J.M.D.-G.)
- Correspondence: (J.L.); (M.-L.N.); (V.B.); Tel.: +34-967-599-200 (ext. 2926) (V.B.); Fax: +34-967-599-327 (V.B.)
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Ren S, Zhang X, Hu Y, Wu J, Ju Y, Sun X, Liu Y, Shan B. Blocking the Notch signal transduction pathway promotes tumor growth in osteosarcoma by affecting polarization of TAM to M2 phenotype. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1057. [PMID: 33145276 PMCID: PMC7575992 DOI: 10.21037/atm-20-3881] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background Osteosarcoma is a primary malignant tumor that seriously affects the health and life of patients. It is of great clinical significance to explore the molecular mechanism of osteosarcoma development and develop the corresponding therapeutic targets. Th1/Th2 cytokines in the normal human body are in a state of dynamic balance. When this balance is destroyed, it is related to many diseases such as a tumor, autoimmune disease, microbial infection, transplant rejection, among many others. Method The model of mouse tumor-associated macrophage (TAM) was induced by being co-cultured with inducer granulocyte-macrophage colony stimulating factor (GM-CSF) and osteosarcoma S180 cells. The Notch1 knockout mice were obtained by gene targeting technology. The distribution of M1- and M2-type TAMs in the tumor was visualized by immunofluorescence staining. And the western-blot testing was used to detect and quantified the protein level of Notch1 and Th1/Th2-type cytokines. Results In this study, the polarization of TAMs to the M2 phenotype occurred after coculture with osteosarcoma S180 cells and secretion level Th1/Th2-type cytokines changed. Also, the expression level of Notch1 reduced significantly. Further, the critical transcription factor Notch1 of the Notch signaling pathway was knocked out in mice. The tumor volume of Notch1 knockout mice was significantly more extensive than of the control mice. The results of microstructural observation on tumor showed that M2-type TAMs infiltrated into tumor increased with increased expression of Th2-type cytokines, but M1-type TAMs reduced with reduced expression of Th1-type cytokines. Conclusions According to our results, the Notch signal transduction pathway participates in tumor occurrence and growth with a negative role by maintaining Th1/Th2 balance.
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Affiliation(s)
- Shuguang Ren
- The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiangmei Zhang
- The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yueyang Hu
- The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jianhua Wu
- The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yingchao Ju
- The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xu Sun
- Hospital of Stomatology Hebei Medical University, Shijiazhuang, China
| | - Yunjiang Liu
- The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Baoen Shan
- The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
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Xie X, Zu M, Zhang L, Bai T, Wei L, Huang W, Ji GJ, Qiu B, Hu P, Tian Y, Wang K. A common variant of the NOTCH4 gene modulates functional connectivity of the occipital cortex and its relationship with schizotypal traits. BMC Psychiatry 2020; 20:363. [PMID: 32646407 PMCID: PMC7346398 DOI: 10.1186/s12888-020-02773-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 06/29/2020] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Schizotypal traits are considered as inheritable traits and the endophenotype for schizophrenia. A common variant in the NOTCH4 gene, rs204993, has been linked with schizophrenia, but the neural underpinnings are largely unknown. METHODS In present study, we compared the differences of brain functions between different genotypes of rs204993 and its relationship with schizotypal traits among 402 Chinese Han healthy volunteers. The brain function was evaluated with functional connectivity strength (FCS) using the resting-state functional magnetic resonance image(rs-fMRI). The schizotypal traits were measured by the schizotypal personality questionnaire (SPQ). RESULTS Our results showed that carriers with the AA genotype showed reduced FCS in the left occipital cortex when compared with carriers with the AG and GG genotypes, and the carriers with the AG genotype showed reduced FCS in the left occipital cortex when compared with carriers with the GG genotype. The FCS values in the left occipital lobe were negatively associated with the SPQ scores and its subscale scores within the carriers with the GG genotype, but not within the carriers with AA or AG genotype. CONCLUSION Our results suggested that the common variant in the NOTCH4 gene, rs204993, modulates the function of the occipital cortex, which may contribute to schizotypal traits. These findings provide insight for genetic effects on schizotypal traits and its potential neural substrate.
