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Agueda-Oyarzabal M, Isidor MS, Plucińska K, Ingerslev LR, Dmytriyeva O, Petersen PSS, Laftih S, Pontoppidan AB, Henningsen JB, Rupar K, Brown EL, Schwartz TW, Barrès R, Gerhart-Hines Z, Schéele CC, Emanuelli B. Transcriptomic signatures of cold acclimated adipocytes reveal CXCL12 as a Brown autocrine and paracrine chemokine. Mol Metab 2025; 93:102102. [PMID: 39848402 PMCID: PMC11841078 DOI: 10.1016/j.molmet.2025.102102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 01/16/2025] [Accepted: 01/18/2025] [Indexed: 01/25/2025] Open
Abstract
Besides its thermogenic capacity, brown adipose tissue (BAT) performs important secretory functions that regulate metabolism. However, the BAT microenvironment and factors involved in BAT homeostasis and adaptation to cold remain poorly characterized. We therefore aimed to study brown adipocyte-derived secreted factors that may be involved in adipocyte function and/or may orchestrate intercellular communications. For this, mRNA levels in mature adipocytes from mouse adipose depots were assessed using RNA sequencing upon chronic cold acclimation, and bioinformatic analysis was used to identify secreted factors. Among 858 cold-sensitive transcripts in BAT adipocytes were 210 secreted factor-encoding genes, and Cxcl12 was the top brown adipocyte-enriched cytokine. Cxcl12 mRNA expression analysis by RT-qPCR and fluorescence in situ hybridization specified Cxcl12 distribution in various cell types, and indicated its enrichment in cold-acclimated brown adipocytes. We found that CXCL12 secretion from BAT was increased after chronic cold, yet its level in plasma remained unchanged, suggesting a local/paracrine function. Cxcl12 knockdown in mature brown adipocytes impaired thermogenesis, as assessed by norepinephrine (NE)-induced glycerol release and mitochondrial respiration. However, knockdown of Cxcl12 did not impact β-adrenergic signaling, suggesting that CXCL12 regulates adipocyte function downstream of the β-adrenergic pathway. Moreover, we provide evidence for CXCL12 to exert intercellular cross-talk via its capacity to promote macrophage chemotaxis and neurite outgrowth. Collectively, our results indicate that CXCL12 is a brown adipocyte-enriched, cold-induced secreted factor involved in adipocyte function and the BAT microenvironment communication network.
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Affiliation(s)
- Marina Agueda-Oyarzabal
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Marie S Isidor
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Kaja Plucińska
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lars R Ingerslev
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Oksana Dmytriyeva
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Patricia S S Petersen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sara Laftih
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Axel B Pontoppidan
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jo B Henningsen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Kaja Rupar
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Erin L Brown
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Thue W Schwartz
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Romain Barrès
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Institut de Pharmacologie Moléculaire et Cellulaire, Université Côte d'Azur & Centre National pour la Recherche Scientifique (CNRS), Valbonne, 06560, France
| | - Zachary Gerhart-Hines
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Camilla C Schéele
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Brice Emanuelli
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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Wang S, Xia D, Dou W, Chen A, Xu S. Bioactive Porous Composite Implant Guides Mesenchymal Stem Cell Differentiation and Migration to Accelerate Bone Reconstruction. Int J Nanomedicine 2024; 19:12111-12127. [PMID: 39583325 PMCID: PMC11586122 DOI: 10.2147/ijn.s479893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Accepted: 10/30/2024] [Indexed: 11/26/2024] Open
Abstract
Background Delayed healing and non-healing of bone defects pose significant challenges in clinical practice, with metal materials increasingly recognized for their significance in addressing these issues. Among these materials, Strontium (Sr) and Zinc (Zn) have emerged as promising agents for promoting bone repair. Building upon this insight, this research evaluates the impact of a porous Sr@Zn@SiO2 nanocomposite implant on bone regeneration, aiming to advance the field of bone repair. Methods The preparation of the Sr@Zn@SiO2 composite implant involves various techniques such as roasting, centrifugation, and washing. The material's composition is examined, and its microstructure and element distribution are analyzed using TEM and elemental scanning technology. In vitro experiments entail the isolation and characterization of BMSCs followed by safety assessments of the implant material, evaluation of cell migration capabilities, and relevant proliferation markers. Mechanistically, this study delves into key targets associated with significant changes in the osteogenic process. In vivo experiments involve establishing a rat femur bone defect model, followed by assessment of the osteogenic potential of Sr@Zn@SiO2 using Micro-CT imaging and tissue section staining. Results Through in vivo and in vitro investigations, we validate the osteogenic efficacy of the Sr@Zn@SiO2 composite implant. In vitro analyses demonstrate that porous Sr@Zn@SiO2 nanocomposite materials upregulate BMP-2 expression, leading to the activation of Smad1/5/9 phosphorylation and subsequent activation of downstream osteogenic genes, culminating in BMSCs osteogenic differentiation and bone proliferation. And the migration of BMSCs is closely related to the high expression of CXCL12/CXCR4, which will also provide the conditions for osteogenesis. In vivo, the osteogenic ability of Sr@Zn@SiO2 was also confirmed in rats. Conclusion In our research, the porous Sr@Zn@SiO2 composite implant displays prominent osteogenic effect and promotes the migration and differentiation of BMSCs to promote bone defect healing. This bioactive implant has surgical application potential in the future.
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Affiliation(s)
- Sheng Wang
- Department of Traumatic Orthopedics, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434, People’s Republic of China
| | - Demeng Xia
- Department of Traumatic Orthopedics, Changhai Hospital, Naval Medical University, Shanghai, 200433, People’s Republic of China
- Department of Clinical Medicine, Hainan Health Vocational College, Haikou, 570100, People’s Republic of China
| | - Wenxue Dou
- Department of Stomatology, Shanghai East Hospital, Tongji University, Shanghai, 200120, People’s Republic of China
| | - Aimin Chen
- Department of Traumatic Orthopedics, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434, People’s Republic of China
| | - Shuogui Xu
- Department of Traumatic Orthopedics, Changhai Hospital, Naval Medical University, Shanghai, 200433, People’s Republic of China
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Ruminski PG, Rettig MP, DiPersio JF. Development of VLA4 and CXCR4 Antagonists for the Mobilization of Hematopoietic Stem and Progenitor Cells. Biomolecules 2024; 14:1003. [PMID: 39199390 PMCID: PMC11353233 DOI: 10.3390/biom14081003] [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: 06/28/2024] [Revised: 07/29/2024] [Accepted: 08/02/2024] [Indexed: 09/01/2024] Open
Abstract
The treatment of patients diagnosed with hematologic malignancies typically includes hematopoietic stem cell transplantation (HSCT) as part of a therapeutic standard of care. The primary graft source of hematopoietic stem and progenitor cells (HSPCs) for HSCT is mobilized from the bone marrow into the peripheral blood of allogeneic donors or patients. More recently, these mobilized HSPCs have also been the source for gene editing strategies to treat diseases such as sickle-cell anemia. For a HSCT to be successful, it requires the infusion of a sufficient number of HSPCs that are capable of adequate homing to the bone marrow niche and the subsequent regeneration of stable trilineage hematopoiesis in a timely manner. Granulocyte-colony-stimulating factor (G-CSF) is currently the most frequently used agent for HSPC mobilization. However, it requires five or more daily infusions to produce an adequate number of HSPCs and the use of G-CSF alone often results in suboptimal stem cell yields in a significant number of patients. Furthermore, there are several undesirable side effects associated with G-CSF, and it is contraindicated for use in sickle-cell anemia patients, where it has been linked to serious vaso-occlusive and thrombotic events. The chemokine receptor CXCR4 and the cell surface integrin α4β1 (very late antigen 4 (VLA4)) are both involved in the homing and retention of HSPCs within the bone marrow microenvironment. Preclinical and/or clinical studies have shown that targeted disruption of the interaction of the CXCR4 or VLA4 receptors with their endogenous ligands within the bone marrow niche results in the rapid and reversible mobilization of HSPCs into the peripheral circulation and is synergistic when combined with G-CSF. In this review, we discuss the roles CXCR4 and VLA4 play in bone marrow homing and retention and will summarize more recent development of small-molecule CXCR4 and VLA4 inhibitors that, when combined, can synergistically improve the magnitude, quality and convenience of HSPC mobilization for stem cell transplantation and ex vivo gene therapy after the administration of just a single dose. This optimized regimen has the potential to afford a superior alternative to G-CSF for HSPC mobilization.
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Affiliation(s)
| | | | - John F. DiPersio
- Division of Oncology, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Ave., St Louis, MO 63105, USA
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Abbasifard M, Bagherzadeh K, Khorramdelazad H. The story of clobenpropit and CXCR4: can be an effective drug in cancer and autoimmune diseases? Front Pharmacol 2024; 15:1410104. [PMID: 39070795 PMCID: PMC11272485 DOI: 10.3389/fphar.2024.1410104] [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: 03/31/2024] [Accepted: 06/25/2024] [Indexed: 07/30/2024] Open
Abstract
Clobenpropit is a histamine H3 receptor antagonist and has developed as a potential therapeutic drug due to its ability to inhibit CXCR4, a chemokine receptor involved in autoimmune diseases and cancer pathogenesis. The CXCL12/CXCR4 axis involves several biological phenomena, including cell proliferation, migration, angiogenesis, inflammation, and metastasis. Accordingly, inhibiting CXCR4 can have promising clinical outcomes in patients with malignancy or autoimmune disorders. Based on available knowledge, Clobenpropit can effectively regulate the release of monocyte-derived inflammatory cytokine in autoimmune diseases such as juvenile idiopathic arthritis (JIA), presenting a potential targeted target with possible advantages over current therapeutic approaches. This review summarizes the intricate interplay between Clobenpropit and CXCR4 and the molecular mechanisms underlying their interactions, comprehensively analyzing their impact on immune regulation. Furthermore, we discuss preclinical and clinical investigations highlighting the probable efficacy of Clobenpropit for managing autoimmune diseases and cancer. Through this study, we aim to clarify the immunomodulatory role of Clobenpropit and its advantages and disadvantages as a novel therapeutic opportunity.
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Affiliation(s)
- Mitra Abbasifard
- Department of Internal Medicine, School of Medicine, Ali-Ibn Abi-Talib Hospital, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Kowsar Bagherzadeh
- Eye Research Center, The Five Senses Health Institute, Rassoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Khorramdelazad
- Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
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Gao C, Zhang H, Wang Y, Wang S, Guo X, Han Y, Zhao H, An X. Global Transcriptomic and Characteristics Comparisons between Mouse Fetal Liver and Bone Marrow Definitive Erythropoiesis. Cells 2024; 13:1149. [PMID: 38995000 PMCID: PMC11240549 DOI: 10.3390/cells13131149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 06/30/2024] [Accepted: 07/02/2024] [Indexed: 07/13/2024] Open
Abstract
Erythropoiesis occurs first in the yolk sac as a transit "primitive" form, then is gradually replaced by the "definitive" form in the fetal liver (FL) during fetal development and in the bone marrow (BM) postnatally. While it is well known that differences exist between primitive and definitive erythropoiesis, the similarities and differences between FL and BM definitive erythropoiesis have not been studied. Here we performed comprehensive comparisons of erythroid progenitors and precursors at all maturational stages sorted from E16.5 FL and adult BM. We found that FL cells at all maturational stages were larger than their BM counterparts. We further found that FL BFU-E cells divided at a faster rate and underwent more cell divisions than BM BFU-E. Transcriptome comparison revealed that genes with increased expression in FL BFU-Es were enriched in cell division. Interestingly, the expression levels of glucocorticoid receptor Nr3c1, Myc and Myc downstream target Ccna2 were significantly higher in FL BFU-Es, indicating the role of the Nr3c1-Myc-Ccna2 axis in the enhanced proliferation/cell division of FL BFU-E cells. At the CFU-E stage, the expression of genes associated with hemoglobin biosynthesis were much higher in FL CFU-Es, indicating more hemoglobin production. During terminal erythropoiesis, overall temporal patterns in gene expression were conserved between the FL and BM. While biological processes related to translation, the tricarboxylic acid cycle and hypoxia response were upregulated in FL erythroblasts, those related to antiviral signal pathway were upregulated in BM erythroblasts. Our findings uncovered previously unrecognized differences between FL and BM definitive erythropoiesis and provide novel insights into erythropoiesis.
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Affiliation(s)
- Chengjie Gao
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China; (C.G.)
- Laboratory of Membrane Biology, New York Blood Center, New York, NY 10065, USA
| | - Huan Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China; (C.G.)
| | - Yaomei Wang
- Laboratory of Membrane Biology, New York Blood Center, New York, NY 10065, USA
- Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Shihui Wang
- Institute of Hematology, People’s Hospital of Zhengzhou University, Zhengzhou 450003, China
| | - Xinhua Guo
- Laboratory of Membrane Biology, New York Blood Center, New York, NY 10065, USA
| | - Yongshuai Han
- Laboratory of Membrane Biology, New York Blood Center, New York, NY 10065, USA
| | - Huizhi Zhao
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China; (C.G.)
| | - Xiuli An
- Laboratory of Membrane Biology, New York Blood Center, New York, NY 10065, USA
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Lee D, Benvie AM, Steiner BM, Kolba NJ, Ford JG, McCabe SM, Jiang Y, Berry DC. Smooth muscle cell-derived Cxcl12 directs macrophage accrual and sympathetic innervation to control thermogenic adipose tissue. Cell Rep 2024; 43:114169. [PMID: 38678562 PMCID: PMC11413973 DOI: 10.1016/j.celrep.2024.114169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 04/11/2024] [Accepted: 04/15/2024] [Indexed: 05/01/2024] Open
Abstract
Sympathetic innervation of brown adipose tissue (BAT) controls mammalian adaptative thermogenesis. However, the cellular and molecular underpinnings contributing to BAT innervation remain poorly defined. Here, we show that smooth muscle cells (SMCs) support BAT growth, lipid utilization, and thermogenic plasticity. Moreover, we find that BAT SMCs express and control the bioavailability of Cxcl12. SMC deletion of Cxcl12 fosters brown adipocyte lipid accumulation, reduces energy expenditure, and increases susceptibility to diet-induced metabolic dysfunction. Mechanistically, we find that Cxcl12 stimulates CD301+ macrophage recruitment and supports sympathetic neuronal maintenance. Administering recombinant Cxcl12 to obese mice or leptin-deficient (Ob/Ob) mice is sufficient to boost macrophage presence and drive sympathetic innervation to restore BAT morphology and thermogenic responses. Altogether, our data reveal an SMC chemokine-dependent pathway linking immunological infiltration and sympathetic innervation as a rheostat for BAT maintenance and thermogenesis.
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Affiliation(s)
- Derek Lee
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Abigail M Benvie
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Benjamin M Steiner
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Nikolai J Kolba
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Josie G Ford
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Sean M McCabe
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Yuwei Jiang
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Daniel C Berry
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
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Li X, Chen W, Liu D, Chen P, Wang S, Li F, Chen Q, Lv S, Li F, Chen C, Guo S, Yuan W, Li P, Hu Z. Pathological progression of osteoarthritis: a perspective on subchondral bone. Front Med 2024; 18:237-257. [PMID: 38619691 DOI: 10.1007/s11684-024-1061-y] [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: 11/21/2023] [Accepted: 01/17/2024] [Indexed: 04/16/2024]
Abstract
Osteoarthritis (OA) is a degenerative bone disease associated with aging. The rising global aging population has led to a surge in OA cases, thereby imposing a significant socioeconomic burden. Researchers have been keenly investigating the mechanisms underlying OA. Previous studies have suggested that the disease starts with synovial inflammation and hyperplasia, advancing toward cartilage degradation. Ultimately, subchondral-bone collapse, sclerosis, and osteophyte formation occur. This progression is deemed as "top to bottom." However, recent research is challenging this perspective by indicating that initial changes occur in subchondral bone, precipitating cartilage breakdown. In this review, we elucidate the epidemiology of OA and present an in-depth overview of the subchondral bone's physiological state, functions, and the varied pathological shifts during OA progression. We also introduce the role of multifunctional signal pathways (including osteoprotegerin (OPG)/receptor activator of nuclear factor-kappa B ligand (RANKL)/receptor activator of nuclear factor-kappa B (RANK), and chemokine (CXC motif) ligand 12 (CXCL12)/CXC motif chemokine receptor 4 (CXCR4)) in the pathology of subchondral bone and their role in the "bottom-up" progression of OA. Using vivid pattern maps and clinical images, this review highlights the crucial role of subchondral bone in driving OA progression, illuminating its interplay with the condition.
