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Greenman R, Weston CJ. CCL24 and Fibrosis: A Narrative Review of Existing Evidence and Mechanisms. Cells 2025; 14:105. [PMID: 39851534 PMCID: PMC11763828 DOI: 10.3390/cells14020105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Revised: 01/06/2025] [Accepted: 01/10/2025] [Indexed: 01/26/2025] Open
Abstract
Tissue fibrosis results from a dysregulated and chronic wound healing response accompanied by chronic inflammation and angiogenesis. Regardless of the affected organ, fibrosis shares the following common hallmarks: the recruitment of immune cells, fibroblast activation/proliferation, and excessive extracellular matrix deposition. Chemokines play a pivotal role in initiating and advancing these fibrotic processes. CCL24 (eotaxin-2) is a chemokine secreted by immune cells and epithelial cells, which promotes the trafficking of immune cells and the activation of profibrotic cells through CCR3 receptor binding. Higher levels of CCL24 and CCR3 were found in the tissue and sera of patients with fibro-inflammatory diseases, including primary sclerosing cholangitis (PSC), systemic sclerosis (SSc), and metabolic dysfunction-associated steatohepatitis (MASH). This review delves into the intricate role of CCL24 in fibrotic diseases, highlighting its impact on fibrotic, immune, and vascular pathways. We focus on the preclinical and clinical evidence supporting the therapeutic potential of blocking CCL24 in diseases that involve excessive inflammation and fibrosis.
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Affiliation(s)
| | - Chris J. Weston
- Department of Immunology and Immunotherapy, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham B15 2TT, UK
- National Institute for Health and Care Research (NIHR), Birmingham Biomedical Research Centre, Birmingham B15 2TT, UK
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Mor A, Friedman S, Hashmueli S, Peled A, Pinzani M, Frankel M, Safadi R. Targeting CCL24 in Inflammatory and Fibrotic Diseases: Rationale and Results from Three CM-101 Phase 1 Studies. Drug Saf 2024; 47:869-881. [PMID: 38822943 PMCID: PMC11324678 DOI: 10.1007/s40264-024-01436-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/17/2024] [Indexed: 06/03/2024]
Abstract
BACKGROUND Overexpression of C-C motif chemokine ligand 24 (CCL24) is associated with inflammatory and fibrotic diseases, including primary sclerosing cholangitis (PSC), systemic sclerosis, metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). CM-101 is a humanized monoclonal antibody that neutralizes CCL24 to attenuate inflammation and fibrosis in preclinical models. Here we report the results from two Phase 1a studies investigating the safety and tolerability of intravenous (IV) and subcutaneous (SC) CM-101 in healthy participants, and in one Phase 1b study of IV and SC CM-101 in patients with MASLD without evidence of MASH. METHODS In each dose group (0.75 mg/kg, 2.5 mg/kg, 5.0 mg/kg, and 10.0 mg/kg) of the single-center, double-blind, placebo-controlled Phase 1a IV study, healthy volunteers were randomized 3:1 to receive a single IV infusion of CM-101 or placebo. In another Phase 1a, single-center, double-blind placebo-controlled study, healthy volunteers were randomized 3:1 to receive a single SC injection of CM-101 5.0 mg/kg or placebo. In the multicenter, double-blind, placebo-controlled Phase 1b MASLD study, patients with MASLD without evidence of MASH were randomized 3:1 to receive the following: cohort 1, IV CM-101 2.5 mg/kg or placebo, and cohort 2, SC CM-101 5.0 mg/kg or placebo every three weeks for 12 weeks. The primary endpoints (for all these studies) were safety, tolerability, and serum pharmacokinetic parameters of CM-101. RESULTS In each study, adverse events were rare and mild to moderate. The CM-101 pharmacokinetics profile was typical of a monoclonal antibody, with a terminal half-life of approximately 19 days when given IV and approximately 17 days when given as SC injection. In patients with MASLD without evidence of MASH, CM-101 was associated with decreased serum levels of inflammatory, fibrotic, and collagen turnover biomarkers. CONCLUSIONS In healthy volunteers and patients with MASLD without evidence of MASH, IV and SC CM-101 was well tolerated at doses ranging from 0.75 mg/kg to10.0 mg/kg and engaged its target (i.e., CCL24), indicating therapeutic potential in treating inflammatory and fibrotic diseases. CLINICAL TRIAL RETROSPECTIVELY REGISTRATION NCT06025851, NCT06037577, and NCT06044467. Date of registration: September 2023.
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MESH Headings
- Humans
- Double-Blind Method
- Male
- Female
- Adult
- Middle Aged
- Chemokine CCL24
- Antibodies, Monoclonal, Humanized/adverse effects
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/pharmacokinetics
- Antibodies, Monoclonal, Humanized/pharmacology
- Injections, Subcutaneous
- Dose-Response Relationship, Drug
- Inflammation/drug therapy
- Young Adult
- Fibrosis/drug therapy
- Aged
- Fatty Liver/drug therapy
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Affiliation(s)
- Adi Mor
- Chemomab Therapeutics, Kiryat Atidim, Building 7, 6158002, Tel Aviv, Israel.
| | - Scott Friedman
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sharon Hashmueli
- Chemomab Therapeutics, Kiryat Atidim, Building 7, 6158002, Tel Aviv, Israel
| | - Amnon Peled
- Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital, Jerusalem, Israel
| | - Massimo Pinzani
- UCL Institute for Liver and Digestive Health, University College of London, Royal Free Hospital, London, UK
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK
| | - Matthew Frankel
- Chemomab Therapeutics, Kiryat Atidim, Building 7, 6158002, Tel Aviv, Israel
| | - Rifaat Safadi
- Department of Medicine, Liver Institute, Hebrew University, Hadassah Medical Organization, Jerusalem, Israel
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Pham HN, Pham L, Sato K. Navigating the liver landscape: upcoming pharmacotherapies for primary sclerosing cholangitis. Expert Opin Pharmacother 2024; 25:895-906. [PMID: 38813599 DOI: 10.1080/14656566.2024.2362263] [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: 04/07/2024] [Accepted: 05/28/2024] [Indexed: 05/31/2024]
Abstract
INTRODUCTION Primary sclerosing cholangitis (PSC) is a bile duct disorder characterized by ductular reaction, hepatic inflammation, and liver fibrosis. The pathogenesis of PSC is still undefined, and treatment options for patients are limited. Previous clinical trials evaluated drug candidates targeting various cellular functions and pathways, such as bile acid signaling and absorption, gut bacteria and permeability, and lipid metabolisms. However, most of phase III clinical trials for PSC were disappointing, except vancomycin therapy, and there are still no established medications for PSC with efficacy and safety confirmed by phase IV clinical trials. AREAS COVERED This review summarizes the currently ongoing or completed clinical studies for PSC, which are phase II or further, and discusses therapeutic targets and strategies, limitations, and future directions and possibilities of PSC treatments. A literature search was conducted in PubMed and ClinicalTrials.gov utilizing the combination of the searched term 'primary sclerosing cholangitis' with other keywords, such as 'clinical trials,' 'antibiotics,' or drug names. Clinical trials at phase II or further were included for consideration. EXPERT OPINION Only vancomycin demonstrated promising therapeutic effects in the phase III clinical trial. Other drug candidates showed futility or inconsistent results, and the search for novel PSC treatments is still ongoing.
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Affiliation(s)
- Hoang Nam Pham
- Department of Life Sciences, University of Science and Technology of Hanoi, Vietnam Academy of Science and Technology, Hanoi, Vietnam
| | - Linh Pham
- Department of Science and Mathematics, Texas A&M University - Central Texas, Killeen, TX, USA
| | - Keisaku Sato
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA
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Ergun P, Kipcak S, Selvi Gunel N, Yildirim Sozmen E, Bor S. Inflammatory responses in esophageal mucosa before and after laparoscopic antireflux surgery. World J Gastrointest Surg 2024; 16:871-881. [PMID: 38577078 PMCID: PMC10989346 DOI: 10.4240/wjgs.v16.i3.871] [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: 12/05/2023] [Revised: 01/12/2024] [Accepted: 02/28/2024] [Indexed: 03/22/2024] Open
Abstract
BACKGROUND Currently, the primary treatment for gastroesophageal reflux is acid suppression with proton pump inhibitors, but they are not a cure, and some patients don't respond well or refuse long-term use. Therefore, alternative therapies are needed to understand the disease and develop better treatments. Laparoscopic anti-reflux surgery (LARS) can resolve symptoms of these patients and plays a significant role in evaluating esophageal healing after preventing harmful effects. Successful LARS improves typical gastroesophageal reflux symptoms in most patients, mainly by reducing the exposure time to gastric contents in the esophagus. Amelioration of the inflammatory response and a recovery response in the esophageal epithelium is expected following the cessation of the noxious attack. AIM To explore the role of inflammatory biomolecules in LARS and assess the time required for esophageal epithelial recovery. METHODS Of 22 patients with LARS (pre- and post/5.8 ± 3.8 months after LARS) and 25 healthy controls (HCs) were included. All subjects underwent 24-h multichannel intraluminal impedance-pH monitoring and upper gastrointestinal endoscopy, during which esophageal biopsy samples were collected using endoscopic techniques. Inflammatory molecules in esophageal biopsies were investigated by reverse transcription-polymerase chain reaction and multiplex-enzyme-linked immunosorbent assay. RESULTS Post-LARS samples showed significant increases in proinflammatory cytokines [interleukin (IL)-1β, interferon-γ, C-X-C chemokine ligand 2 (CXCL2)], anti-inflammatory cytokines [CC chemokine ligand (CCL) 11, CCL13, CCL17, CCL26, CCL1, CCL7, CCL8, CCL24, IL-4, IL-10], and homeostatic cytokines (CCL27, CCL20, CCL19, CCL23, CCL25, CXCL12, migration inhibitory factor) compared to both HCs and pre-LARS samples. CCL17 and CCL21 levels were higher in pre-LARS than in HCs (P < 0.05). The mRNA expression levels of AKT1, fibroblast growth factor 2, HRAS, and mitogen-activated protein kinase 4 were significantly decreased post-LARS vs pre-LARS. CCL2 and epidermal growth factor gene levels were significantly increased in the pre-LARS compared to the HCs (P < 0.05). CONCLUSION The presence of proinflammatory proteins post-LARS suggests ongoing inflammation in the epithelium. Elevated homeostatic cytokine levels indicate cell balance is maintained for about 6 months after LARS. The anti-inflammatory response post-LARS shows suppression of inflammatory damage and ongoing postoperative recovery.
