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Huang XQ, Wu L, Xue CY, Rao CY, Fang QQ, Chen Y, Xie C, Rao SX, Chen SY, Li F. Non-invasively differentiate non-alcoholic steatohepatitis by visualizing hepatic integrin αvβ3 expression with a targeted molecular imaging modality. World J Hepatol 2024; 16:1290-1305. [PMID: 39606168 PMCID: PMC11586745 DOI: 10.4254/wjh.v16.i11.1290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 08/27/2024] [Accepted: 10/20/2024] [Indexed: 11/06/2024] Open
Abstract
BACKGROUND Non-invasive methods to diagnose non-alcoholic steatohepatitis (NASH), an inflammatory subtype of non-alcoholic fatty liver disease (NAFLD), are currently unavailable. AIM To develop an integrin αvβ3-targeted molecular imaging modality to differentiate NASH. METHODS Integrin αvβ3 expression was assessed in Human LO2 hepatocytes Scultured with palmitic and oleic acids (FFA). Hepatic integrin αvβ3 expression was analyzed in rabbits fed a high-fat diet (HFD) and in rats fed a high-fat, high-carbohydrate diet (HFCD). After synthesis, cyclic arginine-glycine-aspartic acid peptide (cRGD) was labeled with gadolinium (Gd) and used as a contrast agent in magnetic resonance imaging (MRI) performed on mice fed with HFCD. RESULTS Integrin αvβ3 was markedly expressed on FFA-cultured hepatocytes, unlike the control hepatocytes. Hepatic integrin αvβ3 expression significantly increased in both HFD-fed rabbits and HFCD-fed rats as simple fatty liver (FL) progressed to steatohepatitis. The distribution of integrin αvβ3 in the liver of NASH cases largely overlapped with albumin-positive staining areas. In comparison to mice with simple FL, the relative liver MRI-T1 signal value at 60 minutes post-injection of Gd-labeled cRGD was significantly increased in mice with steatohepatitis (P < 0.05), showing a positive correlation with the NAFLD activity score (r = 0.945; P < 0.01). Hepatic integrin αvβ3 expression was significantly upregulated during NASH development, with hepatocytes being the primary cells expressing integrin αvβ3. CONCLUSION After using Gd-labeled cRGD as a tracer, NASH was successfully distinguished by visualizing hepatic integrin αvβ3 expression with MRI.
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Affiliation(s)
- Xiao-Quan Huang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Ling Wu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Chun-Yan Xue
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Chen-Yi Rao
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Qing-Qing Fang
- Department of Gastroenterology, Minhang Hospital, Fudan University, Shanghai 201100, China
| | - Ying Chen
- Department of Gastroenterology, Minhang Hospital, Fudan University, Shanghai 201100, China
| | - Cao Xie
- Department of Pharmacy, Fudan University, Shanghai 200032, China
| | - Sheng-Xiang Rao
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Shi-Yao Chen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Department of Gastroenterology, Minhang Hospital, Fudan University, Shanghai 201100, China
| | - Feng Li
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Department of Gastroenterology, Minhang Hospital, Fudan University, Shanghai 201100, China.