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Affiliation(s)
- Xuefei Li
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Wenhua Chen
- Research and Development Center of Chinese Medicine Resources and Biotechnology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Dan Liu
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Pinghua Chen
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Shiyun Wang
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Fangfang Li
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Qian Chen
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Shunyi Lv
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Fangyu Li
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Chen Chen
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Suxia Guo
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Weina Yuan
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Pan Li
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Zhijun Hu
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
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Vora N, Patel P, Gajjar A, Ladani P, Konat A, Bhanderi D, Gadam S, Prajjwal P, Sharma K, Arunachalam SP. Gene therapy for heart failure: A novel treatment for the age old disease. Dis Mon 2024; 70:101636. [PMID: 37734966 DOI: 10.1016/j.disamonth.2023.101636] [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] [Indexed: 09/23/2023]
Abstract
Across the globe, cardiovascular disease (CVD) is the leading cause of mortality. According to reports, around 6.2 million people in the United states have heart failure. Current standards of care for heart failure can delay but not prevent progression of disease. Gene therapy is one of the novel treatment modalities that promises to fill this limitation in the current standard of care for Heart Failure. In this paper we performed an extensive search of the literature on various advances made in gene therapy for heart failure till date. We review the delivery methods, targets, current applications, trials, limitations and feasibility of gene therapy for heart failure. Various methods have been employed till date for administering gene therapies including but not limited to arterial and venous infusion, direct myocardial injection and pericardial injection. Various strategies such as AC6 expression, S100A1 protein upregulation, VEGF-B and SDF-1 gene therapy have shown promise in recent preclinical trials. Furthermore, few studies even show that stimulation of cardiomyocyte proliferation such as through cyclin A2 overexpression is a realistic avenue. However, a considerable number of obstacles need to be overcome for gene therapy to be part of standard treatment of care such as definitive choice of gene, gene delivery systems and a suitable method for preclinical trials and clinical trials on patients. Considering the challenges and taking into account the recent advances in gene therapy research, there are encouraging signs to indicate gene therapy for heart failure to be a promising treatment modality for the future. However, the time and feasibility of this option remains in a situation of balance.
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Affiliation(s)
- Neel Vora
- B. J. Medical College, Ahmedabad, India
| | - Parth Patel
- Pramukhswami Medical College, Karamsad, India
| | | | | | - Ashwati Konat
- University School of Sciences, Gujarat University, Ahmedabad, India
| | | | | | | | - Kamal Sharma
- U. N. Mehta Institute of Cardiology and Research Centre, Ahmedabad, India.
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Sunderraj A, Cunha LM, Avila M, Alexandria S, Ferreira AM, de Oliveira-da Silva LC, Ribeiro ALP, Nunes MDCP, Sabino EC, Landay A, Kalil J, Chevillard C, Cunha-Neto E, Feinstein MJ. Parasite DNA and Markers of Decreased Immune Activation Associate Prospectively with Cardiac Functional Decline over 10 Years among Trypanosoma cruzi Seropositive Individuals in Brazil. Int J Mol Sci 2023; 25:44. [PMID: 38203212 PMCID: PMC10779141 DOI: 10.3390/ijms25010044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 11/27/2023] [Accepted: 12/12/2023] [Indexed: 01/12/2024] Open
Abstract
Parasitemia and inflammatory markers are cross-sectionally associated with chronic Chagas cardiomyopathy (CCC) among patients with Trypanosoma cruzi. However, the prospective association of the parasite load and host immune response-related characteristics with CCC (that is, progressors) among T. cruzi seropositive individuals has only been partially defined. In a cohort of T. cruzi seropositive patients in Montes Claros and São Paulo, Brazil who were followed over 10 years, we identified the association of a baseline T. cruzi parasite load and systemic markers of inflammation with a decline in cardiac function and/or the presence of cardiac congestion 10 years later. The progressors (n = 21) were individuals with a significant decline in the left ventricular ejection fraction and/or elevated markers of cardiac congestion after 10 years. The controls (n = 31) had normal markers of cardiac function and congestion at the baseline and at the follow-up. They were matched with the progressors on age, sex, and genetic ancestry. The progressors had higher mean parasite loads at the baseline than the controls (18.3 vs. 0.605 DNA parasite equivalents/20 mL, p < 0.05). Of the 384 inflammation-related proteins analyzed, 47 differed significantly at a false discovery rate- (FDR-) corrected p < 0.05 between the groups. There were 44 of these 47 proteins that were significantly higher in the controls compared to in the progressors, including the immune activation markers CCL21, CXCL12, and HCLS1 and several of the tumor necrosis factor superfamily of proteins. Among the individuals who were seropositive for T. cruzi at the baseline and who were followed over 10 years, those with incident CCC at the 10-year marker had a comparatively higher baseline of T. cruzi parasitemia and lower baseline markers of immune activation and chemotaxis. These findings generate the hypothesis that the early impairment of pathogen-killing immune responses predisposes individuals to CCC, which merits further study.
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Affiliation(s)
- Ashwin Sunderraj
- Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Luisa Marin Cunha
- Faculdade de Ciências Médicas de Santos, UNILUS, Santos 11045-101, Brazil
| | - Matheus Avila
- Faculdade de Ciências Médicas de Santos, UNILUS, Santos 11045-101, Brazil
| | - Shaina Alexandria
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
| | - Ariela Mota Ferreira
- Graduate Program in Health Sciences, State University of Montes Claros, Montes Claros 39401-089, Brazil;
| | | | - Antonio L. P. Ribeiro
- Department of Internal Medicine, Federal University of Minas Gerais, Belo Horizonte 31270-901, Brazil; (A.L.P.R.); (M.d.C.P.N.)
| | - Maria do Carmo Pereira Nunes
- Department of Internal Medicine, Federal University of Minas Gerais, Belo Horizonte 31270-901, Brazil; (A.L.P.R.); (M.d.C.P.N.)
| | - Ester C. Sabino
- Institute of Tropical Medicine, University of São Paulo, São Paulo 05403-000, Brazil; (L.C.d.O.-d.S.)
| | - Alan Landay
- Division of Geriatrics and Gerontology, Department of Medicine, Rush University Medical Center, Chicago, IL 60612, USA
| | - Jorge Kalil
- Laboratory of Immunology, Heart Institute Instituto do Coração (InCor), School of Medicine, University of São Paulo, São Paulo 05403-000, Brazil;
| | - Christophe Chevillard
- Institut MarMaRa, TAGC Theories and Approaches of Genomic Complexity, Aix Marseille Université, 13385 Marseille, France;
| | - Edecio Cunha-Neto
- Laboratory of Immunology, Heart Institute Instituto do Coração (InCor), School of Medicine, University of São Paulo, São Paulo 05403-000, Brazil;
| | - Matthew J. Feinstein
- Division of Cardiology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
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Bao S, Darvishi M, H Amin A, Al-Haideri MT, Patra I, Kashikova K, Ahmad I, Alsaikhan F, Al-Qaim ZH, Al-Gazally ME, Kiasari BA, Tavakoli-Far B, Sidikov AA, Mustafa YF, Akhavan-Sigari R. CXC chemokine receptor 4 (CXCR4) blockade in cancer treatment. J Cancer Res Clin Oncol 2023; 149:7945-7968. [PMID: 36905421 DOI: 10.1007/s00432-022-04444-w] [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: 05/25/2022] [Accepted: 10/19/2022] [Indexed: 03/12/2023]
Abstract
CXC chemokine receptor type 4 (CXCR4) is a member of the G protein-coupled receptors (GPCRs) superfamily and is specific for CXC chemokine ligand 12 (CXCL12, also known as SDF-1), which makes CXCL12/CXCR4 axis. CXCR4 interacts with its ligand, triggering downstream signaling pathways that influence cell proliferation chemotaxis, migration, and gene expression. The interaction also regulates physiological processes, including hematopoiesis, organogenesis, and tissue repair. Multiple evidence revealed that CXCL12/CXCR4 axis is implicated in several pathways involved in carcinogenesis and plays a key role in tumor growth, survival, angiogenesis, metastasis, and therapeutic resistance. Several CXCR4-targeting compounds have been discovered and used for preclinical and clinical cancer therapy, most of which have shown promising anti-tumor activity. In this review, we summarized the physiological signaling of the CXCL12/CXCR4 axis and described the role of this axis in tumor progression, and focused on the potential therapeutic options and strategies to block CXCR4.
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Affiliation(s)
- Shunshun Bao
- The First Clinical Medical College, Xuzhou Medical University, 221000, Xuzhou, China
| | - Mohammad Darvishi
- Infectious Diseases and Tropical Medicine Research Center (IDTMRC), Department of Aerospace and Subaquatic Medicine, AJA University of Medicinal Sciences, Tehran, Iran
| | - Ali H Amin
- Deanship of Scientific Research, Umm Al-Qura University, 21955, Makkah, Saudi Arabia
- Zoology Department, Faculty of Science, Mansoura University, 35516, Mansoura, Egypt
| | - Maysoon T Al-Haideri
- Department of Physiotherapy, Cihan University-Erbil, Erbil, Kurdistan Region, Iraq
| | - Indrajit Patra
- An Independent Researcher, National Institute of Technology Durgapur, Durgapur, West Bengal, India
| | | | - Irfan Ahmad
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Fahad Alsaikhan
- College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia
| | | | | | - Bahman Abedi Kiasari
- Virology Department, Faculty of Veterinary Medicine, The University of Tehran, Tehran, Iran.
| | - Bahareh Tavakoli-Far
- Dietary Supplements and Probiotic Research Center, Alborz University of Medical Sciences, Karaj, Iran.
- Department of Physiology and Pharmacology, Faculty of Medicine, Alborz University of Medical Sciences, Karaj, Iran.
| | - Akmal A Sidikov
- Rector, Ferghana Medical Institute of Public Health, Ferghana, Uzbekistan
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center Tuebingen, Tübingen, Germany
- Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University, Warsaw, Poland
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11
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Yang X, Yang L. Current understanding of the genomic abnormities in premature ovarian failure: chance for early diagnosis and management. Front Med (Lausanne) 2023; 10:1194865. [PMID: 37332766 PMCID: PMC10274511 DOI: 10.3389/fmed.2023.1194865] [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: 03/27/2023] [Accepted: 05/17/2023] [Indexed: 06/20/2023] Open
Abstract
Premature ovarian failure (POF) is an insidious cause of female infertility and a devastating condition for women. POF also has a strong familial and heterogeneous genetic background. Management of POF is complicated by the variable etiology and presentation, which are generally characterized by abnormal hormone levels, gene instability and ovarian dysgenesis. To date, abnormal regulation associated with POF has been found in a small number of genes, including autosomal and sex chromosomal genes in folliculogenesis, granulosa cells, and oocytes. Due to the complex genomic contributions, ascertaining the exact causative mechanisms has been challenging in POF, and many pathogenic genomic characteristics have yet to be elucidated. However, emerging research has provided new insights into genomic variation in POF as well as novel etiological factors, pathogenic mechanisms and therapeutic intervention approaches. Meanwhile, scattered studies of transcriptional regulation revealed that ovarian cell function also depends on specific biomarker gene expression, which can influence protein activities, thus causing POF. In this review, we summarized the latest research and issues related to the genomic basis for POF and focused on insights gained from their biological effects and pathogenic mechanisms in POF. The present integrated studies of genomic variants, gene expression and related protein abnormalities were structured to establish the role of etiological genes associated with POF. In addition, we describe the design of some ongoing clinical trials that may suggest safe, feasible and effective approaches to improve the diagnosis and therapy of POF, such as Filgrastim, goserelin, resveratrol, natural plant antitoxin, Kuntai capsule et al. Understanding the candidate genomic characteristics in POF is beneficial for the early diagnosis of POF and provides appropriate methods for prevention and drug treatment. Additional efforts to clarify the POF genetic background are necessary and are beneficial for researchers and clinicians regarding genetic counseling and clinical practice. Taken together, recent genomic explorations have shown great potential to elucidate POF management in women and are stepping from the bench to the bedside.
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Affiliation(s)
- Xu Yang
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Lin Yang
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
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12
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Olivero G, Grilli M, Marchi M, Pittaluga A. Metamodulation of presynaptic NMDA receptors: New perspectives for pharmacological interventions. Neuropharmacology 2023; 234:109570. [PMID: 37146939 DOI: 10.1016/j.neuropharm.2023.109570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/26/2023] [Accepted: 05/02/2023] [Indexed: 05/07/2023]
Abstract
Metamodulation shifted the scenario of the central neuromodulation from a simplified unimodal model to a multimodal one. It involves different receptors/membrane proteins physically associated or merely colocalized that act in concert to control the neuronal functions influencing each other. Defects or maladaptation of metamodulation would subserve neuropsychiatric disorders or even synaptic adaptations relevant to drug dependence. Therefore, this "vulnerability" represents a main issue to be deeply analyzed to predict its aetiopathogenesis, but also to propose targeted pharmaceutical interventions. The review focusses on presynaptic release-regulating NMDA receptors and on some of the mechanisms of their metamodulation described in the literature. Attention is paid to the interactors, including both ionotropic and metabotropic receptors, transporters and intracellular proteins, which metamodulate their responsiveness in physiological conditions but also undergo adaptation that are relevant to neurological dysfunctions. All these structures are attracting more and more the interest as promising druggable targets for the treatment of NMDAR-related central diseases: these substances would not exert on-off control of the colocalized NMDA receptors (as usually observed with NMDAR full agonists/antagonists), but rather modulate their functions, with the promise of limiting side effects that would favor their translation from preclinic to clinic.
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Affiliation(s)
- Guendalina Olivero
- Department of Pharmacy, University of Genoa, Viale Cembrano 4, 16148, Genoa, Italy
| | - Massimo Grilli
- Department of Pharmacy, University of Genoa, Viale Cembrano 4, 16148, Genoa, Italy; Inter-University Center for the Promotion of the 3Rs Principles in Teaching & Research (Centro 3R), 16148, Genoa, Italy.
| | - Mario Marchi
- Department of Pharmacy, University of Genoa, Viale Cembrano 4, 16148, Genoa, Italy
| | - Anna Pittaluga
- Department of Pharmacy, University of Genoa, Viale Cembrano 4, 16148, Genoa, Italy; Inter-University Center for the Promotion of the 3Rs Principles in Teaching & Research (Centro 3R), 16148, Genoa, Italy
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13
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The role of MEOX1 in non-neoplastic and neoplastic diseases. Biomed Pharmacother 2023; 158:114068. [PMID: 36495659 DOI: 10.1016/j.biopha.2022.114068] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 12/01/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022] Open
Abstract
Targeted gene therapy has shown durable efficacy in non-neoplastic and neoplastic patients. Therefore, finding a suitable target has become a key area of research. Mesenchyme homeobox 1 (MEOX1) is a transcriptional factor that plays a significant role in regulation of somite development. Evidence indicates that abnormalities in MEOX1 expression and function are associated with a variety of pathologies, including non-neoplastic and neoplastic diseases. MEOX1 expression is upregulated during progression of most diseases and plays a critical role in maintenance of the cellular phenotypes such as cell differentiation, cell cycle arrest and senescence, migration, and proliferation. Therefore, MEOX1 may become an important molecular target and therapeutic target. This review will discuss the current state of knowledge on the role of MEOX1 in different diseases.
