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Viola H, Chen LH, Jo S, Washington K, Selva C, Li A, Feng D, Giacalone V, Stephenson ST, Cottrill K, Mohammad A, Williams E, Qu X, Lam W, Ng NL, Fitzpatrick A, Grunwell J, Tirouvanziam R, Takayama S. High-throughput quantitation of human neutrophil recruitment and functional responses in an air-blood barrier array. APL Bioeng 2025; 9:026110. [PMID: 40290728 PMCID: PMC12033047 DOI: 10.1063/5.0220367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 11/19/2024] [Indexed: 04/30/2025] Open
Abstract
Dysregulated neutrophil recruitment drives many pulmonary diseases, but most preclinical screening methods are unsuited to evaluate pulmonary neutrophilia, limiting progress toward therapeutics. Namely, high-throughput therapeutic assays typically exclude critical neutrophilic pathophysiology, including blood-to-lung recruitment, dysfunctional activation, and resulting impacts on the air-blood barrier. To meet the conflicting demands of physiological complexity and high throughput, we developed an assay of 96-well leukocyte recruitment in an air-blood barrier array (L-ABBA-96) that enables in vivo-like neutrophil recruitment compatible with downstream phenotyping by automated flow cytometry. We modeled acute respiratory distress syndrome (ARDS) with neutrophil recruitment to 20 ng/mL epithelial-side interleukin 8 and found a dose-dependent reduction in recruitment with physiologic doses of baricitinib, a JAK1/2 inhibitor recently Food and Drug Administration-approved for severe Coronavirus Disease 2019 ARDS. Additionally, neutrophil recruitment to patient-derived cystic fibrosis sputum supernatant induced disease-mimetic recruitment and activation of healthy donor neutrophils and upregulated endothelial e-selectin. Compared to 24-well assays, the L-ABBA-96 reduces required patient sample volumes by 25 times per well and quadruples throughput per plate. Compared to microfluidic assays, the L-ABBA-96 recruits two orders of magnitude more neutrophils per well, enabling downstream flow cytometry and other standard biochemical assays. This novel pairing of high-throughput in vitro modeling of organ-level lung function with parallel high-throughput leukocyte phenotyping substantially advances opportunities for pathophysiological studies, personalized medicine, and drug testing applications.
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Affiliation(s)
| | - Liang-Hsin Chen
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA
| | - Seongbin Jo
- School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA
| | - Kendra Washington
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA
| | - Cauviya Selva
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA
| | - Andrea Li
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA
| | - Daniel Feng
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA
| | | | | | | | | | - Evelyn Williams
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA
| | - Xianggui Qu
- Department of Mathematics and Statistics, Oakland University, Rochester, Michigan 48309, USA
| | | | | | | | - Jocelyn Grunwell
- Department of Pediatrics, Division of Critical Care Medicine, Emory University School of Medicine and Children's Healthcare of Atlanta at Arthur M. Blank Hospital, Atlanta, Georgia 30322, USA
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2
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Jomova K, Alomar SY, Valko R, Liska J, Nepovimova E, Kuca K, Valko M. Flavonoids and their role in oxidative stress, inflammation, and human diseases. Chem Biol Interact 2025; 413:111489. [PMID: 40147618 DOI: 10.1016/j.cbi.2025.111489] [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: 06/02/2024] [Revised: 02/23/2025] [Accepted: 03/24/2025] [Indexed: 03/29/2025]
Abstract
Oxidative stress and chronic inflammation are important drivers in the pathogenesis and progression of many chronic diseases, such as cancers of the breast, kidney, lung, and others, autoimmune diseases (rheumatoid arthritis), cardiovascular diseases (hypertension, atherosclerosis, arrhythmia), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease), mental disorders (depression, schizophrenia, bipolar disorder), gastrointestinal disorders (inflammatory bowel disease, colorectal cancer), and other disorders. With the increasing demand for less toxic and more tolerable therapies, flavonoids have the potential to effectively modulate the responsiveness to conventional therapy and radiotherapy. Flavonoids are polyphenolic compounds found in fruits, vegetables, grains, and plant-derived beverages. Six of the twelve structurally different flavonoid subgroups are of dietary significance and include anthocyanidins (e.g. pelargonidin, cyanidin), flavan-3-ols (e.g. epicatechin, epigallocatechin), flavonols (e.g. quercetin, kaempferol), flavones (e.g. luteolin, baicalein), flavanones (e.g. hesperetin, naringenin), and isoflavones (daidzein, genistein). The health benefits of flavonoids are related to their structural characteristics, such as the number and position of hydroxyl groups and the presence of C2C3 double bonds, which predetermine their ability to chelate metal ions, terminate ROS (e.g. hydroxyl radicals formed by the Fenton reaction), and interact with biological targets to trigger a biological response. Based on these structural characteristics, flavonoids can exert both antioxidant or prooxidant properties, modulate the activity of ROS-scavenging enzymes and the expression and activation of proinflammatory cytokines (e.g., interleukin-1beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α)), induce apoptosis and autophagy, and target key signaling pathways, such as the nuclear factor erythroid 2-related factor 2 (Nrf2) and Bcl-2 family of proteins. This review aims to briefly discuss the mutually interconnected aspects of oxidative and inflammatory mechanisms, such as lipid peroxidation, protein oxidation, DNA damage, and the mechanism and resolution of inflammation. The major part of this article discusses the role of flavonoids in alleviating oxidative stress and inflammation, two common components of many human diseases. The results of epidemiological studies on flavonoids are also presented.
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Affiliation(s)
- Klaudia Jomova
- Department of Chemistry, Faculty of Natural Sciences, Constantine the Philosopher University in Nitra, Nitra, 949 74, Slovakia
| | - Suliman Y Alomar
- Zoology Department, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Richard Valko
- Zoology Department, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Jan Liska
- Institute of Histology and Embryology, Faculty of Medicine, Comenius University, 811 08, Bratislava, Slovakia
| | - Eugenie Nepovimova
- Department of Chemistry, Faculty of Sciences, University of Hradec Kralove, 50003, Hradec Kralove, Czech Republic; Center of Advanced Innovation Technologies, VSB-Technical University of Ostrava, Ostrava-Poruba, 708 00, Czech Republic
| | - Kamil Kuca
- Center of Advanced Innovation Technologies, VSB-Technical University of Ostrava, Ostrava-Poruba, 708 00, Czech Republic; Biomedical Research Center, University Hospital Hradec Kralove, 5005, Hradec Kralove, Czech Republic
| | - Marian Valko
- Faculty of Chemical and Food Technology, Slovak University of Technology, 812 37, Bratislava, Slovakia.
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3
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Kim HB, Kim H, Oh SH, Kang MJ, Park JH, Lee SB, Shim S, Lee HJ, Yoo KC, Jang H. Bixin alleviates radiation-induced intestinal damage via inflammation regulation and barrier recovery. Int J Radiat Biol 2025:1-10. [PMID: 40397619 DOI: 10.1080/09553002.2025.2505523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 04/15/2025] [Accepted: 05/05/2025] [Indexed: 05/23/2025]
Abstract
PURPOSE Radiotherapy for cancer treatment or unintentional exposure to ionizing radiation causes severe damage to the unaffected tissues of the digestive system, including gastrointestinal (GI) tract. Radiation exposure leads to an inflammatory response, and uncontrolled inflammation exacerbates radiation-induced tissue injury. Bixin is a liposoluble apocarotenoid isolated from Bixa orrellana seeds, which effectively attenuates several inflammatory diseases. In this study, we investigated whether bixin mitigated radiation-induced intestinal damage through an examination of its role in inflammation and the protection of the epithelial barrier. MATERIALS AND METHODS To determine the therapeutic effects of bixin in treating radiation-induced intestinal damage, we carried out histological analyses, inflammatory response examinations, and barrier function assessments using a mouse model of radiation-induced enteropathy. RESULTS We uncovered that bixin effectively mitigates radiation-induced enteropathy by suppressing the inflammatory response, reducing inflammatory cell accumulation, and limiting cytokine expression in the radiation-induced intestinal injury. In a mouse model of acute radiation-induced intestinal injury, treatment with bixin enhanced nuclear factor erythroid-2-related factor 2 (NRF2) activation and promoted tight junction expression in the epithelium, while also hindering bacterial translocation to the mesenteric lymph nodes. CONCLUSION Bixin represents a potential therapeutic candidate for the treatment of radiation-induced enteropathy.
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Affiliation(s)
- Han Byul Kim
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Science, Seoul, Korea
| | - Hyewon Kim
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Science, Seoul, Korea
| | - Su-Hyun Oh
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Science, Seoul, Korea
| | - Min-Ji Kang
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Science, Seoul, Korea
| | - Jung Hwan Park
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Science, Seoul, Korea
| | - Seung Bum Lee
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Science, Seoul, Korea
| | - Sehwan Shim
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Science, Seoul, Korea
| | - Hae-June Lee
- College of Veterinary Medicine, Jeju National University, Jeju, Korea
| | - Ki-Chun Yoo
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Science, Seoul, Korea
| | - Hyosun Jang
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Science, Seoul, Korea
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4
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Chmielewski PP, Strzelec B, Mozdziak P, Kempisty B. Neutrophil-to-Lymphocyte Ratio as a Prognostic Biomarker for Long-Term Survival in Older Adults at a Mental Health Care Center: A Historical Cohort Analysis. J Clin Med 2025; 14:2509. [PMID: 40217958 PMCID: PMC11989978 DOI: 10.3390/jcm14072509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 03/24/2025] [Accepted: 04/03/2025] [Indexed: 04/14/2025] Open
Abstract
Background/Objectives: Identifying reliable biomarkers for healthy aging and longevity is a fundamental challenge in aging research and medical sciences. The neutrophil-to-lymphocyte ratio (NLR) is a readily measurable indicator of immune balance that reflects the interplay between innate immune activation and adaptive immune suppression. Methods: This study examined NLR values in 204 physically healthy residents (98 men and 106 women) stratified into four lifespan categories based on death certificates. Page's test and ordinal regression (Cumulative Link Model) were used to assess trends with longevity. Results: In men, a downward trend in NLR values was observed. In women, a significant age-related decline in NLR was identified, with longer-lived individuals showing notably lower NLR values compared to their shorter-lived counterparts. The findings suggest that lower NLR is associated with longer survival, particularly in older women, reflecting superior immune regulation and reduced systemic inflammation. Conversely, elevated NLR may indicate immune dysfunction and heightened inflammatory burden. Conclusions: The results of this study complement existing findings, reinforcing the critical importance of immune balance in supporting healthy aging and longevity. These findings also underscore the potential of NLR as a robust biomarker for evaluating immune function and anticipating resilience to age-related decline, offering a practical tool for assessing immune health in the aging population.
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Affiliation(s)
- Piotr Paweł Chmielewski
- Division of Anatomy, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, 6a Chalubinskiego Street, 50-368 Wroclaw, Poland;
| | - Bartłomiej Strzelec
- 2nd Department of General Surgery and Surgical Oncology, Medical University Hospital, 50-345 Wroclaw, Poland;
| | - Paul Mozdziak
- Prestige Department of Poultry Science, College of Agriculture and Life Sciences, North Carolina State University, Raleigh, NC 27695-7608, USA;
| | - Bartosz Kempisty
- Division of Anatomy, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, 6a Chalubinskiego Street, 50-368 Wroclaw, Poland;
- Prestige Department of Poultry Science, College of Agriculture and Life Sciences, North Carolina State University, Raleigh, NC 27695-7608, USA;
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University, 87-100 Toruń, Poland
- Center of Assisted Reproduction, Department of Obstetrics and Gynecology, University Hospital and Masaryk University, 625 00 Brno, Czech Republic
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5
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Wahnou H, El Kebbaj R, Hba S, Ouadghiri Z, El Faqer O, Pinon A, Liagre B, Limami Y, Duval RE. Neutrophils and Neutrophil-Based Drug Delivery Systems in Anti-Cancer Therapy. Cancers (Basel) 2025; 17:1232. [PMID: 40227814 PMCID: PMC11988188 DOI: 10.3390/cancers17071232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2025] [Revised: 04/01/2025] [Accepted: 04/02/2025] [Indexed: 04/15/2025] Open
Abstract
Neutrophils, the most abundant white blood cells, play a dual role in cancer progression. While they can promote tumor growth, metastasis, and immune suppression, they also exhibit anti-tumorigenic properties by attacking cancer cells and enhancing immune responses. This review explores the complex interplay between neutrophils and the tumor microenvironment (TME), highlighting their ability to switch between pro- and anti-tumor phenotypes based on external stimuli. Pro-tumorigenic neutrophils facilitate tumor growth through mechanisms such as neutrophil extracellular traps (NETs), secretion of pro-inflammatory cytokines, and immune evasion strategies. They contribute to angiogenesis, tumor invasion, and metastasis by releasing vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). Conversely, anti-tumor neutrophils enhance cytotoxicity by generating reactive oxygen species (ROS), promoting antibody-dependent cell-mediated cytotoxicity (ADCC), and activating other immune cells such as cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Recent advances in neutrophil-based drug delivery systems have harnessed their tumor-homing capabilities to improve targeted therapy. Neutrophil-mimicking nanoparticles and membrane-coated drug carriers offer enhanced drug accumulation in tumors, reduced systemic toxicity, and improved therapeutic outcomes. Additionally, strategies to modulate neutrophil activity, such as inhibiting their immunosuppressive functions or reprogramming them towards an anti-tumor phenotype, are emerging as promising approaches in cancer immunotherapy. Understanding neutrophil plasticity and their interactions with the TME provides new avenues for therapeutic interventions. Targeting neutrophil-mediated mechanisms could enhance existing cancer treatments and lead to the development of novel immunotherapies, ultimately improving patient survival and clinical outcomes.
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Affiliation(s)
- Hicham Wahnou
- Laboratory of Immunology and Biodiversity, Faculty of Sciences Ain Chock, Hassan II University, B.P 2693, Maarif, Casablanca 20100, Morocco; (H.W.); (S.H.); (Z.O.); (O.E.F.)
| | - Riad El Kebbaj
- Sciences and Engineering of Biomedicals, Biophysics and Health Laboratory, Higher Institute of Health Sciences, Hassan First University, Settat 26000, Morocco;
| | - Soufyane Hba
- Laboratory of Immunology and Biodiversity, Faculty of Sciences Ain Chock, Hassan II University, B.P 2693, Maarif, Casablanca 20100, Morocco; (H.W.); (S.H.); (Z.O.); (O.E.F.)