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Affiliation(s)
- Pelin Ergun
- Department of Otolaryngology, Medical College of Wisconsin, Milwaukee, WI 53226, United States
- Division of Gastroenterology, Ege University, Faculty of Medicine, Ege Reflux Group, Izmir 35100, Turkiye
| | - Sezgi Kipcak
- Division of Gastroenterology, Ege University, Faculty of Medicine, Ege Reflux Group, Izmir 35100, Turkiye
- Department of Medical Biology, Ege University, Faculty of Medicine, Izmir 35100, Turkiye
| | - Nur Selvi Gunel
- Department of Medical Biology, Ege University, Faculty of Medicine, Izmir 35100, Turkiye
| | - Eser Yildirim Sozmen
- Department of Medical Biochemistry, Ege University, Faculty of Medicine, Izmir 35100, Turkiye
| | - Serhat Bor
- Division of Gastroenterology, Ege University, Faculty of Medicine, Ege Reflux Group, Izmir 35100, Turkiye
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Meizlish ML, Kimura Y, Pope SD, Matta R, Kim C, Philip NH, Meyaard L, Gonzalez A, Medzhitov R. Mechanosensing regulates tissue repair program in macrophages. SCIENCE ADVANCES 2024; 10:eadk6906. [PMID: 38478620 PMCID: PMC10936955 DOI: 10.1126/sciadv.adk6906] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 01/29/2024] [Indexed: 03/17/2024]
Abstract
Tissue-resident macrophages play important roles in tissue homeostasis and repair. However, how macrophages monitor and maintain tissue integrity is not well understood. The extracellular matrix (ECM) is a key structural and organizational component of all tissues. Here, we find that macrophages sense the mechanical properties of the ECM to regulate a specific tissue repair program. We show that macrophage mechanosensing is mediated by cytoskeletal remodeling and can be performed in three-dimensional environments through a noncanonical, integrin-independent mechanism analogous to amoeboid migration. We find that these cytoskeletal dynamics also integrate biochemical signaling by colony-stimulating factor 1 and ultimately regulate chromatin accessibility to control the mechanosensitive gene expression program. This study identifies an "amoeboid" mode of ECM mechanosensing through which macrophages may regulate tissue repair and fibrosis.
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Affiliation(s)
- Matthew L. Meizlish
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Yoshitaka Kimura
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
| | - Scott D. Pope
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
| | - Rita Matta
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Catherine Kim
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Naomi H. Philip
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
| | - Linde Meyaard
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Oncode Institute, Utrecht, Netherlands
| | - Anjelica Gonzalez
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Ruslan Medzhitov
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
- Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA
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Wang X, Zhang Y, Song A, Wang H, Wu Y, Chang W, Tian B, Xu J, Dai H, Ma Q, Wang C, Zhou X. A Printable Hydrogel Loaded with Medicinal Plant Extract for Promoting Wound Healing. Adv Healthc Mater 2024; 13:e2303017. [PMID: 38273733 DOI: 10.1002/adhm.202303017] [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: 09/09/2023] [Revised: 01/16/2024] [Indexed: 01/27/2024]
Abstract
How to promote wound healing is still a major challenge in the healthcare while macrophages are a critical component of the healing process. Compared to various bioactive drugs, many plants have been reported to facilitate the wound healing process by regulating the immune response of wounds. In this work, a Three-dimensional (3D) printed hydrogel scaffold loaded with natural Centella asiatica extract (CA extract) is developed for wound healing. This CA@3D scaffold uses gelatin (Gel) and sodium alginate (SA) with CA extract as bio-ink for 3D printing. The CA extract contains a variety of bioactive compounds that make the various active ingredients in Centella asiatica work in concert. The printed CA@3D scaffold can fit the shape of wound, orchestrate the macrophages and immune responses within the wound, and promote wound healing compared to commercial wound dressings. The underlying mechanism of promoting wound healing is also illuminated by applying multi-omic analyses. Moreover, the CA extract loaded 3D scaffold also showed great ability to promote wound healing in diabetic chronic wounds. Due to its ease of preparation, low-cost, biosafety, and therapeutic outcomes, this work proposes an effective strategy for promoting chronic wound healing.
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Affiliation(s)
- Xiaoyu Wang
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Yue Zhang
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Anning Song
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Heng Wang
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Yi Wu
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Wenju Chang
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215123, China
- Department of Orthopedics, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, 233004, China
| | - Bo Tian
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215123, China
| | - Jialu Xu
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Huaxing Dai
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Qingle Ma
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Chao Wang
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Xiaozhong Zhou
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215123, China
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7
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Pan J, Ye F, Li H, Yu C, Mao J, Xiao Y, Chen H, Wu J, Li J, Fei L, Wu Y, Meng X, Guo G, Wang Y. Dissecting the immune discrepancies in mouse liver allograft tolerance and heart/kidney allograft rejection. Cell Prolif 2024; 57:e13555. [PMID: 37748771 PMCID: PMC10905343 DOI: 10.1111/cpr.13555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 08/23/2023] [Accepted: 09/15/2023] [Indexed: 09/27/2023] Open
Abstract
The liver is the most tolerogenic of transplanted organs. However, the mechanisms underlying liver transplant tolerance are not well understood. The comparison between liver transplantation tolerance and heart/kidney transplantation rejection will deepen our understanding of tolerance and rejection in solid organs. Here, we built a mouse model of liver, heart and kidney allograft and performed single-cell RNA sequencing of 66,393 cells to describe the cell composition and immune cell interactions at the early stage of tolerance or rejection. We also performed bulk RNA-seq of mouse liver allografts from Day 7 to Day 60 post-transplantation to map the dynamic transcriptional variation in spontaneous tolerance. The transcriptome of lymphocytes and myeloid cells were characterized and compared in three types of organ allografts. Cell-cell interaction networks reveal the coordinated function of Kupffer cells, macrophages and their associated metabolic processes, including insulin receptor signalling and oxidative phosphorylation in tolerance induction. Cd11b+ dendritic cells (DCs) in liver allografts were found to inhibit cytotoxic T cells by secreting anti-inflammatory cytokines such as Il10. In summary, we profiled single-cell transcriptome analysis of mouse solid organ allografts. We characterized the immune microenvironment of mouse organ allografts in the acute rejection state (heart, kidney) and tolerance state (liver).
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Affiliation(s)
- Jun Pan
- Department of Thyroid Surgery, the First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
| | - Fang Ye
- Liangzhu LaboratoryZhejiang UniversityHangzhouChina
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Hui Li
- Key Laboratory of Combined Multiorgan Transplantation, Ministry of Public Health, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
| | - Chengxuan Yu
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Jiajia Mao
- Kidney Disease Center, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
| | - Yanyu Xiao
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Haide Chen
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Junqing Wu
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Jiaqi Li
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Lijiang Fei
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Yijun Wu
- Department of Thyroid Surgery, the First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
| | - Xiaoming Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of PharmacyAnhui Medical University, The Key Laboratory of Anti‐inflammatory of Immune Medicines, Ministry of EducationHefeiChina
| | - Guoji Guo
- Liangzhu LaboratoryZhejiang UniversityHangzhouChina
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative MedicineDr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative MedicineHangzhouZhejiangChina
| | - Yingying Wang
- Kidney Disease Center, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
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Greenman R, Snir T, Katav A, Aricha R, Mishalian I, Hay O, Frankel M, Lawler J, Saffioti F, Pinzani M, Thorburn D, Peled A, Mor A, Vaknin I. The Role of CCL24 in Primary Sclerosing Cholangitis: Bridging Patient Serum Proteomics to Preclinical Data. Cells 2024; 13:209. [PMID: 38334601 PMCID: PMC10854794 DOI: 10.3390/cells13030209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/15/2024] [Accepted: 01/19/2024] [Indexed: 02/10/2024] Open
Abstract
Primary sclerosing cholangitis (PSC) is an inflammatory and fibrotic biliary disease lacking approved treatment. We studied CCL24, a chemokine shown to be overexpressed in damaged bile ducts, and its involvement in key disease-related mechanisms. Serum proteomics of PSC patients and healthy controls (HC) were analyzed using the Olink® proximity extension assay and compared based on disease presence, fibrosis severity, and CCL24 levels. Disease-related canonical pathways, upstream regulators, and toxicity functions were elevated in PSC patients compared to HC and further elevated in patients with high CCL24 levels. In vitro, a protein signature in CCL24-treated hepatic stellate cells (HSCs) differentiated patients by disease severity. In mice, CCL24 intraperitoneal injection selectively recruited neutrophils and monocytes. Treatment with CM-101, a CCL24-neutralizing antibody, in an α-naphthylisothiocyanate (ANIT)-induced cholestasis mouse model effectively inhibited accumulation of peribiliary neutrophils and macrophages while reducing biliary hyperplasia and fibrosis. Furthermore, in PSC patients, CCL24 levels were correlated with upregulation of monocyte and neutrophil chemotaxis pathways. Collectively, these findings highlight the distinct role of CCL24 in PSC, influencing disease-related mechanisms, affecting immune cells trafficking and HSC activation. Its blockade with CM-101 reduces inflammation and fibrosis and positions CCL24 as a promising therapeutic target in PSC.