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Otálora-Otálora BA, Payán-Gómez C, López-Rivera JJ, Pedroza-Aconcha NB, Aristizábal-Guzmán C, Isaza-Ruget MA, Álvarez-Moreno CA. Global transcriptomic network analysis of the crosstalk between microbiota and cancer-related cells in the oral-gut-lung axis. Front Cell Infect Microbiol 2024; 14:1425388. [PMID: 39228892 PMCID: PMC11368877 DOI: 10.3389/fcimb.2024.1425388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 07/15/2024] [Indexed: 09/05/2024] Open
Abstract
Background The diagnosis and treatment of lung, colon, and gastric cancer through the histologic characteristics and genomic biomarkers have not had a strong impact on the mortality rates of the top three global causes of death by cancer. Methods Twenty-five transcriptomic analyses (10 lung cancer, 10 gastric cancer, and 5 colon cancer datasets) followed our own bioinformatic pipeline based on the utilization of specialized libraries from the R language and DAVID´s gene enrichment analyses to identify a regulatory metafirm network of transcription factors and target genes common in every type of cancer, with experimental evidence that supports its relationship with the unlocking of cell phenotypic plasticity for the acquisition of the hallmarks of cancer during the tumoral process. The network's regulatory functional and signaling pathways might depend on the constant crosstalk with the microbiome network established in the oral-gut-lung axis. Results The global transcriptomic network analysis highlighted the impact of transcription factors (SOX4, TCF3, TEAD4, ETV4, and FOXM1) that might be related to stem cell programming and cancer progression through the regulation of the expression of genes, such as cancer-cell membrane receptors, that interact with several microorganisms, including human T-cell leukemia virus 1 (HTLV-1), the human papilloma virus (HPV), the Epstein-Barr virus (EBV), and SARS-CoV-2. These interactions can trigger the MAPK, non-canonical WNT, and IFN signaling pathways, which regulate key transcription factor overexpression during the establishment and progression of lung, colon, and gastric cancer, respectively, along with the formation of the microbiome network. Conclusion The global transcriptomic network analysis highlights the important interaction between key transcription factors in lung, colon, and gastric cancer, which regulates the expression of cancer-cell membrane receptors for the interaction with the microbiome network during the tumorigenic process.
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Affiliation(s)
| | - César Payán-Gómez
- Dirección Académica, Universidad Nacional de Colombia, Sede de La Paz, La Paz, Colombia
| | - Juan Javier López-Rivera
- Grupo de Investigación INPAC, Specialized Laboratory, Clinica Universitaria Colombia, Clínica Colsanitas S.A., Bogotá, Colombia
| | | | - Claudia Aristizábal-Guzmán
- Grupo de Investigación INPAC, Unidad de Investigación, Fundación Universitaria Sanitas, Bogotá, Colombia
| | - Mario Arturo Isaza-Ruget
- Keralty, Sanitas International Organization, Grupo de Investigación INPAC, Fundación Universitaria Sanitas, Bogotá, Colombia
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Ellergezen P, Coşkun BN, Çeçen GS, Bozkurt ZY, Ağca H, Dalkılıç HE, Çavun S. Assessment of α 9β 1 ıntegrın as a new dıagnostıc and therapeutıc target ın Behcet's dısease. Clin Exp Med 2023; 23:5345-5353. [PMID: 37728818 DOI: 10.1007/s10238-023-01173-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 08/15/2023] [Indexed: 09/21/2023]
Abstract
This study aimed to investigate the roles of α9β1 integrin and its ligands in Behçet's disease (BD) by examining serum levels and gene expressions. 15 healthy controls and 30 BD patients (14 active and 16 inactive) were included in the study. Serum levels of ITGA9, ITGB1, TNC, OPN, VCAM-1, VEGF, TSP1, TGM2, Emilin-1, and vWF, were measured by ELISA. Gene expressions of α9β1 (ITGA9 and ITGB1) and its ligands (TNC and SPP1) were evaluated by RT-PCR. Laboratory findings (CRP, ESR, HGB, WBC, RBC, neutrophil, lymphocyte, PLT, RDW, MPV, PCT, and HLA-B51) were obtained from the electronic database. Active BD patients had higher serum levels of α9β1 integrin and its ligands than inactive patients and healthy controls. No significant difference was observed between healthy controls and inactive patients. Gene expressions of ITGB1 and SPP1 were increased in both patient groups compared to healthy controls. ITGA9 and TNC gene expression levels were lower in the active group than in the inactive group. No noticeable differences were found in ITGB1 and SPP1 gene expressions between the patient groups. BD patients exhibited elevated CRP, ESR, WBC, neutrophil, PLT, and PCT levels, while HGB, RBC, and RDW values were lower than healthy controls. Active patients had higher CRP, ESR, WBC, neutrophil, and PLT levels. Significant positive correlations were found between CRP, ESR, WBC, neutrophil, PLT, PCT and serum levels of α9β1 integrin and its ligands. Increased release of α9β1 integrin and its ligands is associated with BD, suggesting their potential as markers for disease severity.