- Univ. Limoges, LABCiS, UR 22722, F-87000 Limoges, France; (A.P.); (B.L.)
| | - Zaynab Ouadghiri
- Laboratory of Immunology and Biodiversity, Faculty of Sciences Ain Chock, Hassan II University, B.P 2693, Maarif, Casablanca 20100, Morocco; (H.W.); (S.H.); (Z.O.); (O.E.F.)
| | - Othman El Faqer
- Laboratory of Immunology and Biodiversity, Faculty of Sciences Ain Chock, Hassan II University, B.P 2693, Maarif, Casablanca 20100, Morocco; (H.W.); (S.H.); (Z.O.); (O.E.F.)
| | - Aline Pinon
- Univ. Limoges, LABCiS, UR 22722, F-87000 Limoges, France; (A.P.); (B.L.)
| | - Bertrand Liagre
- Univ. Limoges, LABCiS, UR 22722, F-87000 Limoges, France; (A.P.); (B.L.)
| | - Youness Limami
- Sciences and Engineering of Biomedicals, Biophysics and Health Laboratory, Higher Institute of Health Sciences, Hassan First University, Settat 26000, Morocco;
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6
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Vaezi A, Rafiei SKS, Amiri B, Rezvanimehr A, Naji abhary M, Mahdavi P, Abbasalizadeh M, Yavari G, Sattari MS, Kheirandish A, Erabi G, Zadeh FV, Rasekh F, Pormehr‐yabandeh A, Mohagheghi SZ, Zaraj H, Abdi A, Dadkhah PA, Deravi N. The Impact of Malignancy on the Risk of Venous Thromboembolism in Pregnant Women: A Systematic Review. Health Sci Rep 2025; 8:e70456. [PMID: 40226174 PMCID: PMC11985895 DOI: 10.1002/hsr2.70456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 12/28/2024] [Accepted: 01/25/2025] [Indexed: 04/15/2025] Open
Abstract
Background and Aims Venous thromboembolism (VTE) is a distinct malignancy complication that raises the risk of demise in cancer patients by up to thrice. However, pregnant females have a 4-5 times greater chance of getting VTE than nonpregnant women. The current systematic review aimed to elucidate the impact of malignancy on the risk of VTE in pregnant females. Methods We carried out a systematic search in multiple databases, including PubMed (Medline), Google Scholar, and Scopus, up to January 2023. Finally, 441 related articles were extracted from the databases. After screening the title, abstract, and full text, seven articles were included in the study. Results Seven studies (six cohorts and one cross-sectional) with 58,854,195 pregnant females (22,396 cancer patients) were included. These studies were done in the United States of America, Canada, Brazil, and Denmark. All of the studies except one study demonstrated that cancer in pregnant patients increased the risk of deep vein thrombosis (DVT). The risk of VTE prevalence in pregnant females with a record of malignancy was significantly higher than in free cancer groups, and the highest aOR was correlated to myeloid leukemia. Conclusions Evidence in this systematic review showed that pregnant women with malignancy are more susceptible to VTE and other coagulation disorders. Physicians and health policymakers should be of high vigilance to pregnancy-associated VTE, especially in women who have cancer.
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Affiliation(s)
- Ali Vaezi
- Student Research Committee, School of MedicineTehran University of Medical SciencesTehranIran
| | | | - Bita Amiri
- Cardiovascular Research CenterTabriz University of Medical SciencesTabrizIran
| | - Ali Rezvanimehr
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA)Universal Scientific Education and Research Network (USERN)TehranIran
- Faculty of Medicine, Tehran Medical Sciences BranchIslamic Azad UniversityTehranIran
| | - Maryam Naji abhary
- Department of Midwifery, School of Nursing & MidwiferyMashhad University of Medical SciencesMashhadIran
| | - Pariya Mahdavi
- Student Research Committee, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Mohammad Abbasalizadeh
- Student Research CommitteeTabriz University of Medical SciencesTabrizIran
- Research Center for Evidence-Based Medicine, Iranian EBM Centre: A JBI Centre of Excellence, Faculty of MedicineTabriz University of Medical SciencesTabrizIran
| | - Ghazale Yavari
- Student Research Committee, School of MedicineShahroud University of Medical SciencesShahroudIran
| | | | - Ali Kheirandish
- Student Research Committee, Faculty of PharmacyMazandaran University of Medical SciencesSariIran
| | - Gisou Erabi
- Student Research CommitteeUrmia University of Medical SciencesUrmiaIran
| | - Foad Vakili Zadeh
- Student Research Committee, School of MedicineGuilan University of Medical SciencesRashtIran
| | - Fatemeh Rasekh
- Student Research Committee, School of MedicineShiraz University of Medical ScienceShirazIran
| | | | | | - Hoda Zaraj
- Tehran University‐Caspian CampusTehranIran
| | - Amir Abdi
- Student Research Committee, School of Medicine, Tehran Medical SciencesIslamic Azad UniversityTehranIran
| | | | - Niloofar Deravi
- Student Research Committee, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
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7
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Christo PJ, Vortsman E, Gharibo C, LeQuang JAK, Pergolizzi JV. Considering Long-Acting Synthetic Cannabidiol for Chronic Pain: A Narrative Review. Cureus 2025; 17:e81577. [PMID: 40313449 PMCID: PMC12045650 DOI: 10.7759/cureus.81577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Accepted: 03/27/2025] [Indexed: 05/03/2025] Open
Abstract
Chronic pain is prevalent and challenging to treat. Cannabinoids, in particular cannabidiol (CBD), have been evaluated as analgesics without the issues of tolerance or dependence. Side effects tend to be mild and infrequent. These products have multiple routes of administration and composition, and some are available over the counter, allowing pain patients to self-medicate. Most self-medicated CBD are plant-derived extracts administered as either oils, pills, or by inhalation. During the early 1960s, CBD was chemically synthesized for the first time, but it was not yet approved for medical use; synthetic CBD has been and continues to be studied in clinical trials for numerous indications, including chronic pain, neuropathic pain, and pain in cancer. However, studies are often small, populations heterogeneous, and some results are equivocal. Research is lively, with over 60 studies reported on ClinicalTrials.gov. Multimodal CBD therapy may hold promise, particularly in combination with palmitoylethanolamide. Greater patient education and training for physicians and other healthcare providers are needed along with more comprehensive studies. Considering the problem of chronic pain, further intensive study of synthetic CBD for pain control is warranted to meet this unmet clinical need. This is particularly important in the context of long-lasting administration methods that enable easy dosing and support long-term use for patients dealing with persistent and often debilitating symptoms.
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Affiliation(s)
- Paul J Christo
- Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Eugene Vortsman
- Department of Emergency Medicine, Northwell Health, Long Island Jewish Medical Center, New York, USA
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8
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Xu X, Xu P, Shen G, Peng X, Liu Z, Chen C, Yu W, Su Z, Lin J, Zheng G, Ye G, Wang P, Xie Z, Wu Y, Shen H, Li J. Targeting macrophage polarization by inhibiting Pim2 alleviates inflammatory arthritis via metabolic reprogramming. Cell Mol Immunol 2025; 22:418-436. [PMID: 40000906 PMCID: PMC11955556 DOI: 10.1038/s41423-025-01268-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 01/25/2025] [Accepted: 02/06/2025] [Indexed: 02/27/2025] Open
Abstract
Macrophage polarization and energy metabolic reprogramming play pivotal roles in the onset and progression of inflammatory arthritis. Moreover, although previous studies have reported that the proviral integration of Moloney virus 2 (Pim2) kinase is involved in various cancers through the mediation of aerobic glycolysis in cancer cells, its role in inflammatory arthritis remains unclear. In this study, we demonstrated that multiple metabolic enzymes are activated upon Pim2 upregulation during M1 macrophage polarization. Specifically, Pim2 directly phosphorylates PGK1-S203, PDHA1-S300, and PFKFB2-S466, thereby promoting glycolytic reprogramming. Pim2 expression was elevated in macrophages from patients with inflammatory arthritis and collagen-induced arthritis (CIA) model mice. Conditional knockout of Pim2 in macrophages or administration of the Pim2 inhibitor HJ-PI01 attenuated arthritis development by inhibiting M1 macrophage polarization. Through molecular docking and dynamic simulation, bexarotene was identified as an inhibitor of Pim2 that inhibits glycolysis and downstream M1 macrophage polarization, thereby mitigating the progression of inflammatory arthritis. For targeted treatment, neutrophil membrane-coated bexarotene (Bex)-loaded PLGA-based nanoparticles (NM@NP-Bex) were developed to slow the progression of inflammatory arthritis by suppressing the polarization of M1 macrophages, and these nanoparticles (NPs) exhibited superior therapeutic effects with fewer side effects. Taken together, the results of our study demonstrated that targeting Pim2 inhibition could effectively alleviate inflammatory arthritis via glycolysis inhibition and reversal of the M1/M2 macrophage imbalance. NM@NPs loaded with bexarotene could represent a promising targeted strategy for the treatment of inflammatory arthritis.
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Affiliation(s)
- Xiaojun Xu
- Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518033, PR China
- Guangdong Provincial Clinical Research Center for Orthopedic Diseases, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518033, PR China
| | - Peitao Xu
- Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518033, PR China
- Guangdong Provincial Clinical Research Center for Orthopedic Diseases, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518033, PR China
| | - Guozhen Shen
- Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518033, PR China
- Guangdong Provincial Clinical Research Center for Orthopedic Diseases, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518033, PR China
| | - Xiaoshuai Peng
- Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518033, PR China
- Guangdong Provincial Clinical Research Center for Orthopedic Diseases, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518033, PR China
| | - Zhidong Liu
- Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518033, PR China
- Guangdong Provincial Clinical Research Center for Orthopedic Diseases, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518033, PR China
| | - Chaoqiang Chen
- Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518033, PR China
- Guangdong Provincial Clinical Research Center for Orthopedic Diseases, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518033, PR China
| | - Wenhui Yu
- Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518033, PR China
- Guangdong Provincial Clinical Research Center for Orthopedic Diseases, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518033, PR China
| | - Zepeng Su
- Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518033, PR China
- Guangdong Provincial Clinical Research Center for Orthopedic Diseases, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518033, PR China
| | - Jiajie Lin
- Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518033, PR China
- Guangdong Provincial Clinical Research Center for Orthopedic Diseases, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518033, PR China
| | - Guan Zheng
- Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518033, PR China
- Guangdong Provincial Clinical Research Center for Orthopedic Diseases, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518033, PR China
| | - Guiwen Ye
- Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518033, PR China
- Guangdong Provincial Clinical Research Center for Orthopedic Diseases, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518033, PR China
| | - Peng Wang
- Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518033, PR China
- Guangdong Provincial Clinical Research Center for Orthopedic Diseases, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518033, PR China
| | - Zhongyu Xie
- Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518033, PR China
- Guangdong Provincial Clinical Research Center for Orthopedic Diseases, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518033, PR China
| | - Yanfeng Wu
- Guangdong Provincial Clinical Research Center for Orthopedic Diseases, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518033, PR China.
- Center for Biotherapy, The Eighth Affiliated Hospital of Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518033, PR China.
| | - Huiyong Shen
- Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518033, PR China.
- Guangdong Provincial Clinical Research Center for Orthopedic Diseases, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518033, PR China.
| | - Jinteng Li
- Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518033, PR China.
- Guangdong Provincial Clinical Research Center for Orthopedic Diseases, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518033, PR China.
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9
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Su Q, Li Y, Wen C, Li L, Ye Q, Chen M, Xie L, Hu C, Wu H. Causal Relationship Between Immune Cells and Venous Thromboembolism: A Bidirectional Two-Sample Mendelian Randomization Study. Vasc Health Risk Manag 2025; 21:181-195. [PMID: 40160216 PMCID: PMC11954403 DOI: 10.2147/vhrm.s497476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 03/07/2025] [Indexed: 04/02/2025] Open
Abstract
Introduction Manny evidence indicates that numerous immune cells are linked to the onset and progression of VTE, though the causal relationship remains unclear. To determine the association between immune cells and VTE, we performed a bidirectional two-sample Mendelian randomization (MR) study. Methods A comprehensive MR analysis was conducted to ascertain the causal relationship between immune cell signatures and VTE. Leveraging publicly available genetic data, we examined the causal associations between 731 immune cell signatures and the risk of VTE. The analysis encompassed four types of immune signatures, namely median fluorescence intensities, relative cell counts, absolute cell counts, and morphological parameters. We employed the two-sample MR analysis, used the inverse variance-weighted (IVW) approach as the primary analytical method. Rigorous sensitivity analyses were employed to validate the robustness, heterogeneity, and presence of horizontal pleiotropy in the results. Furthermore, the reverse MR analysis was implemented to confirm the existence of reverse causal relationships. Results Eighteen immune cell signatures were found to have nominally significant associations with VTE according to the IVW method. The level of CD14 expression on CD14+ CD16+ monocytes (OR 0.95) and ten other phenotypes were identified as protective factors against VTE. Conversely, the percentage of HLA DR+ T cells among lymphocytes (OR 1.03) and six other phenotypes were identified as risk factors associated with an increased likelihood of VTE. The expression level of CX3CR1 on CD14- CD16+ monocytes showed a potential bidirectional causal relationship. Conclusion Our study identified 18 types of immune cell signatures that could impact VTE development, offering novel insights for future mechanistic and clinical studies in this field. Further studies to prospectively validate our findings are needed.
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Affiliation(s)
- Qiwen Su
- School of Clinical Medicine, North Sichuan Medical College, Nanchong, People’s Republic of China
- Department of Vascular Surgery, Dazhou Central Hospital, Dazhou, People’s Republic of China
| | - Yue Li
- School of Clinical Medicine, North Sichuan Medical College, Nanchong, People’s Republic of China
- Department of Vascular Surgery, Dazhou Central Hospital, Dazhou, People’s Republic of China
| | - Cheng Wen
- School of Clinical Medicine, North Sichuan Medical College, Nanchong, People’s Republic of China
- Department of Vascular Surgery, Dazhou Central Hospital, Dazhou, People’s Republic of China
| | - Lilong Li
- School of Clinical Medicine, North Sichuan Medical College, Nanchong, People’s Republic of China
- Department of Vascular Surgery, Dazhou Central Hospital, Dazhou, People’s Republic of China
| | - Qianling Ye
- Department of Vascular Surgery, Dazhou Central Hospital, Dazhou, People’s Republic of China
| | - Ming Chen
- Department of Vascular Surgery, Dazhou Central Hospital, Dazhou, People’s Republic of China
| | - Linyang Xie
- School of Clinical Medicine, North Sichuan Medical College, Nanchong, People’s Republic of China
- Department of Vascular Surgery, Dazhou Central Hospital, Dazhou, People’s Republic of China
| | - Chenming Hu
- School of Clinical Medicine, North Sichuan Medical College, Nanchong, People’s Republic of China
- Department of Vascular Surgery, Dazhou Central Hospital, Dazhou, People’s Republic of China
| | - Huaping Wu
- School of Clinical Medicine, North Sichuan Medical College, Nanchong, People’s Republic of China
- Department of Vascular Surgery, Dazhou Central Hospital, Dazhou, People’s Republic of China
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10
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Lian Y, Lai X, Wu C, Wang L, Shang J, Zhang H, Jia S, Xing W, Liu H. The roles of neutrophils in cardiovascular diseases. Front Cardiovasc Med 2025; 12:1526170. [PMID: 40176832 PMCID: PMC11961988 DOI: 10.3389/fcvm.2025.1526170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 03/04/2025] [Indexed: 04/05/2025] Open
Abstract
The immune response plays a vital role in the development of cardiovascular diseases (CVDs). As a crucial component of the innate immune system, neutrophils are involved in the initial inflammatory response following cardiovascular injury, thereby inducing subsequent damage and promoting recovery. Neutrophils exert their functional effects in tissues through various mechanisms, including activation and the formation of neutrophil extracellular traps (NETs). Once activated, neutrophils are recruited to the site of injury, where they release inflammatory mediators and cytokines. This study discusses the main mechanisms associated with neutrophil activity and proposes potential new therapeutic targets. In this review, we systematically summarize the diverse phenotypes of neutrophils in disease regulatory mechanisms, different modes of cell death, and focus on the relevance of neutrophils to various CVDs, including atherosclerosis, acute coronary syndrome, myocardial ischemia/reperfusion injury, hypertension, atrial fibrillation, heart failure, and viral myocarditis. Finally, we also emphasize the preclinical/clinical translational significance of neutrophil-targeted strategies.
