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1
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Xu X, Li R, Mo O, Liu K, Li J, Hao P. Cell-type deconvolution for bulk RNA-seq data using single-cell reference: a comparative analysis and recommendation guideline. Brief Bioinform 2024; 26:bbaf031. [PMID: 39899596 PMCID: PMC11789683 DOI: 10.1093/bib/bbaf031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 12/06/2024] [Accepted: 01/20/2025] [Indexed: 02/05/2025] Open
Abstract
The accurate estimation of cell type proportions in tissues is crucial for various downstream analyses. With the increasing availability of single-cell sequencing data, numerous deconvolution methods that use single-cell RNA sequencing data as a reference have been developed. However, a unified understanding of how these deconvolution approaches perform in practical applications is still lacking. To address this, we systematically assessed the accuracy and robustness of nine deconvolution methods that use single-cell RNA sequencing data as a reference, evaluating them on real bulk data with cell proportions verified through flow cytometry, as well as simulated bulk data generated from five single-cell RNA sequencing datasets. Our study highlights the importance of several factors-including reference dataset construction strategies, dataset size, cell type subdivision, and cell type inconsistency-on the accuracy and robustness of deconvolution results. We also propose a set of recommended guidelines for software users in diverse scenarios.
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Affiliation(s)
- Xintian Xu
- Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, 320 Yueyang Road, Xuhui District, Shanghai 200031, China
- University of Chinese Academy of Sciences, 1 Yanqihu East Road, Huairou District, Beijing 100039, China
| | - Rui Li
- Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, 320 Yueyang Road, Xuhui District, Shanghai 200031, China
- University of Chinese Academy of Sciences, 1 Yanqihu East Road, Huairou District, Beijing 100039, China
| | - Ouyang Mo
- Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, 320 Yueyang Road, Xuhui District, Shanghai 200031, China
- University of Chinese Academy of Sciences, 1 Yanqihu East Road, Huairou District, Beijing 100039, China
| | - Kai Liu
- Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, 320 Yueyang Road, Xuhui District, Shanghai 200031, China
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Xuhui District, Shanghai 200032, China
| | - Justin Li
- Department of Mathematics, University of Connecticut, 352 Mansfield Road, Storrs, CT 06269, USA
| | - Pei Hao
- Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, 320 Yueyang Road, Xuhui District, Shanghai 200031, China
- University of Chinese Academy of Sciences, 1 Yanqihu East Road, Huairou District, Beijing 100039, China
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Li YC, Lee YC, Murakami M, Huang YH, Hung TH, Wu YS, Ambudkar SV, Wu CP. The colony-stimulating factor-1 receptor inhibitor edicotinib counteracts multidrug resistance in cancer cells by inhibiting ABCG2-mediated drug efflux. Biomed Pharmacother 2024; 180:117554. [PMID: 39405897 DOI: 10.1016/j.biopha.2024.117554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 09/24/2024] [Accepted: 10/08/2024] [Indexed: 11/14/2024] Open
Abstract
Chemotherapy treatment faces a major obstacle with the emergence of multidrug resistance (MDR), often attributed to the elevated expression of ATP-binding cassette (ABC) transporters such as ABCG2 and ABCB1 in cancer cells. These transporters hinder the efficacy of cytotoxic drugs via ATP hydrolysis-dependent efflux, leading to diminished intracellular drug levels. The scarcity of approved treatments for multidrug resistant cancers necessitates exploration of alternative strategies, including drug repositioning of molecular targeted agents to counteract ABCG2-mediated MDR in multidrug-resistant cancer cells. This study investigates the potential of edicotinib, a selective colony-stimulating factor-1 receptor (CSF-1R) tyrosine kinase inhibitor that is currently undergoing clinical trials for various diseases, to reverse MDR in ABCG2-overexpressing cancer cells. Our findings reveal that by attenuating the drug-efflux function of ABCG2 without altering its expression, edicotinib improves drug-induced apoptosis and reverses MDR in ABCG2-overexpressing multidrug-resistant cancer cells at non-toxic concentrations. Through ATPase activity analysis and molecular docking, potential interaction sites for edicotinib on ABCG2 were identified. These results underscore an additional pharmacological benefit of edicotinib against ABCG2 activity, suggesting its potential incorporation into combination therapies for patients with ABCG2-overexpressing tumors. Further research is warranted to validate these findings and explore their clinical implications.