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Affiliation(s)
- Pınar Ellergezen
- Bursa Uludag University Faculty of Medicine, Department of Medical Pharmacology, Bursa Uludag University, Gorukle Campus, 16059, Nilufer-Bursa, Turkey.
| | - Belkıs Nihan Coşkun
- Bursa Uludag University Faculty of Medicine, Department of Rheumatology, Bursa Uludag University, Gorukle Campus, 16059, Nilufer-Bursa, Turkey
| | - Gülce Sevdar Çeçen
- Bursa Uludag University Faculty of Medicine, Department of Medical Pharmacology, Bursa Uludag University, Gorukle Campus, 16059, Nilufer-Bursa, Turkey
| | - Zeynep Yılmaz Bozkurt
- Bursa Uludag University Faculty of Medicine, Department of Rheumatology, Bursa Uludag University, Gorukle Campus, 16059, Nilufer-Bursa, Turkey
| | - Harun Ağca
- Bursa Uludag University Faculty of Medicine, Department of Medical Microbiology, Bursa Uludag University, Gorukle Campus, 16059, Nilufer-Bursa, Turkey
| | - Hüseyin Ediz Dalkılıç
- Bursa Uludag University Faculty of Medicine, Department of Rheumatology, Bursa Uludag University, Gorukle Campus, 16059, Nilufer-Bursa, Turkey
| | - Sinan Çavun
- Bursa Uludag University Faculty of Medicine, Department of Medical Pharmacology, Bursa Uludag University, Gorukle Campus, 16059, Nilufer-Bursa, Turkey
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Garg A, Karhana S, Bano A, Khan IA, Reeta, Nidhi, Khan MA. Network pharmacology and molecular docking study-based approach to explore mechanism of benzimidazole-based anthelmintics for the treatment of lung cancer. J Biomol Struct Dyn 2023; 42:10739-10760. [PMID: 37740654 DOI: 10.1080/07391102.2023.2258419] [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: 11/07/2022] [Accepted: 09/07/2023] [Indexed: 09/24/2023]
Abstract
Emerging studies have reported the potential anticancer activity of benzimidazole-based anthelmintics (BBA) against lung cancer (LC). However, mechanism underlying the anticancer activity of BBA is unclear. Therefore, in the current study, network pharmacology and molecular docking-based approach were used to explore the potential molecular mechanism for the treatment of LC. The potential targets for BBA were obtained from multiple databases including SwissTargetPrediction, Drug Bank, Therapeutic Target Database, and Comparative Toxicogenomics Database while LC targets were collected from DisGeNet gene discovery platform, Integrated Genomic Database of NSCLC, Catalogue of Somatic Mutations in Cancer and Online Mendelian Inheritance in Man database. Protein-protein interaction (PPI) diagram of common targets was constructed using STRING online platform. Topological analysis was performed using Cytoscape and gene enrichment analysis was conducted using FunRich software. Highest degree targets were then confirmed using molecular docking and molecular dynamics simulations. The BBA were prioritized according to their S scores, with ricobendazole ranking highest followed by flubendazole, fenbendazole, mebendazole, triclabendazole, albendazole, oxibendazole, parbendazole, thiabendazole and oxfendazole. The potential targets of BBA identified using topological analysis and molecular docking were found to be CCND1 (cyclin D1), EGFR (Epidermal Growth Factor Receptor), ERBB2 (Erb-B2 Receptor Tyrosine Kinase 2/CD340), PTGS2 (Prostaglandin-endoperoxide synthase 2), and SRC (Proto-oncogene tyrosine-protein kinase). Furthermore, molecular dynamics confirmed that CCND1 and EGFR are the potential targets of ricobendazole for the treatment of LC. BBA can be further explored as a therapeutic strategy for the treatment of lung cancer under in vitro and in vivo studies.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Aakriti Garg
- Centre for Translational & Clinical Research, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, India
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Sonali Karhana
- Centre for Translational & Clinical Research, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, India
| | - Aysha Bano
- Centre for Translational & Clinical Research, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, India
| | - Imran A Khan
- Department of Chemistry, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, India
| | - Reeta