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Affiliation(s)
- Yanjie Lian
- Department of Cardiovascular Medicine, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Xiaolei Lai
- Department of Cardiovascular Medicine, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Cong Wu
- Beijing Hospital of Traditional Chinese Medicine, Huairou Hospital, Beijing, China
| | - Li Wang
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - JuJu Shang
- Department of Cardiovascular Medicine, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Heyi Zhang
- Department of Cardiovascular Medicine, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Sihan Jia
- Department of Cardiovascular Medicine, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Wenlong Xing
- Department of Cardiovascular Medicine, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Hongxu Liu
- Department of Cardiovascular Medicine, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
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11
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Kotlyarov S, Oskin D. The Role of Inflammation in the Pathogenesis of Comorbidity of Chronic Obstructive Pulmonary Disease and Pulmonary Tuberculosis. Int J Mol Sci 2025; 26:2378. [PMID: 40141021 PMCID: PMC11942565 DOI: 10.3390/ijms26062378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Revised: 02/23/2025] [Accepted: 03/05/2025] [Indexed: 03/28/2025] Open
Abstract
The comorbid course of chronic obstructive pulmonary disease (COPD) and pulmonary tuberculosis is an important medical and social problem. Both diseases, although having different etiologies, have many overlapping relationships that mutually influence their course and prognosis. The aim of the current review is to discuss the role of different immune mechanisms underlying inflammation in COPD and pulmonary tuberculosis. These mechanisms are known to involve both the innate and adaptive immune system, including various cellular and intercellular interactions. There is growing evidence that immune mechanisms involved in the pathogenesis of both COPD and tuberculosis may jointly contribute to the tuberculosis-associated obstructive pulmonary disease (TOPD) phenotype. Several studies have reported prior tuberculosis as a risk factor for COPD. Therefore, the study of the mechanisms that link COPD and tuberculosis is of considerable clinical interest.
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Affiliation(s)
- Stanislav Kotlyarov
- Department of Nursing, Ryazan State Medical University, 390026 Ryazan, Russia
| | - Dmitry Oskin
- Department of Infectious Diseases and Phthisiology, Ryazan State Medical University, 390026 Ryazan, Russia
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12
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Chee YJ, Dalan R, Cheung C. The Interplay Between Immunity, Inflammation and Endothelial Dysfunction. Int J Mol Sci 2025; 26:1708. [PMID: 40004172 PMCID: PMC11855323 DOI: 10.3390/ijms26041708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 02/04/2025] [Accepted: 02/12/2025] [Indexed: 02/27/2025] Open
Abstract
The endothelium is pivotal in multiple physiological processes, such as maintaining vascular homeostasis, metabolism, platelet function, and oxidative stress. Emerging evidence in the past decade highlighted the immunomodulatory function of endothelium, serving as a link between innate, adaptive immunity and inflammation. This review examines the regulation of the immune-inflammatory axis by the endothelium, discusses physiological immune functions, and explores pathophysiological processes leading to endothelial dysfunction in various metabolic disturbances, including hyperglycemia, obesity, hypertension, and dyslipidaemia. The final section focuses on the novel, repurposed, and emerging therapeutic targets that address the immune-inflammatory axis in endothelial dysfunction.
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Affiliation(s)
- Ying Jie Chee
- Department of Endocrinology, Tan Tock Seng Hospital, Singapore 308433, Singapore;
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore;
| | - Rinkoo Dalan
- Department of Endocrinology, Tan Tock Seng Hospital, Singapore 308433, Singapore;
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore;
| | - Christine Cheung
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore;
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138632, Singapore
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13
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He W, Yan L, Hu D, Hao J, Liou Y, Luo G. Neutrophil heterogeneity and plasticity: unveiling the multifaceted roles in health and disease. MedComm (Beijing) 2025; 6:e70063. [PMID: 39845896 PMCID: PMC11751288 DOI: 10.1002/mco2.70063] [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: 09/02/2024] [Revised: 11/04/2024] [Accepted: 12/11/2024] [Indexed: 01/24/2025] Open
Abstract
Neutrophils, the most abundant circulating leukocytes, have long been recognized as key players in innate immunity and inflammation. However, recent discoveries unveil their remarkable heterogeneity and plasticity, challenging the traditional view of neutrophils as a homogeneous population with a limited functional repertoire. Advances in single-cell technologies and functional assays have revealed distinct neutrophil subsets with diverse phenotypes and functions and their ability to adapt to microenvironmental cues. This review provides a comprehensive overview of the multidimensional landscape of neutrophil heterogeneity, discussing the various axes along which diversity manifests, including maturation state, density, surface marker expression, and functional polarization. We highlight the molecular mechanisms underpinning neutrophil plasticity, focusing on the complex interplay of signaling pathways, transcriptional regulators, and epigenetic modifications that shape neutrophil responses. Furthermore, we explore the implications of neutrophil heterogeneity and plasticity in physiological processes and pathological conditions, including host defense, inflammation, tissue repair, and cancer. By integrating insights from cutting-edge research, this review aims to provide a framework for understanding the multifaceted roles of neutrophils and their potential as therapeutic targets in a wide range of diseases.
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Affiliation(s)
- Weifeng He
- Institute of Burn ResearchState Key Laboratory of Trauma and Chemical Poisoningthe First Affiliated Hospital of Army Medical University (the Third Military Medical University)ChongqingChina
- Chongqing Key Laboratory for Wound Repair and Tissue RegenerationChongqingChina
| | - Lingfeng Yan
- Institute of Burn ResearchState Key Laboratory of Trauma and Chemical Poisoningthe First Affiliated Hospital of Army Medical University (the Third Military Medical University)ChongqingChina
- Chongqing Key Laboratory for Wound Repair and Tissue RegenerationChongqingChina
| | - Dongxue Hu
- Department of Biological SciencesFaculty of ScienceNational University of SingaporeSingaporeSingapore
| | - Jianlei Hao
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University)Jinan UniversityZhuhaiGuangdongChina
- The Biomedical Translational Research InstituteFaculty of Medical ScienceJinan UniversityGuangzhouGuangdongChina
| | - Yih‐Cherng Liou
- Department of Biological SciencesFaculty of ScienceNational University of SingaporeSingaporeSingapore
- National University of Singapore (NUS) Graduate School for Integrative Sciences and EngineeringNational University of SingaporeSingaporeSingapore
| | - Gaoxing Luo
- Institute of Burn ResearchState Key Laboratory of Trauma and Chemical Poisoningthe First Affiliated Hospital of Army Medical University (the Third Military Medical University)ChongqingChina
- Chongqing Key Laboratory for Wound Repair and Tissue RegenerationChongqingChina
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14
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Moreno Alfonso JC, Barbosa-Velásquez S, Delgado-Miguel C, Molina Caballero A, Hernández-Martín S, Pérez Martínez A, Yárnoz Irazábal MC. Exploring the utility of cellular indices in the diagnosis of ulcerative colitis. GASTROENTEROLOGIA Y HEPATOLOGIA 2025:502349. [PMID: 39827908 DOI: 10.1016/j.gastrohep.2025.502349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 12/12/2024] [Accepted: 01/13/2025] [Indexed: 01/22/2025]
Abstract
AIM To describe the usefulness of cellular indices in the diagnosis of ulcerative colitis (UC). METHODS Diagnostic study of patients under 15 years of age undergoing colonoscopy±esophagogastroduodenoscopy for suspected inflammatory bowel disease between 2015 and 2022 in a pediatric hospital. Patients with normal biopsy and anatomopathological diagnosis of UC were included. Using the area under the ROC curve, the values of platelet-lymphocyte ratio (PLR), neutrophil-lymphocyte ratio (NLR) and monocyte-lymphocyte ratio (MLR), calculated by dividing the number of platelets, neutrophils, and monocytes by the number of lymphocytes, respectively, were compared to establish the sensitivity, specificity, predictive values and odds ratio of each parameter in the diagnosis of UC. RESULTS Twenty-six patients were included: 14 with normal biopsy and 12 with UC. PLR and MLR values were significantly higher in patients with UC (p<0.05). The sensitivity, specificity, and negative predictive value of PLR, NLR and MLR for diagnosing UC were 58%, 83% and 91%; 85%, 35% and 50%; 70%, 71% and 87%, respectively. The biomarker with the highest diagnostic performance was MLR with a cutoff point of 0.235, area under the curve of 0.735 and odds ratio of 11 (95% CI 1.1-109.6; p=0.041). CONCLUSIONS MLR has a high sensitivity, negative predictive value, and odds ratio in the pre-endoscopic diagnosis of ulcerative colitis. These findings, although exploratory, suggest that MLR could be useful in clinical practice in the initial diagnostic workup of UC, and perhaps in the future in the prioritization of endoscopic studies according to MLR values.
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Affiliation(s)
- Julio César Moreno Alfonso
- Department of Pediatric Surgery, Hospital Universitario de Navarra, Pamplona, Navarra, Spain; Doctoral School, Universidad Pública de Navarra (UPNA), Pamplona, Navarra, Spain.
| | - Sharom Barbosa-Velásquez
- Hospital Universitario de Álava, Jose Atxotegi Kalea, s/n, Txagorritxu, 01009 Vitoria-Gasteiz, Araba, Spain
| | - Carlos Delgado-Miguel
- Department of Pediatric Surgery, Fundación Jiménez Díaz University Hospital, Avenida de los Reyes Católicos, 2, 28040 Madrid, Spain; Institute for Health Research IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain
| | - Ada Molina Caballero
- Department of Pediatric Surgery, Hospital Universitario de Navarra, Pamplona, Navarra, Spain
| | - Sara Hernández-Martín
- Department of Pediatric Surgery, Hospital Universitario de Navarra, Pamplona, Navarra, Spain
| | - Alberto Pérez Martínez
- Department of Pediatric Surgery, Hospital Universitario de Navarra, Pamplona, Navarra, Spain
| | - María Concepción Yárnoz Irazábal
- Doctoral School, Universidad Pública de Navarra (UPNA), Pamplona, Navarra, Spain; Department of General and Digestive Surgery, Hospital Universitario de Navarra, Pamplona, Navarra, Spain
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15
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Shao CL, Meng WT, Wang YC, Liu JJ, Ning K, Hou XX, Guo HD. Regulating NETs contributes to a novel antiatherogenic effect of MTHSWD via inhibiting endothelial injury and apoptosis. Int Immunopharmacol 2024; 143:113368. [PMID: 39418732 DOI: 10.1016/j.intimp.2024.113368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 10/05/2024] [Accepted: 10/06/2024] [Indexed: 10/19/2024]
Abstract
Neutrophil extracellular traps (NETs) are implicated in the occurrence and progression of atherosclerosis (AS), which can result in adverse cardiovascular events. We investigated the potential mechanism of action of Modified Taohong Siwu Decoction (MTHSWD) against AS based on its effect on NETs. A model of unstable plaque in AS was established by tandem stenosis (TS) of the right common carotid artery in ApoE-/- mice combined with a western diet (WD). The research found that MTHSWD reduced the weight of mice with AS to varying degrees, and significantly decreased the levels of plasma total cholesterol (TC) and triglycerides (TG). Meanwhile, we found that MTHSWD not only significantly improved cardiac EF, FS, cardiac hypertrophy, and ventricular remodeling, but also ameliorated the silent and depressed hypoactivity state caused by AS in ApoE-/- mice. Additionally, the study revealed that MTHSWD improved the severity of AS, protected the vascular structure, increased plaque stability and vessel patency. It also significantly reduced vascular cell apoptosis, platelet aggregation, and the presence of inflammatory cells such as neutrophils (NEUs), as well as the expression of neutrocyte elastase (NE) and myeloperoxidase (MPO), which are components of NETs. Subsequently, NEUs studies have shown that MTHSWD not only significantly reduces the dsDNA content of NETs, but also lowers the expression of NETs components NE and citH3. NETs treating the human umbilical vein endothelial cells (HUVECs) demonstrated that NETs differentially increased the protein expression of endothelial inflammatory adhesion factors CD62P, VCAM-1 and ICAM-1, while significantly decreasing the viability of HUVECs. Pharmacological treatment discovered that MTHSWD significantly improved HUVECs viability impaired by NETs, and promoted the growth and proliferation of endothelial cells. Furthermore, it significantly reduced early and late apoptosis of HUVECs caused by NETs, decreased the expression of pro-apoptotic proteins BAX and Cleaved-Caspase-3, and increased the expression of anti-apoptotic protein Bcl-2. Thus, study suggests that MTHSWD may improve body weight, lipid levels, cardiac function, vigour, and the severity of AS in ApoE-/- AS mice. The novel effect of MTHSWD against AS may be attributed to the inhibition of endothelial injury and apoptosis through the regulation of NETs. This, in turn, reduces the levels of platelets, inflammatory cells, and components of NETs in AS plaques, achieving a benign cycle that protects endothelial cells and vascular structure and function. This result provides some clues and evidence for studying the mechanism of action and clinical application of MTHSWD and its active ingredients against AS.
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MESH Headings
- Animals
- Apoptosis/drug effects
- Atherosclerosis/drug therapy
- Atherosclerosis/pathology
- Extracellular Traps/drug effects
- Extracellular Traps/metabolism
- Humans
- Male
- Mice
- Human Umbilical Vein Endothelial Cells
- Mice, Inbred C57BL
- Drugs, Chinese Herbal/pharmacology
- Drugs, Chinese Herbal/therapeutic use
- Neutrophils/drug effects
- Neutrophils/immunology
- Apolipoproteins E/genetics
- Mice, Knockout
- Disease Models, Animal
- Plaque, Atherosclerotic/drug therapy
- Plaque, Atherosclerotic/pathology
- Mice, Knockout, ApoE
- Cells, Cultured
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Affiliation(s)
- Chang-le Shao
- School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wan-Ting Meng
- School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ya-Chao Wang
- School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jia-Jia Liu
- School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ke Ning
- School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Xin-Xin Hou
- School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Hai-Dong Guo
- School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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16
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Zhang Y, Cao Y, Zhang X, Lin J, Jiang M, Zhang X, Dai X, Zhang X, Liu Y, Ge W, Qiang H, Li C, Sun D. Single-Cell RNA Sequencing Uncovers Pathological Processes and Crucial Targets for Vascular Endothelial Injury in Diabetic Hearts. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2405543. [PMID: 39475009 DOI: 10.1002/advs.202405543] [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: 05/21/2024] [Revised: 10/18/2024] [Indexed: 12/19/2024]
Abstract
Cardiovascular disease remains the leading cause of high mortality in individuals with diabetes mellitus. Endothelial injury is a major contributing factor for vascular dysfunction in diabetes. However, the precise mechanisms underlying endothelial cell injury and their heterogeneity in diabetes remains elusive. In this study, single-cell sequencing is performed in heart tissues from leptin receptor knock-out (db/db) diabetic mice at various pathological stages. Through cell cluster identification, differential gene analysis, intercellular communication analysis, pseudo time analysis, and transcription factor analysis, a novel mechanism of cardiac vascular endothelial damage in diabetes is identified. Specifically, a single-cell transcription map of cardiac vascular endothelial cells is presented in db/db mice. Diverse cellular clusters are found to play vital roles under diabetes-induced damage, highlighting crucial transcription factors involved in their regulation. In addition, the essential transcription factor Ets1 is found to protect against vascular endothelial injury in db/db mice. In summary, the work provides a comprehensive understanding of the development of diabetic cardiac vascular endothelial damage and the heterogeneity of the cells involved. These findings offer valuable insights into potential treatments and assessments of diabetic cardiovascular endothelial damage.