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Affiliation(s)
| | - Tom Snir
- Chemomab Therapeutics Ltd., Tel Aviv 6158002, Israel
| | - Avi Katav
- Chemomab Therapeutics Ltd., Tel Aviv 6158002, Israel
| | | | - Inbal Mishalian
- Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital Jerusalem, Jerusalem 91120, Israel
| | - Ophir Hay
- Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital Jerusalem, Jerusalem 91120, Israel
| | | | - John Lawler
- Chemomab Therapeutics Ltd., Tel Aviv 6158002, Israel
| | - Francesca Saffioti
- UCL Institute for Liver and Digestive Health, University College of London, London NW3 2PF, UK
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
- Department of Gastroenterology and Hepatology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UK
| | - Massimo Pinzani
- UCL Institute for Liver and Digestive Health, University College of London, London NW3 2PF, UK
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
| | - Douglas Thorburn
- UCL Institute for Liver and Digestive Health, University College of London, London NW3 2PF, UK
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
| | - Amnon Peled
- Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital Jerusalem, Jerusalem 91120, Israel
| | - Adi Mor
- Chemomab Therapeutics Ltd., Tel Aviv 6158002, Israel
| | - Ilan Vaknin
- Chemomab Therapeutics Ltd., Tel Aviv 6158002, Israel
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9
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Wang S, Li G, Liang X, Wu Z, Chen C, Zhang F, Niu J, Li X, Yan J, Wang N, Li J, Wang Y. Small Extracellular Vesicles Derived from Altered Peptide Ligand-Loaded Dendritic Cell Act as A Therapeutic Vaccine for Spinal Cord Injury Through Eliciting CD4 + T cell-Mediated Neuroprotective Immunity. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2304648. [PMID: 38037457 PMCID: PMC10797491 DOI: 10.1002/advs.202304648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 10/13/2023] [Indexed: 12/02/2023]
Abstract
The balance among different CD4+ T cell subsets is crucial for repairing the injured spinal cord. Dendritic cell (DC)-derived small extracellular vesicles (DsEVs) effectively activate T-cell immunity. Altered peptide ligands (APLs), derived from myelin basic protein (MBP), have been shown to affect CD4+ T cell subsets and reduce neuroinflammation levels. However, the application of APLs is challenging because of their poor stability and associated side effects. Herein, it is demonstrate that DsEVs can act as carriers for APL MBP87-99 A91 (A91-DsEVs) to induce the activation of 2 helper T (Th2) and regulatory T (Treg) cells for spinal cord injury (SCI) in mice. These stimulated CD4+ T cells can efficiently "home" to the lesion area and establish a beneficial microenvironment through inducing the activation of M2 macrophages/microglia, inhibiting the expression of inflammatory cytokines, and increasing the release of neurotrophic factors. The microenvironment mediated by A91-DsEVs may enhance axon regrowth, protect neurons, and promote remyelination, which may support the recovery of motor function in the SCI model mice. In conclusion, using A91-DsEVs as a therapeutic vaccine may help induce neuroprotective immunity in the treatment of SCI.
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Affiliation(s)
- Sikai Wang
- Department of Orthopedic SurgerySecond Affiliated Hospital of Harbin Medical UniversityNo. 246 Baojian RoadHarbin150086China
- Heilongjiang Provincial Key Laboratory of Hard Tissue Development and RegenerationThe Second Affiliated Hospital of Harbin Medical UniversityNo. 246 Baojian RoadHarbin150086China
| | - Guanglei Li
- Department of Orthopedic SurgerySecond Affiliated Hospital of Harbin Medical UniversityNo. 246 Baojian RoadHarbin150086China
| | - Xiongjie Liang
- Department of Orthopedic SurgerySecond Affiliated Hospital of Harbin Medical UniversityNo. 246 Baojian RoadHarbin150086China
| | - Zexuan Wu
- Department of Orthopedic SurgerySecond Affiliated Hospital of Harbin Medical UniversityNo. 246 Baojian RoadHarbin150086China
| | - Chao Chen
- Faculty of Medicine and DentistryUniversity of AlbertaEdmontonT5C 0T2Canada
| | - Fawang Zhang
- Department of Orthopedic SurgerySecond Affiliated Hospital of Harbin Medical UniversityNo. 246 Baojian RoadHarbin150086China
| | - Jiawen Niu
- Department of Orthopedic SurgerySecond Affiliated Hospital of Harbin Medical UniversityNo. 246 Baojian RoadHarbin150086China
- Heilongjiang Provincial Key Laboratory of Hard Tissue Development and RegenerationThe Second Affiliated Hospital of Harbin Medical UniversityNo. 246 Baojian RoadHarbin150086China
| | - Xuefeng Li
- Department of Orthopedic SurgerySecond Affiliated Hospital of Harbin Medical UniversityNo. 246 Baojian RoadHarbin150086China
| | - Jinglong Yan
- Department of Orthopedic SurgerySecond Affiliated Hospital of Harbin Medical UniversityNo. 246 Baojian RoadHarbin150086China
| | - Nanxiang Wang
- Department of Orthopedic SurgerySecond Affiliated Hospital of Harbin Medical UniversityNo. 246 Baojian RoadHarbin150086China
| | - Jing Li
- Department of Pathology and Electron MicroscopyFaculty of Basic Medical ScienceHarbin Medical UniversityNo. 157 Baojian RoadHarbin150086China
| | - Yufu Wang
- Department of Orthopedic SurgerySecond Affiliated Hospital of Harbin Medical UniversityNo. 246 Baojian RoadHarbin150086China
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10
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Elbaz-Hayoun S, Rinsky B, Hagbi-Levi S, Grunin M, Chowers I. CCR1 mediates Müller cell activation and photoreceptor cell death in macular and retinal degeneration. eLife 2023; 12:e81208. [PMID: 37903056 PMCID: PMC10615370 DOI: 10.7554/elife.81208] [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: 06/19/2022] [Accepted: 10/04/2023] [Indexed: 11/01/2023] Open
Abstract
Mononuclear cells are involved in the pathogenesis of retinal diseases, including age-related macular degeneration (AMD). Here, we examined the mechanisms that underlie macrophage-driven retinal cell death. Monocytes were extracted from patients with AMD and differentiated into macrophages (hMdɸs), which were characterized based on proteomics, gene expression, and ex vivo and in vivo properties. Using bioinformatics, we identified the signaling pathway involved in macrophage-driven retinal cell death, and we assessed the therapeutic potential of targeting this pathway. We found that M2a hMdɸs were associated with retinal cell death in retinal explants and following adoptive transfer in a photic injury model. Moreover, M2a hMdɸs express several CCRI (C-C chemokine receptor type 1) ligands. Importantly, CCR1 was upregulated in Müller cells in models of retinal injury and aging, and CCR1 expression was correlated with retinal damage. Lastly, inhibiting CCR1 reduced photic-induced retinal damage, photoreceptor cell apoptosis, and retinal inflammation. These data suggest that hMdɸs, CCR1, and Müller cells work together to drive retinal and macular degeneration, suggesting that CCR1 may serve as a target for treating these sight-threatening conditions.
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Affiliation(s)
- Sarah Elbaz-Hayoun
- Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of JerusalemJerusalemIsrael
| | - Batya Rinsky
- Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of JerusalemJerusalemIsrael
| | - Shira Hagbi-Levi
- Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of JerusalemJerusalemIsrael
| | - Michelle Grunin
- Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of JerusalemJerusalemIsrael
| | - Itay Chowers
- Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of JerusalemJerusalemIsrael
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11
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Tan N, Lubel J, Kemp W, Roberts S, Majeed A. Current Therapeutics in Primary Sclerosing Cholangitis. J Clin Transl Hepatol 2023; 11:1267-1281. [PMID: 37577219 PMCID: PMC10412694 DOI: 10.14218/jcth.2022.00068s] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 01/01/2023] [Accepted: 01/20/2023] [Indexed: 07/03/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is an orphan, cholestatic liver disease that is characterized by inflammatory biliary strictures with variable progression to end-stage liver disease. Its pathophysiology is poorly understood. Chronic biliary inflammation is likely driven by immune dysregulation, gut dysbiosis, and environmental exposures resulting in gut-liver crosstalk and bile acid metabolism disturbances. There is no proven medical therapy that alters disease progression in PSC, with the commonly prescribed ursodeoxycholic acid being shown to improve liver biochemistry at low-moderate doses (15-23 mg/kg/day) but not alter transplant-free survival or liver-related outcomes. Liver transplantation is the only option for patients who develop end-stage liver disease or refractory complications of PSC. Immunosuppressive and antifibrotic agents have not proven to be effective, but there is promise for manipulation of the gut microbiome with fecal microbiota transplantation and antibiotics. Bile acid manipulation via alternate synthetic bile acids such as norursodeoxycholic acid, or interaction at a transcriptional level via nuclear receptor agonists and fibrates have shown potential in phase II trials in PSC with several leading to larger phase III trials. In view of the enhanced malignancy risk, statins, and aspirin show potential for reducing the risk of colorectal cancer and cholangiocarcinoma in PSC patients. For patients who develop clinically relevant strictures with cholestatic symptoms and worsening liver function, balloon dilatation is safer compared with biliary stent insertion with equivalent clinical efficacy.