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Affiliation(s)
- Yen-Ching Li
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Yun-Chieh Lee
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Megumi Murakami
- Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Yang-Hui Huang
- Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 10507, Taiwan
| | - Tai-Ho Hung
- Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 10507, Taiwan; Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Department of Obstetrics and Gynecology, Keelung Chang Gung Memorial Hospital, Keelung 20401, Taiwan
| | - Yu-Shan Wu
- Department of Chemistry, Tunghai University, Taichung 40704, Taiwan
| | - Suresh V Ambudkar
- Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
| | - Chung-Pu Wu
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 10507, Taiwan; Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
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3
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Su S, Liu T, Zheng JY, Wu HC, Keng VW, Zhang SJ, Li XX. Huang Lian Jie Du decoction attenuated colitis via suppressing the macrophage Csf1r/Src pathway and modulating gut microbiota. Front Immunol 2024; 15:1375781. [PMID: 39391314 PMCID: PMC11464287 DOI: 10.3389/fimmu.2024.1375781] [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: 01/24/2024] [Accepted: 08/30/2024] [Indexed: 10/12/2024] Open
Abstract
Introduction Ulcerative colitis, a subtype of chronic inflammatory bowel disease (IBD), is characterized by relapsing colonic inflammation and ulcers. The traditional Chinese herbal formulation Huang Lian Jie Du (HLJD) decoction is used clinically to treat diarrhea and colitis. However, the mechanisms associated with the effects of treatment remain unclear. This study aims to elucidate the molecular mechanistic effects of HLJD formulation on colitis. Methods Chronic colitis in mice was induced by adding 1% dextran sulfate sodium (DSS) to their drinking water continuously for 8 weeks, and HLJD decoction at the doses of 2 and 4 g/kg was administered orally to mice daily from the second week until experimental endpoint. Stool consistency scores, blood stool scores, and body weights were recorded weekly. Disease activity index (DAI) was determined before necropsy, where colon tissues were collected for biochemical analyses. In addition, the fecal microbiome of treated mice was characterized using 16S rRNA amplicon sequencing. Results HLJD decoction at doses of 2 and 4 g/kg relieved DSS-induced chronic colitis in mice by suppressing inflammation through compromised macrophage activity in colonic tissues associated with the colony-stimulating factor 1 receptor (Csf1r)/Src pathway. Furthermore, the HLJD formula could modify the gut microbiota profile by decreasing the abundance of Bacteroides, Odoribacter, Clostridium_sensu_stricto_1, and Parasutterella. In addition, close correlations between DAI, colon length, spleen weight, and gut microbiota were identified. Discussion Our findings revealed that the HLJD formula attenuated DSS-induced chronic colitis by reducing inflammation via Csf1r/Src-mediated macrophage infiltration, as well as modulating the gut microbiota profile.
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Affiliation(s)
- Shan Su
- State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Neurology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Ting Liu
- Department of Pharmacy, Shenzhen Children’s Hospital, Shenzhen, China
| | - Jia-Yi Zheng
- State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Neurology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Hai-Cui Wu
- Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
| | - Vincent W. Keng
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
- Research Center for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China
| | - Shi-Jie Zhang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Neurology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Xiao-Xiao Li
- Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
- Research Center for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China
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Hui W, Pu S, Gao X, Wang Y, Zha X, Ding K, Zhang X, Cheng D, Shi H, Luo Z. Evaluation of a Positron Emission Tomography Tracer Targeting Colony-Stimulating Factor 1 Receptor for Detecting Pulmonary Inflammation. Mol Pharm 2024; 21:3979-3991. [PMID: 38935927 DOI: 10.1021/acs.molpharmaceut.4c00337] [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: 06/29/2024]
Abstract
Colony-stimulating factor 1 receptor (CSF1R) is a type III receptor tyrosine kinase that is crucial for immune cell activation, survival, proliferation, and differentiation. Its expression significantly increases in macrophages during inflammation, playing a crucial role in regulating inflammation resolution and termination. Consequently, CSF1R has emerged as a critical target for both therapeutic intervention and imaging of inflammatory diseases. Herein, we have developed a radiotracer, 1-[4-((7-(dimethylamino)quinazolin-4-yl)oxy)phenyl]-3-(4-[18F]fluorophenyl)urea ([18F]17), for in vivo positron emission tomography (PET) imaging of CSF1R. Compound 17 exhibits a comparable inhibitory potency against CSF1R as the well-known CSF1R inhibitor PLX647. The radiosynthesis of [18F]17 was successfully performed by radiofluorination of aryltrimethyltin precursor with a yield of approximately 12% at the end of synthesis, maintaining a purity exceeding 98%. In vivo stability and biodistribution studies demonstrate that [18F]17 remains >90% intact at 30 min postinjection, with no defluorination observed even at 60 min postinjection. The PET/CT imaging study in lipopolysaccharide-induced pulmonary inflammation mice indicates that [18F]17 offers a more sensitive characterization of pulmonary inflammation compared to traditional [18F]FDG. Notably, [18F]17 shows a higher discrepancy in uptake ratio between mice with pulmonary inflammation and the sham group. Furthermore, the variations in [18F]17 uptake ratio observed on day 7 and day 14 correspond to lung density changes observed in CT imaging. Moreover, the expression levels of CSF1R on day 7 and day 14 follow a trend similar to the uptake pattern of [18F]17, indicating its potential for accurately characterizing CSF1R expression levels and effectively monitoring the pulmonary inflammation progression. These results strongly suggest that [18F]17 has promising prospects as a CSF1R PET tracer, providing diagnostic opportunities for pulmonary inflammatory diseases.