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Affiliation(s)
- Yan Zhang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Yang Cao
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Xuebin Zhang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Jie Lin
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Mengyuan Jiang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Xiao Zhang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Xinchun Dai
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Xiaohua Zhang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Yue Liu
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Wen Ge
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Huanhuan Qiang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Congye Li
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Dongdong Sun
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
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17
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Ma Y, Zhao Y, Zhang X. Factors affecting neutrophil functions during sepsis: human microbiome and epigenetics. J Leukoc Biol 2024; 116:672-688. [PMID: 38734968 DOI: 10.1093/jleuko/qiae107] [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: 12/07/2023] [Revised: 04/02/2024] [Accepted: 04/11/2024] [Indexed: 05/13/2024] Open
Abstract
Sepsis is a severe disease that occurs when the body's immune system reacts excessively to infection. The body's response, which includes an intense antibacterial reaction, can damage its tissues and organs. Neutrophils are the major components of white blood cells in circulation, play a vital role in innate immunity while fighting against infections, and are considered a feature determining sepsis classification. There is a plethora of basic research detailing neutrophil functioning, among which, the study of neutrophil extracellular traps is providing novel insights into mechanisms and treatments of sepsis. This review explores their functions, dysfunctions, and influences in the context of sepsis. The interplay between neutrophils and the human microbiome and the impact of DNA methylation on neutrophil function in sepsis are crucial areas of study. The interaction between neutrophils and the human microbiome is complex, particularly in the context of sepsis, where dysbiosis may occur. We highlight the importance of deciphering neutrophils' functional alterations and their epigenetic features in sepsis because it is critical for defining sepsis endotypes and opening up the possibility for novel diagnostic methods and therapy. Specifically, epigenetic signatures are pivotal since they will provide a novel implication for a sepsis diagnostic method when used in combination with the cell-free DNA. Research is exploring how specific patterns of DNA methylation in neutrophils, detectable in cell-free DNA, could serve as biomarkers for the early detection of sepsis.
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Affiliation(s)
- Yina Ma
- Department of Urology Surgery, Beijing Chaoyang Hospital, Capital Medical University, Shijingshan District, Beijing 100043, China
| | - Yu Zhao
- Department of Urology Surgery, Beijing Chaoyang Hospital, Capital Medical University, Shijingshan District, Beijing 100043, China
| | - Xin Zhang
- Department of Urology Surgery, Beijing Chaoyang Hospital, Capital Medical University, Shijingshan District, Beijing 100043, China
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18
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Martinez Bravo G, Annarapu G, Carmona E, Nawarskas J, Clark R, Novelli E, Mota Alvidrez RI. Platelets in Thrombosis and Atherosclerosis: A Double-Edged Sword. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:1608-1621. [PMID: 38885926 PMCID: PMC11373056 DOI: 10.1016/j.ajpath.2024.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 04/16/2024] [Accepted: 05/16/2024] [Indexed: 06/20/2024]
Abstract
This review focuses on the dual role of platelets in atherosclerosis and thrombosis, exploring their involvement in inflammation, angiogenesis, and plaque formation, as well as their hemostatic and prothrombotic functions. Beyond their thrombotic functions, platelets engage in complex interactions with diverse cell types, influencing disease resolution and progression. The contribution of platelet degranulation helps in the formation of atheromatous plaque, whereas the reciprocal interaction with monocytes adds complexity. Alterations in platelet membrane receptors and signaling cascades contribute to advanced atherosclerosis, culminating in atherothrombotic events. Understanding these multifaceted roles of platelets will lead to the development of targeted antiplatelet strategies for effective cardiovascular disease prevention and treatment. Understanding platelet functions in atherosclerosis and atherothrombosis at different stages of disease will be critical for designing targeted treatments and medications to prevent or cure the disease Through this understanding, platelets can be targeted at specific times in the atherosclerosis process, possibly preventing the development of atherothrombosis.
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Affiliation(s)
| | - Gowtham Annarapu
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Emely Carmona
- School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - James Nawarskas
- Pharmaceutical Sciences-Pharmacy Practice, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico
| | - Ross Clark
- Cell Biology and Physiology, University of New Mexico, Albuquerque, New Mexico; Clinical and Translational Science Center, University of New Mexico, Albuquerque, New Mexico
| | - Enrico Novelli
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania; School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Roberto I Mota Alvidrez
- Biomedical Engineering Department, University of New Mexico, Albuquerque, New Mexico; Pharmaceutical Sciences-Pharmacy Practice, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico; Clinical and Translational Science Center, University of New Mexico, Albuquerque, New Mexico.
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19
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Calo CJ, Patil T, Palizzi M, Wheeler N, Hind LE. Collagen concentration regulates neutrophil extravasation and migration in response to infection in an endothelium dependent manner. Front Immunol 2024; 15:1405364. [PMID: 39021568 PMCID: PMC11251947 DOI: 10.3389/fimmu.2024.1405364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 06/17/2024] [Indexed: 07/20/2024] Open
Abstract
Introduction As the body's first line of defense against disease and infection, neutrophils must efficiently navigate to sites of inflammation; however, neutrophil dysregulation contributes to the pathogenesis of numerous diseases that leave people susceptible to infections. Many of these diseases are also associated with changes to the protein composition of the extracellular matrix. While it is known that neutrophils and endothelial cells, which play a key role in neutrophil activation, are sensitive to the mechanical and structural properties of the extracellular matrix, our understanding of how protein composition in the matrix affects the neutrophil response to infection is incomplete. Methods To investigate the effects of extracellular matrix composition on the neutrophil response to infection, we used an infection-on-a-chip microfluidic device that replicates a portion of a blood vessel endothelium surrounded by a model extracellular matrix. Model blood vessels were fabricated by seeding human umbilical vein endothelial cells on 2, 4, or 6 mg/mL type I collagen hydrogels. Primary human neutrophils were loaded into the endothelial lumens and stimulated by adding the bacterial pathogen Pseudomonas aeruginosa to the surrounding matrix. Results Collagen concentration did not affect the cell density or barrier function of the endothelial lumens. Upon infectious challenge, we found greater neutrophil extravasation into the 4 mg/mL collagen gels compared to the 6 mg/mL collagen gels. We further found that extravasated neutrophils had the highest migration speed and distance in 2mg/mL gels and that these values decreased with increasing collagen concentration. However, these phenomena were not observed in the absence of an endothelial lumen. Lastly, no differences in the percent of extravasated neutrophils producing reactive oxygen species were observed across the various collagen concentrations. Discussion Our study suggests that neutrophil extravasation and migration in response to an infectious challenge are regulated by collagen concentration in an endothelial cell-dependent manner. The results demonstrate how the mechanical and structural aspects of the tissue microenvironment affect the neutrophil response to infection. Additionally, these findings underscore the importance of developing and using microphysiological systems for studying the regulatory factors that govern the neutrophil response.
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Affiliation(s)
| | | | | | | | - Laurel E. Hind
- Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, CO, United States
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20
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Cabrera LE, Tietäväinen J, Jokiranta ST, Mäkelä S, Vaheri A, Mustonen J, Vapalahti O, Kanerva M, Strandin T. Maturing neutrophils of lower density associate with thrombocytopenia in Puumala orthohantavirus-caused hemorrhagic fever with renal syndrome. Front Immunol 2024; 15:1419787. [PMID: 39011044 PMCID: PMC11246883 DOI: 10.3389/fimmu.2024.1419787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 05/29/2024] [Indexed: 07/17/2024] Open
Abstract
Puumala orthohantavirus-caused hemorrhagic fever with renal syndrome (PUUV-HFRS) is characterized by strong neutrophil activation. Neutrophils are the most abundant immune cell type in the circulation and are specially equipped to rapidly respond to infections. They are more heterogenous than previously appreciated, with specific neutrophil subsets recently implicated in inflammation and immunosuppression. Furthermore, neutrophils can be divided based on their density to either low-density granulocytes (LDGs) or "normal density" polymorphonuclear cell (PMN) fractions. In the current study we aimed to identify and characterize the different neutrophil subsets in the circulation of PUUV-HFRS patients. PMNs exhibited an activation of antiviral pathways, while circulating LDGs were increased in frequency following acute PUUV-HFRS. Furthermore, cell surface marker expression analysis revealed that PUUV-associated LDGs are primarily immature and most likely reflect an increased neutrophil production from the bone marrow. Interestingly, both the frequency of LDGs and the presence of a "left shift" in blood associated with the extent of thrombocytopenia, one of the hallmarks of severe HFRS, suggesting that maturing neutrophils could play a role in disease pathogenesis. These results imply that elevated circulating LDGs might be a general finding in acute viral infections. However, in contrast to the COVID-19 associated LDGs described previously, the secretome of PUUV LDGs did not show significant immunosuppressive ability, which suggests inherent biological differences in the LDG responses that can be dependent on the causative virus or differing infection kinetics.
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Affiliation(s)
- Luz E Cabrera
- Viral Zoonosis Research Unit, Department of Virology, Medicum, University of Helsinki, Helsinki, Finland
| | - Johanna Tietäväinen
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
| | - Suvi T Jokiranta
- Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland
- Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Satu Mäkelä
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
| | - Antti Vaheri
- Viral Zoonosis Research Unit, Department of Virology, Medicum, University of Helsinki, Helsinki, Finland
| | - Jukka Mustonen
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
| | - Olli Vapalahti
- Viral Zoonosis Research Unit, Department of Virology, Medicum, University of Helsinki, Helsinki, Finland
| | - Mari Kanerva
- Infectious Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Tomas Strandin
- Viral Zoonosis Research Unit, Department of Virology, Medicum, University of Helsinki, Helsinki, Finland
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21
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Simmons SR, Herring SE, Tchalla EYI, Lenhard AP, Bhalla M, Bou Ghanem EN. Activating A1 adenosine receptor signaling boosts early pulmonary neutrophil recruitment in aged mice in response to Streptococcus pneumoniae infection. Immun Ageing 2024; 21:34. [PMID: 38840213 PMCID: PMC11151497 DOI: 10.1186/s12979-024-00442-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 05/29/2024] [Indexed: 06/07/2024]
Abstract
BACKGROUND Streptococcus pneumoniae (pneumococcus) is a leading cause of pneumonia in older adults. Successful control of pneumococci requires robust pulmonary neutrophil influx early in infection. However, aging is associated with aberrant neutrophil recruitment and the mechanisms behind that are not understood. Here we explored how neutrophil recruitment following pneumococcal infection changes with age and the host pathways regulating this. RESULTS Following pneumococcal infection there was a significant delay in early neutrophil recruitment to the lungs of aged mice. Neutrophils from aged mice showed defects in trans-endothelial migration in vitro compared to young controls. To understand the pathways involved, we examined immune modulatory extracellular adenosine (EAD) signaling, that is activated upon cellular damage. Signaling through the lower affinity A2A and A2B adenosine receptors had no effect on neutrophil recruitment to infected lungs. In contrast, inhibition of the high affinity A1 receptor in young mice blunted neutrophil recruitment to the lungs following infection. A1 receptor inhibition decreased expression of CXCR2 on circulating neutrophils, which is required for trans-endothelial migration. Indeed, A1 receptor signaling on neutrophils was required for their ability to migrate across endothelial cells in response to infection. Aging was not associated with defects in EAD production or receptor expression on neutrophils. However, agonism of A1 receptor in aged mice rescued the early defect in neutrophil migration to the lungs and improved control of bacterial burden. CONCLUSIONS This study suggests age-driven defects in EAD damage signaling can be targeted to rescue the delay in pulmonary neutrophil migration in response to bacterial pneumonia.
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Affiliation(s)
- Shaunna R Simmons
- Department of Microbiology and Immunology, School of Medicine, University at Buffalo, Buffalo, NY, USA
| | - Sydney E Herring
- Department of Microbiology and Immunology, School of Medicine, University at Buffalo, Buffalo, NY, USA
| | - Essi Y I Tchalla
- Department of Microbiology and Immunology, School of Medicine, University at Buffalo, Buffalo, NY, USA
| | - Alexsandra P Lenhard
- Department of Microbiology and Immunology, School of Medicine, University at Buffalo, Buffalo, NY, USA
| | - Manmeet Bhalla
- Department of Microbiology and Immunology, School of Medicine, University at Buffalo, Buffalo, NY, USA
| | - Elsa N Bou Ghanem
- Department of Microbiology and Immunology, School of Medicine, University at Buffalo, Buffalo, NY, USA.
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22
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Yuan S, Hu Q. Convergence of nanomedicine and neutrophils for drug delivery. Bioact Mater 2024; 35:150-166. [PMID: 38318228 PMCID: PMC10839777 DOI: 10.1016/j.bioactmat.2024.01.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 01/20/2024] [Accepted: 01/21/2024] [Indexed: 02/07/2024] Open
Abstract
Neutrophils have recently emerged as promising carriers for drug delivery due to their unique properties including rapid response toward inflammation, chemotaxis, and transmigration. When integrated with nanotechnology that has enormous advantages in improving treatment efficacy and reducing side effects, neutrophil-based nano-drug delivery systems have expanded the repertoire of nanoparticles employed in precise therapeutic interventions by either coating nanoparticles with their membranes, loading nanoparticles inside living cells, or engineering chimeric antigen receptor (CAR)-neutrophils. These neutrophil-inspired therapies have shown superior biocompatibility, targeting ability, and therapeutic robustness. In this review, we summarized the benefits of combining neutrophils and nanotechnologies, the design principles and underlying mechanisms, and various applications in disease treatments. The challenges and prospects for neutrophil-based drug delivery systems were also discussed.
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Affiliation(s)
- Sichen Yuan
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, United States
- Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53705, United States
- Wisconsin Center for NanoBioSystems, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, United States
| | - Quanyin Hu
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, United States
- Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53705, United States
- Wisconsin Center for NanoBioSystems, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, United States
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23
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Chen K, Zhou A, Zhou X, He J, Xu Y, Ning X. Cellular Trojan Horse initiates bimetallic Fe-Cu MOF-mediated synergistic cuproptosis and ferroptosis against malignancies. SCIENCE ADVANCES 2024; 10:eadk3201. [PMID: 38598629 PMCID: PMC11006215 DOI: 10.1126/sciadv.adk3201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 03/05/2024] [Indexed: 04/12/2024]
Abstract
Disruptions in metal balance can trigger a synergistic interplay of cuproptosis and ferroptosis, offering promising solutions to enduring challenges in oncology. Here, we have engineered a Cellular Trojan Horse, named MetaCell, which uses live neutrophils to stably internalize thermosensitive liposomal bimetallic Fe-Cu MOFs (Lip@Fe-Cu-MOFs). MetaCell can instigate cuproptosis and ferroptosis, thereby enhancing treatment efficacy. Mirroring the characteristics of neutrophils, MetaCell can evade the immune system and not only infiltrate tumors but also respond to inflammation by releasing therapeutic components, thereby surmounting traditional treatment barriers. Notably, Lip@Fe-Cu-MOFs demonstrate notable photothermal effects, inciting a targeted release of Fe-Cu-MOFs within cancer cells and amplifying the synergistic action of cuproptosis and ferroptosis. MetaCell has demonstrated promising treatment outcomes in tumor-bearing mice, effectively eliminating solid tumors and forestalling recurrence, leading to extended survival. This research provides great insights into the complex interplay between copper and iron homeostasis in malignancies, potentially paving the way for innovative approaches in cancer treatment.