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Affiliation(s)
- Natassia Tan
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - John Lubel
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - William Kemp
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - Stuart Roberts
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - Ammar Majeed
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
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12
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Cheng S, Zou Y, Zhang M, Bai S, Tao K, Wu J, Shi Y, Wu Y, Lu Y, He K, Sun P, Su X, Hou S, Han B. Single-cell RNA sequencing reveals the heterogeneity and intercellular communication of hepatic stellate cells and macrophages during liver fibrosis. MedComm (Beijing) 2023; 4:e378. [PMID: 37724132 PMCID: PMC10505372 DOI: 10.1002/mco2.378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 08/11/2023] [Accepted: 08/24/2023] [Indexed: 09/20/2023] Open
Abstract
Uncontrolled and excessive progression of liver fibrosis is thought to be the prevalent pathophysiological cause of liver cirrhosis and hepatocellular cancer, and there are currently no effective antifibrotic therapeutic options available. Intercellular communication and cellular heterogeneity in the liver are involved in the progression of liver fibrosis, but the exact nature of the cellular phenotypic changes and patterns of interregulatory remain unclear. Here, we performed single-cell RNA sequencing on nonparenchymal cells (NPCs) isolated from normal and fibrotic mouse livers. We identified eight main types of cells, including endothelial cells, hepatocytes, dendritic cells, B cells, natural killer/T (NK/T) cells, hepatic stellate cells (HSCs), cholangiocytes and macrophages, and revealed that macrophages and HSCs exhibit the most variance in transcriptional profile. Further analyses of HSCs and macrophage subpopulations and ligand-receptor interaction revealed a high heterogeneity characterization and tightly interregulated network of these two groups of cells in liver fibrosis. Finally, we uncovered a profibrotic Thbs1+ macrophage subcluster, which expands in mouse and human fibrotic livers, activating HSCs via PI3K/AKT/mTOR signaling pathway. Our findings decode unanticipated insights into the heterogeneity of HSCs and macrophages and their intercellular crosstalk at a single-cell level, and may provide potential therapeutic strategies in liver fibrosis.
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Affiliation(s)
- Sheng Cheng
- Department of General SurgeryTongren HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Key Laboratory for Translational Research and Innovative Therapeutics of Gastrointestinal OncologyHongqiao International Institute of MedicineTongren HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yunhan Zou
- Department of Biochemistry and Molecular Cell BiologyShanghai Key Laboratory for Tumor Microenvironment and InflammationShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Man Zhang
- Key Laboratory of Systems Biomedicine (Ministry of Education)Shanghai Center for Systems BiomedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Shihao Bai
- Key Laboratory of Systems Biomedicine (Ministry of Education)Shanghai Center for Systems BiomedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Kun Tao
- Department of PathologyTongren HospitalShanghai Jiaotong University School of MedicineShanghaiChina
| | - Jiaoxiang Wu
- Key Laboratory for Translational Research and Innovative Therapeutics of Gastrointestinal OncologyHongqiao International Institute of MedicineTongren HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yi Shi
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric DisordersBio‐X InstitutesShanghai Jiao Tong UniversityShanghaiChina
- eHealth Program of Shanghai Anti‐Doping LaboratoryShanghai University of SportShanghaiChina
| | - Yuelan Wu
- Key Laboratory for Translational Research and Innovative Therapeutics of Gastrointestinal OncologyHongqiao International Institute of MedicineTongren HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yinzhong Lu
- Key Laboratory for Translational Research and Innovative Therapeutics of Gastrointestinal OncologyHongqiao International Institute of MedicineTongren HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Department of AnesthesiologyTongren Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Kunyan He
- Key Laboratory of Systems Biomedicine (Ministry of Education)Shanghai Center for Systems BiomedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Peng Sun
- Department of General SurgeryTongren HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Xianbin Su
- Key Laboratory of Systems Biomedicine (Ministry of Education)Shanghai Center for Systems BiomedicineShanghai Jiao Tong UniversityShanghaiChina
- eHealth Program of Shanghai Anti‐Doping LaboratoryShanghai University of SportShanghaiChina
| | - Shangwei Hou
- Department of AnesthesiologyTongren Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Bo Han
- Department of General SurgeryTongren HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Key Laboratory for Translational Research and Innovative Therapeutics of Gastrointestinal OncologyHongqiao International Institute of MedicineTongren HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
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13
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Sharma P, Joshi RV, Pritchard R, Xu K, Eicher MA. Therapeutic Antibodies in Medicine. Molecules 2023; 28:6438. [PMID: 37764213 PMCID: PMC10535987 DOI: 10.3390/molecules28186438] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 08/05/2023] [Accepted: 08/28/2023] [Indexed: 09/29/2023] Open
Abstract
Antibody engineering has developed into a wide-reaching field, impacting a multitude of industries, most notably healthcare and diagnostics. The seminal work on developing the first monoclonal antibody four decades ago has witnessed exponential growth in the last 10-15 years, where regulators have approved monoclonal antibodies as therapeutics and for several diagnostic applications, including the remarkable attention it garnered during the pandemic. In recent years, antibodies have become the fastest-growing class of biological drugs approved for the treatment of a wide range of diseases, from cancer to autoimmune conditions. This review discusses the field of therapeutic antibodies as it stands today. It summarizes and outlines the clinical relevance and application of therapeutic antibodies in treating a landscape of diseases in different disciplines of medicine. It discusses the nomenclature, various approaches to antibody therapies, and the evolution of antibody therapeutics. It also discusses the risk profile and adverse immune reactions associated with the antibodies and sheds light on future applications and perspectives in antibody drug discovery.
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Affiliation(s)
- Prerna Sharma
- Geisinger Commonwealth School of Medicine, Scranton, PA 18509, USA
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14
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Wang Z, Xu H, Chen M, Lu Y, Zheng L, Ma L. CCL24/CCR3 axis plays a central role in angiotensin II-induced heart failure by stimulating M2 macrophage polarization and fibroblast activation. Cell Biol Toxicol 2023; 39:1413-1431. [PMID: 36131165 PMCID: PMC10425496 DOI: 10.1007/s10565-022-09767-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 08/26/2022] [Indexed: 11/02/2022]
Abstract
AIMS We aimed to investigate the effect and mechanism of pleiotropic chemokine CCL24 in heart failure. METHODS AND RESULTS Compared with normal donators, the expression of CCL24 and number of cardiac M2 macrophages in heart were higher in heart failure patients, the same as plasma CCL24. Treatment with CCL24 antibody hindered Ang II (1500 ng/kg/min)-induced cardiac adverse remodeling through preventing cardiac hypertrophy and fibrosis. RNA-seq showed that CCL24/CCR3 axis was involved in immune and inflammatory responses. Single-cell analysis of cytometry by time of flight (CyTOF) revealed that CCL24 antibody decreased the M2 macrophage and monocyte polarization during Ang II stimulation. Immunofluorescence co-localization analysis confirmed the expression of CCR3 in macrophage and fibroblasts. Then, in vitro experiments confirmed that CCL24/CCR3 axis was also involved in cardiac primary fibroblast activation through its G protein-coupled receptor function. CONCLUSION CCL24/CCR3 axis plays a crucial part in cardiac remodeling by stimulating M2 macrophage polarization and cardiac fibroblast activation. Cardiac M2 macrophages, CCL24 and circulation CCL24 increased in heart failure patients. Treatment with CCL24 Ab hindered Ang II induced cardiac structural dysfunction and electrical remodeling. In CCL24 Ab group RNA-seq found that it was related to immune responses and hypertrophic cardiomyopathy, CytoF revealed M2 macrophages and monocytes decreased obviously. In vitro,CCL24 promoted activation and migration of cardiac fibroblast.
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Affiliation(s)
- Zhen Wang
- Department of Cardiothoracic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China
| | - Hongfei Xu
- Department of Cardiothoracic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China
| | - Miao Chen
- Department of Cardiothoracic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China
| | - Yunlong Lu
- Department of Cardiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China
| | - Liangrong Zheng
- Department of Cardiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China.
| | - Liang Ma
- Department of Cardiothoracic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China.
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15
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Abstract
Systemic sclerosis (SSc) is a chronic immune-mediated disease characterized by microangiopathy, immune dysregulation, and progressive fibrosis of the skin and internal organs. Though not fully understood, the pathogenesis of SSc is dominated by microvascular injury, endothelial dysregulation, and immune response that are thought to be associated with fibroblast activation and related fibrogenesis. Among the main clinical subsets, diffuse SSc (dSSc) is a progressive form with rapid and disseminated skin thickening accompanied by internal organ fibrosis and dysfunction. Despite recent advances and multiple randomized clinical trials in early dSSc patients, an effective disease-modifying treatment for progressive skin fibrosis is still missing, and there is a crucial need to identify new targets for therapeutic intervention. Eotaxin-2 (CCL24) is a chemokine secreted by immune cells and epithelial cells, which promotes trafficking of immune cells and activation of pro-fibrotic cells through CCR3 receptor binding. Higher levels of CCL24 and CCR3 were found in the skin and sera of patients with SSc compared with healthy controls; elevated levels of CCL24 and CCR3 were associated with fibrosis and predictive of greater lung function deterioration. Growing evidence supports the potency of a CCL24-blocking antibody as an anti-inflammatory and anti-fibrotic modulating agent in multiple preclinical models that involve liver, skin, and lung inflammation and fibrosis. This review highlights the role of CCL24 in orchestrating immune, vascular, and fibrotic pathways, and the potential of CCL24 inhibition as a novel treatment for SSc.