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Affiliation(s)
- Wenxue Hui
- School of Biomedical Engineering & State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Suyun Pu
- School of Biomedical Engineering & State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China
- School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Xinyan Gao
- School of Biomedical Engineering & State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Yunze Wang
- Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xiaochuan Zha
- School of Biomedical Engineering & State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Kezhi Ding
- School of Biomedical Engineering & State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China
- School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Xiaoyu Zhang
- School of Biomedical Engineering & State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China
| | - Dengfeng Cheng
- Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Hongcheng Shi
- Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Zonghua Luo
- School of Biomedical Engineering & State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China
- Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
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Bjørnstad F, Havik S, Aarhus TI, Mahdi I, Unger A, Habenberger P, Degenhart C, Eickhoff J, Klebl BM, Sundby E, Hoff BH. Pyrrolopyrimidine based CSF1R inhibitors: Attempted departure from Flatland. Eur J Med Chem 2024; 265:116053. [PMID: 38141285 DOI: 10.1016/j.ejmech.2023.116053] [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: 11/09/2023] [Revised: 12/08/2023] [Accepted: 12/11/2023] [Indexed: 12/25/2023]
Abstract
The colony-stimulating factor 1 receptor (CSF1R) is an attractive target for inflammation disorders and cancers. Based on a series of pyrrolo[2,3-d]pyrimidine containing two carbo-aromatic rings, we have searched for new CSF1R inhibitors having a higher fraction of sp3-atoms. The phenyl unit in the 4-amino group could efficiently be replaced by tetrahydropyran (THP) retaining inhibitor potency. Exchanging the 6-aryl group with cyclohex-2-ene units also resulted in highly potent compounds, while fully saturated ring systems at C-6 led to a loss of activity. The structure-activity relationship study evaluating THP containing pyrrolo[2,3-d]pyrimidine derivates identified several highly active inhibitors by enzymatic studies. A comparison of 11 pairs of THP and aromatic compounds showed that inhibitors containing THP had clear benefits in terms of enzymatic potency, solubility, and cell toxicity. Guided by cellular experiments in Ba/F3 cells, five CSF1R inhibitors were further profiled in ADME assays, indicating the para-aniline derivative 16t as the most attractive compound for further development.
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Affiliation(s)
- Frithjof Bjørnstad
- Department of Chemistry, Norwegian University of Science and Technology (NTNU), Høgskoleringen 5, NO-7491, Trondheim, Norway; Department of Material Science, Norwegian University of Science and Technology (NTNU), NO-7491, Trondheim, Norway
| | - Simen Havik
- Department of Chemistry, Norwegian University of Science and Technology (NTNU), Høgskoleringen 5, NO-7491, Trondheim, Norway
| | - Thomas Ihle Aarhus
- Department of Chemistry, Norwegian University of Science and Technology (NTNU), Høgskoleringen 5, NO-7491, Trondheim, Norway; Lead Discovery Center GmbH (LDC), Otto-Hahn-Strasse 15, 44227, Dortmund, Germany
| | - Iktedar Mahdi
- Department of Chemistry, Norwegian University of Science and Technology (NTNU), Høgskoleringen 5, NO-7491, Trondheim, Norway
| | - Anke Unger
- Lead Discovery Center GmbH (LDC), Otto-Hahn-Strasse 15, 44227, Dortmund, Germany
| | - Peter Habenberger
- Lead Discovery Center GmbH (LDC), Otto-Hahn-Strasse 15, 44227, Dortmund, Germany
| | - Carsten Degenhart
- Lead Discovery Center GmbH (LDC), Otto-Hahn-Strasse 15, 44227, Dortmund, Germany
| | - Jan Eickhoff
- Lead Discovery Center GmbH (LDC), Otto-Hahn-Strasse 15, 44227, Dortmund, Germany
| | - Bert M Klebl
- Lead Discovery Center GmbH (LDC), Otto-Hahn-Strasse 15, 44227, Dortmund, Germany
| | - Eirik Sundby
- Department of Material Science, Norwegian University of Science and Technology (NTNU), NO-7491, Trondheim, Norway
| | - Bård Helge Hoff
- Department of Chemistry, Norwegian University of Science and Technology (NTNU), Høgskoleringen 5, NO-7491, Trondheim, Norway.