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Affiliation(s)
- Kerong Chen
- National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, Chemistry and Biomedicine Innovation Center, College of Engineering and Applied Sciences, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University, Nanjing 210093, P. R. China
| | - Anwei Zhou
- National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, Chemistry and Biomedicine Innovation Center, School of Physics, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University, Nanjing 210093, P. R. China
| | - Xinyuan Zhou
- National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, Chemistry and Biomedicine Innovation Center, College of Engineering and Applied Sciences, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University, Nanjing 210093, P. R. China
| | - Jielei He
- National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, Chemistry and Biomedicine Innovation Center, College of Engineering and Applied Sciences, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University, Nanjing 210093, P. R. China
| | - Yurui Xu
- National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, Chemistry and Biomedicine Innovation Center, College of Engineering and Applied Sciences, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University, Nanjing 210093, P. R. China
| | - Xinghai Ning
- National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, Chemistry and Biomedicine Innovation Center, College of Engineering and Applied Sciences, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University, Nanjing 210093, P. R. China
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Simmons SR, Herring SE, Tchalla EYI, Lenhard AP, Bhalla M, Bou Ghanem EN. Activating A1 adenosine receptor signaling boosts early pulmonary neutrophil recruitment in aged mice in response to Streptococcus pneumoniae infection. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.08.574741. [PMID: 38260350 PMCID: PMC10802397 DOI: 10.1101/2024.01.08.574741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
Background Streptococcus pneumoniae (pneumococcus) is a leading cause of pneumonia in older adults. Successful control of pneumococci requires robust pulmonary neutrophil influx early in infection. However, aging is associated with aberrant neutrophil recruitment and the mechanisms behind that are not understood. Here we explored how neutrophil recruitment following pneumococcal infection changes with age and the host pathways regulating this. Results Following pneumococcal infection there was a significant delay in early neutrophil recruitment to the lungs of aged mice. Neutrophils from aged mice showed defects in trans-endothelial migration in vitro compared to young controls. To understand the pathways involved, we examined immune modulatory extracellular adenosine (EAD) signaling, that is activated upon cellular damage. Signaling through the lower affinity A2A and A2B adenosine receptors had no effect on neutrophil recruitment to infected lungs. In contrast, inhibition of the high affinity A1 receptor in young mice blunted neutrophil recruitment to the lungs following infection. A1 receptor inhibition decreased expression of CXCR2 on circulating neutrophils, which is required for transendothelial migration. Indeed, A1 receptor signaling on neutrophils was required for their ability to migrate across endothelial cells in response to infection. Aging was not associated with defects in EAD production or receptor expression on neutrophils. However, agonism of A1 receptor in aged mice rescued the early defect in neutrophil migration to the lungs and improved control of bacterial burden. Conclusions This study suggests age-driven defects in EAD damage signaling can be targeted to rescue the delay in pulmonary neutrophil migration in response to bacterial pneumonia.
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25
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Duggal S, Rawat S, Siddqui G, Vishwakarma P, Samal S, Banerjee A, Vrati S. Dengue virus infection in mice induces bone marrow myeloid cell differentiation and generates Ly6Glow immature neutrophils with modulated functions. J Leukoc Biol 2024; 115:130-148. [PMID: 37648666 DOI: 10.1093/jleuko/qiad099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 07/13/2023] [Accepted: 08/15/2023] [Indexed: 09/01/2023] Open
Abstract
While neutrophil activation during dengue virus infection is known, the effect of dengue virus infection on neutrophil biogenesis has not been studied. We demonstrate that dengue virus serotype 2 induces the differentiation of mice progenitor cells ex vivo toward the CD11b+Ly6C+Ly6G+ granulocyte population. We further observed an expansion of CD11b+Ly6CintLy6Glow myeloid cells in the bone marrow of dengue virus serotype 2-infected AG129 mice with low CXCR2 expression, implying an immature population. Additionally, dengue virus serotype 2 alone could induce the differentiation of promyelocyte cell line HL-60 into neutrophil-like cells, as evidenced by increased expression of CD10, CD66b, CD16, CD11b, and CD62L, corroborating the preferential shift toward neutrophil differentiation by dengue virus serotype 2 in the mouse model of dengue infection. The functional analysis showed that dengue virus serotype 2-induced neutrophil-like cells exhibited reduced phagocytic activity and enhanced NETosis, as evidenced by the increased production of myeloperoxidase, citrullinated histones, extracellular DNA, and superoxide. These neutrophil-like cells lose their ability to proliferate irreversibly and undergo arrest in the G0 to G1 phase of the cell cycle. Further studies show that myeloperoxidase-mediated signaling operating through the reactive oxygen species axis may be involved in dengue virus serotype 2-induced proliferation and differentiation of bone marrow cells as ABAH, a myeloperoxidase inhibitor, limits cell proliferation in vitro and ex vivo, affects the cell cycle, and reduces reactive oxygen species production. Additionally, myeloperoxidase inhibitor reduced NETosis and vascular leakage in dengue virus serotype 2-infected AG129 mice. Our study thus provides evidence that dengue virus serotype 2 can accelerate the differentiation of bone marrow progenitor cells into neutrophils through myeloperoxidase and modulate their functions.
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Affiliation(s)
- Shweta Duggal
- Laboratory of Virology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad Gurgaon Expressway, Faridabad-121001, Haryana, India
| | - Surender Rawat
- Laboratory of Virology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad Gurgaon Expressway, Faridabad-121001, Haryana, India
| | - Gazala Siddqui
- Influenza and Respiratory Virus Laboratory, Centre for Virus Research, Therapeutics and Vaccines, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad Gurgaon Expressway, Faridabad-121001, Haryana, India
| | - Preeti Vishwakarma
- Influenza and Respiratory Virus Laboratory, Centre for Virus Research, Therapeutics and Vaccines, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad Gurgaon Expressway, Faridabad-121001, Haryana, India
| | - Sweety Samal
- Influenza and Respiratory Virus Laboratory, Centre for Virus Research, Therapeutics and Vaccines, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad Gurgaon Expressway, Faridabad-121001, Haryana, India
| | - Arup Banerjee
- Laboratory of Virology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad Gurgaon Expressway, Faridabad-121001, Haryana, India
| | - Sudhanshu Vrati
- Laboratory of Virology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad Gurgaon Expressway, Faridabad-121001, Haryana, India
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26
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McGrouther DA. Hand infection: a management approach based on a new understanding of combined bacterial and neutrophil mediated tissue damage. J Hand Surg Eur Vol 2023; 48:838-848. [PMID: 37218740 DOI: 10.1177/17531934231174819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Concepts of tissue damage from sepsis are rooted in the works of Pasteur regarding colonization by microorganisms, and Lister's observation of avoiding suppuration by their exclusion. The reactive inflammation has been considered a beneficial defence mechanism. A more complex biology is now unfolding of pathogenic mechanisms with toxins produced by the organisms now being placed in a broad category of virulence factors. Neutrophils are key cells in providing innate immunity and their trafficking to sites of infection results in entry to the extracellular space where they attack pathogens by release of the contents of neutrophil granules and neutrophil extracellular traps. There is now considerable evidence that much of the tissue damage in infection is due to excessive host innate immunological reaction; a hyperinflammatory response, whether localized or systemic. In addition to traditional surgical methods of drainage and decompression there is now a focus on dilution of inflammatory mediators. This emerging knowledge can potentially alter the way we approach hand infections.
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27
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Martinez Naya N, Kelly J, Corna G, Golino M, Abbate A, Toldo S. Molecular and Cellular Mechanisms of Action of Cannabidiol. Molecules 2023; 28:5980. [PMID: 37630232 PMCID: PMC10458707 DOI: 10.3390/molecules28165980] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 08/05/2023] [Accepted: 08/07/2023] [Indexed: 08/27/2023] Open
Abstract
Cannabidiol (CBD) is the primary non-psychoactive chemical from Cannabis Sativa, a plant used for centuries for both recreational and medicinal purposes. CBD lacks the psychotropic effects of Δ9-tetrahydrocannabinol (Δ9-THC) and has shown great therapeutic potential. CBD exerts a wide spectrum of effects at a molecular, cellular, and organ level, affecting inflammation, oxidative damage, cell survival, pain, vasodilation, and excitability, among others, modifying many physiological and pathophysiological processes. There is evidence that CBD may be effective in treating several human disorders, like anxiety, chronic pain, psychiatric pathologies, cardiovascular diseases, and even cancer. Multiple cellular and pre-clinical studies using animal models of disease and several human trials have shown that CBD has an overall safe profile. In this review article, we summarize the pharmacokinetics data, the putative mechanisms of action of CBD, and the physiological effects reported in pre-clinical studies to give a comprehensive list of the findings and major effects attributed to this compound.
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Affiliation(s)
- Nadia Martinez Naya
- Robert M. Berne Cardiovascular Research Center, Division of Cardiovascular Medicine, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA; (N.M.N.); (J.K.); (A.A.)
| | - Jazmin Kelly
- Robert M. Berne Cardiovascular Research Center, Division of Cardiovascular Medicine, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA; (N.M.N.); (J.K.); (A.A.)
| | - Giuliana Corna
- Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 22903, USA; (G.C.); (M.G.)
- Interventional Cardiology Department, Hospital Italiano de Buenos Aires, Buenos Aires 1199, Argentina
| | - Michele Golino
- Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 22903, USA; (G.C.); (M.G.)
- Department of Medicine and Surgery, University of Insubria, 2110 Varese, Italy
| | - Antonio Abbate
- Robert M. Berne Cardiovascular Research Center, Division of Cardiovascular Medicine, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA; (N.M.N.); (J.K.); (A.A.)
- Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 22903, USA; (G.C.); (M.G.)
| | - Stefano Toldo
- Robert M. Berne Cardiovascular Research Center, Division of Cardiovascular Medicine, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA; (N.M.N.); (J.K.); (A.A.)
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28
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Zhao Y, Zhang H, Zhang Q, Tao H. Research Progress of Neutrophil-Mediated Drug Delivery Strategies for Inflammation-Related Disease. Pharmaceutics 2023; 15:1881. [PMID: 37514067 PMCID: PMC10384340 DOI: 10.3390/pharmaceutics15071881] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 06/23/2023] [Accepted: 06/27/2023] [Indexed: 07/30/2023] Open
Abstract
As the most abundant white blood cells in humans, neutrophils play a key role in acute and chronic inflammation, suggesting that these cells are a key component of targeted therapies for various inflammation-related diseases. Specific enzyme-responsive or specific ligand-modified polymer nanoparticles are beneficial for improving drug efficacy, reducing toxicity, and enhancing focal site retention. However, there remain significant challenges in biomedical applications of these synthetic polymer nanoparticles, mainly due to their rapid clearance by the reticuloendothelial system. In recent years, biomimetic drug delivery systems such as neutrophils acting directly as drug carriers or neutrophil-membrane-coated nanoparticles have received increasing attention due to the natural advantages of neutrophils. Thus, neutrophil-targeted, neutrophil-assisted, or neutrophil-coated nanoparticles exhibit a prolonged blood circulation time and improved accumulation at the site of inflammation. Despite recent advancements, further clinical research must be performed to evaluate neutrophil-based delivery systems for future biomedical application in the diagnosis and treatment of related inflammatory diseases. In this review, we have summarized new exciting developments and challenges in neutrophil-mediated drug delivery strategies for treating inflammation-related diseases.
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Affiliation(s)
- Yang Zhao
- Department of Pharmaceutics, 96602 Hospital of Chinese People's Liberation Army, Kunming 650233, China
| | - Haigang Zhang
- Department of Pharmacology, College of Pharmacy, Army Medical University, Chongqing 400038, China
| | - Qixiong Zhang
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, Innovation Center of Advanced Pharmaceutical & Artificial Intelligence, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Hui Tao
- Department of Pharmacology, College of Pharmacy, Army Medical University, Chongqing 400038, China
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Yang Z, Sun L, Wang H. Identification of mitophagy-related genes with potential clinical utility in myocardial infarction at transcriptional level. Front Cardiovasc Med 2023; 10:1166324. [PMID: 37304955 PMCID: PMC10250750 DOI: 10.3389/fcvm.2023.1166324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 05/09/2023] [Indexed: 06/13/2023] Open
Abstract
Background Myocardial infarction (MI) ranks among the most prevalent cardiovascular diseases. Insufficient blood flow to the coronary arteries always leads to ischemic necrosis of the cardiac muscle. However, the mechanism of myocardial injury after MI remains unclear. This article aims to explore the potential common genes between mitophagy and MI and to construct a suitable prediction model. Methods Two Gene Expression Omnibus (GEO) datasets (GSE62646 and GSE59867) were used to screen the differential expression genes in peripheral blood. SVM, RF, and LASSO algorithm were employed to find MI and mitophagy-related genes. Moreover, DT, KNN, RF, SVM and LR were conducted to build the binary models, and screened the best model to further external validation (GSE61144) and internal validation (10-fold cross validation and Bootstrap), respectively. The performance of various machine learning models was compared. In addition, immune cell infiltration correlation analysis was conducted with MCP-Counter and CIBERSORT. Results We finally identified ATG5, TOMM20, MFN2 transcriptionally differed between MI and stable coronary artery diseases. Both internal and external validation supported that these three genes could accurately predict MI withAUC = 0.914 and 0.930 by logistic regression, respectively. Additionally, functional analysis suggested that monocytes and neutrophils might be involved in mitochondrial autophagy after myocardial infarction. Conclusion The data showed that the transcritional levels of ATG5, TOMM20 and MFN2 in patients with MI were significantly different from the control group, which might be helpful to further accurately diagnose diseases and have potential application value in clinical practice.
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Affiliation(s)
- Zhikai Yang
- Department of Cardiology, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Liang Sun
- The NHC Key Laboratory of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| | - Hua Wang
- Department of Cardiology, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
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de Jesus AA, Chen G, Yang D, Brdicka T, Ruth NM, Bennin D, Cebecauerova D, Malcova H, Freeman H, Martin N, Svojgr K, Passo MH, Bhuyan F, Alehashemi S, Rastegar AT, Uss K, Kardava L, Marrero B, Duric I, Omoyinmi E, Peldova P, Lee CCR, Kleiner DE, Hadigan CM, Hewitt SM, Pittaluga S, Carmona-Rivera C, Calvo KR, Shah N, Balascakova M, Fink DL, Kotalova R, Parackova Z, Peterkova L, Kuzilkova D, Campr V, Sramkova L, Biancotto A, Brooks SR, Manes C, Meffre E, Harper RL, Kuehn H, Kaplan MJ, Brogan P, Rosenzweig SD, Merchant M, Deng Z, Huttenlocher A, Moir SL, Kuhns DB, Boehm M, Skvarova Kramarzova K, Goldbach-Mansky R. Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome. Nat Commun 2023; 14:1502. [PMID: 36932076 PMCID: PMC10022554 DOI: 10.1038/s41467-023-36941-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 02/22/2023] [Indexed: 03/19/2023] Open
Abstract
Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases; pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. Here we identified three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation. Two patients developed liver fibrosis in their first year of life. Next-generation sequencing identified two de novo truncating variants in the Src-family tyrosine kinase, LYN, p.Y508*, p.Q507* and a de novo missense variant, p.Y508F, that result in constitutive activation of Lyn kinase. Functional studies revealed increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of β2-integrins on patient neutrophils that increase neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation; and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatinib. Our findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis.