- Institute of Nuclear Medicine and Allied Sciences (INMAS), DRDO, New Delhi, India
| | - Nidhi
- Centre for Translational & Clinical Research, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, India
| | - Mohd Ashif Khan
- Centre for Translational & Clinical Research, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, India
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Zhang Q, Zhang S, Chen J, Xie Z. The Interplay between Integrins and Immune Cells as a Regulator in Cancer Immunology. Int J Mol Sci 2023; 24:6170. [PMID: 37047140 PMCID: PMC10093897 DOI: 10.3390/ijms24076170] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 03/20/2023] [Accepted: 03/22/2023] [Indexed: 04/14/2023] Open
Abstract
Integrins are a group of heterodimers consisting of α and β subunits that mediate a variety of physiological activities of immune cells, including cell migration, adhesion, proliferation, survival, and immunotolerance. Multiple types of integrins act differently on the same immune cells, while the same integrin may exert various effects on different immune cells. In the development of cancer, integrins are involved in the regulation of cancer cell proliferation, invasion, migration, and angiogenesis; conversely, integrins promote immune cell aggregation to mediate the elimination of tumors. The important roles of integrins in cancer progression have provided valuable clues for the diagnosis and targeted treatment of cancer. Furthermore, many integrin inhibitors have been investigated in clinical trials to explore effective regimens and reduce side effects. Due to the complexity of the mechanism of integrin-mediated cancer progression, challenges remain in the research and development of cancer immunotherapies (CITs). This review enumerates the effects of integrins on four types of immune cells and the potential mechanisms involved in the progression of cancer, which will provide ideas for more optimal CIT in the future.
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Affiliation(s)
- Qingfang Zhang
- College of Basic Medical, Nanchang University, Nanchang 330006, China
- Queen Mary School, Medical Department, Nanchang University, Nanchang 330031, China
| | - Shuo Zhang
- College of Basic Medical, Nanchang University, Nanchang 330006, China
- Queen Mary School, Medical Department, Nanchang University, Nanchang 330031, China
| | - Jianrui Chen
- College of Basic Medical, Nanchang University, Nanchang 330006, China
- Queen Mary School, Medical Department, Nanchang University, Nanchang 330031, China
| | - Zhenzhen Xie
- College of Basic Medical, Nanchang University, Nanchang 330006, China
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Cho SK, Lee K, Woo JH, Choi JH. Macrophages Promote Ovarian Cancer-Mesothelial Cell Adhesion by Upregulation of ITGA2 and VEGFC in Mesothelial Cells. Cells 2023; 12:384. [PMID: 36766725 PMCID: PMC9913165 DOI: 10.3390/cells12030384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/15/2023] [Accepted: 01/18/2023] [Indexed: 01/24/2023] Open
Abstract
Ovarian cancer is a metastatic disease that frequently exhibits extensive peritoneal dissemination. Recent studies have revealed that noncancerous cells inside the tumor microenvironment, such as macrophages and mesothelial cells, may play a role in ovarian cancer metastasis. In this study, we found that human ovarian cancer cells (A2780 and SKOV3) adhered more to human mesothelial Met5A cells stimulated by macrophages (M-Met5A) in comparison to unstimulated control Met5A cells. The mRNA sequencing revealed that 94 adhesion-related genes, including FMN1, ITGA2, COL13A1, VEGFC, and NRG1, were markedly upregulated in M-Met5A cells. Knockdown of ITGA2 and VEGFC in M-Met5A cells significantly inhibited the adhesion of ovarian cancer cells. Inhibition of the JNK and Akt signaling pathways suppressed ITGA2 and VEGFC expression in M-Met5A cells as well as ovarian cancer-mesothelial cell adhesion. Furthermore, increased production of CC chemokine ligand 2 (CCL2) and CCL5 by macrophages elevated ovarian cancer-mesothelial cell adhesion. These findings imply that macrophages may play a significant role in ovarian cancer-mesothelial cell adhesion by inducing the mesothelial expression of adhesion-related genes via the JNK and Akt pathways.