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Niu Y, Cao S, Ma X, Xu Z, Wu H. Multiple cytokine analyses identify CSF1 as a robust biomarker for predicting postoperative recurrence in chronic rhinosinusitis with nasal polyps. Int Immunopharmacol 2024; 127:111430. [PMID: 38142640 DOI: 10.1016/j.intimp.2023.111430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 12/10/2023] [Accepted: 12/19/2023] [Indexed: 12/26/2023]
Abstract
OBJECTIVE Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous disease with a high rate of postoperative recurrence. This study aimed to discover potential biomarkers by analyzing multiple cytokine profiles in serum to predict postoperative recurrence in CRSwNP and to explore the underlying mechanisms. METHODS In this prospective study, we enrolled 18 healthy controls (HC) and 60 CRSwNP patients and analyzed the baseline serum cytokine profiles using the Luminex assay. Patients were followed up for more than 2 years and divided into non-recurrence and Recurrence groups. The differentially expressed cytokines were validated in the serum and tissue samples in a validation cohort, and their predictive values for recurrence were evaluated. RESULTS Fifty-four CRSwNP patients completed the follow-up schedule, including 37 patients in the non-Recurrence group and 17 patients in the Recurrence group. Multiple cytokine analyses showed that serum CD40, CD40L, IL-18, IL-8, MCP1, and CSF1 levels were elevated in the CRSwNP group, especially in the Recurrence group, compared to the HC group. Receiver operating characteristic curves (ROC) and Kaplan-Meier survival analysis showed that serum levels of CD40, CD40L, and CSF1 were closely associated with the risk of postoperative recurrence. Further validation results showed that both serum and tissue mRNA levels of CD40, CD40L, and CSF1 were significantly higher in the Recurrence group in comparison with the non-recurrence and HC groups, and tissue CSF1 mRNA expression exhibited a robust value for predicting the CRSwNP recurrence. Immunofluorescence results revealed that CSF1 was enhanced in the recurrent CRSwNP patients, especially in the epithelial cell area, and CSF1 expressions were augmented when patients suffered postoperative recurrence. CONCLUSIONS Circulating cytokine profiles may affect the risk of postoperative recurrence in CRSwNP patients. Our discovery-validation results suggested that CSF1 might serve as a robust biomarker for predicting CRSwNP recurrence.
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Affiliation(s)
- Yan Niu
- Department of Otolaryngology Head and Neck Surgery, the Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Shouming Cao
- Department of Otolaryngology Head and Neck Surgery, the Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Xiaoyu Ma
- Department of Otolaryngology Head and Neck Surgery, the Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Zhaoxiong Xu
- Department of Otolaryngology Head and Neck Surgery, the Second People's Hospital of Xuanwei City, Xuanwei, China
| | - Haiying Wu
- Department of Otolaryngology Head and Neck Surgery, the Second Affiliated Hospital of Kunming Medical University, Kunming, China.
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Alkubaisi BO, Aljobowry R, Ali SM, Sultan S, Zaraei SO, Ravi A, Al-Tel TH, El-Gamal MI. The latest perspectives of small molecules FMS kinase inhibitors. Eur J Med Chem 2023; 261:115796. [PMID: 37708796 DOI: 10.1016/j.ejmech.2023.115796] [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: 07/03/2023] [Revised: 09/03/2023] [Accepted: 09/04/2023] [Indexed: 09/16/2023]
Abstract
FMS kinase is a type III tyrosine kinase receptor that plays a central role in the pathophysiology and management of several diseases, including a range of cancer types, inflammatory disorders, neurodegenerative disorders, and bone disorders among others. In this review, the pathophysiological pathways of FMS kinase in different diseases and the recent developments of its monoclonal antibodies and inhibitors during the last five years are discussed. The biological and biochemical features of these inhibitors, including binding interactions, structure-activity relationships (SAR), selectivity, and potencies are discussed. The focus of this article is on the compounds that are promising leads and undergoing advanced clinical investigations, as well as on those that received FDA approval. In this article, we attempt to classify the reviewed FMS inhibitors according to their core chemical structure including pyridine, pyrrolopyridine, pyrazolopyridine, quinoline, and pyrimidine derivatives.