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Affiliation(s)
- Adriana A de Jesus
- Translational Autoinflammatory Diseases Section (TADS), Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Guibin Chen
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Dan Yang
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Tomas Brdicka
- Laboratory of Leukocyte Signaling, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Natasha M Ruth
- Medical University of South Carolina, Charleston, SC, USA
| | - David Bennin
- Departments of Pediatrics and Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI, USA
| | - Dita Cebecauerova
- Second Faculty of Medicine, Charles University/University Hospital Motol, Prague, Czech Republic
| | - Hana Malcova
- Second Faculty of Medicine, Charles University/University Hospital Motol, Prague, Czech Republic
| | | | - Neil Martin
- Royal Hospital for Children, Glasgow, Scotland
| | - Karel Svojgr
- Second Faculty of Medicine, Charles University/University Hospital Motol, Prague, Czech Republic
| | - Murray H Passo
- Medical University of South Carolina, Charleston, SC, USA
| | - Farzana Bhuyan
- Translational Autoinflammatory Diseases Section (TADS), Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Sara Alehashemi
- Translational Autoinflammatory Diseases Section (TADS), Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Andre T Rastegar
- Translational Autoinflammatory Diseases Section (TADS), Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Katsiaryna Uss
- Translational Autoinflammatory Diseases Section (TADS), Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Lela Kardava
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Bernadette Marrero
- Translational Autoinflammatory Diseases Section (TADS), Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Iris Duric
- Laboratory of Leukocyte Signaling, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Ebun Omoyinmi
- Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Petra Peldova
- Second Faculty of Medicine, Charles University/University Hospital Motol, Prague, Czech Republic
| | | | - David E Kleiner
- National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | | | - Stephen M Hewitt
- National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Stefania Pittaluga
- National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Carmelo Carmona-Rivera
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | | | - Nirali Shah
- National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Miroslava Balascakova
- Second Faculty of Medicine, Charles University/University Hospital Motol, Prague, Czech Republic
| | - Danielle L Fink
- Collaborative Clinical Research Branch/Neutrophil Monitoring Laboratory, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA
| | - Radana Kotalova
- Second Faculty of Medicine, Charles University/University Hospital Motol, Prague, Czech Republic
| | - Zuzana Parackova
- Second Faculty of Medicine, Charles University/University Hospital Motol, Prague, Czech Republic
| | - Lucie Peterkova
- Second Faculty of Medicine, Charles University/University Hospital Motol, Prague, Czech Republic
| | - Daniela Kuzilkova
- Second Faculty of Medicine, Charles University/University Hospital Motol, Prague, Czech Republic
| | - Vit Campr
- Second Faculty of Medicine, Charles University/University Hospital Motol, Prague, Czech Republic
| | - Lucie Sramkova
- Second Faculty of Medicine, Charles University/University Hospital Motol, Prague, Czech Republic
| | | | - Stephen R Brooks
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | | | | | - Rebecca L Harper
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Hyesun Kuehn
- Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Mariana J Kaplan
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Paul Brogan
- Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | | | - Melinda Merchant
- AstraZeneca Research Based Biopharmaceutical Company, Waltham, MA, USA
| | - Zuoming Deng
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Anna Huttenlocher
- Departments of Pediatrics and Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI, USA
| | - Susan L Moir
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Douglas B Kuhns
- Collaborative Clinical Research Branch/Neutrophil Monitoring Laboratory, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA
| | - Manfred Boehm
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | | | - Raphaela Goldbach-Mansky
- Translational Autoinflammatory Diseases Section (TADS), Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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Interactions between Platelets and Tumor Microenvironment Components in Ovarian Cancer and Their Implications for Treatment and Clinical Outcomes. Cancers (Basel) 2023; 15:cancers15041282. [PMID: 36831623 PMCID: PMC9953912 DOI: 10.3390/cancers15041282] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/07/2023] [Accepted: 02/13/2023] [Indexed: 02/19/2023] Open
Abstract
Platelets, the primary operatives of hemostasis that contribute to blood coagulation and wound healing after blood vessel injury, are also involved in pathological conditions, including cancer. Malignancy-associated thrombosis is common in ovarian cancer patients and is associated with poor clinical outcomes. Platelets extravasate into the tumor microenvironment in ovarian cancer and interact with cancer cells and non-cancerous elements. Ovarian cancer cells also activate platelets. The communication between activated platelets, cancer cells, and the tumor microenvironment is via various platelet membrane proteins or mediators released through degranulation or the secretion of microvesicles from platelets. These interactions trigger signaling cascades in tumors that promote ovarian cancer progression, metastasis, and neoangiogenesis. This review discusses how interactions between platelets, cancer cells, cancer stem cells, stromal cells, and the extracellular matrix in the tumor microenvironment influence ovarian cancer progression. It also presents novel potential therapeutic approaches toward this gynecological cancer.
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Man Y, Kucukal E, Liu S, An R, Goreke U, Wulftange WJ, Sekyonda Z, Bode A, Little JA, Manwani D, Stavrou EX, Gurkan UA. A microfluidic device for assessment of E-selectin-mediated neutrophil recruitment to inflamed endothelium and prediction of therapeutic response in sickle cell disease. Biosens Bioelectron 2023; 222:114921. [PMID: 36521205 PMCID: PMC9850363 DOI: 10.1016/j.bios.2022.114921] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 11/13/2022] [Accepted: 11/15/2022] [Indexed: 11/25/2022]
Abstract
Neutrophil recruitment to the inflamed endothelium is a multistep process and is of utmost importance in the development of the hallmark vaso-occlusive crisis in sickle cell disease (SCD). However, there lacks a standardized, clinically feasible approach for assessing neutrophil recruitment to the inflamed endothelium for individualized risk stratification and therapeutic response prediction in SCD. Here, we describe a microfluidic device functionalized with E-selectin, a critical endothelial receptor for the neutrophil recruitment process, as a strategy to assess neutrophil binding under physiologic flow in normoxia and clinically relevant hypoxia in SCD. We show that hypoxia significantly enhances neutrophil binding to E-selectin and promotes the formation of neutrophil-platelet aggregates. Moreover, we identified two distinct patient populations: a more severe clinical phenotype with elevated lactate dehydrogenase levels and absolute reticulocyte counts but lowered fetal hemoglobin levels associated with constitutively less neutrophil binding to E-selectin. Mechanistically, we demonstrate that the extent of neutrophil activation correlates with membrane L-selectin shedding, resulting in the loss of ligand interaction sites with E-selectin. We also show that inhibition of E-selectin significantly reduces leukocyte recruitment to activated endothelial cells. Our findings add mechanistic insight into neutrophil-endothelial interactions under hypoxia and provide a clinically feasible means for assessing neutrophil binding to E-selectin using clinical whole blood samples, which can help guide therapeutic decisions for SCD patients.
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Affiliation(s)
- Yuncheng Man
- Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - Erdem Kucukal
- Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - Shichen Liu
- Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - Ran An
- Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - Utku Goreke
- Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - William J Wulftange
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - Zoe Sekyonda
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - Allison Bode
- Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH, USA; Department of Medicine, Hematology and Oncology Division, CWRU School of Medicine, Cleveland, OH, USA
| | - Jane A Little
- Department of Hematology, UNC Blood Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Deepa Manwani
- Department of Pediatrics, Albert Einstein College of Medicine/Children's Hospital at Montefiore, Bronx, NY, USA
| | - Evi X Stavrou
- Department of Medicine, Hematology and Oncology Division, CWRU School of Medicine, Cleveland, OH, USA; Medicine Service, Section of Hematology-Oncology, Louis Stokes Cleveland Veterans Administration Medical Center, Cleveland, OH, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA
| | - Umut A Gurkan
- Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH, USA; Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
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Influenza Virus Infection Increases Host Susceptibility To Secondary Infection with Pseudomonas aeruginosa, and This Is Attributed To Neutrophil Dysfunction through Reduced Myeloperoxidase Activity. Microbiol Spectr 2023; 11:e0365522. [PMID: 36475755 PMCID: PMC9927171 DOI: 10.1128/spectrum.03655-22] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Secondary bacterial infection greatly increased the morbidity and mortality of influenza virus infection. To investigate the underlying mechanism by which influenza impairs the pulmonary defense against secondary Pseudomonas aeruginosa (P. aeruginosa) infection, we established a lethal mouse model in which to study secondary P. aeruginosa infection after influenza virus infection. We found a significant increase in host susceptibility to a secondary infection with P. aeruginosa in mice after an influenza virus infection, and this was accompanied by severe immunopathology and pulmonary inflammation. Importantly, we demonstrated that neutrophils were essential for P. aeruginosa clearance in secondarily infected mice. Further, we revealed that influenza impaired the phagocytosis and digestion functions of pulmonary neutrophils for P. aeruginosa clearance. We identified that the activity of reactive oxygen species (ROS) and the myeloperoxidase (MPO) activity of neutrophils in the lungs played an important role in antibacterial host defense in influenza-infected lungs. Hereby, influenza virus infection causes deficient MPO activity in neutrophils, and this contributes to the increased susceptibility to secondary P. aeruginosa infection. Treatment with Bacillus Calmette-Guerin polysaccharide nucleic acid (BCG-PSN) prior to secondary P. aeruginosa infection may improve the function of neutrophils, resulting in significantly reduced lethality during secondary P. aeruginosa infection. We also demonstrated that treatment with anti-influenza immune serum during the early stage of an influenza virus infection could decrease the disease severity of secondary P. aeruginosa infection. Our findings suggest that improving the MPO activity of neutrophils may provide a therapeutic strategy for viral-bacterial coinfection. IMPORTANCE A secondary bacterial infection, such as that of P. aeruginosa, often occurs after a pulmonary virus infection and contributes to severe disease. However, the underlying mechanisms responsible for viral-bacterial synergy in the lung remain largely unknown. In this study, we reported that influenza virus infection increases a host’s susceptibility to secondary infection by P. aeruginosa by reducing the MPO activity of neutrophils. We also demonstrated that treatment with BCG-PSN or anti-influenza immune serum prior to secondary P. aeruginosa infection can reduce the disease severity. Our findings suggest that improving the MPO activity of neutrophils may provide a therapeutic strategy for viral-bacterial coinfection.
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The Dilemma of HSV-1 Oncolytic Virus Delivery: The Method Choice and Hurdles. Int J Mol Sci 2023; 24:ijms24043681. [PMID: 36835091 PMCID: PMC9962028 DOI: 10.3390/ijms24043681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 02/03/2023] [Accepted: 02/08/2023] [Indexed: 02/15/2023] Open
Abstract
Oncolytic viruses (OVs) have emerged as effective gene therapy and immunotherapy drugs. As an important gene delivery platform, the integration of exogenous genes into OVs has become a novel path for the advancement of OV therapy, while the herpes simplex virus type 1 (HSV-1) is the most commonly used. However, the current mode of administration of HSV-1 oncolytic virus is mainly based on the tumor in situ injection, which limits the application of such OV drugs to a certain extent. Intravenous administration offers a solution to the systemic distribution of OV drugs but is ambiguous in terms of efficacy and safety. The main reason is the synergistic role of innate and adaptive immunity of the immune system in the response against the HSV-1 oncolytic virus, which is rapidly cleared by the body's immune system before it reaches the tumor, a process that is accompanied by side effects. This article reviews different administration methods of HSV-1 oncolytic virus in the process of tumor treatment, especially the research progress in intravenous administration. It also discusses immune constraints and solutions of intravenous administration with the intent to provide new insights into HSV-1 delivery for OV therapy.
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A Comprehensive Review of Risk Factors for Venous Thromboembolism: From Epidemiology to Pathophysiology. Int J Mol Sci 2023; 24:ijms24043169. [PMID: 36834580 PMCID: PMC9964264 DOI: 10.3390/ijms24043169] [Citation(s) in RCA: 108] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/29/2023] [Accepted: 02/02/2023] [Indexed: 02/09/2023] Open
Abstract
Venous thromboembolism (VTE) is the third most common cause of death worldwide. The incidence of VTE varies according to different countries, ranging from 1-2 per 1000 person-years in Western Countries, while it is lower in Eastern Countries (<1 per 1000 person-years). Many risk factors have been identified in patients developing VTE, but the relative contribution of each risk factor to thrombotic risk, as well as pathogenetic mechanisms, have not been fully described. Herewith, we provide a comprehensive review of the most common risk factors for VTE, including male sex, diabetes, obesity, smoking, Factor V Leiden, Prothrombin G20210A Gene Mutation, Plasminogen Activator Inhibitor-1, oral contraceptives and hormonal replacement, long-haul flight, residual venous thrombosis, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, trauma and fractures, pregnancy, immobilization, antiphospholipid syndrome, surgery and cancer. Regarding the latter, the incidence of VTE seems highest in pancreatic, liver and non-small cells lung cancer (>70 per 1000 person-years) and lowest in breast, melanoma and prostate cancer (<20 per 1000 person-years). In this comprehensive review, we summarized the prevalence of different risk factors for VTE and the potential molecular mechanisms/pathogenetic mediators leading to VTE.
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Effect of Supplemental Oxygen on von Willebrand Factor Activity and Ristocetin Cofactor Activity in Patients at Risk for Cardiovascular Complications Undergoing Moderate-to High-Risk Major Noncardiac Surgery-A Secondary Analysis of a Randomized Trial. J Clin Med 2023; 12:jcm12031222. [PMID: 36769870 PMCID: PMC9918071 DOI: 10.3390/jcm12031222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 01/30/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Increased von Willebrand Factor (vWF) activity mediates platelet adhesion and might be a contributor to the development of thrombotic complications after surgery. Although in vitro studies have shown that hyperoxia induces endovascular damage, the effect of perioperative supplemental oxygen as a possible trigger for increased vWF activity has not been investigated yet. We tested our primary hypothesis that the perioperative administration of 80% oxygen concentration increases postoperative vWF activity as compared to 30% oxygen concentration in patients at risk of cardiovascular complications undergoing major noncardiac surgery. A total of 260 patients were randomly assigned to receive 80% versus 30% oxygen throughout surgery and for two hours postoperatively. We assessed vWF activity and Ristocetin cofactor activity in all patients shortly before the induction of anesthesia, within two hours after surgery and on the first and third postoperative day. Patient characteristics were similar in both groups. We found no significant difference in vWF activity in the overall perioperative time course between both randomization groups. We observed significantly increased vWF activity in the overall study population throughout the postoperative time course. Perioperative supplemental oxygen showed no significant effect on postoperative vWF and Ristocetin cofactor activity in cardiac risk patients undergoing major noncardiac surgery. In conclusion, we found no significant influence of supplemental oxygen in patients undergoing major non-cardiac surgery on postoperative vWF activity and Ristocetin cofactor activity.
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Ledderose C, Hashiguchi N, Valsami EA, Rusu C, Junger WG. Optimized flow cytometry assays to monitor neutrophil activation in human and mouse whole blood samples. J Immunol Methods 2023; 512:113403. [PMID: 36502881 DOI: 10.1016/j.jim.2022.113403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 11/10/2022] [Accepted: 12/05/2022] [Indexed: 12/13/2022]
Abstract
Polymorphonuclear neutrophils (PMNs) protect the host from invading microorganisms. However, excessively activated PMNs can also cause damage to host tissues under inflammatory conditions. Here we developed simple assays to determine the activation state of PMNs in human whole blood that contains soluble mediators known to influence PMN functions. Because mouse models are widely used to study the role of PMNs in infectious and inflammatory diseases, we adapted these assays for the rapid and reliable assessment of PMN functions in murine blood samples. Freshly collected whole blood samples were stimulated with agonists of the formyl peptide receptors (FPR) of PMNs and changes in reactive oxygen species (ROS) production and the expression of CD11b, CD62L (L-selectin), CD66b, and CD63 on the cell surface were analyzed with flow cytometry. We optimized these assays to minimize inadvertent interferences such as cell stress generated during sample handling and the loss of plasma mediators that regulate PMN functions. Human PMNs readily responded to the FPR agonist N-formyl-methionyl-leucyl-phenylalanine (fMLP). The most sensitive responses of human PMNs to fMLP were CD11b, CD62L, and CD66b expression with half maximal effective concentrations (EC50) of 5, 8, and 6 nM fMLP, respectively. CD63 expression and ROS production required markedly higher fMLP concentrations with EC50 values of 19 and 50 nM fMLP, respectively. Mouse PMNs did not respond well to fMLP and required significantly higher concentrations of the FPR agonist WKYMVm (W-peptide) to achieve equivalent cell activation. The most sensitive response of mouse PMNs was ROS production with an EC50 of 38 nM W-peptide. Because mice do not express CD66b, we only assessed the expression of CD62L, CD11b, and CD63 with EC50 values of 54, 119, and 355 nM W-peptide, respectively. Validation of our optimized assays showed that they sensitively detect the responses of human PMNs to priming with endotoxin in vitro as well as the corresponding responses of murine PMNs to bacterial infection in a sepsis model. We conclude that these optimized assays could be useful tools for the monitoring of patients with infections, sepsis, and other inflammatory conditions as well as for the design and interpretation of preclinical studies of these diseases in mouse models.