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Affiliation(s)
| | | | - Alexandra Balbir-Gurman
- Rheumatology Institute, Rambam Health Care Campus, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel
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16
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Jin Y, Heo KS. Experimental model and novel therapeutic targets for non-alcoholic fatty liver disease development. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2023; 27:299-310. [PMID: 37386828 PMCID: PMC10316197 DOI: 10.4196/kjpp.2023.27.4.299] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 05/18/2023] [Accepted: 05/19/2023] [Indexed: 07/01/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a complex disorder characterized by the accumulation of fat in the liver in the absence of excessive alcohol consumption. It is one of the most common liver diseases worldwide, affecting approximately 25% of the global population. It is closely associated with obesity, type 2 diabetes, and metabolic syndrome. Moreover, NAFLD can progress to non-alcoholic steatohepatitis, which can cause liver cirrhosis, liver failure, and hepatocellular carcinoma. Currently, there are no approved drugs for the treatment of NAFLD. Therefore, the development of effective drugs is essential for NAFLD treatment. In this article, we discuss the experimental models and novel therapeutic targets for NAFLD. Additionally, we propose new strategies for the development of drugs for NAFLD.
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Affiliation(s)
- Yujin Jin
- College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 34134, Korea
| | - Kyung-Sun Heo
- College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 34134, Korea
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17
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Greenman R, Segal-Salto M, Barashi N, Hay O, Katav A, Levi O, Vaknin I, Aricha R, Aharoni S, Snir T, Mishalian I, Olam D, Amer J, Salhab A, Safadi R, Maor Y, Trivedi P, Weston CJ, Saffioti F, Hall A, Pinzani M, Thorburn D, Peled A, Mor A. CCL24 regulates biliary inflammation and fibrosis in primary sclerosing cholangitis. JCI Insight 2023; 8:e162270. [PMID: 37345655 PMCID: PMC10371243 DOI: 10.1172/jci.insight.162270] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 05/04/2023] [Indexed: 06/23/2023] Open
Abstract
ˆCCL24 is a pro-fibrotic, pro-inflammatory chemokine expressed in several chronic fibrotic diseases. In the liver, CCL24 plays a role in fibrosis and inflammation, and blocking CCL24 led to reduced liver injury in experimental models. We studied the role of CCL24 in primary sclerosing cholangitis (PSC) and evaluated the potential therapeutic effect of blocking CCL24 in this disease. Multidrug resistance gene 2-knockout (Mdr2-/-) mice demonstrated CCL24 expression in liver macrophages and were used as a relevant experimental PSC model. CCL24-neutralizing monoclonal antibody, CM-101, significantly improved inflammation, fibrosis, and cholestasis-related markers in the biliary area. Moreover, using spatial transcriptomics, we observed reduced proliferation and senescence of cholangiocytes following CCL24 neutralization. Next, we demonstrated that CCL24 expression was elevated under pro-fibrotic conditions in primary human cholangiocytes and macrophages, and it induced proliferation of primary human hepatic stellate cells and cholangiocytes, which was attenuated following CCL24 inhibition. Correspondingly, CCL24 was found to be highly expressed in liver biopsies of patients with PSC. CCL24 serum levels correlated with Enhanced Liver Fibrosis score, most notably in patients with high alkaline phosphatase levels. These results suggest that blocking CCL24 may have a therapeutic effect in patients with PSC by reducing liver inflammation, fibrosis, and cholestasis.
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Affiliation(s)
| | | | | | - Ophir Hay
- Gene Therapy Institute, Hadassah Hebrew University Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Avi Katav
- Chemomab Therapeutics Ltd., Tel Aviv, Israel
| | - Omer Levi
- Chemomab Therapeutics Ltd., Tel Aviv, Israel
| | - Ilan Vaknin
- Chemomab Therapeutics Ltd., Tel Aviv, Israel
| | | | | | - Tom Snir
- Chemomab Therapeutics Ltd., Tel Aviv, Israel
| | - Inbal Mishalian
- Gene Therapy Institute, Hadassah Hebrew University Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Devorah Olam
- Gene Therapy Institute, Hadassah Hebrew University Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Johnny Amer
- Institute of Gastroenterology and Liver Diseases, Department of Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Ahmad Salhab
- Institute of Gastroenterology and Liver Diseases, Department of Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Rifaat Safadi
- Institute of Gastroenterology and Liver Diseases, Department of Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Yaakov Maor
- Institute of Gastroenterology and Hepatology, Kaplan Medical Center, Rehovot, Israel
| | - Palak Trivedi
- National Institute for Health and Care Research Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom
| | - Christopher J Weston
- National Institute for Health and Care Research Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom
| | - Francesca Saffioti
- University College London Institute for Liver and Digestive Health, London, United Kingdom
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, United Kingdom
- Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Andrew Hall
- University College London Institute for Liver and Digestive Health, London, United Kingdom
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, United Kingdom
| | - Massimo Pinzani
- University College London Institute for Liver and Digestive Health, London, United Kingdom
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, United Kingdom
| | - Douglas Thorburn
- University College London Institute for Liver and Digestive Health, London, United Kingdom
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, United Kingdom
| | - Amnon Peled
- Gene Therapy Institute, Hadassah Hebrew University Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Adi Mor
- Chemomab Therapeutics Ltd., Tel Aviv, Israel
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18
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Hammond TC, Messmer S, Frank JA, Lukins D, Colwell R, Lin AL, Pennypacker KR. Gut microbial dysbiosis correlates with stroke severity markers in aged rats. FRONTIERS IN STROKE 2022; 1:1026066. [PMID: 36825211 PMCID: PMC9945937 DOI: 10.3389/fstro.2022.1026066] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Background An imbalanced gut microbial community, or dysbiosis, has been shown to occur following stroke. It is possible that this dysbiosis negatively impacts stroke recovery and rehabilitation. Species level resolution measurements of the gut microbiome following stroke are needed to develop and test precision interventions such as probiotic or fecal microbiota transplant therapies that target the gut microbiome. Previous studies have used 16S rRNA amplicon sequencing in young male mice to obtain broad profiling of the gut microbiome at the genus level following stroke, but further investigations will be needed with whole genome shotgun sequencing in aged rats of both sexes to obtain species level resolution in a model which will better translate to the demographics of human stroke patients. Methods Thirty-nine aged male and female rats underwent middle cerebral artery occlusion. Fecal samples were collected before stroke and 3 days post stroke to measure gut microbiome. Machine learning was used to identify the top ranked bacteria which were changed following stroke. MRI imaging was used to obtain infarct and edema size and cerebral blood flow (CBF). ELISA was used to obtain inflammatory markers. Results Dysbiosis was demonstrated by an increase in pathogenic bacteria such as Butyricimonas virosa (15.52 fold change, p < 0.0001), Bacteroides vulgatus (7.36 fold change, p < 0.0001), and Escherichia coli (47.67 fold change, p < 0.0001). These bacteria were positively associated with infarct and edema size and with the inflammatory markers Ccl19, Ccl24, IL17a, IL3, and complement C5; they were negatively correlated with CBF. Conversely, beneficial bacteria such as Ruminococcus flavefaciens (0.14 fold change, p < 0.0001), Akkermansia muciniphila (0.78 fold change, p < 0.0001), and Lactobacillus murinus (0.40 fold change, p < 0.0001) were decreased following stroke and associated with all the previous parameters in the opposite direction of the pathogenic species. There were not significant microbiome differences between the sexes. Conclusion The species level resolution measurements found here can be used as a foundation to develop and test precision interventions targeting the gut microbiome following stroke. Probiotics that include Ruminococcus flavefaciens, Akkermansia muciniphila, and Lactobacillus murinus should be developed to target the deficit following stroke to measure the impact on stroke severity.
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Affiliation(s)
- Tyler C. Hammond
- Lin Brain Lab, Department of Neuroscience, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, United States
| | - Sarah Messmer
- Department of Neurology, The Center for Advanced Translational Stroke Science, University of Kentucky, Lexington, KY, United States
| | - Jacqueline A. Frank
- Department of Neurology, The Center for Advanced Translational Stroke Science, University of Kentucky, Lexington, KY, United States
| | - Doug Lukins
- Department of Radiology, University of Kentucky, Lexington, KY, United States
| | | | - Ai-Ling Lin
- Division of Biological Sciences and Institute for Data Science and Informatics, Department of Radiology, University of Missouri, Columbia, MO, United States
| | - Keith R. Pennypacker
- Department of Neurology, The Center for Advanced Translational Stroke Science, University of Kentucky, Lexington, KY, United States
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19
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Zhang D, Zhang Y, Sun B. The Molecular Mechanisms of Liver Fibrosis and Its Potential Therapy in Application. Int J Mol Sci 2022; 23:ijms232012572. [PMID: 36293428 PMCID: PMC9604031 DOI: 10.3390/ijms232012572] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 09/27/2022] [Accepted: 10/03/2022] [Indexed: 11/16/2022] Open
Abstract
Liver fibrosis results from repeated and persistent liver damage. It can start with hepatocyte injury and advance to inflammation, which recruits and activates additional liver immune cells, leading to the activation of the hepatic stellate cells (HSCs). It is the primary source of myofibroblasts (MFs), which result in collagen synthesis and extracellular matrix protein accumulation. Although there is no FDA and EMA-approved anti-fibrotic drug, antiviral therapy has made remarkable progress in preventing or even reversing the progression of liver fibrosis, but such a strategy remains elusive for patients with viral, alcoholic or nonalcoholic steatosis, genetic or autoimmune liver disease. Due to the complexity of the etiology, combination treatments affecting two or more targets are likely to be required. Here, we review the pathogenic mechanisms of liver fibrosis and signaling pathways involved, as well as various molecular targets for liver fibrosis treatment. The development of efficient drug delivery systems that target different cells in liver fibrosis therapy is also summarized. We highlight promising anti-fibrotic events in clinical trial and preclinical testing, which include small molecules and natural compounds. Last, we discuss the challenges and opportunities in developing anti-fibrotic therapies.