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Affiliation(s)
- Seung-Kye Cho
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Kijun Lee
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul 02447, Republic of Korea
- Division of Molecular Biology, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Jeong-Hwa Woo
- Division of Molecular Biology, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Jung-Hye Choi
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul 02447, Republic of Korea
- Division of Molecular Biology, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea
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Pang X, He X, Qiu Z, Zhang H, Xie R, Liu Z, Gu Y, Zhao N, Xiang Q, Cui Y. Targeting integrin pathways: mechanisms and advances in therapy. Signal Transduct Target Ther 2023; 8:1. [PMID: 36588107 PMCID: PMC9805914 DOI: 10.1038/s41392-022-01259-6] [Citation(s) in RCA: 346] [Impact Index Per Article: 173.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 11/14/2022] [Accepted: 11/21/2022] [Indexed: 01/03/2023] Open
Abstract
Integrins are considered the main cell-adhesion transmembrane receptors that play multifaceted roles as extracellular matrix (ECM)-cytoskeletal linkers and transducers in biochemical and mechanical signals between cells and their environment in a wide range of states in health and diseases. Integrin functions are dependable on a delicate balance between active and inactive status via multiple mechanisms, including protein-protein interactions, conformational changes, and trafficking. Due to their exposure on the cell surface and sensitivity to the molecular blockade, integrins have been investigated as pharmacological targets for nearly 40 years, but given the complexity of integrins and sometimes opposite characteristics, targeting integrin therapeutics has been a challenge. To date, only seven drugs targeting integrins have been successfully marketed, including abciximab, eptifibatide, tirofiban, natalizumab, vedolizumab, lifitegrast, and carotegrast. Currently, there are approximately 90 kinds of integrin-based therapeutic drugs or imaging agents in clinical studies, including small molecules, antibodies, synthetic mimic peptides, antibody-drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, imaging agents, etc. A serious lesson from past integrin drug discovery and research efforts is that successes rely on both a deep understanding of integrin-regulatory mechanisms and unmet clinical needs. Herein, we provide a systematic and complete review of all integrin family members and integrin-mediated downstream signal transduction to highlight ongoing efforts to develop new therapies/diagnoses from bench to clinic. In addition, we further discuss the trend of drug development, how to improve the success rate of clinical trials targeting integrin therapies, and the key points for clinical research, basic research, and translational research.
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Affiliation(s)
- Xiaocong Pang
- grid.411472.50000 0004 1764 1621Department of Pharmacy, Peking University First Hospital, Xishiku Street, Xicheng District, 100034 Beijing, China ,grid.411472.50000 0004 1764 1621Institute of Clinical Pharmacology, Peking University First Hospital, Xueyuan Road 38, Haidian District, 100191 Beijing, China
| | - Xu He
- grid.411472.50000 0004 1764 1621Department of Pharmacy, Peking University First Hospital, Xishiku Street, Xicheng District, 100034 Beijing, China ,grid.411472.50000 0004 1764 1621Institute of Clinical Pharmacology, Peking University First Hospital, Xueyuan Road 38, Haidian District, 100191 Beijing, China
| | - Zhiwei Qiu
- grid.411472.50000 0004 1764 1621Department of Pharmacy, Peking University First Hospital, Xishiku Street, Xicheng District, 100034 Beijing, China ,grid.411472.50000 0004 1764 1621Institute of Clinical Pharmacology, Peking University First Hospital, Xueyuan Road 38, Haidian District, 100191 Beijing, China
| | - Hanxu Zhang
- grid.411472.50000 0004 1764 1621Department of Pharmacy, Peking University First Hospital, Xishiku Street, Xicheng District, 100034 Beijing, China ,grid.411472.50000 0004 1764 1621Institute of Clinical Pharmacology, Peking University First Hospital, Xueyuan Road 38, Haidian District, 100191 Beijing, China
| | - Ran Xie
- grid.411472.50000 0004 1764 1621Department of Pharmacy, Peking University First Hospital, Xishiku Street, Xicheng District, 100034 Beijing, China ,grid.411472.50000 0004 1764 1621Institute of Clinical Pharmacology, Peking University First Hospital, Xueyuan Road 38, Haidian District, 100191 Beijing, China
| | - Zhiyan Liu
- grid.411472.50000 0004 1764 1621Department of Pharmacy, Peking University First Hospital, Xishiku Street, Xicheng District, 100034 Beijing, China ,grid.411472.50000 0004 1764 1621Institute of Clinical Pharmacology, Peking University First Hospital, Xueyuan Road 38, Haidian District, 100191 Beijing, China
| | - Yanlun Gu
- grid.411472.50000 0004 1764 1621Department of Pharmacy, Peking University First Hospital, Xishiku Street, Xicheng District, 100034 Beijing, China ,grid.411472.50000 0004 1764 1621Institute of Clinical Pharmacology, Peking University First Hospital, Xueyuan Road 38, Haidian District, 100191 Beijing, China
| | - Nan Zhao
- grid.411472.50000 0004 1764 1621Department of Pharmacy, Peking University First Hospital, Xishiku Street, Xicheng District, 100034 Beijing, China ,grid.411472.50000 0004 1764 1621Institute of Clinical Pharmacology, Peking University First Hospital, Xueyuan Road 38, Haidian District, 100191 Beijing, China
| | - Qian Xiang
- Department of Pharmacy, Peking University First Hospital, Xishiku Street, Xicheng District, 100034, Beijing, China. .,Institute of Clinical Pharmacology, Peking University First Hospital, Xueyuan Road 38, Haidian District, 100191, Beijing, China.