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Affiliation(s)
- Xiaohui Xie
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Meidan Zu
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Long Zhang
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Tongjian Bai
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Ling Wei
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
- Collaborative Innovation Center for Neuropsychiatric Disorders and Mental Health, Anhui Medical University, Hefei, 230022, China
- Anhui Province Key Laboratory of Cognition and Neuropsychiatric Disorders, Hefei, 230022, China
| | - Wanling Huang
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Gong-Jun Ji
- Collaborative Innovation Center for Neuropsychiatric Disorders and Mental Health, Anhui Medical University, Hefei, 230022, China
- Anhui Province Key Laboratory of Cognition and Neuropsychiatric Disorders, Hefei, 230022, China
- Department of Medical Psychology, Chaohu Clinical Medical College, Anhui Medical University, Hefei, China
| | - Bensheng Qiu
- Center for Biomedical Engineering, University of Science and Technology of China, Hefei, Anhui, China
| | - Panpan Hu
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
- Collaborative Innovation Center for Neuropsychiatric Disorders and Mental Health, Anhui Medical University, Hefei, 230022, China
- Anhui Province Key Laboratory of Cognition and Neuropsychiatric Disorders, Hefei, 230022, China
| | - Yanghua Tian
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
- Collaborative Innovation Center for Neuropsychiatric Disorders and Mental Health, Anhui Medical University, Hefei, 230022, China
- Anhui Province Key Laboratory of Cognition and Neuropsychiatric Disorders, Hefei, 230022, China
| | - Kai Wang
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
- Collaborative Innovation Center for Neuropsychiatric Disorders and Mental Health, Anhui Medical University, Hefei, 230022, China.
- Anhui Province Key Laboratory of Cognition and Neuropsychiatric Disorders, Hefei, 230022, China.
- Department of Medical Psychology, Chaohu Clinical Medical College, Anhui Medical University, Hefei, China.
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Gratton R, Tricarico PM, Moltrasio C, Lima Estevão de Oliveira AS, Brandão L, Marzano AV, Zupin L, Crovella S. Pleiotropic Role of Notch Signaling in Human Skin Diseases. Int J Mol Sci 2020; 21:E4214. [PMID: 32545758 PMCID: PMC7353046 DOI: 10.3390/ijms21124214] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 06/09/2020] [Accepted: 06/11/2020] [Indexed: 02/07/2023] Open
Abstract
Notch signaling orchestrates the regulation of cell proliferation, differentiation, migration and apoptosis of epidermal cells by strictly interacting with other cellular pathways. Any disruption of Notch signaling, either due to direct mutations or to an aberrant regulation of genes involved in the signaling route, might lead to both hyper- or hypo-activation of Notch signaling molecules and of target genes, ultimately inducing the onset of skin diseases. The mechanisms through which Notch contributes to the pathogenesis of skin diseases are multiple and still not fully understood. So far, Notch signaling alterations have been reported for five human skin diseases, suggesting the involvement of Notch in their pathogenesis: Hidradenitis Suppurativa, Dowling Degos Disease, Adams-Oliver Syndrome, Psoriasis and Atopic Dermatitis. In this review, we aim at describing the role of Notch signaling in the skin, particularly focusing on the principal consequences associated with its alterations in these five human skin diseases, in order to reorganize the current knowledge and to identify potential cellular mechanisms in common between these pathologies.
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Affiliation(s)
- Rossella Gratton
- Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, 34137 Trieste, Italy; (R.G.); (L.Z.); (S.C.)
- Department of Medical Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy
| | - Paola Maura Tricarico
- Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, 34137 Trieste, Italy; (R.G.); (L.Z.); (S.C.)
| | - Chiara Moltrasio
- Dermatology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (C.M.); (A.V.M.)
| | | | - Lucas Brandão
- Department of Pathology, Federal University of Pernambuco, Recife 50670-901, Brazil;
| | - Angelo Valerio Marzano
- Dermatology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (C.M.); (A.V.M.)
| | - Luisa Zupin
- Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, 34137 Trieste, Italy; (R.G.); (L.Z.); (S.C.)
| | - Sergio Crovella
- Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, 34137 Trieste, Italy; (R.G.); (L.Z.); (S.C.)