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Affiliation(s)
- Bilal O Alkubaisi
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Raya Aljobowry
- College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Salma M Ali
- College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Sara Sultan
- College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Seyed-Omar Zaraei
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Anil Ravi
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Taleb H Al-Tel
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates.
| | - Mohammed I El-Gamal
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates; Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
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8
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Mi J, Wu X, Bai X, Yang Y, Yang H. ST2 and CSF-1 as potential druggable targets of inflammatory bowel diseases: Results from two-sample Mendelian randomization study. Clin Transl Sci 2022; 16:236-245. [PMID: 36333983 PMCID: PMC9926074 DOI: 10.1111/cts.13442] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 10/02/2022] [Accepted: 10/11/2022] [Indexed: 11/07/2022] Open
Abstract
Novel druggable targets are warranted for inflammatory bowel disease (IBD) treatment. We aimed to identify novel circulating proteins with causal associations with the risk of IBDs and provide potential therapeutic targets for IBD treatment. We performed a two-sample Mendelian randomization (MR) study to explore the associations of 55 circulating biomarkers on the risk of IBD, Crohn's disease (CD), and ulcerative colitis (UC) by leveraging the summary statistics from large genomewide association studies and protein quantitative trait loci studies. The individual estimate was pooled together by meta-analyses to estimate the causal effects of each outcome. In univariable MR, we identified several circulating proteins showed potential correlation with IBD, UC, and CD. Of note, we observed that a genetically proxied increased level of suppression of tumorigenicity 2 (ST2) was associated with an elevated risk of IBD (odds ratios [ORs] 1.133, 95% confidence interval [CI] 1.091-1.176, p < 0.0001), CD (ORs 1.188, 95% CI 1.103-1.281, p < 0.0001), and UC cohorts (ORs 1.087, 95% CI 1.050-1.125, p < 0.0001). Additionally, we observed a consistent positive correlation between the level of CSF-1 and the increased risk of IBD in individual MR, with statistically significant causal associations in the meta-analyses with ORs equal to 1.217 (IBD, 95% CI 1.115-1.328, p < 0.0001), 1.223 (CD, 95% CI 1.082-1.382, p = 0.0013), and 1.179 (UC, 95% CI 1.055-1.317, p = 0.0037). This study provided evidence for potential casual associations between circulating ST2 and CSF-1 levels, and increased risks of IBD, UC, and CD, implicating potential treatment targets for IBD and subtypes.
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Affiliation(s)
- Jiarui Mi
- Department of Gastroenterology, Peking Union Medical College HospitalPeking Union Medical College and Chinese Academy of Medical SciencesBeijingChina,Graduate SchoolChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Xia Wu
- Department of MedicineTufts Medical CenterMassachusettsBostonUSA
| | - Xiaoyin Bai
- Department of Gastroenterology, Peking Union Medical College HospitalPeking Union Medical College and Chinese Academy of Medical SciencesBeijingChina
| | - Yang Yang
- Department of Pharmacy, Peking Union Medical College HospitalPeking Union Medical College and Chinese Academy of Medical SciencesBeijingChina
| | - Hong Yang
- Department of Gastroenterology, Peking Union Medical College HospitalPeking Union Medical College and Chinese Academy of Medical SciencesBeijingChina
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9
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Cellular Carcinogenesis: Role of Polarized Macrophages in Cancer Initiation. Cancers (Basel) 2022; 14:cancers14112811. [PMID: 35681791 PMCID: PMC9179569 DOI: 10.3390/cancers14112811] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/26/2022] [Accepted: 06/02/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Inflammation is a hallmark of many cancers. Macrophages are key participants in innate immunity and important drivers of inflammation. When chronically polarized beyond normal homeostatic responses to infection, injury, or aging, macrophages can express several pro-carcinogenic phenotypes. In this review, evidence supporting polarized macrophages as endogenous sources of carcinogenesis is discussed. In addition, the depletion or modulation of macrophages by small molecule inhibitors and probiotics are reviewed as emerging strategies in cancer prevention. Abstract Inflammation is an essential hallmark of cancer. Macrophages are key innate immune effector cells in chronic inflammation, parainflammation, and inflammaging. Parainflammation is a form of subclinical inflammation associated with a persistent DNA damage response. Inflammaging represents low-grade inflammation due to the dysregulation of innate and adaptive immune responses that occur with aging. Whether induced by infection, injury, or aging, immune dysregulation and chronic macrophage polarization contributes to cancer initiation through the production of proinflammatory chemokines/cytokines and genotoxins and by modulating immune surveillance. This review presents pre-clinical and clinical evidence for polarized macrophages as endogenous cellular carcinogens in the context of chronic inflammation, parainflammation, and inflammaging. Emerging strategies for cancer prevention, including small molecule inhibitors and probiotic approaches, that target macrophage function and phenotype are also discussed.