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Anderson AM, Bhondoekhan F, Curanovic D, Connelly MA, Otvos JD, Post WS, Michos ED, Stosor V, Levine A, Seaberg E, Weinstein AM, Becker JT. Higher Soluble CD163 in Blood Is Associated With Significant Depression Symptoms in Men With HIV. J Acquir Immune Defic Syndr 2022; 91:325-333. [PMID: 35969468 PMCID: PMC9588493 DOI: 10.1097/qai.0000000000003063] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 05/31/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND People with HIV (PWH) are more likely to experience depression, a highly morbid disease. More evidence is needed to better understand mechanisms of depression in PWH. We evaluated a panel of blood biomarkers in relation to depression symptoms in the Multicenter AIDS Cohort Study (MACS). SETTING Four sites in the United States. METHODS A cross-sectional analysis was performed within the MACS, a prospective study of cisgender men with and without HIV. Depression was assessed with the Center for Epidemiological Studies-Depression Scale, and six blood biomarkers were measured: GlycA, high sensitivity C-reactive protein (CRP), interleukin-6, CCL2, soluble CD14 (sCD14), and soluble CD163 (sCD163). Using univariable and multivariable logistic regression, the biomarkers and other factors were evaluated in relation to significant depression symptoms (SDS) by Center for Epidemiological Studies-Depression score ≥16. RESULTS 784 men were analyzed; most of whom (63%) were PWH. PWH were more likely to have SDS (32% vs. 21%). In univariable analysis, higher GlycA, CRP, and sCD163 concentrations were associated with SDS. In multivariable analysis, however, only higher sCD163 concentration was associated with SDS (odds ratio = 2.30, 95% CI = 1.11 to 4.76). This relationship was driven by the PWH group (odds ratio = 2.72, 95% CI = 1.12 to 6.58) and remained significant when controlling for antidepressant use. Lack of college education was also associated with SDS. CONCLUSIONS Higher sCD163, a marker of macrophage activation, was significantly associated with significant depression symptoms in the MACS. Further research on this biomarker and macrophage activation in general is warranted to better understand and treat depression in PWH.
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Affiliation(s)
- Albert M Anderson
- Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Druid Hills, GA
| | - Fiona Bhondoekhan
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
| | | | | | | | - Wendy S Post
- Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Erin D Michos
- Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Valentina Stosor
- Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Andrew Levine
- Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA; and
| | - Eric Seaberg
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
| | - Andrea M Weinstein
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - James T Becker
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA
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15
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Chen J, Wang K, Ye S, Meng X, Jia X, Huang Y, Ma Q. Tyrosine kinase receptor RON activates MAPK/RSK/CREB signal pathway to enhance CXCR4 expression and promote cell migration and invasion in bladder cancer. Aging (Albany NY) 2022; 14:7093-7108. [PMID: 36103228 PMCID: PMC9512502 DOI: 10.18632/aging.204279] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 08/23/2022] [Indexed: 11/25/2022]
Abstract
Bladder cancer (BC) is one of the most lethal malignancies worldwide. The poor survival may be due to a high proportion of tumor metastasis. RON and CXCR4 are the key regulators of cell motility in BC, while the relationship between RON and CXCR4 remains elusive. In the present study, immunohistochemistry analysis of BC and adjacent normal tissues found that higher RON expression was positively correlated with CXCR4 expression. Inhibiting and replenishing RON level were used to regulate CXCR4 expression, observing the effects on migration and invasion of BC cells. Overexpression of RON reversed the inhibited cell migration and invasion following siCXCR4 treatment. Conversely, overexpression of CXCR4 restored the inhibition of cell migration and invasion caused by shRON. The activation of RON-MAPK/RSK/CREB pathway was demonstrated in BC cells under MSP treatment. Dual luciferase and CHIP assay showed that p-CREB targeted CXCR4 by binding to its CRE sequence. RON knockdown suppressed BC tumor growth in xenograft mouse tumors, accompanied by reduced expression of CXCR4. In conclusion, our data adds evidence that RON, a membrane tyrosine kinase receptor, promotes BC migration and invasion not only by itself, but also by activating MAPK/RSK/CREB signaling pathway to enhance CXCR4 expression.
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Affiliation(s)
- Junfeng Chen
- Translational Research Laboratory for Urology, The Key Laboratory of Ningbo City, Ningbo First Hospital, The Affiliated Hospital of Ningbo University, Ningbo 315010, Zhejiang, China
- Ningbo Clinical Research Center for Urological Disease, Ningbo First Hospital, The Affiliated Hospital of Ningbo University, Ningbo 315010, Zhejiang, China
| | - Kejie Wang
- Translational Research Laboratory for Urology, The Key Laboratory of Ningbo City, Ningbo First Hospital, The Affiliated Hospital of Ningbo University, Ningbo 315010, Zhejiang, China
- Ningbo Clinical Research Center for Urological Disease, Ningbo First Hospital, The Affiliated Hospital of Ningbo University, Ningbo 315010, Zhejiang, China
| | - Shazhou Ye
- Translational Research Laboratory for Urology, The Key Laboratory of Ningbo City, Ningbo First Hospital, The Affiliated Hospital of Ningbo University, Ningbo 315010, Zhejiang, China
- Ningbo Clinical Research Center for Urological Disease, Ningbo First Hospital, The Affiliated Hospital of Ningbo University, Ningbo 315010, Zhejiang, China
| | - Xiangyu Meng
- Translational Research Laboratory for Urology, The Key Laboratory of Ningbo City, Ningbo First Hospital, The Affiliated Hospital of Ningbo University, Ningbo 315010, Zhejiang, China
- Ningbo Clinical Research Center for Urological Disease, Ningbo First Hospital, The Affiliated Hospital of Ningbo University, Ningbo 315010, Zhejiang, China
| | - Xiaolong Jia
- Ningbo Clinical Research Center for Urological Disease, Ningbo First Hospital, The Affiliated Hospital of Ningbo University, Ningbo 315010, Zhejiang, China
| | - Youju Huang
- College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, Zhejiang, China
| | - Qi Ma
- Translational Research Laboratory for Urology, The Key Laboratory of Ningbo City, Ningbo First Hospital, The Affiliated Hospital of Ningbo University, Ningbo 315010, Zhejiang, China
- Ningbo Clinical Research Center for Urological Disease, Ningbo First Hospital, The Affiliated Hospital of Ningbo University, Ningbo 315010, Zhejiang, China
- Comprehensive Urogenital Cancer Center, Ningbo First Hospital, The affiliated Hospital of Ningbo University, Ningbo 315010, Zhejiang, China
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16
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Faisal M, Hassan M, Kumar A, Zubair M, Jamal M, Menghwar H, Saad M, Kloczkowski A. Hematopoietic Stem and Progenitor Cells (HSPCs) and Hematopoietic Microenvironment: Molecular and Bioinformatic Studies of the Zebrafish Models. Int J Mol Sci 2022; 23:7285. [PMID: 35806290 PMCID: PMC9266955 DOI: 10.3390/ijms23137285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 06/25/2022] [Accepted: 06/25/2022] [Indexed: 02/01/2023] Open
Abstract
Hematopoietic stem cells (HSCs) reside in a specialized microenvironment in a peculiar anatomic location which regulates the maintenance of stem cells and controls its functions. Recent scientific progress in experimental technologies have enabled the specific detection of epigenetic factors responsible for the maintenance and quiescence of the hematopoietic niche, which has improved our knowledge of regulatory mechanisms. The aberrant role of RNA-binding proteins and their impact on the disruption of stem cell biology have been reported by a number of recent studies. Despite recent modernization in hematopoietic microenvironment research avenues, our comprehension of the signaling mechanisms and interactive pathways responsible for integration of the hematopoietic niche is still limited. In the past few decades, zebrafish usage with regards to exploratory studies of the hematopoietic niche has expanded our knowledge for deeper understanding of novel cellular interactions. This review provides an update on the functional roles of different genetic and epigenetic factors and molecular signaling events at different sections of the hematopoietic microenvironment. The explorations of different molecular approaches and interventions of latest web-based tools being used are also outlined. This will help us to get more mechanistic insights and develop therapeutic options for the malignancies.
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Affiliation(s)
- Muhammad Faisal
- Division of Hematology, College of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA;
| | - Mubashir Hassan
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA;
| | - Aman Kumar
- Department of Ophthalmology and Vision Sciences, The Ohio State University, Columbus, OH 43210, USA;
| | - Muhammad Zubair
- Department of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China;
| | - Muhammad Jamal
- Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan 430072, China;
| | - Harish Menghwar
- Axe Molecular Endocrinology and Nephrology, CHU de Quebec-Research Center (CHUL), Laval University, Quebec City, QC G1V 4G2, Canada;
| | - Muhammad Saad
- Department of Animal Sciences, The Ohio State University, Columbus, OH 43205, USA;
| | - Andrzej Kloczkowski
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA;
- Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA
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17
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Ha SE, Jin B, Jorgensen BG, Zogg H, Wei L, Singh R, Park C, Kurahashi M, Kim S, Baek G, Poudrier SM, Lee MY, Sanders KM, Ro S. Transcriptome profiling of subepithelial PDGFRα cells in colonic mucosa reveals several cell-selective markers. PLoS One 2022; 17:e0261743. [PMID: 35560163 PMCID: PMC9106222 DOI: 10.1371/journal.pone.0261743] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 12/08/2021] [Indexed: 11/19/2022] Open
Abstract
Subepithelial platelet-derived growth factor receptor alpha (PDGFRα)+ cells found in the colonic mucosal tissue come in close contact with epithelial cells, immune cells, neurons, capillaries, and lymphatic networks. Mucosal subepithelial PDGFRα+ cells (MuPαC) are important regulators in various intestinal diseases including fibrosis and inflammation. However, the transcriptome of MuPαC has not yet been elucidated. Using Pdgfra-eGFP mice and flow cytometry, we isolated colonic MuPαC and obtained their transcriptome data. In analyzing the transcriptome, we identified three novel, and selectively expressed, markers (Adamdec1, Fin1, and Col6a4) found in MuPαC. In addition, we identified a unique set of MuPαC-enriched genetic signatures including groups of growth factors, transcription factors, gap junction proteins, extracellular proteins, receptors, cytokines, protein kinases, phosphatases, and peptidases. These selective groups of genetic signatures are linked to the unique cellular identity and function of MuPαC. Furthermore, we have added this MuPαC transcriptome data to our Smooth Muscle Genome Browser that contains the transcriptome data of jejunal and colonic smooth muscle cells (SMC), interstitial cells of Cajal (ICC), and smooth muscle resident PDGFRα+ cells: (https://med.unr.edu/physio/transcriptome). This online resource provides a comprehensive reference of all currently known genetic transcripts expressed in primary MuPαC in the colon along with smooth muscle resident PDGFRα cells, SMC, and ICC in the murine colon and jejunum.
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Affiliation(s)
- Se Eun Ha
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America
| | - Byungchang Jin
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America
| | - Brian G. Jorgensen
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America
| | - Hannah Zogg
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America
| | - Lai Wei
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America
| | - Rajan Singh
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America
| | - Chanjae Park
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America
| | - Masaaki Kurahashi
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Lowa, Lowa City, Lowa, United States of America
| | - Sei Kim
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America
| | - Gain Baek
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America
| | - Sandra M. Poudrier
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America
| | - Moon Young Lee
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America
- Department of Physiology, Wonkwang Digestive Disease Research Institute and Institute of Wonkwang Medical Science, School of Medicine, Wonkwang University, Iksan, Chonbuk, Korea
| | - Kenton M. Sanders
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America
| | - Seungil Ro
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America
- * E-mail:
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18
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Wang X, Han X, Qiu Y, Sun J. Magnetic Nano-Sized SDF-1 Particles Show Promise for Application in Stem Cell-Based Repair of Damaged Tissues. Front Bioeng Biotechnol 2022; 10:831256. [PMID: 35573238 PMCID: PMC9091189 DOI: 10.3389/fbioe.2022.831256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 02/24/2022] [Indexed: 11/13/2022] Open
Abstract
Stem cell-based therapy is a promising option for repair of injured tissue. Stem cells have homing characteristics and can be mobilized to the injury sites following activation, under the regulation of the SDF-1/CXCR4 axis. However, a sufficient level of stem cell aggregation and retention is essential for ensuring favorable repair outcomes. Problems related to stem cell delivery/recruitment efficiency and retention in the injury site are among the main challenges faced during in vivo studies on stem cell therapy. In this study, we designed an SDF-1(alpha) magnetic nanoparticle delivery system for stem cell recruitment. We expressed and purified a biotin-labeled SDF-1(alpha) protein and immobilized it on streptavidin-modified magnetic nanoparticles (MNP) through the streptavidin-biotin linkage, with an efficiency of approximately 14%. The physicochemical properties of the SDF-MNP in glycerol buffer were similar to those of the streptavidin-modified MNP. Further evidence suggested that SDF-MNP barely show cytotoxicity even at a concentration of 125 µg/ml MNP and have a promising chemotaxis effect on mesenchymal stem cells in vitro and in vivo. Our study provides a strategy for the assembly of magnetic nanoparticle carrier systems for protein factors, as well as preliminary evidence for the application of SDF-MNP in stem cell-based therapy for the regeneration of injured bone tissue.
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Affiliation(s)
- Xu Wang
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China
- The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, China
| | - XinXin Han
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Yi Qiu
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Jianbo Sun
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China
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Luyten K, Van Loy T, Cawthorne C, Deroose CM, Schols D, Bormans G, Cleeren F. D-Peptide-Based Probe for CXCR4-Targeted Molecular Imaging and Radionuclide Therapy. Pharmaceutics 2021; 13:pharmaceutics13101619. [PMID: 34683912 PMCID: PMC8537445 DOI: 10.3390/pharmaceutics13101619] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 09/16/2021] [Accepted: 09/29/2021] [Indexed: 12/29/2022] Open
Abstract
Positron emission tomography (PET) imaging of the C-X-C chemokine receptor 4 (CXCR4) with [68Ga]PentixaFor has intrinsic diagnostic value and is used to select patients for personalized CXCR4-targeted radionuclide therapy with its therapeutic radiopharmaceutical companion [177Lu]PentixaTher. However, a CXCR4-targeting radiopharmaceutical labeled with fluorine-18 is still of high value due to its favorable characteristics over gallium-68. Furthermore, clinical results with [177Lu]PentixaTher are promising, but there is still room for improvement regarding pharmacokinetics and dosimetry profile. Therefore, this study aimed to develop innovative CXCR4-targeting radiopharmaceuticals, both for diagnostic and therapeutic purposes, starting from a D-amino acid-based peptide probe (DV1-k-(DV3)) that conserves high CXCR4 binding affinity after radiolabeling. AlF-NOTA-DV1-k-(DV3) showed similar in vitro binding affinity to human CXCR4 (hCXCR4) compared to [natGa]PentixaFor (half-maximal inhibitory concentration (IC50): 5.3 ± 0.9 nM and 8.6 ± 1.1 nM, respectively) and also binds to murine CXCR4 (mCXCR4) (IC50: 33.4 ± 13.5 nM) while [natGa]PentixaFor is selective for hCXCR4 (IC50 > 1000 nM for mCXCR4). Both the diagnostic radiotracers based on the DV1-k-(DV3) vector platform, [18F]AlF-NOTA-DV1-k-(DV3) and [68Ga]Ga-DOTA-DV1-k-(DV3), and their therapeutic companion [177Lu]Lu-DOTA-DV1-k-(DV3) were successfully produced in high yield, demonstrated high in vitro and in vivo stability, and have the same favorable pharmacokinetic profile. Furthermore, in wild-type mice and a hCXCR4-expressing tumor model, [18F]AlF-NOTA-DV1-k-(DV3) shows CXCR4-specific targeting in mCXCR4-expressing organs such as liver (mean standardized uptake value (SUVmean) 8.2 ± 1.0 at 75 min post-injection (p.i.)), spleen (SUVmean 2.5 ± 1.0 at 75 min p.i.), and bone (SUVmean 0.4 ± 0.1 at 75 min p.i., femur harboring bone marrow) that can be blocked with the CXCR4 antagonist AMD3100. However, in a hCXCR4-expressing tumor model, tumor uptake of [18F]AlF-NOTA-DV1-k-(DV3) was significantly lower (SUVmean 0.6 ± 0.2) compared to [68Ga]PentixaFor (SUVmean 2.9). This might be explained by the high affinity of [18F]AlF-NOTA-DV1-k-(DV3) toward both mCXCR4 and hCXCR4. High mCXCR4 expression in mouse liver results in a large fraction of [18F]AlF-NOTA-DV1-k-(DV3) that is sequestered to the liver, resulting despite its similar in vitro affinity for hCXCR4, in lower tumor accumulation compared to [68Ga]PentixaFor. As CXCR4 is not expressed in healthy human liver, the findings in mice are not predictive for the potential clinical performance of this novel class of CXCR4-targeting radiotracers. In conclusion, the DV1-k-(DV3) scaffold is a promising vector platform for translational CXCR4-directed research.