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Affiliation(s)
- Danyan Zhang
- School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Yaguang Zhang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
- Correspondence: (Y.Z.); (B.S.); Tel.: +86-21-5492-1375 (Y.Z.); +86-21-5492-1375 (B.S.)
| | - Bing Sun
- School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
- Correspondence: (Y.Z.); (B.S.); Tel.: +86-21-5492-1375 (Y.Z.); +86-21-5492-1375 (B.S.)
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20
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Najimi M, Michel S, Binda MM, Gellynck K, Belmonte N, Mazza G, Gordillo N, Vainilovich Y, Sokal E. Human Allogeneic Liver-Derived Progenitor Cells Significantly Improve NAFLD Activity Score and Fibrosis in Late-Stage NASH Animal Model. Cells 2022; 11:cells11182854. [PMID: 36139429 PMCID: PMC9497074 DOI: 10.3390/cells11182854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 09/05/2022] [Accepted: 09/06/2022] [Indexed: 11/26/2022] Open
Abstract
Accumulated experimental and clinical evidence supports the development of human allogeneic liver-derived progenitor cells (HALPCs) to treat fibro-inflammatory liver diseases. The aim of the present study was to evaluate their therapeutic effect in a non-alcoholic steatohepatitis (NASH)-STAM mouse model. The immune signaling characteristics of HALPCs were first assessed in vitro. Upon inflammation treatment, HALPCs secreted large amounts of potent bioactive prostaglandin E2 and indoleamine 2,3-dioxygenase, which significantly reduced CD4+ T-lymphocyte proliferation and secretion of proinflammatory cytokines. In vivo, HALPCs were intravenously administered as single or triple shots (of a dose of 12.5 × 106 cells/kg BW) in STAM mice. Transplantation of HALPCs was associated with a significant decrease in the NAFLD activity score at an early stage and in both inflammation and hepatocyte ballooning scores in late-stage NASH. Sirius red staining analyses revealed decreased collagen deposition in the pericentral region at both stages of NASH. Altogether, these findings showed the anti-inflammatory and anti-fibrotic features of HALPCs in an in vivo NASH model, which suggests their potential to reverse the progression of this chronic fibro-inflammatory disease.
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Affiliation(s)
- Mustapha Najimi
- Cellaïon, 1435 Mont-Saint-Guibert, Belgium
- UCLouvain, Laboratory of Pediatric Hepatology and Cell Therapy (PEDI), Institute of Experimental and Clinical Research (IREC), 1200 Brussels, Belgium
- Correspondence: (M.N.); (E.S.); Tel.: +32-10-39-43-00 (M.N.)
| | | | | | | | | | | | | | | | - Etienne Sokal
- Cellaïon, 1435 Mont-Saint-Guibert, Belgium
- UCLouvain, Laboratory of Pediatric Hepatology and Cell Therapy (PEDI), Institute of Experimental and Clinical Research (IREC), 1200 Brussels, Belgium
- Correspondence: (M.N.); (E.S.); Tel.: +32-10-39-43-00 (M.N.)
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21
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Fang T, Wang H, Pan X, Little PJ, Xu S, Weng J. Mouse models of nonalcoholic fatty liver disease (NAFLD): pathomechanisms and pharmacotherapies. Int J Biol Sci 2022; 18:5681-5697. [PMID: 36263163 PMCID: PMC9576517 DOI: 10.7150/ijbs.65044] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 06/29/2022] [Indexed: 01/12/2023] Open
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) increases year by year, and as a consequence, NAFLD has become one of the most prevalent liver diseases worldwide. Unfortunately, no pharmacotherapies for NAFLD have been approved by the United States Food and Drug Administration despite promising pre-clinical benefits; this situation highlights the urgent need to explore new therapeutic targets for NAFLD and for the discovery of effective therapeutic drugs. The mouse is one of the most commonly used models to study human disease and develop novel pharmacotherapies due to its small size, low-cost and ease in genetic engineering. Different mouse models are used to simulate various stages of NAFLD induced by dietary and/or genetic intervention. In this review, we summarize the newly described patho-mechanisms of NAFLD and review the preclinical mouse models of NAFLD (based on the method of induction) and appraises the use of these models in anti-NAFLD drug discovery. This article will provide a useful resource for researchers to select the appropriate model for research based on the research question being addressed.
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Affiliation(s)
- Tingyu Fang
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei 230001, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
| | - Xiaoyue Pan
- Department of Foundations of Medicine, New York University Long Island School of Medicine, Mineola, New York, NY 11501, USA
| | - Peter J. Little
- School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, 4102 Australia
| | - Suowen Xu
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei 230001, China
| | - Jianping Weng
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei 230001, China
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22
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Costain AH, Phythian-Adams AT, Colombo SAP, Marley AK, Owusu C, Cook PC, Brown SL, Webb LM, Lundie RJ, Borger JG, Smits HH, Berriman M, MacDonald AS. Dynamics of Host Immune Response Development During Schistosoma mansoni Infection. Front Immunol 2022; 13:906338. [PMID: 35958580 PMCID: PMC9362740 DOI: 10.3389/fimmu.2022.906338] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 05/23/2022] [Indexed: 12/27/2022] Open
Abstract
Schistosomiasis is a disease of global significance, with severity and pathology directly related to how the host responds to infection. The immunological narrative of schistosomiasis has been constructed through decades of study, with researchers often focussing on isolated time points, cell types and tissue sites of interest. However, the field currently lacks a comprehensive and up-to-date understanding of the immune trajectory of schistosomiasis over infection and across multiple tissue sites. We have defined schistosome-elicited immune responses at several distinct stages of the parasite lifecycle, in three tissue sites affected by infection: the liver, spleen, and mesenteric lymph nodes. Additionally, by performing RNA-seq on the livers of schistosome infected mice, we have generated novel transcriptomic insight into the development of schistosome-associated liver pathology and fibrosis across the breadth of infection. Through depletion of CD11c+ cells during peak stages of schistosome-driven inflammation, we have revealed a critical role for CD11c+ cells in the co-ordination and regulation of Th2 inflammation during infection. Our data provide an updated and high-resolution account of how host immune responses evolve over the course of murine schistosomiasis, underscoring the significance of CD11c+ cells in dictating host immunopathology against this important helminth infection.
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Affiliation(s)
- Alice H. Costain
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
| | | | - Stefano A. P. Colombo
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom
| | - Angela K. Marley
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom
| | - Christian Owusu
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom
| | - Peter C. Cook
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, United Kingdom
| | - Sheila L. Brown
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom
| | - Lauren M. Webb
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom
- Department of Immunology, University of Washington, Seattle, WA, United States
| | | | | | - Hermelijn H. Smits
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
| | - Matthew Berriman
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom
- Wellcome Centre for Integrative Parasitology, University of Glasgow, Glasgow, United Kingdom
| | - Andrew S. MacDonald
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom
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23
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Lasrado N, Borcherding N, Arumugam R, Starr TK, Reddy J. Dissecting the cellular landscape and transcriptome network in viral myocarditis by single-cell RNA sequencing. iScience 2022; 25:103865. [PMID: 35243228 PMCID: PMC8861636 DOI: 10.1016/j.isci.2022.103865] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 12/11/2021] [Accepted: 01/28/2022] [Indexed: 11/25/2022] Open
Abstract
Coxsackievirus B3 (CVB3)-induced myocarditis is commonly employed to study viral pathogenesis in mice. Chronically affected mice may develop dilated cardiomyopathy, which may involve the mediation of immune and nonimmune cells. To dissect this complexity, we performed single-cell RNA sequencing on heart cells from healthy and myocarditic mice, leading us to note significant proportions of myeloid cells, T cells, and fibroblasts. Although the transcriptomes of myeloid cells were mainly of M2 phenotype, the Th17 cells, CTLs, and Treg cells had signatures critical for cytotoxic functions. Fibroblasts were heterogeneous expressing genes important in fibrosis and regulation of inflammation and immune responses. The intercellular communication networks revealed unique interactions and signaling pathways in the cardiac cellulome, whereas myeloid cells and T cells had upregulated unique transcription factors modulating cardiac remodeling functions. Together, our data suggest that M2 cells, T cells, and fibroblasts may cooperatively or independently participate in the pathogenesis of viral myocarditis.