- Department of Medical Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy
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Notch-Hes1 Signaling Regulates IL-17A + γδ +T Cell Expression and IL-17A Secretion of Mouse Psoriasis-Like Skin Inflammation. Mediators Inflamm 2020; 2020:8297134. [PMID: 32454795 PMCID: PMC7240798 DOI: 10.1155/2020/8297134] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Accepted: 04/22/2020] [Indexed: 02/06/2023] Open
Abstract
Purpose To evaluate the regulating effect of Notch-Hes1 signaling on IL-17A+γδ+T cell expression and IL-17A secretion in mouse psoriasis-like skin inflammation. Materials and Methods Experimental mice were randomly divided into control group, model group (5% imiquimod- (IMQ-) treated mice), and intervention group (IMQ and γ-secretase inhibitor DAPT cotreated mice). The severity of psoriasis-like skin inflammation was evaluated by target lesion score based on the clinical psoriasis area and severity index (PASI). Flow cytometry detected IL-17A+γδ+T cell percentage. Quantitative real-time RT-PCR detected Hes1 mRNA expression. Enzyme-linked immunosorbent assay and western blot measured IL-17A serum concentration and protein expression. Additionally, splenic single cells from model mice were treated by DAPT to further evaluate the inhibitory effect of blocking Notch-Hes1 signaling on IL-17A+γδ+T cell differentiation and IL-17A secretion. Results The spleen index, IL-17A+γδ+T cell percentage, Hes1 mRNA expression, IL-17A serum concentration, and protein expression were all significantly higher in model mice than control mice, while dramatically reduced in intervention mice by DAPT treatment, which also obviously alleviated the target lesion score, epidermal hyperplasia, and dermal inflammatory cell infiltration of intervention mice. In vitro study demonstrated that DAPT treatment could result in dose-dependent decrease of IL-17A+γδ+T cell percentage and IL-17A secretion in splenic single cells of model mice.
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Zhao G, Zhang Y, Zhao Z, Cai H, Zhao X, Yang T, Chen W, Yao C, Wang Z, Wang Z, Han C, Wang H. MiR-153 reduces stem cell-like phenotype and tumor growth of lung adenocarcinoma by targeting Jagged1. Stem Cell Res Ther 2020; 11:170. [PMID: 32375892 PMCID: PMC7201619 DOI: 10.1186/s13287-020-01679-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Revised: 03/27/2020] [Accepted: 04/15/2020] [Indexed: 12/15/2022] Open
Abstract
Background Cancer stem cells (CSCs) have been proposed to be responsible for tumor recurrence and chemo-resistance. Previous studies suggested that miR-153 played essential roles in lung cancer. However, the molecular mechanism of miR-153 in regulating the stemness of non-small cell lung cancer (NSCLC) remains poorly understood. In this study, we investigated the role of miR-153 in regulation of the stemness of NSCLC. Methods The stemness property of lung stem cancer cells was detected by sphere formation assay, immunofluorescence, and Western blot. Luciferase reporter assay was performed to investigate the direct binding of miR-153 to the 3′-UTR of JAG1 mRNA. Animal study was conducted to evaluate the effect of miR-153 on tumor growth in vivo. The clinical relevance of miR-153 in NSCLC was evaluated by Rt-PCR and Kaplan-Meier analysis. Results MiR-153 expression was decreased in lung cancer tissues. Reduced miR-153 expression was associated with lung metastasis and poor overall survival of lung cancer patients. Jagged1, one of the ligands of Notch1, is targeted by miR-153 and inversely correlates with miR-153 in human lung samples. More importantly, we found that miR-153 inhibited stem cell-like phenotype and tumor growth of lung adenocarcinoma through inactivating the Jagged1/Notch1 axis. Conclusion MiR-153 suppresses the stem cell-like phenotypes and tumor growth of lung adenocarcinoma by targeting Jagged1 and provides a potential therapeutic target in lung cancer therapy.
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Affiliation(s)
- Guoli Zhao
- Institute of Basic Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250062, Shandong, China.,School of Medicine and Life Science, University of Jinan-Shandong Academy of Medical Sciences, Jinan, 250062, Shandong, China
| | - Yueying Zhang
- Institute of Basic Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250062, Shandong, China. .,School of Medicine and Life Science, University of Jinan-Shandong Academy of Medical Sciences, Jinan, 250062, Shandong, China.