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Affiliation(s)
- Kaat Luyten
- Laboratory for Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium; (K.L.); (G.B.)
| | - Tom Van Loy
- Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium; (T.V.L.); (D.S.)
| | - Christopher Cawthorne
- Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, 3000 Leuven, Belgium; (C.C.); (C.M.D.)
| | - Christophe M. Deroose
- Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, 3000 Leuven, Belgium; (C.C.); (C.M.D.)
| | - Dominique Schols
- Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium; (T.V.L.); (D.S.)
| | - Guy Bormans
- Laboratory for Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium; (K.L.); (G.B.)
| | - Frederik Cleeren
- Laboratory for Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium; (K.L.); (G.B.)
- Correspondence:
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20
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Moghbeli M. MicroRNAs as the critical regulators of Cisplatin resistance in ovarian cancer cells. J Ovarian Res 2021; 14:127. [PMID: 34593006 PMCID: PMC8485521 DOI: 10.1186/s13048-021-00882-1] [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: 10/22/2020] [Accepted: 09/14/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Ovarian cancer (OC) is one of the leading causes of cancer related deaths among women. Due to the asymptomatic tumor progression and lack of efficient screening methods, majority of OC patients are diagnosed in advanced tumor stages. A combination of surgical resection and platinum based-therapy is the common treatment option for advanced OC patients. However, tumor relapse is observed in about 70% of cases due to the treatment failure. Cisplatin is widely used as an efficient first-line treatment option for OC; however cisplatin resistance is observed in a noticeable ratio of cases. Regarding, the severe cisplatin side effects, it is required to clarify the molecular biology of cisplatin resistance to improve the clinical outcomes of OC patients. Cisplatin resistance in OC is associated with abnormal drug transportation, increased detoxification, abnormal apoptosis, and abnormal DNA repair ability. MicroRNAs (miRNAs) are critical factors involved in cell proliferation, apoptosis, and chemo resistance. MiRNAs as non-invasive and more stable factors compared with mRNAs, can be introduced as efficient markers of cisplatin response in OC patients. MAIN BODY In present review, we have summarized all of the miRNAs that have been associated with cisplatin resistance in OC. We also categorized the miRNAs based on their targets to clarify their probable molecular mechanisms during cisplatin resistance in ovarian tumor cells. CONCLUSIONS It was observed that miRNAs mainly exert their role in cisplatin response through regulation of apoptosis, signaling pathways, and transcription factors in OC cells. This review highlighted the miRNAs as important regulators of cisplatin response in ovarian tumor cells. Moreover, present review paves the way of suggesting a non-invasive panel of prediction markers for cisplatin response among OC patients.
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Affiliation(s)
- Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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21
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Wu Y, Li YJ, Shi LL, Liu Y, Wang Y, Bao X, Xu W, Yao LY, Mbadhi MN, Chen L, Li S, Li XY, Zhang ZF, Zhao S, Zhang RN, Chen SY, Zhang JX, Jun-mingTang. Spatio-temporal model of Meox1 expression control involvement of Sca-1-positive stem cells in neointima formation through the synergistic effect of Rho/CDC42 and SDF-1α/CXCR4. Stem Cell Res Ther 2021; 12:387. [PMID: 34233723 PMCID: PMC8262022 DOI: 10.1186/s13287-021-02466-8] [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: 03/22/2021] [Accepted: 06/19/2021] [Indexed: 08/30/2023] Open
Abstract
AIMS Neointimal hyperplasia remains a major obstacle in vascular regeneration. Sca-1-positive progenitor cells residing within the vascular adventitia play a crucial role in the assemblage of vascular smooth muscle cell (VSMC) and the formation of the intimal lesion. However, the underlying mechanisms during vascular injury are still unknown. METHODS AND RESULTS Aneointimal formation rat model was prepared by carotid artery injury using 2F-Forgaty. After vascular injury, Meox1 expressions time-dependently increased during the neointima formation, with its levels concurrently increasing in the adventitia, media, and neointima. Meox1 was highly expressed in the adventitia on the first day after vascular injury compared to the expression levels in the media. Conversely, by the 14th day post-injury, Meox1 was extensively expressed more in the media and neointima than the adventitia. Analogous to the change of Meox1 in injured artery, Sca-1+ progenitor cells increased in the adventitia wall in a time-dependent manner and reached peak levels on the 7th day after injury. More importantly, this effect was abolished by Meox1 knockdown with shRNA. The enhanced expression of SDF-1α after vascular injury was associated with the markedly enhanced expression levels of Sca1+ progenitor cell, and these levels were relatively synchronously increased within neointima by the 7th day after vascular injury. These special effects were abolished by the knockdown of Meox1 with shRNA and inhibition of CXCR4 by its inhibitor, AMD3100. Finally, Meox1 concurrently regulated SDF-1α expressions in VSMC via activating CDC42, and CDC42 inhibition abolished these effects by its inhibitor, ZCL278. Also, Meox1 was involved in activation of the CXCR4 expression of Sca-1+ progenitor cells by CDC42. CONCLUSIONS Spatio-temporal model of Meox1 expression regulates theSca-1+progenitor cell migration during the formation of the neointima through the synergistic effect of Rho/CDC42 and SDF-1α/CXCR4.
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Affiliation(s)
- Yan Wu
- Department of Physiology, Hubei Key Laboratory of Embryonic Stem Cell Research, Faculty of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China.
| | - Yuan-Jin Li
- Hebei Medical University, Shijiazhuang, 050017, Hebei, People's Republic of China.
| | - Liu-Liu Shi
- Department of Physiology, Hubei Key Laboratory of Embryonic Stem Cell Research, Faculty of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China.
| | - Yun Liu
- Department of Physiology, Hubei Key Laboratory of Embryonic Stem Cell Research, Faculty of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China
| | - Yan Wang
- Department of Physiology, Hubei Key Laboratory of Embryonic Stem Cell Research, Faculty of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China
| | - Xin Bao
- Department of Physiology, Hubei Key Laboratory of Embryonic Stem Cell Research, Faculty of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China
| | - Wei Xu
- Department of Physiology, Hubei Key Laboratory of Embryonic Stem Cell Research, Faculty of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China
| | - Lu-Yuan Yao
- Department of Physiology, Hubei Key Laboratory of Embryonic Stem Cell Research, Faculty of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China
| | - Magdaleena Naemi Mbadhi
- Department of Physiology, Hubei Key Laboratory of Embryonic Stem Cell Research, Faculty of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China
| | - Long Chen
- Cental Lab, Guoyao-Dongfeng Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China
| | - Shan Li
- Department of Biochemistry, Faculty of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China
| | - Xing-Yuan Li
- Department of Physiology, Hubei Key Laboratory of Embryonic Stem Cell Research, Faculty of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China
| | - Zhi-Feng Zhang
- Department of Physiology, Hubei Key Laboratory of Embryonic Stem Cell Research, Faculty of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China.,Faculty of Basic Medical Sciences, Institute of Biomedicine, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China
| | - Sen Zhao
- Department of Physiology, Hubei Key Laboratory of Embryonic Stem Cell Research, Faculty of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China
| | - Ruo-Nan Zhang
- Department of Physiology, Hubei Key Laboratory of Embryonic Stem Cell Research, Faculty of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China
| | - Shi-You Chen
- The Department of Surgery, University of Missouri, Columbia, USA
| | - Jing-Xuan Zhang
- Department of Physiology, Hubei Key Laboratory of Embryonic Stem Cell Research, Faculty of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China. .,Faculty of Basic Medical Sciences, Institute of Biomedicine, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China.
| | - Jun-mingTang
- Department of Physiology, Hubei Key Laboratory of Embryonic Stem Cell Research, Faculty of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China. .,Faculty of Basic Medical Sciences, Institute of Biomedicine, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China.
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22
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Inhibition of SDF-1/CXCR4 Axis to Alleviate Abnormal Bone Formation and Angiogenesis Could Improve the Subchondral Bone Microenvironment in Osteoarthritis. BIOMED RESEARCH INTERNATIONAL 2021; 2021:8852574. [PMID: 34136574 PMCID: PMC8179778 DOI: 10.1155/2021/8852574] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 04/23/2021] [Accepted: 05/08/2021] [Indexed: 01/07/2023]
Abstract
The pathogenesis of the osteoarthritis (OA) is complex. Abnormal subchondral bone metabolism is an important cause of this disease. Further understanding on the pathology of the subchondral bone in OA may provide a new therapy. This research is about to investigate the role of SDF-1 in the subchondral bone during the pathological process of OA. In vitro, Transwell was used to test the migratory ability of bone marrow mesenchymal stem cells (BMSCs) and human umbilical vein endothelial cells (HUVECs). Western blot presented the protein level after SDF-1 treatment in BMSCs and HUVESs. Alizarin red was used to assess the ability of osteogenic differentiation. To inhibit SDF-1 signaling pathway in vivo, AMD3100 (SDF-1 receptor blocker) was continuously delivered via miniosmotic pump for 4 weeks in mice after performing anterior cruciate ligament transaction surgery. Micro-CT, histology staining, immunofluorescence, immunohistochemistry, and TRAP staining were used to assess the role of SDF-1 on osteogenesis and angiogenesis in the subchondral bone. Our results showed that SDF-1 could recruit BMSCs, activate the p-ERK pathway, and enhance osteogenic differentiation. SDF-1 promoted the ability of proliferation, migration and tube formation of HUVECs by activating the ERK and AKT signaling pathways. In an animal study, inhibition of SDF-1/CXCR4 axis could significantly reduce subchondral osteogenesis differentiation and H-type vessel formation. Furthermore, the AMD3100-treated group showed less cartilage destruction and bone resorption. Our research shows that SDF-1 alters the microenvironment of the subchondral bone by promoting osteoid islet formation and abnormal H-type angiogenesis in the subchondral bone, resulting in articular cartilage degeneration.
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23
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Jia Y, Liu Y, Han Z, Tian R. Identification of potential gene signatures associated with osteosarcoma by integrated bioinformatics analysis. PeerJ 2021; 9:e11496. [PMID: 34123594 PMCID: PMC8164836 DOI: 10.7717/peerj.11496] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 04/30/2021] [Indexed: 12/21/2022] Open
Abstract
Background Osteosarcoma (OS) is the most primary malignant bone cancer in children and adolescents with a high mortality rate. This work aims to screen novel potential gene signatures associated with OS by integrated microarray analysis of the Gene Expression Omnibus (GEO) database. Material and Methods The OS microarray datasets were searched and downloaded from GEO database to identify differentially expressed genes (DEGs) between OS and normal samples. Afterwards, the functional enrichment analysis, protein–protein interaction (PPI) network analysis and transcription factor (TF)-target gene regulatory network were applied to uncover the biological function of DEGs. Finally, two published OS datasets (GSE39262 and GSE126209) were obtained from GEO database for evaluating the expression level and diagnostic values of key genes. Results In total 1,059 DEGs (569 up-regulated DEGs and 490 down-regulated DEGs) between OS and normal samples were screened. Functional analysis showed that these DEGs were markedly enriched in 214 GO terms and 54 KEGG pathways such as pathways in cancer. Five genes (CAMP, METTL7A, TCN1, LTF and CXCL12) acted as hub genes in PPI network. Besides, METTL7A, CYP4F3, TCN1, LTF and NETO2 were key genes in TF-gene network. Moreover, Pax-6 regulated four key genes (TCN1, CYP4F3, NETO2 and CXCL12). The expression levels of four genes (METTL7A, TCN1, CXCL12 and NETO2) in GSE39262 set were consistent with our integration analysis. The expression levels of two genes (CXCL12 and NETO2) in GSE126209 set were consistent with our integration analysis. ROC analysis of GSE39262 set revealed that CYP4F3, CXCL12, METTL7A, TCN1 and NETO2 had good diagnostic values for OS patients. ROC analysis of GSE126209 set revealed that CXCL12, METTL7A, TCN1 and NETO2 had good diagnostic values for OS patients.
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Affiliation(s)
- Yutao Jia
- Department of Spine Surgery, Tianjin Union Medical Center, Tianjin, China
| | - Yang Liu
- Department of Spine Surgery, Tianjin Union Medical Center, Tianjin, China
| | - Zhihua Han
- Department of Anesthesiology, Tianjin Union Medical Center, Tianjin, China
| | - Rong Tian
- Department of Spine Surgery, Tianjin Union Medical Center, Tianjin, China
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24
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Nash WT, Okusa MD. Chess Not Checkers: Complexities Within the Myeloid Response to the Acute Kidney Injury Syndrome. Front Med (Lausanne) 2021; 8:676688. [PMID: 34124107 PMCID: PMC8187556 DOI: 10.3389/fmed.2021.676688] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 04/26/2021] [Indexed: 12/23/2022] Open
Abstract
Immune dysregulation in acute kidney injury (AKI) is an area of intense interest which promises to enhance our understanding of the disease and how to manage it. Macrophages are a heterogeneous and dynamic population of immune cells that carry out multiple functions in tissue, ranging from maintenance to inflammation. As key sentinels of their environment and the major immune population in the uninjured kidney, macrophages are poised to play an important role in the establishment and pathogenesis of AKI. These cells have a profound capacity to orchestrate downstream immune responses and likely participate in skewing the kidney environment toward either pathogenic inflammation or injury resolution. A clear understanding of macrophage and myeloid cell dynamics in the development of AKI will provide valuable insight into disease pathogenesis and options for intervention. This review considers evidence in the literature that speaks to the role and regulation of macrophages and myeloid cells in AKI. We also highlight barriers or knowledge gaps that need to be addressed as the field advances.