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10
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Monteleone G, Franzè E, Troncone E, Maresca C, Marafini I. Interleukin-34 Mediates Cross-Talk Between Stromal Cells and Immune Cells in the Gut. Front Immunol 2022; 13:873332. [PMID: 35529879 PMCID: PMC9073079 DOI: 10.3389/fimmu.2022.873332] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 03/25/2022] [Indexed: 12/18/2022] Open
Abstract
Initially known as a cytokine produced by and regulating the function of monocytes and macrophages, interleukin-34 (IL-34) can be synthesized by many cell types and interacts with receptors expressed by multiple immune and non-immune cells. IL-34 is constitutively expressed in the healthy human small intestine and colon and its production is markedly increased in damaged gut of patients with Crohn's disease and patients with ulcerative colitis, the main forms of chronic inflammatory bowel diseases (IBD) in human beings. Circumstantial evidence suggests that, in these pathologies, IL-34 plays a crucial role in mediating cross-talk between immune cells and stromal cells, thereby promoting activation of signalling pathways, which amplify the ongoing mucosal inflammation as well as production of fibrogenic molecules. In this article, we summarize the available data supporting the multiple effects of IL-34 in human IBD with particular attention to the role of the cytokine in immune and stromal cell interactions.
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Affiliation(s)
- Giovanni Monteleone
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
- *Gastroenterology Unit, Policlinico Tor Vergata, Rome, Italy
| | - Eleonora Franzè
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Edoardo Troncone
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
- *Gastroenterology Unit, Policlinico Tor Vergata, Rome, Italy
| | - Claudia Maresca
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Irene Marafini
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
- *Gastroenterology Unit, Policlinico Tor Vergata, Rome, Italy
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Clark R, Lira-Junior R, Johannsen G, Boström EA. Colony-stimulating factor-1 receptor blockade attenuates inflammation in inflamed gingival tissue explants. J Periodontal Res 2021; 56:1141-1153. [PMID: 34510422 DOI: 10.1111/jre.12926] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 08/26/2021] [Indexed: 12/26/2022]
Abstract
BACKGROUND AND OBJECTIVE Colony-stimulating factor-1 receptor (CSF-1R) regulates myeloid cell function and mediates osteoclastogenesis. CSF-1R blockade has been suggested as a potential therapeutic target to halt inflammation and bone resorption; however, the expression and function of CSF-1R in human gingiva is yet unknown. METHODS Gingival tissue was collected from 22 non-periodontitis controls and 31 periodontitis (PD) patients. CSF-1R expression in gingival tissue was assessed with q-PCR, western blot, and immunohistochemistry (IHC). Cell surface expression of CSF-1R was analyzed by flow cytometry. The effects of CSF-1R inhibition on the production of inflammatory mediators by inflamed gingival tissue explants and peripheral blood mononuclear cells (PBMCs) were assessed with a bead-based multiplex array and ELISA. RESULTS CSF-1R protein expression was increased in gingival tissue from PD patients compared with controls as assessed with western blot (1.5-fold increase) and IHC (4.5-fold increase). Similar proportions of HLA-DR+ CD64+ cells and comparable CSF-1R expression in this cell population were found in gingival tissue from PD patients and controls. In peripheral blood monocytes, CSF-1R was predominantly expressed by non-classical and intermediate monocytes. Targeting CSF-1R in gingival tissue explants attenuated the production of MMP-1, MMP-2, MMP-12, and MMP-13. The blocking in PBMCs attenuated the production of IL-8 and MMP-9. CONCLUSION These results indicate that CSF-1R is elevated in PD, and its inhibition attenuates inflammatory mediators in the inflamed gingival tissue and circulating myeloid cells. Together these findings suggest that CSF-1R might be involved in regulating inflammatory processes in PD, and a potential therapeutic target to reduce the harmful inflammation.