| | - Zhonghua Zhao
- Department of Rehabilitation and Physiotherapy, The People's Hospital of Huaiyin, Jinan, 250000, China
| | - Haibo Cai
- Department of Thoracic Surgery, The Affiliated First People's Hospital of Jining Medical University, Jining, 272011, Shandong, China
| | - Xiaogang Zhao
- Department of Thoracic Surgery, The Second Hospital of Shandong University, Jinan, 250000, Shandong, China
| | - Tong Yang
- Institute of Basic Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250062, Shandong, China.,School of Medicine and Life Science, University of Jinan-Shandong Academy of Medical Sciences, Jinan, 250062, Shandong, China
| | - Weijun Chen
- Department of Medical Oncology, Yantaishan Hospital, Yantai, 264000, Shandong, China
| | - Chengfang Yao
- Institute of Basic Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250062, Shandong, China.,School of Medicine and Life Science, University of Jinan-Shandong Academy of Medical Sciences, Jinan, 250062, Shandong, China
| | - Zhaopeng Wang
- Institute of Basic Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250062, Shandong, China
| | - Zhaoxia Wang
- Institute of Basic Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250062, Shandong, China
| | - Chen Han
- Institute of Basic Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250062, Shandong, China
| | - Hengxiao Wang
- Institute of Basic Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250062, Shandong, China
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Assmus AM, Mullins JJ, Brown CM, Mullins LJ. Cellular plasticity: A mechanism for homeostasis in the kidney. Acta Physiol (Oxf) 2020; 229:e13447. [PMID: 31991057 DOI: 10.1111/apha.13447] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 01/15/2020] [Accepted: 01/24/2020] [Indexed: 12/30/2022]
Abstract
Cellular plasticity is a topical subject with interest spanning a wide range of fields from developmental biology to regenerative medicine. Even the nomenclature is a subject of debate, and the underlying mechanisms are still under investigation. On top of injury repair, cell plasticity is a constant physiological process in adult organisms and tissues, in response to homeostatic challenges. In this review we discuss two examples of plasticity for the maintenance of homeostasis in the renal system-namely the renin-producing juxtaglomerular cells (JG cells) and cortical collecting duct (CCD) cells. JG cells show plasticity through recruitment mechanisms, answering the demand for an increase in renin production. In the CCD, cells appear to have the ability to transdifferentiate between principal and intercalated cells to help maintain the highly regulated solute transport levels of that segment. These two cases highlight the complexity of plasticity processes and the role they can play in the kidney.
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Affiliation(s)
- Adrienne M. Assmus
- The University of Edinburgh ‐ Cardiovascular Science (CVS) Queen's Medical Research Institute Edinburgh Scotland UK
| | - John J. Mullins
- The University of Edinburgh ‐ Cardiovascular Science (CVS) Queen's Medical Research Institute Edinburgh Scotland UK
| | - Cara M. Brown
- The University of Edinburgh ‐ Cardiovascular Science (CVS) Queen's Medical Research Institute Edinburgh Scotland UK
| | - Linda J. Mullins
- The University of Edinburgh ‐ Cardiovascular Science (CVS) Queen's Medical Research Institute Edinburgh Scotland UK
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Zohny SF, Zamzami MA, Al-Malki AL, Trabulsi NH. Highly Expressed DLL4 and JAG1: Their Role in Incidence of Breast Cancer Metastasis. Arch Med Res 2020; 51:145-152. [PMID: 32111499 DOI: 10.1016/j.arcmed.2019.12.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 12/12/2019] [Accepted: 12/31/2019] [Indexed: 01/02/2023]
Abstract
BACKGROUND The role of Notch signaling dysregulation in causing metastatic breast cancer is not yet elucidated, therefore, this study aimed to investigate the expression of DLL4 and JAG1 in metastatic breast cancer. Moreover, we examined the possible association between clinicopathological features and studied parameters. DESIGN AND METHODS A total of 90 patients with invasive ductal breast carcinomas (52 non-metastatic and 38 metastatic) were enrolled in the current study. Furthermore, there were 42 patients with benign breast diseases. The mRNA and protein expression of DLL4 and JAG1 were analyzed by RT-PCR and ELISA, respectively in breast cell lysates. RESULTS The mRNA and protein expression of DLL4 and JAG1 were obviously higher in patients with breast cancer compared to patients with benign breast diseases and in metastatic versus non-metastatic breast cancer. A significant positive correlation was declared between DLL4 and JAG1 at both mRNA and protein levels in metastatic and localized breast cancer patients. Highly expressed mRNA and protein of DLL4 and JAG1 were associated with late tumor stages; moreover, upregulation of mRNA and protein of JAG1 was correlated with poorly differentiated tumors. CONCLUSION Our data emphasize that overexpression of DLL4 and JAG1 could predict the development of distant metastasis in breast cancer patients.