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Affiliation(s)
- William T Nash
- Division of Nephrology, Department of Medicine, Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia, Charlottesville, VA, United States
| | - Mark D Okusa
- Division of Nephrology, Department of Medicine, Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia, Charlottesville, VA, United States
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25
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Hsiao CC, Sankowski R, Prinz M, Smolders J, Huitinga I, Hamann J. GPCRomics of Homeostatic and Disease-Associated Human Microglia. Front Immunol 2021; 12:674189. [PMID: 34054860 PMCID: PMC8160299 DOI: 10.3389/fimmu.2021.674189] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 04/22/2021] [Indexed: 12/24/2022] Open
Abstract
G-protein-coupled receptors (GPCRs) are critical sensors affecting the state of eukaryotic cells. To get systematic insight into the GPCRome of microglia, we analyzed publicly available RNA-sequencing data of bulk and single cells obtained from human and mouse brains. We identified 17 rhodopsin and adhesion family GPCRs robustly expressed in microglia from human brains, including the homeostasis-associated genes CX3CR1, GPR34, GPR183, P2RY12, P2RY13, and ADGRG1. Expression of these microglial core genes was lost upon culture of isolated cells ex vivo but could be acquired by human induced pluripotent stem cell (iPSC)-derived microglial precursors transplanted into mouse brains. CXCR4 and PTGER4 were higher expressed in subcortical white matter compared to cortical grey matter microglia, and ADGRG1 was downregulated in microglia obtained from normal-appearing white and grey matter tissue of multiple sclerosis (MS) brains. Single-cell RNA sequencing of microglia from active lesions, obtained early during MS, revealed downregulation of homeostasis-associated GPCR genes and upregulation of CXCR4 expression in a small subset of MS-associated lesional microglia. Functional presence of low levels of CXCR4 on human microglia was confirmed using flow cytometry and transwell migration towards SDF-1. Microglia abundantly expressed the GPCR down-stream signaling mediator genes GNAI2 (αi2), GNAS (αs), and GNA13 (α13), the latter particularly in white matter. Drugs against several microglia GPCRs are available to target microglia in brain diseases. In conclusion, transcriptome profiling allowed us to identify expression of GPCRs that may contribute to brain (patho)physiology and have diagnostic and therapeutic potential in human microglia.
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Affiliation(s)
- Cheng-Chih Hsiao
- Department of Experimental Immunology, Amsterdam institute for Infection and Immunity, Amsterdam University Medical Centers, Amsterdam, Netherlands.,Neuroimmunology Research Group, Netherlands Institute for Neuroscience, Amsterdam, Netherlands
| | - Roman Sankowski
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Marco Prinz
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany.,Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Joost Smolders
- Neuroimmunology Research Group, Netherlands Institute for Neuroscience, Amsterdam, Netherlands.,MS Center ErasMS, Departments of Neurology and Immunology, Erasmus Medical Center, Rotterdam, Netherlands
| | - Inge Huitinga
- Neuroimmunology Research Group, Netherlands Institute for Neuroscience, Amsterdam, Netherlands.,Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, Netherlands
| | - Jörg Hamann
- Department of Experimental Immunology, Amsterdam institute for Infection and Immunity, Amsterdam University Medical Centers, Amsterdam, Netherlands.,Neuroimmunology Research Group, Netherlands Institute for Neuroscience, Amsterdam, Netherlands
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26
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Fontenete S, Lerche CM, Paasch U, Perez-Moreno M, Olesen UH, Haedersdal M. Tumor Clearance and Immune Cell Recruitment in UV-Induced Murine Squamous Cell Carcinoma Exposed to Ablative Fractional Laser and Imiquimod Treatment. Lasers Surg Med 2021; 53:1227-1237. [PMID: 33811359 DOI: 10.1002/lsm.23406] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 02/23/2021] [Indexed: 01/08/2023]
Abstract
BACKGROUND AND OBJECTIVES Keratinocyte carcinoma (KC) is the most common cancer worldwide, and squamous cell carcinoma (SCC) is the second most frequent subtype. Ablative fractional laser (AFL)-assisted drug delivery significantly enhances the uptake of topically applied drugs. The objective of this study was to assess tumor response and perform a descriptive characterization of the local recruitment of immune cells and systemic immune mediator levels in an ultraviolet radiation (UVR)-induced murine SCC model after AFL treatment alone and combined with topical imiquimod. STUDY DESIGN/MATERIALS AND METHODS Immunocompetent hairless mice (C3·Cg/TifBomTac, n = 74) were irradiated with solar-simulated UVR until 3-mm SCCs developed. The mice were divided into four interventional groups: AFL alone, AFL + imiquimod, imiquimod alone, and untreated SCC controls. AFL was given as a single treatment, whereas imiquimod was applied daily until the mice were euthanized on Days 0, 2, 7, or 14. SCCs were photographed and measured (mm) to assess the therapeutic response. Skin samples were processed for histopathological and immunohistochemical analyses, as well as for flow cytometry. Cytokine expression changes in sera were analyzed using ELISpot cytokine arrays. RESULTS Treatment of mouse SCCs with AFL + imiquimod induced the most robust immune cell infiltration and the greatest proportion of tumor clearance compared to other interventions. Early innate immune cell infiltration was induced by AFL + imiquimod treatment as the number of neutrophils and macrophages had increased fourfold within 2 days of treatment initiation compared with untreated SCC control mice (P < 0.05). AFL treatment alone had a more limited effect, with a fourfold increase in neutrophils (P < 0.05) but no significant increase in the number of macrophages. Correspondingly, treatment with AFL + imiquimod had the greatest effects on the adaptive immune cell recruitment: CD4+ T-helper cells increased threefold at Day 7 compared with untreated SCCs (P = 0.0001) and, notably, cytotoxic CD8+ T cells increased 14-fold at Day 14 (P = 0.0112). In addition, FOXP3+ regulatory T cells (Tregs) increased 14-fold at Day 7 (P = 0.0026), suggesting the resolution of the inflammatory infiltration. AFL treatment alone induced a moderate immune cell infiltration (a twofold increase in CD4+ T-helper cells, P = 0.0200; a threefold increase in CD8+ T cells, P = 0.0100; and a 14-fold increase in FOXP3+ Tregs at Day 14, P = 0.0021), whereas imiquimod alone did not significantly increase cell counts. AFL + imiquimod treatment increased CXCL12 serum levels threefold at Day 14 (P = 0.0200). CONCLUSION AFL treatment alone and in combination with imiquimod induces substantial tumor clearance associated with local recruitment of innate and adaptive immune cells in UVR-induced murine SCCs. These results may provide a basis for new immunotherapeutic approaches to KC treatment.
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Affiliation(s)
- Silvia Fontenete
- Department of Biology, University of Copenhagen, Universitetsparken 13, Copenhagen, 2100, Denmark
| | - Catharina M Lerche
- Department of Dermatology, Copenhagen University Hospital Bispebjerg and Frederiksberg, Bispebjerg Bakke 23, Copenhagen, 2400, Denmark.,Department of Pharmacy, University of Copenhagen, Universitetsparken 2, Copenhagen, 2100, Denmark
| | - Uwe Paasch
- Department of Dermatology, Copenhagen University Hospital Bispebjerg and Frederiksberg, Bispebjerg Bakke 23, Copenhagen, 2400, Denmark.,Department of Dermatology, Venereology and Allergy, University of Leipzig, Leipzig, 04103, Germany
| | - Mirna Perez-Moreno
- Department of Biology, University of Copenhagen, Universitetsparken 13, Copenhagen, 2100, Denmark
| | - Uffe H Olesen
- Department of Dermatology, Copenhagen University Hospital Bispebjerg and Frederiksberg, Bispebjerg Bakke 23, Copenhagen, 2400, Denmark
| | - Merete Haedersdal
- Department of Dermatology, Copenhagen University Hospital Bispebjerg and Frederiksberg, Bispebjerg Bakke 23, Copenhagen, 2400, Denmark
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Zhang H, Li X, Li J, Zhong L, Chen X, Chen S. SDF-1 mediates mesenchymal stem cell recruitment and migration via the SDF-1/CXCR4 axis in bone defect. J Bone Miner Metab 2021; 39:126-138. [PMID: 33079278 DOI: 10.1007/s00774-020-01122-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 06/27/2020] [Indexed: 01/07/2023]
Abstract
INTRODUCTION Recent studies have indicated the potential of stem cell therapy in combination with cytokines to restore the bone repair via migration and homing of stem cells to the defected area. The present study aimed to investigate the mobilization and recruitment of mesenchymal stem cells (MSCs) in response to SDF-1. MATERIALS AND METHODS Herein, the knockout rat model of the bone defect (BD) was treated with the induced membrane technique. Then, wild type Wistar rats and SDF-1-knockout rats were selected for the establishment of BD-induced membrane (BD-IM) models and bone-graft (BG) models. The number of MSCs was evaluated by flow cytometry, along with the expression pattern of the SDF-1/CXCR4 axis as well as osteogenic factors was identified by RT-qPCR and Western blot analyses. Finally, the MSC migration ability was assessed by the Transwell assay. RESULTS Our data illustrated that in the induced membrane tissues, the number of MSCs among the BD-IM modeled rats was increased, whereas, a lower number was documented among BG modeled rats. Besides, we found that lentivirus-mediated over-expression of SDF-1 in BG modeled rats could activate the SDF-1/CXCR4 axis, mobilize MSCs into the defect area, and up-regulate the osteogenic proteins. CONCLUSIONS Collectively, our study speculated that up-regulation of SDF-1 promotes the mobilization and migration of MSCs through the activation of the SDF-1/CXCR4 signal pathway.
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Affiliation(s)
- Heli Zhang
- Department of Outpatient, The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Xijing Li
- Department of Emergency, The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Junfeng Li
- Department of Clinical Laboratory, The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Lili Zhong
- Jilin Provincial Key Laboratory On Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Xue Chen
- Department of Orthopedics, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, Changchun, 130041, Jilin, People's Republic of China.
| | - Si Chen
- Department of Geriatric Medicine, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, Changchun, 130041, Jilin, People's Republic of China.
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28
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Hozhabri H, Lashkari A, Razavi SM, Mohammadian A. Integration of gene expression data identifies key genes and pathways in colorectal cancer. Med Oncol 2021; 38:7. [PMID: 33411100 DOI: 10.1007/s12032-020-01448-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 11/21/2020] [Indexed: 12/16/2022]
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumor and prevalent cause of cancer-related death worldwide. In this study, we analyzed the gene expression profiles of patients with CRC with the aim of better understanding the molecular mechanism and key genes in CRC. Four gene expression profiles including, GSE9348, GSE41328, GSE41657, and GSE113513 were downloaded from GEO database. The data were processed using R programming language, in which 319 common differentially expressed genes including 94 up-regulated and 225 down-regulated were identified. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were conducted to find the most significant enriched pathways in CRC. Based on the GO and KEGG pathway analysis, the most important dysregulated pathways were regulation of cell proliferation, biocarbonate transport, Wnt, and IL-17 signaling pathways, and nitrogen metabolism. The protein-protein interaction (PPI) network of the DEGs was constructed using Cytoscape software and hub genes including MYC, CXCL1, CD44, MMP1, and CXCL12 were identified as the most critical hub genes. The present study enhances our understanding of the molecular mechanisms of the CRC, which might potentially be applied in the treatment strategies of CRC as molecular targets and diagnostic biomarkers.
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Affiliation(s)
- Hossein Hozhabri
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
| | - Ali Lashkari
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Seyed-Morteza Razavi
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran.,Salari Institute of Cognitive and Behavioral Disorders (SICBD), Karaj, Alborz, Iran.,Systems Biology Research Lab, Bioinformatics Group, Systems Biology of Next Generation Company (SBNGC), Qom, Iran
| | - Ali Mohammadian
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
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29
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Kouzeli A, Collins PJ, Metzemaekers M, Meyrath M, Szpakowska M, Artinger M, Struyf S, Proost P, Chevigne A, Legler DF, Eberl M, Moser B. CXCL14 Preferentially Synergizes With Homeostatic Chemokine Receptor Systems. Front Immunol 2020; 11:561404. [PMID: 33123134 PMCID: PMC7570948 DOI: 10.3389/fimmu.2020.561404] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 09/02/2020] [Indexed: 11/13/2022] Open
Abstract
Reflecting their importance in immunity, the activity of chemokines is regulated on several levels, including tissue and context-specific expression and availability of their cognate receptor on target cells. Chemokine synergism, affecting both chemokine and chemokine receptor function, has emerged as an additional control mechanism. We previously demonstrated that CXCL14 is a positive allosteric modulator of CXCR4 in its ability to synergize with CXCL12 in diverse cellular responses. Here, we have extended our study to additional homeostatic, as well as a selection of inflammatory chemokine systems. We report that CXCL14 strongly synergizes with low (sub-active) concentrations of CXCL13 and CCL19/CCL21 in in vitro chemotaxis with immune cells expressing the corresponding receptors CXCR5 and CCR7, respectively. CXCL14 by itself was inactive, not only on cells expressing CXCR5 or CCR7 but also on cells expressing any other known conventional or atypical chemokine receptor, as assessed by chemotaxis and/or β-arrestin recruitment assays. Furthermore, synergistic migration responses between CXCL14 and inflammatory chemokines CXCL10/CXCL11 and CCL5, targeting CXCR3 and CCR5, respectively, were marginal and occasional synergistic Ca2+ flux responses were observed. CXCL14 bound to 300-19 cells and interfered with CCL19 binding to CCR7-expressing cells, suggesting that these cellular interactions contributed to the reported CXCL14-mediated synergistic activities. We propose a model whereby tissue-expressed CXCL14 contributes to cell localization under steady-state conditions at sites with prominent expression of homeostatic chemokines.
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Affiliation(s)
- Ariadni Kouzeli
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom
| | - Paul J Collins
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Mieke Metzemaekers
- Laboratory of Molecular Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Max Meyrath
- Department of Infection and Immunity, Immuno-Pharmacology and Interactomics, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg
| | - Martyna Szpakowska
- Department of Infection and Immunity, Immuno-Pharmacology and Interactomics, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg
| | - Marc Artinger
- Biotechnology Institute Thurgau (BITg), University of Konstanz, Kreuzlingen, Switzerland
| | - Sofie Struyf
- Laboratory of Molecular Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Paul Proost
- Laboratory of Molecular Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Andy Chevigne
- Department of Infection and Immunity, Immuno-Pharmacology and Interactomics, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg
| | - Daniel F Legler
- Biotechnology Institute Thurgau (BITg), University of Konstanz, Kreuzlingen, Switzerland
| | - Matthias Eberl
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom
| | - Bernhard Moser
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom
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30
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Discovery of Potential Chemical Probe as Inhibitors of CXCL12 Using Ligand-Based Virtual Screening and Molecular Dynamic Simulation. Molecules 2020; 25:molecules25204829. [PMID: 33092204 PMCID: PMC7594044 DOI: 10.3390/molecules25204829] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/16/2020] [Accepted: 10/16/2020] [Indexed: 11/16/2022] Open
Abstract
CXCL12 are small pro-inflammatory chemo-attractant cytokines that bind to a specific receptor CXCR4 with a role in angiogenesis, tumor progression, metastasis, and cell survival. Globally, cancer metastasis is a major cause of morbidity and mortality. In this study, we targeted CXCL12 rather than the chemokine receptor (CXCR4) because most of the drugs failed in clinical trials due to unmanageable toxicities. Until now, no FDA approved medication has been available against CXCL12. Therefore, we aimed to find new inhibitors for CXCL12 through virtual screening followed by molecular dynamics simulation. For virtual screening, active compounds against CXCL12 were taken as potent inhibitors and utilized in the generation of a pharmacophore model, followed by validation against different datasets. Ligand based virtual screening was performed on the ChEMBL and in-house databases, which resulted in successive elimination through the steps of pharmacophore-based and score-based screenings, and finally, sixteen compounds of various interactions with significant crucial amino acid residues were selected as virtual hits. Furthermore, the binding mode of these compounds were refined through molecular dynamic simulations. Moreover, the stability of protein complexes, Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), and radius of gyration were analyzed, which led to the identification of three potent inhibitors of CXCL12 that may be pursued in the drug discovery process against cancer metastasis.