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Affiliation(s)
- Carola Ledderose
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Naoyuki Hashiguchi
- Department of Surgery, University of California San Diego, San Diego, CA, USA
| | | | - Christian Rusu
- Department of Surgery, University of California San Diego, San Diego, CA, USA
| | - Wolfgang G Junger
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Department of Surgery, University of California San Diego, San Diego, CA, USA.
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Sequence variants in the ITGB2 gene underlying leukocyte adhesion deficiency Type-1 in four consanguineous families. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Kim JM, Kim H, Oh SH, Jang WI, Lee SB, Park M, Kim S, Park S, Shim S, Jang H. Combined Administration of Pravastatin and Metformin Attenuates Acute Radiation-Induced Intestinal Injury in Mouse and Minipig Models. Int J Mol Sci 2022; 23:ijms232314827. [PMID: 36499155 PMCID: PMC9739896 DOI: 10.3390/ijms232314827] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 11/23/2022] [Accepted: 11/24/2022] [Indexed: 12/02/2022] Open
Abstract
Radiation-induced gastrointestinal (GI) damage is one of the critical factors that serve as basis for the lethality of nuclear accidents or terrorism. Further, there are no Food and Drug Administration-approved agents available to mitigate radiation-induced intestinal injury. Although pravastatin (PS) has been shown to exhibit anti-inflammatory and epithelial reconstructive effects following radiation exposure using mouse and minipig models, the treatment failed to improve the survival rate of high-dose irradiated intestinal injury. Moreover, we previously found that metformin (MF), a common drug used for treating type 2 diabetes mellitus, has a mitigating effect on radiation-induced enteropathy by promoting stem cell properties. In this study, we investigated whether the combined administration of PS and MF could achieve therapeutic effects on acute radiation-induced intestinal injury in mouse and minipig models. We found that the combined treatment markedly increased the survival rate and attenuated histological damage in a radiation-induced intestinal injury mouse model, in addition to epithelial barrier recovery, anti-inflammatory effects, and improved epithelial proliferation with stem cell properties. Furthermore, in minipig models, combined treatment with PS and MF ameliorates gross pathological damage in abdominal organs and attenuated radiation-induced intestinal histological damage. Therefore, the combination of PS and MF effectively alleviated radiation-induced intestinal injury in the mouse and minipig models. We believe that the combined use of PS and MF is a promising therapeutic approach for treating radiation-induced intestinal injury.
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Affiliation(s)
- Jung Moon Kim
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul 01812, Republic of Korea
- Department of Veterinary Surgery, College of Veterinary Medicine, Konkuk University, Seoul 05029, Republic of Korea
| | - Hyewon Kim
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul 01812, Republic of Korea
| | - Su Hyun Oh
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul 01812, Republic of Korea
| | - Won Il Jang
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul 01812, Republic of Korea
| | - Seung Bum Lee
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul 01812, Republic of Korea
| | - Mineon Park
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul 01812, Republic of Korea
| | - Soyeon Kim
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul 01812, Republic of Korea
| | - Sunhoo Park
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul 01812, Republic of Korea
| | - Sehwan Shim
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul 01812, Republic of Korea
- Correspondence: (S.S.); (H.J.); Tel.: +82-2-3399-5873 (S.S.); +82-2-970-1302 (H.J.)
| | - Hyosun Jang
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul 01812, Republic of Korea
- Correspondence: (S.S.); (H.J.); Tel.: +82-2-3399-5873 (S.S.); +82-2-970-1302 (H.J.)
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40
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Aymonnier K, Amsler J, Lamprecht P, Salama A, Witko‐Sarsat V. The neutrophil: A key resourceful agent in immune‐mediated vasculitis. Immunol Rev 2022; 314:326-356. [PMID: 36408947 DOI: 10.1111/imr.13170] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The term "vasculitis" refers to a group of rare immune-mediated diseases characterized by the dysregulated immune system attacking blood vessels located in any organ of the body, including the skin, lungs, and kidneys. Vasculitides are classified according to the size of the vessel that is affected. Although this observation is not specific to small-, medium-, or large-vessel vasculitides, patients show a high circulating neutrophil-to-lymphocyte ratio, suggesting the direct or indirect involvement of neutrophils in these diseases. As first responders to infection or inflammation, neutrophils release cytotoxic mediators, including reactive oxygen species, proteases, and neutrophil extracellular traps. If not controlled, this dangerous arsenal can injure the vascular system, which acts as the main transport route for neutrophils, thereby amplifying the initial inflammatory stimulus and the recruitment of immune cells. This review highlights the ability of neutrophils to "set the tone" for immune cells and other cells in the vessel wall. Considering both their long-established and newly described roles, we extend their functions far beyond their direct host-damaging potential. We also review the roles of neutrophils in various types of primary vasculitis, including immune complex vasculitis, anti-neutrophil cytoplasmic antibody-associated vasculitis, polyarteritis nodosa, Kawasaki disease, giant cell arteritis, Takayasu arteritis, and Behçet's disease.
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Affiliation(s)
- Karen Aymonnier
- INSERM U1016, Institut Cochin, Université Paris Cité, CNRS 8104 Paris France
| | - Jennifer Amsler
- INSERM U1016, Institut Cochin, Université Paris Cité, CNRS 8104 Paris France
| | - Peter Lamprecht
- Department of Rheumatology and Clinical Immunology University of Lübeck Lübeck Germany
| | - Alan Salama
- Department of Renal Medicine, Royal Free Hospital University College London London UK
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Mansouri M, Ahmed A, Ahmad SD, McCloskey MC, Joshi IM, Gaborski TR, Waugh RE, McGrath JL, Day SW, Abhyankar VV. The Modular µSiM Reconfigured: Integration of Microfluidic Capabilities to Study In Vitro Barrier Tissue Models under Flow. Adv Healthc Mater 2022; 11:e2200802. [PMID: 35953453 PMCID: PMC9798530 DOI: 10.1002/adhm.202200802] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 08/01/2022] [Indexed: 01/28/2023]
Abstract
Microfluidic tissue barrier models have emerged to address the lack of physiological fluid flow in conventional "open-well" Transwell-like devices. However, microfluidic techniques have not achieved widespread usage in bioscience laboratories because they are not fully compatible with traditional experimental protocols. To advance barrier tissue research, there is a need for a platform that combines the key advantages of both conventional open-well and microfluidic systems. Here, a plug-and-play flow module is developed to introduce on-demand microfluidic flow capabilities to an open-well device that features a nanoporous membrane and live-cell imaging capabilities. The magnetic latching assembly of this design enables bi-directional reconfiguration and allows users to conduct an experiment in an open-well format with established protocols and then add or remove microfluidic capabilities as desired. This work also provides an experimentally-validated flow model to select flow conditions based on the experimental needs. As a proof-of-concept, flow-induced alignment of endothelial cells and the expression of shear-sensitive gene targets are demonstrated, and the different phases of neutrophil transmigration across a chemically stimulated endothelial monolayer under flow conditions are visualized. With these experimental capabilities, it is anticipated that both engineering and bioscience laboratories will adopt this reconfigurable design due to the compatibility with standard open-well protocols.
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Affiliation(s)
- Mehran Mansouri
- Department of Biomedical Engineering, Rochester Institute of Technology, Rochester, NY, 14623, USA
| | - Adeel Ahmed
- Department of Biomedical Engineering, Rochester Institute of Technology, Rochester, NY, 14623, USA
| | - S. Danial Ahmad
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, 14627, USA
| | - Molly C. McCloskey
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, 14627, USA
| | - Indranil M. Joshi
- Department of Biomedical Engineering, Rochester Institute of Technology, Rochester, NY, 14623, USA
| | - Thomas R. Gaborski
- Department of Biomedical Engineering, Rochester Institute of Technology, Rochester, NY, 14623, USA
| | - Richard E. Waugh
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, 14627, USA
| | - James L. McGrath
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, 14627, USA
| | - Steven W. Day
- Department of Biomedical Engineering, Rochester Institute of Technology, Rochester, NY, 14623, USA
| | - Vinay V. Abhyankar
- Department of Biomedical Engineering, Rochester Institute of Technology, Rochester, NY, 14623, USA
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Polonio CM, da Silva P, Russo FB, Hyppolito BRN, Zanluqui NG, Benazzato C, Beltrão-Braga PCB, Muxel SM, Peron JPS. microRNAs Control Antiviral Immune Response, Cell Death and Chemotaxis Pathways in Human Neuronal Precursor Cells (NPCs) during Zika Virus Infection. Int J Mol Sci 2022; 23:ijms231810282. [PMID: 36142200 PMCID: PMC9499039 DOI: 10.3390/ijms231810282] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/23/2022] [Accepted: 08/24/2022] [Indexed: 11/16/2022] Open
Abstract
Viral infections have always been a serious burden to public health, increasing morbidity and mortality rates worldwide. Zika virus (ZIKV) is a flavivirus transmitted by the Aedes aegypti vector and the causative agent of severe fetal neuropathogenesis and microcephaly. The virus crosses the placenta and reaches the fetal brain, mainly causing the death of neuronal precursor cells (NPCs), glial inflammation, and subsequent tissue damage. Genetic differences, mainly related to the antiviral immune response and cell death pathways greatly influence the susceptibility to infection. These components are modulated by many factors, including microRNAs (miRNAs). MiRNAs are small noncoding RNAs that regulate post-transcriptionally the overall gene expression, including genes for the neurodevelopment and the formation of neural circuits. In this context, we investigated the pathways and target genes of miRNAs modulated in NPCs infected with ZIKV. We observed downregulation of miR-302b, miR-302c and miR-194, whereas miR-30c was upregulated in ZIKV infected human NPCs in vitro. The analysis of a public dataset of ZIKV-infected human NPCs evidenced 262 upregulated and 3 downregulated genes, of which 142 were the target of the aforementioned miRNAs. Further, we confirmed a correlation between miRNA and target genes affecting pathways related to antiviral immune response, cell death and immune cells chemotaxis, all of which could contribute to the establishment of microcephaly and brain lesions. Here, we suggest that miRNAs target gene expression in infected NPCs, directly contributing to the pathogenesis of fetal microcephaly.
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Affiliation(s)
- Carolina M. Polonio
- Neuroimmune Interactions Laboratory, Department of Immunology, University of São Paulo, São Paulo 05508-000, Brazil
- Scientific Platform Pasteur-USP (SPPU), University of São Paulo, São Paulo 05508-000, Brazil
| | - Patrick da Silva
- Neuroimmune Interactions Laboratory, Department of Immunology, University of São Paulo, São Paulo 05508-000, Brazil
- Scientific Platform Pasteur-USP (SPPU), University of São Paulo, São Paulo 05508-000, Brazil
| | - Fabiele B. Russo
- Scientific Platform Pasteur-USP (SPPU), University of São Paulo, São Paulo 05508-000, Brazil
- Disease Modeling Laboratory at Department of Microbiology, Institute of Biomedical Sciences, São Paulo 05508-000, Brazil
| | - Brendo R. N. Hyppolito
- Neuroimmune Interactions Laboratory, Department of Immunology, University of São Paulo, São Paulo 05508-000, Brazil
- Immunopathology and Allergy Post Graduate Program, School of Medicine, University of São Paulo, São Paulo 05508-000, Brazil
| | - Nagela G. Zanluqui
- Neuroimmune Interactions Laboratory, Department of Immunology, University of São Paulo, São Paulo 05508-000, Brazil
- Scientific Platform Pasteur-USP (SPPU), University of São Paulo, São Paulo 05508-000, Brazil
- Immunopathology and Allergy Post Graduate Program, School of Medicine, University of São Paulo, São Paulo 05508-000, Brazil
| | - Cecília Benazzato
- Disease Modeling Laboratory at Department of Microbiology, Institute of Biomedical Sciences, São Paulo 05508-000, Brazil
| | - Patrícia C. B. Beltrão-Braga
- Scientific Platform Pasteur-USP (SPPU), University of São Paulo, São Paulo 05508-000, Brazil
- Disease Modeling Laboratory at Department of Microbiology, Institute of Biomedical Sciences, São Paulo 05508-000, Brazil
| | - Sandra M. Muxel
- Neuroimmune Interactions Laboratory, Department of Immunology, University of São Paulo, São Paulo 05508-000, Brazil
- Scientific Platform Pasteur-USP (SPPU), University of São Paulo, São Paulo 05508-000, Brazil
- Correspondence: (S.M.M.); (J.P.S.P.)
| | - Jean Pierre S. Peron
- Neuroimmune Interactions Laboratory, Department of Immunology, University of São Paulo, São Paulo 05508-000, Brazil
- Scientific Platform Pasteur-USP (SPPU), University of São Paulo, São Paulo 05508-000, Brazil
- Immunopathology and Allergy Post Graduate Program, School of Medicine, University of São Paulo, São Paulo 05508-000, Brazil
- Correspondence: (S.M.M.); (J.P.S.P.)
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Matsuda M, Inaba M, Hamaguchi J, Tomita H, Omori M, Shimora H, Sakae H, Kitatani K, Nabe T. Local IL-10 replacement therapy was effective for steroid-insensitive asthma in mice. Int Immunopharmacol 2022; 110:109037. [PMID: 35810490 DOI: 10.1016/j.intimp.2022.109037] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 06/27/2022] [Accepted: 07/04/2022] [Indexed: 01/24/2023]
Abstract
Subgroups of patients with severe asthma showing marked increases in sputum eosinophils and/or neutrophils are insensitive to corticosteroids. Previous reports have shown that exogenous administration of an anti-inflammatory cytokine, interleukin (IL)-10 negatively regulated both eosinophilic and neutrophilic migration into tissues. The objective of this study was to elucidate whether intratracheal IL-10 administration suppresses asthmatic responses in a steroid-insensitive model of mice. Ovalbumin (OVA)-sensitized BALB/c mice were intratracheally challenged with OVA at 500 µg/animal four times. Dexamethasone (1 mg/kg, intraperitoneal) or IL-10 (25 ng/mouse, intratracheal) was administered during the multiple challenges. The number of leukocytes, expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and IL-10 receptor in the lung, and the development of airway remodeling and hyperresponsiveness were evaluated after the fourth challenge. Consistent with our previous study, dexamethasone hardly suppressed the development of airway remodeling and hyperresponsiveness. Although intratracheal IL-10 administration did not affect the development of airway remodeling, the infiltration of eosinophils and neutrophils, and the development of airway hyperresponsiveness were significantly inhibited. Moreover, IL-10 administration significantly decreased the numbers of ICAM-1+ and VCAM-1+ pulmonary vascular endothelial cells, which express IL-10 receptor 1, even though neither production of eosinophilic nor neutrophilic cytokines in the lung was inhibited. Therefore, IL-10 can suppress eosinophil and neutrophil infiltration by inhibiting the proliferation of ICAM-1+ and VCAM-1+ pulmonary vascular endothelial cells, resulting in inhibition of airway hyperresponsiveness in steroid-insensitive asthmatic mice. IL-10 replacement therapy may be clinically useful for the treatment of steroid-insensitive asthma.