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Affiliation(s)
- Ninaad Lasrado
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
| | - Nicholas Borcherding
- Department of Pathology and Immunology, Washington University in St. Louis, St Louis, MO 63130, USA
| | - Rajkumar Arumugam
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
| | - Timothy K. Starr
- Department of Obstetrics and Gynecology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Jay Reddy
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
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24
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Saito M, Harigae Y, Li G, Asano T, Tanaka T, Suzuki H, Kaneko MK, Kato Y. C 3Mab-2: An Anti-Mouse CCR3 Monoclonal Antibody for Immunocytochemistry. Monoclon Antib Immunodiagn Immunother 2022; 41:45-49. [PMID: 35225661 DOI: 10.1089/mab.2021.0050] [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] [Indexed: 12/14/2022] Open
Abstract
The C-C motif chemokine receptor 3 (CCR3) is a G protein-coupled receptor activated by eotaxin-1-3, MCP-2-4, and RANTES. CCR3 is associated with allergic diseases and cancer development and is highly expressed in eosinophils, basophils, and cancer cells. Besides, research on the physiological roles of CCR3 is ongoing. Thus, specific monoclonal antibodies (mAbs) for CCR3 would be useful for diagnostic and therapeutic purposes and for unraveling the function of CCR3. We previously developed an anti-mouse CCR3 (mCCR3) mAb (C3Mab-2; rat IgG2b, kappa) using the Cell-Based Immunization and Screening method and showed that C3Mab-2 could detect endogenous and exogenous mCCR3 in flow cytometry. In this study, we showed that C3Mab-2 and its recombinant antibody (recC3Mab-2f) specifically recognized endogenous mCCR3 in P388 (a mouse lymphocyte-like cell line) and J774-1 (a mouse macrophage-like cell line) cells and are usable in immunocytochemistry.
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Affiliation(s)
- Masaki Saito
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yasuhiro Harigae
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Guanjie Li
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Teizo Asano
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomohiro Tanaka
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroyuki Suzuki
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mika K Kaneko
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yukinari Kato
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan.,Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
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25
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Prikhodko VA, Bezborodkina NN, Okovityi SV. Pharmacotherapy for Non-Alcoholic Fatty Liver Disease: Emerging Targets and Drug Candidates. Biomedicines 2022; 10:274. [PMID: 35203484 PMCID: PMC8869100 DOI: 10.3390/biomedicines10020274] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/22/2022] [Accepted: 01/24/2022] [Indexed: 02/08/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), or metabolic (dysfunction)-associated fatty liver disease (MAFLD), is characterized by high global incidence and prevalence, a tight association with common metabolic comorbidities, and a substantial risk of progression and associated mortality. Despite the increasingly high medical and socioeconomic burden of NAFLD, the lack of approved pharmacotherapy regimens remains an unsolved issue. In this paper, we aimed to provide an update on the rapidly changing therapeutic landscape and highlight the major novel approaches to the treatment of this disease. In addition to describing the biomolecules and pathways identified as upcoming pharmacological targets for NAFLD, we reviewed the current status of drug discovery and development pipeline with a special focus on recent evidence from clinical trials.
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Affiliation(s)
- Veronika A. Prikhodko
- Department of Pharmacology and Clinical Pharmacology, Saint Petersburg State Chemical and Pharmaceutical University, 14A Prof. Popov Str., 197022 St. Petersburg, Russia;
| | - Natalia N. Bezborodkina
- Zoological Institute, Russian Academy of Sciences, 1 Universitetskaya emb., 199034 St. Petersburg, Russia;
| | - Sergey V. Okovityi
- Department of Pharmacology and Clinical Pharmacology, Saint Petersburg State Chemical and Pharmaceutical University, 14A Prof. Popov Str., 197022 St. Petersburg, Russia;
- Scientific, Clinical and Educational Center of Gastroenterology and Hepatology, Saint Petersburg State University, 7/9 Universitetskaya emb., 199034 St. Petersburg, Russia
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26
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Yang M, Khoukaz L, Qi X, Kimchi ET, Staveley-O’Carroll KF, Li G. Diet and Gut Microbiota Interaction-Derived Metabolites and Intrahepatic Immune Response in NAFLD Development and Treatment. Biomedicines 2021; 9:biomedicines9121893. [PMID: 34944709 PMCID: PMC8698669 DOI: 10.3390/biomedicines9121893] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/10/2021] [Accepted: 12/11/2021] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) with pathogenesis ranging from nonalcoholic fatty liver (NAFL) to the advanced form of nonalcoholic steatohepatitis (NASH) affects about 25% of the global population. NAFLD is a chronic liver disease associated with obesity, type 2 diabetes, and metabolic syndrome, which is the most increasing factor that causes hepatocellular carcinoma (HCC). Although advanced progress has been made in exploring the pathogenesis of NAFLD and penitential therapeutic targets, no therapeutic agent has been approved by Food and Drug Administration (FDA) in the United States. Gut microbiota-derived components and metabolites play pivotal roles in shaping intrahepatic immunity during the progression of NAFLD or NASH. With the advance of techniques, such as single-cell RNA sequencing (scRNA-seq), each subtype of immune cells in the liver has been studied to explore their roles in the pathogenesis of NAFLD. In addition, new molecules involved in gut microbiota-mediated effects on NAFLD are found. Based on these findings, we first summarized the interaction of diet-gut microbiota-derived metabolites and activation of intrahepatic immunity during NAFLD development and progression. Treatment options by targeting gut microbiota and important molecular signaling pathways are then discussed. Finally, undergoing clinical trials are selected to present the potential application of treatments against NAFLD or NASH.
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Affiliation(s)
- Ming Yang
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (M.Y.); (L.K.); (X.Q.); (E.T.K.)
| | - Lea Khoukaz
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (M.Y.); (L.K.); (X.Q.); (E.T.K.)
| | - Xiaoqiang Qi
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (M.Y.); (L.K.); (X.Q.); (E.T.K.)
| | - Eric T. Kimchi
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (M.Y.); (L.K.); (X.Q.); (E.T.K.)
- Harry S. Truman Memorial VA Hospital, Columbia, MO 65201, USA
| | - Kevin F. Staveley-O’Carroll
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (M.Y.); (L.K.); (X.Q.); (E.T.K.)
- Harry S. Truman Memorial VA Hospital, Columbia, MO 65201, USA
- Correspondence: (K.F.S.-O.); (G.L.)
| | - Guangfu Li
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (M.Y.); (L.K.); (X.Q.); (E.T.K.)
- Harry S. Truman Memorial VA Hospital, Columbia, MO 65201, USA
- Department of Molecular Microbiology and Immunology, University of Missouri-Columbia, Columbia, MO 65212, USA
- Correspondence: (K.F.S.-O.); (G.L.)
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27
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Wenzel D, Haddadi N, Afshari K, Richmond JM, Rashighi M. Upcoming treatments for morphea. Immun Inflamm Dis 2021; 9:1101-1145. [PMID: 34272836 PMCID: PMC8589364 DOI: 10.1002/iid3.475] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 05/29/2021] [Indexed: 11/25/2022] Open
Abstract
Morphea (localized scleroderma) is a rare autoimmune connective tissue disease with variable clinical presentations, with an annual incidence of 0.4-2.7 cases per 100,000. Morphea occurs most frequently in children aged 2-14 years, and the disease exhibits a female predominance. Insights into morphea pathogenesis are often extrapolated from studies of systemic sclerosis due to their similar skin histopathologic features; however, clinically they are two distinct diseases as evidenced by different demographics, clinical features, disease course and prognosis. An interplay between genetic factors, epigenetic modifications, immune and vascular dysfunction, along with environmental hits are considered as the main contributors to morphea pathogenesis. In this review, we describe potential new therapies for morphea based on both preclinical evidence and ongoing clinical trials. We focus on different classes of therapeutics, including antifibrotic, anti-inflammatory, cellular and gene therapy, and antisenolytic approaches, and how these target different aspects of disease pathogenesis.
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Affiliation(s)
- Dan Wenzel
- Department of DermatologyUniversity of Massachusetts Medical SchoolWorcesterMassachusettsUSA
| | - Nazgol‐Sadat Haddadi
- Department of DermatologyUniversity of Massachusetts Medical SchoolWorcesterMassachusettsUSA
| | - Khashayar Afshari
- Department of DermatologyUniversity of Massachusetts Medical SchoolWorcesterMassachusettsUSA
| | - Jillian M. Richmond
- Department of DermatologyUniversity of Massachusetts Medical SchoolWorcesterMassachusettsUSA
| | - Mehdi Rashighi
- Department of DermatologyUniversity of Massachusetts Medical SchoolWorcesterMassachusettsUSA
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28
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Fraile JM, Palliyil S, Barelle C, Porter AJ, Kovaleva M. Non-Alcoholic Steatohepatitis (NASH) - A Review of a Crowded Clinical Landscape, Driven by a Complex Disease. Drug Des Devel Ther 2021; 15:3997-4009. [PMID: 34588764 PMCID: PMC8473845 DOI: 10.2147/dddt.s315724] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 08/21/2021] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD), characterized by chronic inflammation and accumulation of fat in liver tissue. Affecting estimated 35 million people globally, NASH is the most common chronic liver condition in Western populations, and with patient numbers growing rapidly, the market for NASH therapy is projected to rise to $27.2 B in 2029. Despite this clinical need and attractive commercial opportunity, there are no Food and Drug Administration (FDA)-approved therapies specifically for this disease. Many have tried and unfortunately failed to find a drug, or drug combination, capable of unravelling the complexities of this metabolic condition. At the time of writing this review, only Zydus Cadila’s new drug application for Saroglitazar had been approved (2020) for NASH therapy in India. However, it is hoped that this dearth of therapy options will improve as several drug candidates progress through late-stage clinical development. Obeticholic acid (Intercept Pharmaceuticals), Cenicriviroc (Allergan), Aramchol (Galmed Pharmaceuticals), Resmetirom (Madrigal Pharmaceuticals), Dapagliflozin and Semaglutide (Novo Nordisk) are in advanced Phase 3 clinical trials, while Belapectin (Galectin Therapeutics), MSDC-0602K (Cirius Therapeutics), Lanifibranor (Inventiva), Efruxifermin (Akero) and Tesamorelin (Theratechnologies) are expected to start Phase 3 trials soon. Here, we have performed an exhaustive review of the current therapeutic landscape for this disease and compared, in some detail, the fortunes of different drug classes (biologics vs small molecules) and target molecules. Given the complex pathophysiology of NASH, the use of drug combination, different mechanisms of actions and the targeting of each stage of the disease will likely be required. Hence, the development of a single therapy for NASH seems challenging and unlikely, despite the plethora of later stage trials due to report. We therefore predict that clinical, patient and company interest in pipeline and next-generation therapies will remain high for some time to come.