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31
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Esposito A, Wang L, Li T, Miranda M, Spagnoli A. Role of Prx1-expressing skeletal cells and Prx1-expression in fracture repair. Bone 2020; 139:115521. [PMID: 32629173 PMCID: PMC7484205 DOI: 10.1016/j.bone.2020.115521] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 06/25/2020] [Accepted: 06/29/2020] [Indexed: 12/22/2022]
Abstract
The healing capacity of bones after fracture implies the existence of adult regenerative cells. However, information on identification and functional role of fracture-induced progenitors is still lacking. Paired-related homeobox 1 (Prx1) is expressed during skeletogenesis. We hypothesize that fracture recapitulates Prx1's expression, and Prx1 expressing cells are critical to induce repair. To address our hypothesis, we used a combination of in vivo and in vitro approaches, short and long-term cell tracking analyses of progenies and actively expressing cells, cell ablation studies, and rodent animal models for normal and defective fracture healing. We found that fracture elicits a periosteal and endosteal response of perivascular Prx1+ cells that participate in fracture healing and showed that Prx1-expressing cells have a functional role in the repair process. While Prx1-derived cells contribute to the callus, Prx1's expression decreases concurrently with differentiation into cartilaginous and bone cells, similarly to when Prx1+ cells are cultured in differentiating conditions. We determined that bone morphogenic protein 2 (BMP2), through C-X-C motif-ligand-12 (CXCL12) signaling, modulates the downregulation of Prx1. We demonstrated that fracture elicits an early increase in BMP2 expression, followed by a decrease in CXCL12 that in turn down-regulates Prx1, allowing cells to commit to osteochondrogenesis. In vivo and in vitro treatment with CXCR4 antagonist AMD3100 restored Prx1 expression by modulating the BMP2-CXCL12 axis. Our studies represent a shift in the current research that has primarily focused on the identification of markers for postnatal skeletal progenitors, and instead we characterized the function of a specific population (Prx1+ cells) and their expression marker (Prx1) as a crossroad in fracture repair. The identification of fracture-induced perivascular Prx1+ cells and regulation of Prx1's expression by BMP2 and in turn by CXCL12 in the orchestration of fracture repair, highlights a pathway in which to investigate defective mechanisms and therapeutic targets for fracture non-union.
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Affiliation(s)
- Alessandra Esposito
- Department of Orthopaedic Surgery, Section of Molecular Medicine, Rush University Medical Center, Chicago, IL, USA
| | - Lai Wang
- Department of Internal Medicine, Division of Rheumatology, Rush University Medical Center, Chicago, IL, USA
| | - Tieshi Li
- Department of Pediatrics, University of Nebraska Medical Center, Children's Hospital & Medical Center, Omaha, NE, USA
| | - Mariana Miranda
- Department of Orthopaedic Surgery, Section of Molecular Medicine, Rush University Medical Center, Chicago, IL, USA
| | - Anna Spagnoli
- Department of Orthopaedic Surgery, Section of Molecular Medicine, Rush University Medical Center, Chicago, IL, USA; Department of Pediatrics, Division of Pediatric Endocrinology, Rush University Medical Center, Chicago, IL, USA.
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32
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Rigoni M, Negro S. Signals Orchestrating Peripheral Nerve Repair. Cells 2020; 9:E1768. [PMID: 32722089 PMCID: PMC7464993 DOI: 10.3390/cells9081768] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/19/2020] [Accepted: 07/20/2020] [Indexed: 12/22/2022] Open
Abstract
The peripheral nervous system has retained through evolution the capacity to repair and regenerate after assault from a variety of physical, chemical, or biological pathogens. Regeneration relies on the intrinsic abilities of peripheral neurons and on a permissive environment, and it is driven by an intense interplay among neurons, the glia, muscles, the basal lamina, and the immune system. Indeed, extrinsic signals from the milieu of the injury site superimpose on genetic and epigenetic mechanisms to modulate cell intrinsic programs. Here, we will review the main intrinsic and extrinsic mechanisms allowing severed peripheral axons to re-grow, and discuss some alarm mediators and pro-regenerative molecules and pathways involved in the process, highlighting the role of Schwann cells as central hubs coordinating multiple signals. A particular focus will be provided on regeneration at the neuromuscular junction, an ideal model system whose manipulation can contribute to the identification of crucial mediators of nerve re-growth. A brief overview on regeneration at sensory terminals is also included.
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Affiliation(s)
- Michela Rigoni
- Department of Biomedical Sciences, University of Padua, 35131 Padua, Italy;
- Myology Center (Cir-Myo), University of Padua, 35129 Padua, Italy
| | - Samuele Negro
- Department of Biomedical Sciences, University of Padua, 35131 Padua, Italy;
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33
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Revisiting Cell Death Responses in Fibrotic Lung Disease: Crosstalk between Structured and Non-Structured Cells. Diagnostics (Basel) 2020; 10:diagnostics10070504. [PMID: 32708315 PMCID: PMC7400296 DOI: 10.3390/diagnostics10070504] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 07/16/2020] [Accepted: 07/20/2020] [Indexed: 02/06/2023] Open
Abstract
Fibrosis is a life-threatening disorder caused by excessive formation of connective tissue that can affect several critical organs. Innate immune cells are involved in the development of various disorders, including lung fibrosis. To date, several hematopoietic cell types have been implicated in fibrosis, including pro-fibrotic monocytes like fibrocytes and segregated-nucleus-containing atypical monocytes (SatMs), but the precise cellular and molecular mechanisms underlying its development remain unclear. Repetitive injury and subsequent cell death response are triggering events for lung fibrosis development. Crosstalk between lung structured and non-structured cells is known to regulate the key molecular event. We recently reported that RNA-binding motif protein 7 (RBM7) expression is highly upregulated in the fibrotic lung and plays fundamental roles in fibrosis development. RBM7 regulates nuclear degradation of NEAT1 non-coding RNA, resulting in sustained apoptosis in the lung epithelium and fibrosis. Apoptotic epithelial cells produce CXCL12, which leads to the recruitment of pro-fibrotic monocytes. Apoptosis is also the main source of autoantigens. Recent studies have revealed important functions for natural autoantibodies that react with specific sets of self-antigens and are unique to individual diseases. Here, we review recent insights into lung fibrosis development in association with crosstalk between structured cells like lung epithelial cells and non-structured cells like migrating immune cells, and discuss their relevance to acquired immunity through natural autoantibody production.
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34
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Xu H, Pumiglia K, LaFlamme SE. Laminin-511 and α6 integrins regulate the expression of CXCR4 to promote endothelial morphogenesis. J Cell Sci 2020; 133:jcs246595. [PMID: 32409567 DOI: 10.1242/jcs.246595] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 04/11/2020] [Indexed: 12/25/2022] Open
Abstract
During angiogenesis, endothelial cells engage components of the extracellular matrix through integrin-mediated adhesion. Endothelial expression of laminin-411 and laminin-511 is known to promote vessel stability. However, little is known about the contribution of these laminins to endothelial morphogenesis. We used two organotypic cell culture angiogenesis assays, in conjunction with RNAi approaches, to demonstrate that depletion of either the α4 chain of laminin-411 (LAMA4) or the α5 chain of laminin-511 (LAMA5) from endothelial cells inhibits sprouting and tube formation. Depletion of α6 (ITGA6) integrins resulted in similar phenotypes. Gene expression analysis indicated that loss of either laminin-511 or α6 integrins inhibited the expression of CXCR4, a gene previously associated with angiogenic endothelial cells. Pharmacological or RNAi-dependent inhibition of CXCR4 suppressed endothelial sprouting and morphogenesis. Importantly, expression of recombinant CXCR4 rescued endothelial morphogenesis when α6 integrin expression was inhibited. Additionally, the depletion of α6 integrins from established tubes resulted in the loss of tube integrity and laminin-511. Taken together, our results indicate that α6 integrins and laminin-511 can promote endothelial morphogenesis by regulating the expression of CXCR4 and suggest that the α6-dependent deposition of laminin-511 protects the integrity of established endothelial tubes.
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Affiliation(s)
- Hao Xu
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany NY 12208, USA
| | - Kevin Pumiglia
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany NY 12208, USA
| | - Susan E LaFlamme
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany NY 12208, USA
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35
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Ramakrishnan R, Peña-Martínez P, Agarwal P, Rodriguez-Zabala M, Chapellier M, Högberg C, Eriksson M, Yudovich D, Shah M, Ehinger M, Nilsson B, Larsson J, Hagström-Andersson A, Ebert BL, Bhatia R, Järås M. CXCR4 Signaling Has a CXCL12-Independent Essential Role in Murine MLL-AF9-Driven Acute Myeloid Leukemia. Cell Rep 2020; 31:107684. [PMID: 32460032 PMCID: PMC8109054 DOI: 10.1016/j.celrep.2020.107684] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 02/28/2020] [Accepted: 05/04/2020] [Indexed: 02/07/2023] Open
Abstract
Acute myeloid leukemia (AML) is defined by an accumulation of immature myeloid blasts in the bone marrow. To identify key dependencies of AML stem cells in vivo, here we use a CRISPR-Cas9 screen targeting cell surface genes in a syngeneic MLL-AF9 AML mouse model and show that CXCR4 is a top cell surface regulator of AML cell growth and survival. Deletion of Cxcr4 in AML cells eradicates leukemia cells in vivo without impairing their homing to the bone marrow. In contrast, the CXCR4 ligand CXCL12 is dispensable for leukemia development in recipient mice. Moreover, expression of mutated Cxcr4 variants reveals that CXCR4 signaling is essential for leukemia cells. Notably, loss of CXCR4 signaling in leukemia cells leads to oxidative stress and differentiation in vivo. Taken together, our results identify CXCR4 signaling as essential for AML stem cells by protecting them from differentiation independent of CXCL12 stimulation.
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Affiliation(s)
| | | | - Puneet Agarwal
- Division of Hematology & Oncology, University of Alabama Birmingham, Birmingham, AL 35233, USA
| | | | | | - Carl Högberg
- Division of Clinical Genetics, Lund University, Lund 22184, Sweden
| | - Mia Eriksson
- Division of Clinical Genetics, Lund University, Lund 22184, Sweden
| | - David Yudovich
- Division of Molecular Medicine and Gene Therapy, Lund University, Lund 22184, Sweden
| | - Mansi Shah
- Division of Hematology & Oncology, University of Alabama Birmingham, Birmingham, AL 35233, USA
| | - Mats Ehinger
- Division of Pathology, Department of Clinical Sciences, Skåne University Hospital, Lund University, Lund 22184, Sweden
| | - Björn Nilsson
- Division of Hematology and Transfusion Medicine, Lund University, Lund 22184, Sweden
| | - Jonas Larsson
- Division of Molecular Medicine and Gene Therapy, Lund University, Lund 22184, Sweden
| | | | - Benjamin L Ebert
- Division of Hematology, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Ravi Bhatia
- Division of Hematology & Oncology, University of Alabama Birmingham, Birmingham, AL 35233, USA
| | - Marcus Järås
- Division of Clinical Genetics, Lund University, Lund 22184, Sweden.
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36
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Mizuno S, Yoda M, Kimura T, Shimoda M, Akiyama H, Chiba K, Nakamura M, Horiuchi K. ADAM10 is indispensable for longitudinal bone growth in mice. Bone 2020; 134:115273. [PMID: 32062003 DOI: 10.1016/j.bone.2020.115273] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 02/07/2020] [Accepted: 02/12/2020] [Indexed: 12/12/2022]
Abstract
Skeletal development is a highly sophisticated process in which the expression of a variety of growth factors, signaling molecules, and extracellular matrix proteins is spatially and temporally orchestrated. In the present study, we show that ADAM10, a transmembrane protease that is critically involved in the functional regulation of various membrane-bound molecules, plays an essential role in the longitudinal growth of long bones and in skeletal development. We found that mutant mice lacking ADAM10 in osteochondroprogenitors exhibited marked growth retardation and had shorter long bones than the control mice. Histomorphometric analysis revealed that the mutant mice had a shorter hypertrophic zone and that their hypertrophic chondrocytes were smaller in size than those of the control mice. Unexpectedly, we found that the mRNA expression of the chemokine CXCL12 and its receptor CXCR4 were significantly reduced in cartilage tissues lacking ADAM10. Further, exogenous supplementation of recombinant CXCL12 rescued the defect in the ADAM10-deficient growth plate in an ex vivo culture model. Taken together, our data show a previously unknown role for ADAM10 in skeletal development that involves its regulation of the CXCL12 and CXCR4 signaling pathway.
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Affiliation(s)
- Sakiko Mizuno
- Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Orthopedics, Tokyo Dental College Ichikawa General Hospital, 5-11-13 Sugano, Ichikawa City, Chiba 272-8513, Japan.
| | - Masaki Yoda
- Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Tokuhiro Kimura
- Department of Diagnostic Pathology, Saiseikai Yokohama Tobu Hospital, 3-6-1 Shimosueyoshi, Tsurumi Ward, Yokohama, Kanagawa 230-8765, Japan
| | - Masayuki Shimoda
- Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Haruhiko Akiyama
- Department of Orthopaedic Surgery, Gifu University School of Medicine, 1-1 Yanagido, Gifu, Gifu 501-1194, Japan
| | - Kazuhiro Chiba
- Department of Orthopedic Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan
| | - Masaya Nakamura
- Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Keisuke Horiuchi
- Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Orthopedic Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
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37
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Herhaus P, Lipkova J, Lammer F, Yakushev I, Vag T, Slotta-Huspenina J, Habringer S, Lapa C, Pukrop T, Hellwig D, Wiestler B, Buck AK, Deckert M, Wester HJ, Bassermann F, Schwaiger M, Weber W, Menze B, Keller U. CXCR4-Targeted PET Imaging of Central Nervous System B-Cell Lymphoma. J Nucl Med 2020; 61:1765-1771. [PMID: 32332145 DOI: 10.2967/jnumed.120.241703] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Accepted: 03/19/2020] [Indexed: 12/21/2022] Open
Abstract
C-X-C chemokine receptor 4 (CXCR4) is a transmembrane chemokine receptor involved in growth, survival, and dissemination of cancer, including aggressive B-cell lymphoma. MRI is the standard imaging technology for central nervous system (CNS) involvement of B-cell lymphoma and provides high sensitivity but moderate specificity. Therefore, novel molecular and functional imaging strategies are urgently required. Methods: In this proof-of-concept study, 11 patients with lymphoma of the CNS (8 primary and 3 secondary involvement) were imaged with the CXCR4-directed PET tracer 68Ga-pentixafor. To evaluate the predictive value of this imaging modality, treatment response, as determined by MRI, was correlated with quantification of CXCR4 expression by 68Ga-pentixafor PET in vivo before initiation of treatment in 7 of 11 patients. Results: 68Ga-pentixafor PET showed excellent contrast with the surrounding brain parenchyma in all patients with active disease. Furthermore, initial CXCR4 uptake determined by PET correlated with subsequent treatment response as assessed by MRI. Conclusion: 68Ga-pentixafor PET represents a novel diagnostic tool for CNS lymphoma with potential implications for theranostic approaches as well as response and risk assessment.