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Affiliation(s)
- Samir F Zohny
- Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia; Biochemistry Department, Faculty of Science, Ain Shams University, Abbassia, Cairo, Egypt.
| | - Mazin A Zamzami
- Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Abdulrahman L Al-Malki
- Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Nora H Trabulsi
- Department of Surgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
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Contreras M, Karlsen M, Villar M, Olsen RH, Leknes LM, Furevik A, Yttredal KL, Tartor H, Grove S, Alberdi P, Brudeseth B, de la Fuente J. Vaccination with Ectoparasite Proteins Involved in Midgut Function and Blood Digestion Reduces Salmon Louse Infestations. Vaccines (Basel) 2020; 8:vaccines8010032. [PMID: 31963779 PMCID: PMC7157638 DOI: 10.3390/vaccines8010032] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 01/16/2020] [Accepted: 01/17/2020] [Indexed: 11/16/2022] Open
Abstract
Infestation with the salmon louse Lepeophtheirus salmonis (Copepoda, Caligidae) affects Atlantic salmon (Salmo salar L.) production in European aquaculture. Furthermore, high levels of salmon lice in farms significantly increase challenge pressure against wild salmon populations. Currently, available control methods for salmon louse have limitations, and vaccination appears as an attractive, environmentally sound strategy. In this study, we addressed one of the main limitations for vaccine development, the identification of candidate protective antigens. Based on recent advances in tick vaccine research, herein, we targeted the salmon louse midgut function and blood digestion for the identification of candidate target proteins for the control of ectoparasite infestations. The results of this translational approach resulted in the identification and subsequent evaluation of the new candidate protective antigens, putative Toll-like receptor 6 (P30), and potassium chloride, and amino acid transporter (P33). Vaccination with these antigens provided protection in Atlantic salmon by reducing adult female (P33) or chalimus II (P30) sea lice infestations. These results support the development of vaccines for the control of sea lice infestations.
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Affiliation(s)
- Marinela Contreras
- SaBio, Instituto de Investigación en Recursos Cinegéticos IREC-CSIC-UCLM-JCCM, Ronda de Toledo s/n, 13005 Ciudad Real, Spain; (M.C.); (M.V.); (P.A.)
| | - Marius Karlsen
- Pharmaq AS, P.O. Box 267, Skoyen, N-0213 Oslo, Norway; (M.K.); (R.H.O.); (L.M.L.); (A.F.); (K.L.Y.)
| | - Margarita Villar
- SaBio, Instituto de Investigación en Recursos Cinegéticos IREC-CSIC-UCLM-JCCM, Ronda de Toledo s/n, 13005 Ciudad Real, Spain; (M.C.); (M.V.); (P.A.)
- Biochemistry Section, Faculty of Science and Chemical Technologies, and Regional Centre for Biomedical Research (CRIB), University of Castilla-La Mancha, 13071 Ciudad Real, Spain
| | - Rolf Hetlelid Olsen
- Pharmaq AS, P.O. Box 267, Skoyen, N-0213 Oslo, Norway; (M.K.); (R.H.O.); (L.M.L.); (A.F.); (K.L.Y.)
| | - Lisa Marie Leknes
- Pharmaq AS, P.O. Box 267, Skoyen, N-0213 Oslo, Norway; (M.K.); (R.H.O.); (L.M.L.); (A.F.); (K.L.Y.)
| | - Anette Furevik
- Pharmaq AS, P.O. Box 267, Skoyen, N-0213 Oslo, Norway; (M.K.); (R.H.O.); (L.M.L.); (A.F.); (K.L.Y.)
| | - Karine Lindmo Yttredal
- Pharmaq AS, P.O. Box 267, Skoyen, N-0213 Oslo, Norway; (M.K.); (R.H.O.); (L.M.L.); (A.F.); (K.L.Y.)
| | - Haitham Tartor
- Norwegian Veterinary Institute, 0106 Oslo, Norway; (H.T.); (S.G.)
| | - Soren Grove
- Norwegian Veterinary Institute, 0106 Oslo, Norway; (H.T.); (S.G.)
- Institute of Marine Research, 5005 Bergen, Norway
| | - Pilar Alberdi
- SaBio, Instituto de Investigación en Recursos Cinegéticos IREC-CSIC-UCLM-JCCM, Ronda de Toledo s/n, 13005 Ciudad Real, Spain; (M.C.); (M.V.); (P.A.)
| | - Bjorn Brudeseth
- Pharmaq AS, P.O. Box 267, Skoyen, N-0213 Oslo, Norway; (M.K.); (R.H.O.); (L.M.L.); (A.F.); (K.L.Y.)
- Correspondence: (B.B.); (J.d.l.F.)
| | - José de la Fuente
- SaBio, Instituto de Investigación en Recursos Cinegéticos IREC-CSIC-UCLM-JCCM, Ronda de Toledo s/n, 13005 Ciudad Real, Spain; (M.C.); (M.V.); (P.A.)
- Department of Veterinary Pathobiology, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK 74078, USA
- Correspondence: (B.B.); (J.d.l.F.)
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