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Affiliation(s)
- Julia M Fraile
- Scottish Biologics Facility, University of Aberdeen, Aberdeen, AB25 2ZP, UK.,Elasmogen Ltd, Aberdeen, AB25 2ZP, UK
| | - Soumya Palliyil
- Scottish Biologics Facility, University of Aberdeen, Aberdeen, AB25 2ZP, UK
| | | | - Andrew J Porter
- Scottish Biologics Facility, University of Aberdeen, Aberdeen, AB25 2ZP, UK.,Elasmogen Ltd, Aberdeen, AB25 2ZP, UK
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29
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Drenth JP, Schattenberg JM. The nonalcoholic steatohepatitis (NASH) drug development graveyard: established hurdles and planning for future success. Expert Opin Investig Drugs 2020; 29:1365-1375. [DOI: 10.1080/13543784.2020.1839888] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Joost P.H. Drenth
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Jörn M. Schattenberg
- Department of Medicine, University Medical Centre of the Johannes Gutenberg-University, Mainz, Germany
- Metabolic Liver Research Program, University Medical Centre of the Johannes Gutenberg-University, Mainz, Germany
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30
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Xiao L, Zhang H, Yang X, Mahati S, Wu G, Xiaheding Y, Bao YX, Xiao H. Role of phosphatidylinositol 3-kinase signaling pathway in radiation-induced liver injury. Kaohsiung J Med Sci 2020; 36:990-997. [PMID: 32729224 DOI: 10.1002/kjm2.12279] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 06/02/2020] [Accepted: 06/29/2020] [Indexed: 12/14/2022] Open
Abstract
Transforming growth factor-β1 (TGF-β1) is one of critical cytokines in radiation-induced liver injury. Hepatic stellate cells (HSC) are activated in the early stage of radiation-induced liver injury. However, it is currently unclear whether phosphatidylinositol 3-kinase (PI3K/Akt) signal pathway is activated in radiation-induced liver injury. Herein, male Sprague-Dawley rats were irradiated with 6 MV X-rays (30 Gy) on the right liver. Next, Hematoxylin and eosin staining, Masson staining, and electron microscopy were performed to examine pathological changes. Immunohistochemistry was performed to assess the expression of TGF-β1, α-SMA, and p-Akt (S473) in liver tissues. In vitro, rat HSC cell line HSC-T6 cells were given different doses of 6 MV X-ray irradiation (10 and 20 Gy) and treated with LY294002. The expression of α-SMA and p-Akt in mRNA and protein levels were measured by reverse transcription-polymerase chain reactioin (RT-PCR) and Western blot. TGF-β1 expression was detected by enzyme-linked immuno sorbent assay (ELISA). After irradiation, the liver tissues showed obvious pathological changes, indicating the establishment of the radiation-induced liver injury. Expression levels of TGF-β1, α-SMA, and p-Akt (S473) protein in liver tissues were significantly increased after irradiation, and this increase was in a time-dependent manner, suggesting the activation of HSC and PI3K/Akt signal pathway. in vitro experiments showed that the TGF-β1 secreted by HSCs, and the expression of Akt and α-SMA at mRNA and protein levels were significantly increased in irradiation groups. However, the expression of TGF-β1, Akt, and α-SMA were significantly decreased in PI3K/Akt signal pathway inhibitor LY294002-treated group. Our results suggest that during radiation-induced liver injury, HSCs are activated by TGF-β1-mediated PI3K/Akt signal pathway.
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Affiliation(s)
- Lei Xiao
- Cancer Center of First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.,School of Public Health of Xinjiang Medical University, Urumqi, China
| | - Hua Zhang
- Cancer Center of First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Xin Yang
- Cancer Center of First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Shaya Mahati
- Cancer Center of First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Ge Wu
- Cancer Center of First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Yiliyaer Xiaheding
- Cancer Center of First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Yong-Xing Bao
- Cancer Center of First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Hui Xiao
- School of Public Health of Xinjiang Medical University, Urumqi, China
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31
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Auguet T, Bertran L, Binetti J, Aguilar C, Martínez S, Sabench F, Lopez-Dupla JM, Porras JA, Riesco D, Del Castillo D, Richart C. Relationship between IL-8 Circulating Levels and TLR2 Hepatic Expression in Women with Morbid Obesity and Nonalcoholic Steatohepatitis. Int J Mol Sci 2020; 21:ijms21114189. [PMID: 32545403 PMCID: PMC7312372 DOI: 10.3390/ijms21114189] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 06/08/2020] [Accepted: 06/09/2020] [Indexed: 12/25/2022] Open
Abstract
The progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) is linked to systemic inflammation. Currently, two of the aspects that need further investigation are diagnosis and treatment of NASH. In this sense, the aim of this study was to assess the relationship between circulating levels of cytokines, hepatic expression of toll-like receptors (TLRs), and degrees of NAFLD, and to investigate whether these levels could serve as noninvasive biomarkers of NASH. The present study assessed plasma levels of cytokines in 29 normal-weight women and 82 women with morbid obesity (MO) (subclassified: normal liver (n = 29), simple steatosis (n = 32), and NASH (n = 21)). We used enzyme-linked immunosorbent assays (ELISAs) to quantify cytokine and TLR4 levels and RTqPCR to assess TLRs hepatic expression. IL-1β, IL-8, IL-10, TNF-α, tPAI-1, and MCP-1 levels were increased, and adiponectin levels were decreased in women with MO. IL-8 was significantly higher in MO with NASH than in NL. To sum up, high levels of IL-8 were associated with the diagnosis of NASH in a cohort of women with morbid obesity. Moreover, a positive correlation between TLR2 hepatic expression and IL-8 circulating levels was found.
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Affiliation(s)
- Teresa Auguet
- Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Departament de Medicina i Cirurgia, Institut d’Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili (URV), 43007 Tarragona, Spain; (L.B.); (J.B.); (C.A.); (J.M.L.-D.); (J.A.P.); (C.R.)
- Hospital Universitari de Tarragona Joan XXIII, Servei Medicina Interna, 43007 Tarragona, Spain;
- Correspondence: ; Tel.: +34-97-729-5833
| | - Laia Bertran
- Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Departament de Medicina i Cirurgia, Institut d’Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili (URV), 43007 Tarragona, Spain; (L.B.); (J.B.); (C.A.); (J.M.L.-D.); (J.A.P.); (C.R.)
| | - Jessica Binetti
- Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Departament de Medicina i Cirurgia, Institut d’Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili (URV), 43007 Tarragona, Spain; (L.B.); (J.B.); (C.A.); (J.M.L.-D.); (J.A.P.); (C.R.)
| | - Carmen Aguilar
- Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Departament de Medicina i Cirurgia, Institut d’Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili (URV), 43007 Tarragona, Spain; (L.B.); (J.B.); (C.A.); (J.M.L.-D.); (J.A.P.); (C.R.)
| | - Salomé Martínez
- Hospital Universitari de Tarragona Joan XXIII, Servei Anatomia Patològica, 43007 Tarragona, Spain;
| | - Fàtima Sabench
- Hospital Universitari Sant Joan de Reus, Servei de Cirurgia, Departament de Medicina i Cirurgia, Institut d’Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili (URV), 43204 Reus, Spain; (F.S.); (D.D.C.)
| | - Jesús Miguel Lopez-Dupla
- Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Departament de Medicina i Cirurgia, Institut d’Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili (URV), 43007 Tarragona, Spain; (L.B.); (J.B.); (C.A.); (J.M.L.-D.); (J.A.P.); (C.R.)
- Hospital Universitari de Tarragona Joan XXIII, Servei Medicina Interna, 43007 Tarragona, Spain;
| | - José Antonio Porras
- Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Departament de Medicina i Cirurgia, Institut d’Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili (URV), 43007 Tarragona, Spain; (L.B.); (J.B.); (C.A.); (J.M.L.-D.); (J.A.P.); (C.R.)
- Hospital Universitari de Tarragona Joan XXIII, Servei Medicina Interna, 43007 Tarragona, Spain;
| | - David Riesco
- Hospital Universitari de Tarragona Joan XXIII, Servei Medicina Interna, 43007 Tarragona, Spain;
| | - Daniel Del Castillo
- Hospital Universitari Sant Joan de Reus, Servei de Cirurgia, Departament de Medicina i Cirurgia, Institut d’Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili (URV), 43204 Reus, Spain; (F.S.); (D.D.C.)
| | - Cristóbal Richart
- Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Departament de Medicina i Cirurgia, Institut d’Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili (URV), 43007 Tarragona, Spain; (L.B.); (J.B.); (C.A.); (J.M.L.-D.); (J.A.P.); (C.R.)
- Hospital Universitari de Tarragona Joan XXIII, Servei Medicina Interna, 43007 Tarragona, Spain;
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