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Affiliation(s)
- Reuben Clark
- Department of Dental Medicine, Division of Oral diagnostics and Rehabilitation, Karolinska Institutet, Huddinge, Sweden
| | - Ronaldo Lira-Junior
- Department of Dental Medicine, Division of Oral diagnostics and Rehabilitation, Karolinska Institutet, Huddinge, Sweden
| | - Gunnar Johannsen
- Department of Dental Medicine, Division of Oral Diseases, Karolinska Institutet, Huddinge, Sweden
| | - Elisabeth A Boström
- Department of Dental Medicine, Division of Oral diagnostics and Rehabilitation, Karolinska Institutet, Huddinge, Sweden.,Department of Orofacial Medicine, Folktandvården Stockholms Län AB, Stockholm, Sweden
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Sletta KY, Castells O, Gjertsen BT. Colony Stimulating Factor 1 Receptor in Acute Myeloid Leukemia. Front Oncol 2021; 11:654817. [PMID: 33842370 PMCID: PMC8027480 DOI: 10.3389/fonc.2021.654817] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 03/03/2021] [Indexed: 11/13/2022] Open
Abstract
Acute myeloid leukemia (AML) is an aggressive heterogeneous blood cancer derived from hematopoietic stem cells. Tumor-stromal interactions in AML are of importance for disease development and therapy resistance, and bone marrow stroma seem like an attractive therapeutic target. Of particular interest is colony stimulating factor 1 receptor (CSF1R, M-CSFR, c-FMS, CD115) and its role in regulating plasticity of tumor-associated macrophages. We discuss first the potential of CSF1R-targeted therapy as an attractive concept with regards to the tumor microenvironment in the bone marrow niche. A second therapy approach, supported by preclinical research, also suggests that CSF1R-targeted therapy may increase the beneficial effect of conventional and novel therapeutics. Experimental evidence positioning inhibitors of CSF1R as treatment should, together with data from preclinical and early phase clinical trials, facilitate translation and clinical development of CSF1R-targeted therapy for AML.
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Affiliation(s)
- Kristine Yttersian Sletta
- CCBIO, Centre for Cancer Biomarkers, Department of Clinical Science, Precision Oncology Research Group, University of Bergen, Bergen, Norway
| | - Oriol Castells
- Department of Medicine, Hematology Section, Haukeland University Hospital, Bergen, Norway
| | - Bjørn Tore Gjertsen
- CCBIO, Centre for Cancer Biomarkers, Department of Clinical Science, Precision Oncology Research Group, University of Bergen, Bergen, Norway
- Department of Medicine, Hematology Section, Haukeland University Hospital, Bergen, Norway
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Zhou Y, Zeng J, Tu Y, Li L, Du S, Zhu L, Cang X, Lu J, Zhu M, Liu X. CSF1/CSF1R-mediated Crosstalk Between Choroidal Vascular Endothelial Cells and Macrophages Promotes Choroidal Neovascularization. Invest Ophthalmol Vis Sci 2021; 62:37. [PMID: 33764399 PMCID: PMC7995352 DOI: 10.1167/iovs.62.3.37] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Purpose This study examined the role of the CSF1/CSF1Raxis in the crosstalk between choroidal vascular endothelial cells (CVECs) and macrophages during the formation of choroidal neovascularization (CNV). Methods Quantitative reverse transcriptase (QRT)-PCR, Western blot and ELISA measured the production and release of CSF1 from human choroidal vascular endothelial cells (HCVECs) under hypoxic conditions. Western blot detected CSF1 released from HCVECs under hypoxic conditions that activated the PI3K/AKT/FOXO1 axis in human macrophages via binding to CSF1R. Transwell migration assay, qRT-PCR, and Western blot detected the effect of CSF1 released from HCVECs on macrophage migration and M2 polarization via the CSF1R/PI3K/AKT/FOXO1 pathway. Incorporation of 5-ethynyl-20-deoxyuridine, transwell migration, and tube formation assays detected the effects of CSF1/CSF1R on the behaviors of HCVECs. Fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA), and immunofluorescence detected the effect of blockade of CSF1/CSF1R on mouse laser-induced CNV. Color fundus photograph, ICGA, and FFA detected CNV lesions in neovascular AMD (nAMD) patients. ELISA detected CSF1 and CSF1R in the aqueous humor of age-related cataract and nAMD patients. Results CSF1 released from HCVECs under hypoxic conditions activated the PI3K/AKT/FOXO1 axis in human macrophages via binding to CSF1R, promoting macrophage migration and M2 polarization via up-regulation of the CSF1R/PI3K/AKT/FOXO1 pathway. Human macrophages promoted the proliferation, migration, and tube formation of HCVECs in a CSF1/CSFR1-dependent manner under hypoxic conditions. CSF1/CSF1R blockade ameliorated the formation of mouse laser-induced CNV. CSF1 and CSF1R were increased in the aqueous humor of nAMD patients. Conclusions Our results affirmed the crucial role of CSF1/CSF1R in boosting the formation of CNV and offered potential molecular targets for the treatment of nAMD.