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Affiliation(s)
- Peter Herhaus
- Internal Medicine III, School of Medicine, Technische Universität München, Munich, Germany
| | - Jana Lipkova
- Department of Neuroradiology, School of Medicine, Technische Universität München, Munich, Germany
| | - Felicitas Lammer
- Department of Hematology, Oncology, and Tumor Immunology (Campus Benjamin Franklin), Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Igor Yakushev
- Department of Nuclear Medicine, School of Medicine, Technische Universität München, Munich, Germany
| | - Tibor Vag
- Department of Nuclear Medicine, School of Medicine, Technische Universität München, Munich, Germany
| | | | - Stefan Habringer
- Department of Hematology, Oncology, and Tumor Immunology (Campus Benjamin Franklin), Charité-Universitätsmedizin Berlin, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany
| | - Constantin Lapa
- Department of Nuclear Medicine, Universitätsklinikum Würzburg, Würzburg, Germany.,Department of Nuclear Medicine, University Hospital Augsburg, Augsburg, Germany
| | - Tobias Pukrop
- Internal Medicine III, Universitätsklinikum Regensburg, Regensburg, Germany
| | - Dirk Hellwig
- Department of Nuclear Medicine, Universitätsklinikum Regensburg, Regensburg, Germany
| | - Benedikt Wiestler
- Department of Neuroradiology, School of Medicine, Technische Universität München, Munich, Germany
| | - Andreas K Buck
- Department of Nuclear Medicine, Universitätsklinikum Würzburg, Würzburg, Germany
| | - Martina Deckert
- Insitute of Neuropathology, Faculty of Medicine, University of Cologne, and University Hospital Cologne, Cologne, Germany
| | - Hans-Jürgen Wester
- Institute of Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany
| | - Florian Bassermann
- Internal Medicine III, School of Medicine, Technische Universität München, Munich, Germany
| | - Markus Schwaiger
- Department of Nuclear Medicine, School of Medicine, Technische Universität München, Munich, Germany
| | - Wolfgang Weber
- Department of Neuroradiology, School of Medicine, Technische Universität München, Munich, Germany
| | - Björn Menze
- Informatics Department, Technische Universität München, Munich, Germany
| | - Ulrich Keller
- Internal Medicine III, School of Medicine, Technische Universität München, Munich, Germany .,Department of Hematology, Oncology, and Tumor Immunology (Campus Benjamin Franklin), Charité-Universitätsmedizin Berlin, Berlin, Germany.,Max Delbrück Center for Molecular Medicine, Berlin, Germany; and.,German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany
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Zhang J, Quan LN, Meng Q, Wang HY, Wang J, Yu P, Fu JT, Li YJ, Chen J, Cheng H, Wu QP, Yu XR, Yun HY, Huang SG. miR-548e Sponged by ZFAS1 Regulates Metastasis and Cisplatin Resistance of OC by Targeting CXCR4 and let-7a/BCL-XL/S Signaling Axis. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 20:621-638. [PMID: 32353736 PMCID: PMC7191130 DOI: 10.1016/j.omtn.2020.03.013] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 03/17/2020] [Accepted: 03/27/2020] [Indexed: 12/23/2022]
Abstract
Ovarian cancer (OC) is a severe malignancy featuring a poor prognosis due to rapid metastasis and chemotherapy resistance. In this study, we extensively investigated the upstream and downstream mechanisms of miR-548e in regulating OC progression and cisplatin resistance. Our results indicated that ZFAS1 was highly expressed and promoted OC cell proliferation, migration, invasion, and cisplatin resistance by directly suppressing miR-548e expression. ZFAS1 co-localized with miR-548e in the cytosols of OC cells. miR-548e repressed CXCR4 expression, and elevated CXCR4 expression promoted OC cell proliferation, migration, invasion, and cisplatin resistance. Cisplatin resistance induced by ZFAS1 and CXCR4 overexpression in OC cells was mediated by their suppression on let-7a and elevation of BCL-XL/S expression. ZFAS1 knockdown and miR-548e and let-7a overexpression impaired cisplatin resistance and suppressed lung metastatic nodule formation in nude mice. In conclusion, ZFAS1 binds with miR-548e to enhance CXCR4 expression to promote OC cell proliferation and metastasis, which also enhances cisplatin resistance by suppressing let-7a and elevating BCL-XL/S protein expression.
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Affiliation(s)
- Jing Zhang
- Department of Obstetrics and Gynecology, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, No. 43 Renmin Road, Haidian Island, Haikou 570208, Hainan Province, P.R. China
| | - Li-Ni Quan
- Department of Obstetrics and Gynecology, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, No. 43 Renmin Road, Haidian Island, Haikou 570208, Hainan Province, P.R. China
| | - Qiu Meng
- Department of Obstetrics and Gynecology, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, No. 43 Renmin Road, Haidian Island, Haikou 570208, Hainan Province, P.R. China
| | - Hai-Yan Wang
- Department of Obstetrics and Gynecology, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, No. 43 Renmin Road, Haidian Island, Haikou 570208, Hainan Province, P.R. China
| | - Jie Wang
- Department of Obstetrics and Gynecology, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, No. 43 Renmin Road, Haidian Island, Haikou 570208, Hainan Province, P.R. China
| | - Pin Yu
- Department of Obstetrics and Gynecology, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, No. 43 Renmin Road, Haidian Island, Haikou 570208, Hainan Province, P.R. China
| | - Jian-Tao Fu
- Department of Obstetrics and Gynecology, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, No. 43 Renmin Road, Haidian Island, Haikou 570208, Hainan Province, P.R. China
| | - Ying-Jia Li
- Clinical Laboratory, Third Xiangya Hospital of Central South University, No. 138 Tong Zipo Road, Changsha 410013, Hunan Province, P.R. China
| | - Jin Chen
- Department of Obstetrics and Gynecology, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, No. 43 Renmin Road, Haidian Island, Haikou 570208, Hainan Province, P.R. China
| | - Hong Cheng
- Department of Obstetrics and Gynecology, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, No. 43 Renmin Road, Haidian Island, Haikou 570208, Hainan Province, P.R. China
| | - Qing-Ping Wu
- Department of Obstetrics and Gynecology, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, No. 43 Renmin Road, Haidian Island, Haikou 570208, Hainan Province, P.R. China
| | - Xin-Rong Yu
- Department of Obstetrics and Gynecology, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, No. 43 Renmin Road, Haidian Island, Haikou 570208, Hainan Province, P.R. China
| | - Hong-Ye Yun
- Department of Obstetrics and Gynecology, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, No. 43 Renmin Road, Haidian Island, Haikou 570208, Hainan Province, P.R. China
| | - Shou-Guo Huang
- Department of Obstetrics and Gynecology, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, No. 43 Renmin Road, Haidian Island, Haikou 570208, Hainan Province, P.R. China.
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Singh P, Mohammad KS, Pelus LM. CXCR4 expression in the bone marrow microenvironment is required for hematopoietic stem and progenitor cell maintenance and early hematopoietic regeneration after myeloablation. Stem Cells 2020; 38:849-859. [PMID: 32159901 DOI: 10.1002/stem.3174] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 02/14/2020] [Accepted: 02/28/2020] [Indexed: 11/10/2022]
Abstract
The bone marrow (BM) microenvironment/niche plays a key role in regulating hematopoietic stem and progenitor cell (HSPC) activities; however, mechanisms regulating niche cell function are not well understood. In this study, we show that niche intrinsic expression of the CXCR4 chemokine receptor critically regulates HSPC maintenance during steady state, and promotes early hematopoietic regeneration after myeloablative irradiation. At steady state, chimeric mice with wild-type (WT) HSPC and marrow stroma that lack CXCR4 show decreased HSPC quiescence, and their repopulation capacity was markedly reduced. Mesenchymal stromal cells (MSC) were significantly reduced in the BM of CXCR4 deficient mice, which was accompanied by decreased levels of the HSPC supporting factors stromal cell-derived factor-1 (SDF-1) and stem cell factor (SCF). CXCR4 also plays a crucial role in survival and restoration of BM stromal cells after myeloablative irradiation, where the loss of BM stromal cells was more severe in CXCR4-deficient mice compared to WT mice. In addition, transplantation of WT donor HSPC into CXCR4-deficient recipient mice demonstrated reduced HSPC homing and early hematopoietic reconstitution. We found that CXCR4 signaling attenuates irradiation-induced BM stromal cell loss by upregulating the expression of the antiapoptotic protein Survivin via the PI3K pathway. Our study suggests that SDF-1-CXCR4 signaling in the stromal microenvironment cells plays a crucial role in maintenance of HSPCs during homeostasis, and promotes niche regeneration and early hematopoietic reconstitution after transplantation. Modulation of CXCR4 signaling in the HSPC microenvironment could be a means to enhance hematopoietic recovery after clinical hematopoietic cell transplantation.
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Affiliation(s)
- Pratibha Singh
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.,Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Khalid S Mohammad
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Louis M Pelus
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.,Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
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40
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Orozco-Solis R, Aguilar-Arnal L. Circadian Regulation of Immunity Through Epigenetic Mechanisms. Front Cell Infect Microbiol 2020; 10:96. [PMID: 32232012 PMCID: PMC7082642 DOI: 10.3389/fcimb.2020.00096] [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: 01/09/2020] [Accepted: 02/25/2020] [Indexed: 12/12/2022] Open
Abstract
The circadian clock orchestrates daily rhythms in many physiological, behavioral and molecular processes, providing means to anticipate, and adapt to environmental changes. A specific role of the circadian clock is to coordinate functions of the immune system both at steady-state and in response to infectious threats. Hence, time-of-day dependent variables are found in the physiology of immune cells, host-parasite interactions, inflammatory processes, or adaptive immune responses. Interestingly, the molecular clock coordinates transcriptional-translational feedback loops which orchestrate daily oscillations in expression of many genes involved in cellular functions. This clock function is assisted by tightly controlled transitions in the chromatin fiber involving epigenetic mechanisms which determine how a when transcriptional oscillations occur. Immune cells are no exception, as they also present a functional clock dictating transcriptional rhythms. Hereby, the molecular clock and the chromatin regulators controlling rhythmicity represent a unique scaffold mediating the crosstalk between the circadian and the immune systems. Certain epigenetic regulators are shared between both systems and uncovering them and characterizing their dynamics can provide clues to design effective chronotherapeutic strategies for modulation of the immune system.
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Affiliation(s)
- Ricardo Orozco-Solis
- Laboratorio de Cronobiología y Metabolismo, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - Lorena Aguilar-Arnal
- Departamento de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
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Werner Y, Mass E, Ashok Kumar P, Ulas T, Händler K, Horne A, Klee K, Lupp A, Schütz D, Saaber F, Redecker C, Schultze JL, Geissmann F, Stumm R. Cxcr4 distinguishes HSC-derived monocytes from microglia and reveals monocyte immune responses to experimental stroke. Nat Neurosci 2020; 23:351-362. [PMID: 32042176 PMCID: PMC7523735 DOI: 10.1038/s41593-020-0585-y] [Citation(s) in RCA: 124] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Accepted: 01/02/2020] [Indexed: 12/26/2022]
Abstract
Monocyte-derived and tissue-resident macrophages are ontogenetically distinct components of the innate immune system. Assessment of their respective functions in pathology is complicated by changes to the macrophage phenotype during inflammation. Here we find that Cxcr4-CreER enables permanent genetic labeling of hematopoietic stem cells (HSCs) and distinguishes HSC-derived monocytes from microglia and other tissue-resident macrophages. By combining Cxcr4-CreER-mediated lineage tracing with Cxcr4 inhibition or conditional Cxcr4 ablation in photothrombotic stroke, we find that Cxcr4 promotes initial monocyte infiltration and subsequent territorial restriction of monocyte-derived macrophages to infarct tissue. After transient focal ischemia, Cxcr4 deficiency reduces monocyte infiltration and blunts the expression of pattern recognition and defense response genes in monocyte-derived macrophages. This is associated with an altered microglial response and deteriorated outcomes. Thus, Cxcr4 is essential for an innate-immune-system-mediated defense response after cerebral ischemia. We further propose Cxcr4-CreER as a universal tool to study functions of HSC-derived cells.
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Affiliation(s)
- Yves Werner
- Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany
| | - Elvira Mass
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Developmental Biology of the Immune System, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
| | - Praveen Ashok Kumar
- Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany
| | - Thomas Ulas
- Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany
- PRECISE Platform for Single Cell Genomics and Epigenomics, German Center for Neurodegenerative Diseases and University of Bonn, Bonn, Germany
| | - Kristian Händler
- Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany
- PRECISE Platform for Single Cell Genomics and Epigenomics, German Center for Neurodegenerative Diseases and University of Bonn, Bonn, Germany
| | - Arik Horne
- Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany
| | - Kathrin Klee
- Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany
| | - Amelie Lupp
- Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany
| | - Dagmar Schütz
- Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany
| | - Friederike Saaber
- Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany
| | | | - Joachim L Schultze
- Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany
- PRECISE Platform for Single Cell Genomics and Epigenomics, German Center for Neurodegenerative Diseases and University of Bonn, Bonn, Germany
| | - Frederic Geissmann
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| | - Ralf Stumm
- Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany.
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Kim H, Sung J, Kim H, Ryu H, Cho Park H, Oh YK, Lee HS, Oh KH, Ahn C. Expression and secretion of CXCL12 are enhanced in autosomal dominant polycystic kidney disease. BMB Rep 2020. [PMID: 31186083 PMCID: PMC6675246 DOI: 10.5483/bmbrep.2019.52.7.112] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Autosomal dominant polycystic kidney disease (ADPKD), one of the most common human monogenic diseases (frequency of 1/1000-1/400), is characterized by numerous fluid-filled renal cysts (RCs). Inactivation of the PKD1 or PKD2 gene by germline and somatic mutations is necessary for cyst formation in ADPKD. To mechanistically understand cyst formation and growth, we isolated RCs from Korean patients with ADPKD and immortalized them with human telomerase reverse transcriptase (hTERT). Three hTERT-immortalized RC cell lines were characterized as proximal epithelial cells with germline and somatic PKD1 mutations. Thus, we first established hTERT-immortalized proximal cyst cells with somatic PKD1 mutations. Through transcriptome sequencing and Gene Ontology (GO) analysis, we found that upregulated genes were related to cell division and that downregulated genes were related to cell differentiation. We wondered whether the upregulated gene for the chemokine CXCL12 is related to the mTOR signaling pathway in cyst growth in ADPKD. CXCL12 mRNA expression and secretion were increased in RC cell lines. We then examined CXCL12 levels in RC fluids from patients with ADPKD and found increased CXCL12 levels. The CXCL12 receptor CXC chemokine receptor 4 (CXCR4) was upregulated, and the mTOR signaling pathway, which is downstream of the CXCL12/CXCR4 axis, was activated in ADPKD kidney tissue. To confirm activation of the mTOR signaling pathway by CXCL12 via CXCR4, we treated the RC cell lines with recombinant CXCL12 and the CXCR4 antagonist AMD3100; CXCL12 induced the mTOR signaling pathway, but the CXCR4 antagonist AMD3100 blocked the mTOR signaling pathway. Taken together, these results suggest that enhanced CXCL12 in RC fluids activates the mTOR signaling pathway via CXCR4 in ADPKD cyst growth.