| | - Yimin Cui
- Department of Pharmacy, Peking University First Hospital, Xishiku Street, Xicheng District, 100034, Beijing, China. .,Institute of Clinical Pharmacology, Peking University First Hospital, Xueyuan Road 38, Haidian District, 100191, Beijing, China.
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Ciechanowska A, Rojewska E, Piotrowska A, Barut J, Pawlik K, Ciapała K, Kreiner G, Mika J. New insights into the analgesic properties of the XCL1/XCR1 and XCL1/ITGA9 axes modulation under neuropathic pain conditions - evidence from animal studies. Front Immunol 2022; 13:1058204. [PMID: 36618360 PMCID: PMC9814969 DOI: 10.3389/fimmu.2022.1058204] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022] Open
Abstract
Recent studies have indicated the involvement of chemokine-C-motif ligand 1 (XCL1) in nociceptive transmission; however, the participation of its two receptors, canonical chemokine-C-motif receptor 1 (XCR1) and integrin alpha-9 (ITGA9), recently recognized as a second receptor, has not been clarified to date. The aim was to explore by which of these receptors XCL1 reveals its pronociceptive properties and how the XCL1-XCR1 and XCL1-ITGA9 axes blockade/neutralization influence on pain-related behavior and opioid analgesia in the model of neuropathic pain. In our studies we used Albino Swiss mice which were exposed to the unilateral sciatic nerve chronic constriction injury (CCI) as a neuropathic pain model. Animals received single intrathecal (i.t.) injection of XCL1, XCL1 neutralizing antibodies, antagonist of XCR1 (vMIP-II) and neutralizing antibodies of ITGA9 (YA4), using lumbar puncture technique. Additionally we performed i.t. co-administration of abovementioned neutralizing antibodies and antagonists with single dose of morphine/buprenorphine. To assess pain-related behavior the von Frey and cold plate tests were used. To measure mRNA and protein level the RT-qPCR and Western Blot/Elisa/immunofluorescence techniques were performed, respectively. Statistical analysis was conducted using ANOVA with a Bonferroni correction. Presented studies have shown time-dependent upregulation of the mRNA and/or protein expression of XCL1 in the spinal cord after nerve injury as measured on day 1, 4, 7, 14, and 35. Our immunofluorescence study showed that XCL1 is released by astroglial cells located in the spinal cord, despite the neural localization of its receptors. Our results also provided the first evidence that the blockade/neutralization of both receptors, XCR1 and ITGA9, reversed hypersensitivity after intrathecal XCL1 administration in naive mice; however, neutralization of ITGA9 was more effective. In addition, the results proved that the XCL1 neutralizing antibody and, similarly, the blockade of XCR1 and neutralization of ITGA9 diminished thermal and mechanical hypersensitivity in nerve injury-exposed mice after 7 days. Additionally, neutralization of XCL1 improves morphine analgesia. Moreover, blockade of XCR1 positively influences buprenorphine effectiveness, and neutralization of ITGA9 enhances not only buprenorphine but also morphine analgesia. Therefore, blockade of the XCL1-ITGA9 interaction may serve as an innovative strategy for the polypharmacotherapy of neuropathic pain in combination with opioids.