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Affiliation(s)
- Yamei Zhou
- Department of Pathogen Biology, Medical College, Nantong University, Nantong, Jiangsu, China
| | - Jia Zeng
- Department of Pathogen Biology, Medical College, Nantong University, Nantong, Jiangsu, China
| | - Yuanyuan Tu
- Department of Ophthalmology, Lixiang Eye Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Lele Li
- Department of Ophthalmology, the Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Shu Du
- Department of Ophthalmology, Lixiang Eye Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Linling Zhu
- Department of Ophthalmology, Lixiang Eye Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Xiaomin Cang
- Department of Endocrinology, the Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Jiajie Lu
- Medical College, Nantong University, Nantong, Jiangsu, China
| | - Manhui Zhu
- Department of Ophthalmology, Lixiang Eye Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Xiaojuan Liu
- Department of Pathogen Biology, Medical College, Nantong University, Nantong, Jiangsu, China
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Chen Z, Wu A. Progress and challenge for computational quantification of tissue immune cells. Brief Bioinform 2021; 22:6065002. [PMID: 33401306 DOI: 10.1093/bib/bbaa358] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/23/2020] [Accepted: 11/07/2020] [Indexed: 12/28/2022] Open
Abstract
Tissue immune cells have long been recognized as important regulators for the maintenance of balance in the body system. Quantification of the abundance of different immune cells will provide enhanced understanding of the correlation between immune cells and normal or abnormal situations. Currently, computational methods to predict tissue immune cell compositions from bulk transcriptomes have been largely developed. Therefore, summarizing the advantages and disadvantages is appropriate. In addition, an examination of the challenges and possible solutions for these computational models will assist the development of this field. The common hypothesis of these models is that the expression of signature genes for immune cell types might represent the proportion of immune cells that contribute to the tissue transcriptome. In general, we grouped all reported tools into three groups, including reference-free, reference-based scoring and reference-based deconvolution methods. In this review, a summary of all the currently reported computational immune cell quantification tools and their applications, limitations, and perspectives are presented. Furthermore, some critical problems are found that have limited the performance and application of these models, including inadequate immune cell type, the collinearity problem, the impact of the tissue environment on the immune cell expression level, and the deficiency of standard datasets for model validation. To address these issues, tissue specific training datasets that include all known immune cells, a hierarchical computational framework, and benchmark datasets including both tissue expression profiles and the abundances of all the immune cells are proposed to further promote the development of this field.
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Affiliation(s)
- Ziyi Chen
- Suzhou Institute of Systems Medicine, Center for Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Jiangsu, Suzhou, China
| | - Aiping Wu
- Suzhou Institute of Systems Medicine, Center for Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Jiangsu, Suzhou, China
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Denny WA, Flanagan JU. Small-molecule CSF1R kinase inhibitors; review of patents 2015-present. Expert Opin Ther Pat 2020; 31:107-117. [PMID: 33108917 DOI: 10.1080/13543776.2021.1839414] [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] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Colony stimulating factor 1 receptor (CSF-1R, also known as c-FMS kinase) is in the class III receptor tyrosine kinase family, along with c-Kit, Flt3 and PDGFRα. CSF-1/CSF-1R signaling promotes the differentiation and survival of myeloid progenitors into populations of monocytes, macrophages, dendritic cells and osteoclasts, as well as microglial cells and also recruits host macrophages to develop into tumor-associated macrophages (TAMs), which promote tumor progression and metastasis. AREAS COVERED In the last 5 years, and recently stimulated by the approval of pexidartinib (Turalio™, Daiichi Sankyo) in 2019 for the treatment of tenosynovial giant cell tumors, there has been a large increase in activity (both journal articles and patent applications) around small molecule inhibitors of CSF1R. Features of this work have been the surprising diversity of chemical classes shown to be potent and selective inhibitors, and the breadth of disease states (cancer, arthritis, and 'cytokine storm' syndromes) covered by CSF1R inhibitors. All these aspects are covered in the following sections. EXPERT OPINION The field has developed rapidly from 2014 to the present, with many different chemotypes proving to be potent inhibitors. The range of potential utilities of CSF1R inhibitors has also expanded to include dementia, ulcerative colitis/Crohn's disease, rheumatoid arthritis inflammation, and fibrosis.
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Affiliation(s)
- William A Denny
- Auckland Cancer Society Research Centre, School of Medical Sciences and Maurice Wilkins Centre, University of Auckland , Auckland, New Zealand
| | - Jack U Flanagan
- Auckland Cancer Society Research Centre, School of Medical Sciences and Maurice Wilkins Centre, University of Auckland , Auckland, New Zealand.,Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, University of Auckland , Auckland, New Zealand
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