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Affiliation(s)
- Hyunho Kim
- Center for Medical Innovation, Biomedical Research Institute, Seoul National University Hospital, Seoul 03082, Korea
| | - Jinmo Sung
- Center for Medical Innovation, Biomedical Research Institute, Seoul National University Hospital, Seoul 03082, Korea
| | - Hyunsuk Kim
- Internal Medicine, Hallym University Medical Center, Chuncheon Sacred Heart Hospital, Chuncheon 24253, Korea
| | - Hyunjin Ryu
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Hayne Cho Park
- Department of Internal Medicine, Hallym University Medical Center, Kangnam Sacred Heart Hospital, Seoul 07441, Korea
| | - Yun Kyu Oh
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul 07061, Korea
| | - Hyun-Seob Lee
- Genomics Core Facility, Department of Transdisciplinary Research and Collaboration, Biomedical Research Institute, Seoul National University Hospital, Seoul 03082, Korea
| | - Kook-Hwan Oh
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Curie Ahn
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Korea
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Lu W, He Z, Shi J, Wang Z, Wu W, Liu J, Kang H, Li F, Liang S. AMD3100 Attenuates Post-Traumatic Osteoarthritis by Maintaining Transforming Growth Factor-β1-Induced Expression of Tissue Inhibitor of Metalloproteinase-3 via the Phosphatidylinositol 3-Kinase/Akt Pathway. Front Pharmacol 2020; 10:1554. [PMID: 32038242 PMCID: PMC6987846 DOI: 10.3389/fphar.2019.01554] [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: 09/03/2019] [Accepted: 12/02/2019] [Indexed: 12/20/2022] Open
Abstract
AMD3100 is a small-molecule inhibitor of the C-X-C motif chemokine ligand 12/C-X-C chemokine receptor type 4 (CXCL12/CXCR4) axis, while its role in aggrecan metabolism is unclear. We hypothesized that the AMD3100 modulates the transforming growth factor-β1 (TGF-β1)-induced expression of tissue inhibitor of metalloproteinase-3 (TIMP-3) in chondrocytes. We evaluated expression of CXCL12/CXCR4 and TIMP-3 in the knee joints of rats with and without osteoarthritis (OA) by immunohistochemistry, immunofluorescence, Western blotting, and enzyme-linked immunosorbent assay (ELISA). The rats were divided into sham control, destabilization of the medial meniscus/AMD3100-treated (DMM/AMD3100-treated), and DMM/phosphate-buffered saline (PBS)-treated groups. After 6 weeks, the rats were euthanized and subjected to histological and immunohistochemical analyses. Also, interleukin (IL)-1-pretreated primary chondrocytes were cultured in the presence of empty control (−, −), CXCL12a (+,−), CXCL12a + small interfering RNA (siRNA) CXCR4 (+,+), or CXCL12a + siNC (+NC), and the expression levels of target markers were evaluated by Western blotting and real-time reverse transcription PCR (RT-PCR). The CXCL12/CXCR4 levels were higher, and the expression of TIMP-3 was lower, in the OA rats compared to the healthy control rats. The rats in the DMM/AMD3100-treated group revealed a markedly decreased immunological response and mild pathology. Treatment with CXCL12a increased expression of aggrecan and disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5) and suppressed that of TIMP-3 in IL-1-pretreated primary chondrocytes. TGF-β1 increased expression of TIMP-3, and this increase was reversed by CXCL12a via the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Moreover, these effects were inhibited by the CXCR4 antagonist AMD3100 and the PI3K inhibitor LY303511. In conclusion, inhibition of the CXCL12a/CXCR4 signaling axis maintained TIMP-3 expression via the PI3K/Akt pathway. Our findings provide insight into the mechanism by which AMD3100 prevents OA.
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Affiliation(s)
- Weiwei Lu
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhiyi He
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Shi
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhenggang Wang
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Wu
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian Liu
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hao Kang
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Li
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuang Liang
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Miao M, De Clercq E, Li G. Clinical significance of chemokine receptor antagonists. Expert Opin Drug Metab Toxicol 2020; 16:11-30. [PMID: 31903790 DOI: 10.1080/17425255.2020.1711884] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Introduction: Chemokine receptors are important therapeutic targets for the treatment of many human diseases. This study will provide an overview of approved chemokine receptor antagonists and promising candidates in advanced clinical trials.Areas covered: We will describe clinical aspects of chemokine receptor antagonists regarding their clinical efficacy, mechanisms of action, and re-purposed applications.Expert opinion: Three chemokine antagonists have been approved: (i) plerixafor is a small-molecule CXCR4 antagonist that mobilizes hematopoietic stem cells; (ii) maraviroc is a small-molecule CCR5 antagonist for anti-HIV treatment; and (iii) mogamulizumab is a monoclonal-antibody CCR4 antagonist for the treatment of mycosis fungoides or Sézary syndrome. Moreover, phase 3 trials are ongoing to evaluate many potent candidates, including CCR5 antagonists (e.g. leronlimab), dual CCR2/CCR5 antagonists (e.g. cenicriviroc), and CXCR4 antagonists (e.g. balixafortide, mavorixafor, motixafortide). The success of chemokine receptor antagonists depends on the selective blockage of disease-relevant chemokine receptors which are indispensable for disease progression. Although clinical translation has been slow, antagonists targeting chemokine receptors with multifaced functions offer the potential to treat a broad spectrum of human diseases.
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Affiliation(s)
- Miao Miao
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Hunan, China
| | - Erik De Clercq
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Leuven, Belgium
| | - Guangdi Li
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Hunan, China
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Camilletti MA, Martinez Mayer J, Vishnopolska SA, Perez-Millan MI. From Pituitary Stem Cell Differentiation to Regenerative Medicine. Front Endocrinol (Lausanne) 2020; 11:614999. [PMID: 33542708 PMCID: PMC7851048 DOI: 10.3389/fendo.2020.614999] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 12/01/2020] [Indexed: 11/18/2022] Open
Abstract
The anterior pituitary gland is comprised of specialized cell-types that produce and secrete polypeptide hormones in response to hypothalamic input and feedback from target organs. These specialized cells arise during embryonic development, from stem cells that express SOX2 and the pituitary transcription factor PROP1, which is necessary to establish the stem cell pool and promote an epithelial to mesenchymal-like transition, releasing progenitors from the niche. Human and mouse embryonic stem cells can differentiate into all major hormone-producing cell types of the anterior lobe in a highly plastic and dynamic manner. More recently human induced pluripotent stem cells (iPSCs) emerged as a viable alternative due to their plasticity and high proliferative capacity. This mini-review gives an overview of the major advances that have been achieved to develop protocols to generate pituitary hormone-producing cell types from stem cells and how these mechanisms are regulated. We also discuss their application in pituitary diseases, such as pituitary hormone deficiencies.
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Andersson KE, Fry C, Panicker J, Rademakers K. Which molecular targets do we need to focus on to improve lower urinary tract dysfunction? ICI-RS 2017. Neurourol Urodyn 2019; 37:S117-S126. [PMID: 30133792 DOI: 10.1002/nau.23516] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Accepted: 12/26/2017] [Indexed: 12/18/2022]
Abstract
AIMS Update on some molecular targets for new drugs to improve lower urinary tract (LUT) dysfunction. METHODS Using PubMed, a search for literature on molecular targets in the LUT was performed to identify relevant clinical and animal studies. Keywords were entered as Medical Subject Headings (MeSH) or as text words. The Mesh terms were used in various combinations and usually included the terms lower urinary AND pharmacology. Other Mesh term included: bladder, urethra, CNS, physiology, afferent activity, ATP, prostanoids, cannabinoids, fibrosis. Search results were assessed for their overall relevance to this review. RESULTS In a normal bladder, ATP contributes little to detrusor contraction, but in a diseased bladder ATP may contribute to OAB. Selective decrease of ATP release via adenosine A1 receptor stimulation offers a potential treatment possibility. Candidates for relaxation of the smooth muscle of the urethra can be found among, for example, the receptor subtypes of PGE2 , and PGD2 . Drugs for relaxation of the striated sphincter can target the muscle directly or the spinal sphincter control. Fibrosis is a major problem in LUT dysfunction and agents with an inhibitory effect on the TGFβ pathway, for example relaxin and BMP7, may be promising avenues. Available drugs with a CNS site of action are often limited by low efficacy or adverse effects. Inhibitors of the glycine receptor Gly-T2 or antagonists of the adenosine A2 receptor may be new alternatives. CONCLUSION New molecular targets for drugs aiming at improvement of voiding function can be identified, but their translational impact remains to be established.
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Affiliation(s)
- Karl-Erik Andersson
- Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston Salem NC, and Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Christopher Fry
- Department of Uro-Neurology, The National Hospital for Neurology and Neurosurgery and UCL Institute of Neurology, London, United Kingdom
| | - Jalesh Panicker
- Department of urology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Kevin Rademakers
- Department of urology, Maastricht University Medical Center, Maastricht, The Netherlands
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Zanetti G, Negro S, Megighian A, Mattarei A, Lista F, Fillo S, Rigoni M, Pirazzini M, Montecucco C. A CXCR4 receptor agonist strongly stimulates axonal regeneration after damage. Ann Clin Transl Neurol 2019; 6:2395-2402. [PMID: 31725979 PMCID: PMC6917312 DOI: 10.1002/acn3.50926] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 09/30/2019] [Accepted: 10/02/2019] [Indexed: 12/21/2022] Open
Abstract
Objective To test whether the signaling axis CXCL12α‐CXCR4 is activated upon crush/cut of the sciatic nerve and to test the activity of NUCC‐390, a new CXCR4 agonist, in promoting nerve recovery from damage. Methods The sciatic nerve was either crushed or cut. Expression and localization of CXCL12α and CXCR4 were evaluated by imaging with specific antibodies. Their functional involvement in nerve regeneration was determined by antibody‐neutralization of CXCL12α, and by the CXCR4 specific antagonist AMD3100, using as quantitative read‐out the compound muscle action potential (CMAP). NUCC‐390 activity on nerve regeneration was determined by imaging and CMAP recordings. Results CXCR4 is expressed at the injury site within the axonal compartment, whilst its ligand CXCL12α is expressed in Schwann cells. The CXCL12α‐CXCR4 axis is involved in the recovery of neurotransmission of the injured nerve. More importantly, the small molecule NUCC‐390 is a strong promoter of the functional and anatomical recovery of the nerve, by acting very similarly to CXCL12α. This pharmacological action is due to the capability of NUCC‐390 to foster elongation of motor neuron axons both in vitro and in vivo. Interpretation Imaging and electrophysiological data provide novel and compelling evidence that the CXCL12α‐CXCR4 axis is involved in sciatic nerve repair after crush/cut. This makes NUCC‐390 a strong candidate molecule to stimulate nerve repair by promoting axonal elongation. We propose this molecule to be tested in other models of neuronal damage, to lay the basis for clinical trials on the efficacy of NUCC‐390 in peripheral nerve repair in humans.
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Affiliation(s)
- Giulia Zanetti
- Department of Biomedical Sciences, University of Padua, Padua, Italy
| | - Samuele Negro
- Department of Biomedical Sciences, University of Padua, Padua, Italy
| | - Aram Megighian
- Department of Biomedical Sciences, University of Padua, Padua, Italy.,Padua Neuroscience Center, University of Padua, Padua, Italy
| | - Andrea Mattarei
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy
| | | | - Silvia Fillo
- Scientific Department, Army Medical Center, Roma, Italy
| | - Michela Rigoni
- Department of Biomedical Sciences, University of Padua, Padua, Italy
| | - Marco Pirazzini
- Department of Biomedical Sciences, University of Padua, Padua, Italy
| | - Cesare Montecucco
- Department of Biomedical Sciences, University of Padua, Padua, Italy.,CNR Institute of Neuroscience, Padua, Italy
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48
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Gilbert W, Bragg R, Elmansi AM, McGee-Lawrence ME, Isales CM, Hamrick MW, Hill WD, Fulzele S. Stromal cell-derived factor-1 (CXCL12) and its role in bone and muscle biology. Cytokine 2019; 123:154783. [PMID: 31336263 PMCID: PMC6948927 DOI: 10.1016/j.cyto.2019.154783] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 07/08/2019] [Accepted: 07/16/2019] [Indexed: 02/07/2023]
Abstract
Musculoskeletal disorders are the leading cause of disability worldwide; two of the most prevalent of which are osteoporosis and sarcopenia. Each affect millions in the aging population across the world and the associated morbidity and mortality contributes to billions of dollars in annual healthcare cost. Thus, it is important to better understand the underlying pathologic mechanisms of the disease process. Regulatory chemokine, CXCL12, and its receptor, CXCR4, are recognized to be essential in the recruitment, localization, maintenance, development and differentiation of progenitor stem cells of the musculoskeletal system. CXCL12 signaling results in the development and functional ability of osteoblasts, osteoclasts, satellite cells and myoblasts critical to maintaining musculoskeletal homeostasis. Interestingly, one suggested pathologic mechanism of osteoporosis and sarcopenia is a decline in the regenerative capacity of musculoskeletal progenitor stem cells. Thus, because CXCL12 is critical to progenitor function, a disruption in the CXCL12 signaling axis might play a distinct role in these pathological processes. Therefore, in this article, we perform a review of CXCL12, its physiologic and pathologic function in bone and muscle, and potential targets for therapeutic development.
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Affiliation(s)
- William Gilbert
- Department of Orthopaedic Surgery, Augusta University, Augusta, GA 30912, United States
| | - Robert Bragg
- Department of Orthopaedic Surgery, Augusta University, Augusta, GA 30912, United States
| | - Ahmed M Elmansi
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29403, United States
| | - Meghan E McGee-Lawrence
- Department of Orthopaedic Surgery, Augusta University, Augusta, GA 30912, United States; Cell Biology and Anatomy, Augusta University, Augusta, GA 30912, United States
| | - Carlos M Isales
- Department of Orthopaedic Surgery, Augusta University, Augusta, GA 30912, United States; Department of Medicine, Augusta University, Augusta, GA 30912, United States
| | - Mark W Hamrick
- Department of Orthopaedic Surgery, Augusta University, Augusta, GA 30912, United States; Cell Biology and Anatomy, Augusta University, Augusta, GA 30912, United States
| | - William D Hill
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29403, United States; Ralph H Johnson Veterans Affairs Medical Center, Charleston, SC 29403, United States
| | - Sadanand Fulzele
- Department of Orthopaedic Surgery, Augusta University, Augusta, GA 30912, United States; Cell Biology and Anatomy, Augusta University, Augusta, GA 30912, United States.
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49
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Yang XW, Huang HX, Wang F, Zhou QL, Huang YQ, Qin RZ. Elevated plasma CXCL12/SDF-1 levels are linked with disease severity of postmenopausal osteoporosis. Innate Immun 2019; 26:222-230. [PMID: 31640442 PMCID: PMC7144032 DOI: 10.1177/1753425919883365] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
This study was designed to determine whether plasma CXCL12 levels in postmenopausal osteoporosis (PMOP) patients are related to disease severity. A total of 91 PMOP females were recruited, and 88 postmenopausal non-osteoporotic (PMNOP) women and 90 healthy females were incorporated as controls. Dual-energy X-ray absorptiometry was utilised to explore bone-mineral density (BMD). The Genant semi-quantitative grading scale was used for vertebral fractures, and plasma CXCL12/SDF-1 levels were investigated by ELISA. Plasma TNF-α and C-telopeptide cross-linked collagen type 1 (CTX-1) were also tested. The Oswestry Disability Index (ODI) and a visual analogue scale (VAS) were completed in order to assess clinical severity. Plasma CXCL12 levels were considerably elevated in PMOP females compared to PMNOP women and healthy controls. Plasma CXCL12 concentrations were positively correlated with the Genant grading system. We observed significant and negative correlations of plasma CXCL12 levels with lumbar spine, femoral neck and total hip BMD. Moreover, plasma CXCL12 concentrations were positively correlated to VAS and ODI, as well as plasma TNF-α and CTX-1 levels. In conclusion, elevated plasma CXCL12 levels are correlated with disease severity in PMOP females.
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Affiliation(s)
- Xian-Wen Yang
- Guangdong Provincial Corps Hospital of Chinese People's Armed Police Forces, Guangzhou Medical University, PR China.,The Third Affiliated Hospital of GuangZhou University of Chinese Medicine, PR China
| | - Hong-Xing Huang
- The Third Affiliated Hospital of GuangZhou University of Chinese Medicine, PR China
| | - Fei Wang
- Air Force General Hospital, PR China
| | - Qi-Lin Zhou
- Guangdong Provincial Corps Hospital of Chinese People's Armed Police Forces, Guangzhou Medical University, PR China
| | - Yan-Qiang Huang
- Guangdong Provincial Corps Hospital of Chinese People's Armed Police Forces, Guangzhou Medical University, PR China
| | - Ru-Zi Qin
- Guangdong Provincial Corps Hospital of Chinese People's Armed Police Forces, Guangzhou Medical University, PR China
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50
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miR-140-5p regulates T cell differentiation and attenuates experimental autoimmune encephalomyelitis by affecting CD4+T cell metabolism and DNA methylation. Int Immunopharmacol 2019; 75:105778. [DOI: 10.1016/j.intimp.2019.105778] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 06/30/2019] [Accepted: 07/23/2019] [Indexed: 12/18/2022]
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