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Affiliation(s)
- Agata Ciechanowska
- Department of Pain Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
| | - Ewelina Rojewska
- Department of Pain Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
| | - Anna Piotrowska
- Department of Pain Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
| | - Justyna Barut
- Department of Brain Biochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
| | - Katarzyna Pawlik
- Department of Pain Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
| | - Katarzyna Ciapała
- Department of Pain Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
| | - Grzegorz Kreiner
- Department of Brain Biochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
| | - Joanna Mika
- Department of Pain Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland,*Correspondence: Joanna Mika, ,
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Role of Integrins in Modulating Smooth Muscle Cell Plasticity and Vascular Remodeling: From Expression to Therapeutic Implications. Cells 2022; 11:cells11040646. [PMID: 35203297 PMCID: PMC8870356 DOI: 10.3390/cells11040646] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/03/2022] [Accepted: 02/11/2022] [Indexed: 02/06/2023] Open
Abstract
Smooth muscle cells (SMCs), present in the media layer of blood vessels, are crucial in maintaining vascular homeostasis. Upon vascular injury, SMCs show a high degree of plasticity, undergo a change from a “contractile” to a “synthetic” phenotype, and play an essential role in the pathophysiology of diseases including atherosclerosis and restenosis. Integrins are cell surface receptors, which are involved in cell-to-cell binding and cell-to-extracellular-matrix interactions. By binding to extracellular matrix components, integrins trigger intracellular signaling and regulate several of the SMC function, including proliferation, migration, and phenotypic switching. Although pharmacological approaches, including antibodies and synthetic peptides, have been effectively utilized to target integrins to limit atherosclerosis and restenosis, none has been commercialized yet. A clear understanding of how integrins modulate SMC biology is essential to facilitate the development of integrin-based interventions to combat atherosclerosis and restenosis. Herein, we highlight the importance of integrins in modulating functional properties of SMCs and their implications for vascular pathology.
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Ikeshima-Kataoka H, Sugimoto C, Tsubokawa T. Integrin Signaling in the Central Nervous System in Animals and Human Brain Diseases. Int J Mol Sci 2022; 23:ijms23031435. [PMID: 35163359 PMCID: PMC8836133 DOI: 10.3390/ijms23031435] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 01/24/2022] [Accepted: 01/25/2022] [Indexed: 02/06/2023] Open
Abstract
The integrin family is involved in various biological functions, including cell proliferation, differentiation and migration, and also in the pathogenesis of disease. Integrins are multifunctional receptors that exist as heterodimers composed of α and β subunits and bind to various ligands, including extracellular matrix (ECM) proteins; they are found in many animals, not only vertebrates (e.g., mouse, rat, and teleost fish), but also invertebrates (e.g., planarian flatworm, fruit fly, nematodes, and cephalopods), which are used for research on genetics and social behaviors or as models for human diseases. In the present paper, we describe the results of a phylogenetic tree analysis of the integrin family among these species. We summarize integrin signaling in teleost fish, which serves as an excellent model for the study of regenerative systems and possesses the ability for replacing missing tissues, especially in the central nervous system, which has not been demonstrated in mammals. In addition, functions of astrocytes and reactive astrocytes, which contain neuroprotective subpopulations that act in concert with the ECM proteins tenascin C and osteopontin via integrin are also reviewed. Drug development research using integrin as a therapeutic target could result in breakthroughs for the treatment of neurodegenerative diseases and brain injury in mammals.
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Affiliation(s)
- Hiroko Ikeshima-Kataoka
- Department of Biology, Keio University, 4-1-1, Hiyoshi, Kohoku-ku, Yokohama-shi 223-8521, Japan; (C.S.); (T.T.)
- Faculty of Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555, Japan
- Correspondence:
| | - Chikatoshi Sugimoto
- Department of Biology, Keio University, 4-1-1, Hiyoshi, Kohoku-ku, Yokohama-shi 223-8521, Japan; (C.S.); (T.T.)
| | - Tatsuya Tsubokawa
- Department of Biology, Keio University, 4-1-1, Hiyoshi, Kohoku-ku, Yokohama-shi 223-8521, Japan; (C.S.); (T.T.)
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