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Affiliation(s)
- Masaya Matsuda
- Laboratory of Immunopharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan
| | - Miki Inaba
- Laboratory of Immunopharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan
| | - Junpei Hamaguchi
- Laboratory of Immunopharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan
| | - Hiro Tomita
- Laboratory of Immunopharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan
| | - Miyu Omori
- Laboratory of Immunopharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan
| | - Hayato Shimora
- Laboratory of Immunopharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan
| | - Harumi Sakae
- Laboratory of Immunopharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan
| | - Kazuyuki Kitatani
- Laboratory of Immunopharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan
| | - Takeshi Nabe
- Laboratory of Immunopharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan.
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44
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Cell-based drug delivery systems and their in vivo fate. Adv Drug Deliv Rev 2022; 187:114394. [PMID: 35718252 DOI: 10.1016/j.addr.2022.114394] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/17/2022] [Accepted: 06/07/2022] [Indexed: 11/22/2022]
Abstract
Cell-based drug delivery systems (DDSs) have received attention recently because of their unique biological properties and self-powered functions, such as excellent biocompatibility, low immunogenicity, long circulation time, tissue-homingcharacteristics, and ability to cross biological barriers. A variety of cells, including erythrocytes, stem cells, and lymphocytes, have been explored as functional vectors for the loading and delivery of various therapeutic payloads (e.g., small-molecule and nucleic acid drugs) for subsequent disease treatment. These cell-based DDSs have their own unique in vivo fates, which are attributed to various factors, including their biological properties and functions, the loaded drugs and loading process, physiological and pathological circumstances, and the body's response to these carrier cells, which result in differences in drug delivery efficiency and therapeutic effect. In this review, we summarize the main cell-based DDSs and their biological properties and functions, applications in drug delivery and disease treatment, and in vivo fate and influencing factors. We envision that the unique biological properties, combined with continuing research, will enable development of cell-based DDSs as friendly drug vectors for the safe, effective, and even personalized treatment of diseases.
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Lee HY, You DJ, Taylor-Just AJ, Linder KE, Atkins HM, Ralph LM, De la Cruz G, Bonner JC. Pulmonary exposure of mice to ammonium perfluoro(2-methyl-3-oxahexanoate) (GenX) suppresses the innate immune response to carbon black nanoparticles and stimulates lung cell proliferation. Inhal Toxicol 2022; 34:244-259. [PMID: 35704474 DOI: 10.1080/08958378.2022.2086651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Per- and polyfluoroalkyl substances (PFAS) have been associated with respiratory diseases in humans, yet the mechanisms through which PFAS cause susceptibility to inhaled agents is unknown. Herein, we investigated the effects of ammonium perfluoro(2-methyl-3-oxahexanoate) (GenX), an emerging PFAS, on the pulmonary immune response of mice to carbon black nanoparticles (CBNP). We hypothesized that pulmonary exposure to GenX would increase susceptibility to CBNP through suppression of innate immunity. METHODS Male C57BL/6 mice were exposed to vehicle, 4 mg/kg CBNP, 10 mg/kg GenX, or CBNP and GenX by oropharyngeal aspiration. Bronchoalveolar lavage fluid (BALF) was collected at 1 and 14 days postexposure for cytokines and total protein. Lung tissue was harvested for histopathology, immunohistochemistry (Ki67 and phosphorylated (p)-STAT3), western blotting (p-STAT3 and p-NF-κB), and qRT-PCR for cytokine mRNAs. RESULTS CBNP increased CXCL-1 and neutrophils in BALF at both time points evaluated. However, GenX/CBNP co-exposure reduced CBNP-induced CXCL-1 and neutrophils in BALF. Moreover, CXCL-1, CXCL-2 and IL-1β mRNAs were increased by CBNP in lung tissue but reduced by GenX. Western blotting showed that CBNP induced p-NF-κB in lung tissue, while the GenX/CBNP co-exposed group displayed decreased p-NF-κB. Furthermore, mice exposed to GenX or GenX/CBNP displayed increased numbers of BALF macrophages undergoing mitosis and increased Ki67 immunostaining. This was correlated with increased p-STAT3 by western blotting and immunohistochemistry in lung tissue from mice co-exposed to GenX/CBNP. CONCLUSIONS Pulmonary exposure to GenX suppressed CBNP-induced innate immune response in the lungs of mice yet promoted the proliferation of macrophages and lung epithelial cells.
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Affiliation(s)
- Ho Young Lee
- Toxicology Program, Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA
| | - Dorothy J You
- Toxicology Program, Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA
| | - Alexia J Taylor-Just
- Toxicology Program, Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA
| | - Keith E Linder
- Department of Population Health and Pathobiology, North Carolina State University, Raleigh, NC, USA
| | - Hannah M Atkins
- Department of Population Health and Pathobiology, North Carolina State University, Raleigh, NC, USA.,Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.,Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - Lauren M Ralph
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - Gabriela De la Cruz
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - James C Bonner
- Toxicology Program, Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA
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Zhang Y, Wang Q, Mackay CR, Ng LG, Kwok I. Neutrophil subsets and their differential roles in viral respiratory diseases. J Leukoc Biol 2022; 111:1159-1173. [PMID: 35040189 PMCID: PMC9015493 DOI: 10.1002/jlb.1mr1221-345r] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 12/28/2021] [Accepted: 01/04/2022] [Indexed: 12/19/2022] Open
Abstract
Neutrophils play significant roles in immune homeostasis and as neutralizers of microbial infections. Recent evidence further suggests heterogeneity of neutrophil developmental and activation states that exert specialized effector functions during inflammatory disease conditions. Neutrophils can play multiple roles during viral infections, secreting inflammatory mediators and cytokines that contribute significantly to host defense and pathogenicity. However, their roles in viral immunity are not well understood. In this review, we present an overview of neutrophil heterogeneity and its impact on the course and severity of viral respiratory infectious diseases. We focus on the evidence demonstrating the crucial roles neutrophils play in the immune response toward respiratory infections, using influenza as a model. We further extend the understanding of neutrophil function with the studies pertaining to COVID-19 disease and its neutrophil-associated pathologies. Finally, we discuss the relevance of these results for future therapeutic options through targeting and regulating neutrophil-specific responses.
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Affiliation(s)
- Yuning Zhang
- Department of ResearchNational Skin CentreSingaporeSingapore
| | - Quanbo Wang
- School of Pharmaceutical Sciences, Shandong Analysis and Test CenterQilu University of Technology (Shandong Academy of Sciences)JinanChina
| | - Charles R Mackay
- School of Pharmaceutical Sciences, Shandong Analysis and Test CenterQilu University of Technology (Shandong Academy of Sciences)JinanChina
- Department of Microbiology, Infection and Immunity ProgramBiomedicine Discovery Institute, Monash UniversityMelbourneAustralia
| | - Lai Guan Ng
- Singapore Immunology Network (SIgN)A*STAR (Agency for Science, Technology and Research)BiopolisSingapore
- State Key Laboratory of Experimental HematologyInstitute of Hematology, Chinese Academy of Medical Sciences & Peking Union Medical CollegeTianjinChina
- School of Biological SciencesNanyang Technological UniversitySingaporeSingapore
- Department of Microbiology and ImmunologyImmunology Translational Research Program, Yong Loo Lin School of Medicine, Immunology Program, Life Sciences Institute, National University of SingaporeSingaporeSingapore
- National Cancer Centre SingaporeSingaporeSingapore
| | - Immanuel Kwok
- Singapore Immunology Network (SIgN)A*STAR (Agency for Science, Technology and Research)BiopolisSingapore
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Angus SA, Henderson WR, Banoei MM, Molgat‐Seon Y, Peters CM, Parmar HR, Griesdale DEG, Sekhon M, Sheel AW, Winston BW, Dominelli PB. Therapeutic hypothermia attenuates physiologic, histologic, and metabolomic markers of injury in a porcine model of acute respiratory distress syndrome. Physiol Rep 2022; 10:e15286. [PMID: 35510328 PMCID: PMC9069168 DOI: 10.14814/phy2.15286] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/29/2022] [Accepted: 04/02/2022] [Indexed: 06/14/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a lung injury characterized by noncardiogenic pulmonary edema and hypoxic respiratory failure. The purpose of this study was to investigate the effects of therapeutic hypothermia on short-term experimental ARDS. Twenty adult female Yorkshire pigs were divided into four groups (n = 5 each): normothermic control (C), normothermic injured (I), hypothermic control (HC), and hypothermic injured (HI). Acute respiratory distress syndrome was induced experimentally via intrapulmonary injection of oleic acid. Target core temperature was achieved in the HI group within 1 h of injury induction. Cardiorespiratory, histologic, cytokine, and metabolomic data were collected on all animals prior to and following injury/sham. All data were collected for approximately 12 h from the beginning of the study until euthanasia. Therapeutic hypothermia reduced injury in the HI compared to the I group (histological injury score = 0.51 ± 0.18 vs. 0.76 ± 0.06; p = 0.02) with no change in gas exchange. All groups expressed distinct phenotypes, with a reduction in pro-inflammatory metabolites, an increase in anti-inflammatory metabolites, and a reduction in inflammatory cytokines observed in the HI group compared to the I group. Changes to respiratory system mechanics in the injured groups were due to increases in lung elastance (E) and resistance (R) (ΔE from pre-injury = 46 ± 14 cmH2 O L-1 , p < 0.0001; ΔR from pre-injury: 3 ± 2 cmH2 O L-1 s- , p = 0.30) rather than changes to the chest wall (ΔE from pre-injury: 0.7 ± 1.6 cmH2 O L-1 , p = 0.99; ΔR from pre-injury: 0.6 ± 0.1 cmH2 O L-1 s- , p = 0.01). Both control groups had no change in respiratory mechanics. In conclusion, therapeutic hypothermia can reduce markers of injury and inflammation associated with experimentally induced short-term ARDS.
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Affiliation(s)
- Sarah A. Angus
- Department of KinesiologyUniversity of WaterlooWaterlooOntarioCanada
| | - William R. Henderson
- Division of Critical Care MedicineDepartment of MedicineFaculty of MedicineUniversity of British ColumbiaVancouverBritish ColumbiaCanada
| | - Mohammad M. Banoei
- Department of Critical Care MedicineUniversity of CalgaryCalgaryAlbertaCanada
| | - Yannick Molgat‐Seon
- Department Kinesiology and Applied HealthUniversity of WinnipegWinnipegManitobaCanada
| | - Carli M. Peters
- School of KinesiologyUniversity of British ColumbiaVancouverBritish ColumbiaCanada
| | - Hanna R. Parmar
- School of KinesiologyUniversity of British ColumbiaVancouverBritish ColumbiaCanada
| | - Donald E. G. Griesdale
- Division of Critical Care MedicineDepartment of MedicineFaculty of MedicineUniversity of British ColumbiaVancouverBritish ColumbiaCanada
- Department of AnesthesiologyPharmacology & TherapeuticsUniversity of British ColumbiaVancouverBritish ColumbiaCanada
| | - Mypinder Sekhon
- Division of Critical Care MedicineDepartment of MedicineFaculty of MedicineUniversity of British ColumbiaVancouverBritish ColumbiaCanada
| | - Andrew William Sheel
- School of KinesiologyUniversity of British ColumbiaVancouverBritish ColumbiaCanada
| | - Brent W. Winston
- Department of Critical Care MedicineUniversity of CalgaryCalgaryAlbertaCanada
- Departments of Medicine and Biochemistry & Molecular BiologyUniversity of CalgaryCalgaryAlbertaCanada
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Fan M, Li Z, Hu M, Zhao H, Wang T, Jia Y, Yang R, Wang S, Song J, Liu Y, Jin W. Formononetin attenuates Aβ 25-35-induced adhesion molecules in HBMECs via Nrf2 activation. Brain Res Bull 2022; 183:162-171. [PMID: 35304289 DOI: 10.1016/j.brainresbull.2022.03.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 02/21/2022] [Accepted: 03/12/2022] [Indexed: 01/14/2023]
Abstract
Brain vascular inflammation plays a crucial role in the pathogenesis of Alzheimer's disease (AD). As a central pathogenic factor in AD, the extracellular buildup of amyloid-β (Aβ) induces brain microvascular endothelial cells activation, impairs endothelial structure and function. Formononetin (FMN) has been reported to protect against Alzheimer's disease (AD) and attenuates vascular inflammation in atherosclerosis. However, its involvement in regulating vascular inflammation of AD has not been investigated. In the study, we found that FMN significantly attenuates Aβ25-35-induced expression of adhesion molecules, including intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the human brain microvascular endothelial cells (HBMECs), suggesting that FMN inhibits Aβ25-35-induced brain endothelial cells inflammatory response. Moreover, we observed that FMN attenuates Aβ25-35-induced translocation of NFκB (p65) into the nucleus of HBMECs, and found that FMN treatment induces Nrf2 expression and attenuates Nrf2-Keap1 association in a dose-dependent manner in HBMECs. Furthermore, we demonstrated that Nrf2 silencing significantly attenuates FMN-reduced NFκB (p65) activation and nuclear translocation. Lastly, our results showed that FMN treatment attenuates Aβ25-35-induced adhesion of THP-1 cell to endothelial cell monolayer. Collectively, these findings suggest that FMN attenuates Aβ25-35-induced activation in human brain microvascular endothelial cells, which at least in part was mediated through Nrf2 pathways.
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Affiliation(s)
- Mingyue Fan
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, P.R. China
| | - Zhe Li
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, P.R. China
| | - Ming Hu
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, P.R. China
| | - Haifeng Zhao
- Department of Anesthesiology, Shijiazhuang Obstetrics and Gynecology Hospital, The Fourth Hospital of Shijiazhuang, Shijiazhuang, Hebei, P.R. China
| | - Tianjun Wang
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, P.R. China
| | - Yanqiu Jia
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, P.R. China
| | - Rui Yang
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, P.R. China
| | - Shuo Wang
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, P.R. China
| | - Jiaxi Song
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, P.R. China
| | - Yang Liu
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, P.R. China
| | - Wei Jin
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, P.R. China.
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Kraus RF, Gruber MA. Neutrophils-From Bone Marrow to First-Line Defense of the Innate Immune System. Front Immunol 2022; 12:767175. [PMID: 35003081 PMCID: PMC8732951 DOI: 10.3389/fimmu.2021.767175] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 12/03/2021] [Indexed: 12/16/2022] Open
Abstract
Neutrophils (polymorphonuclear cells; PMNs) form a first line of defense against pathogens and are therefore an important component of the innate immune response. As a result of poorly controlled activation, however, PMNs can also mediate tissue damage in numerous diseases, often by increasing tissue inflammation and injury. According to current knowledge, PMNs are not only part of the pathogenesis of infectious and autoimmune diseases but also of conditions with disturbed tissue homeostasis such as trauma and shock. Scientific advances in the past two decades have changed the role of neutrophils from that of solely immune defense cells to cells that are responsible for the general integrity of the body, even in the absence of pathogens. To better understand PMN function in the human organism, our review outlines the role of PMNs within the innate immune system. This review provides an overview of the migration of PMNs from the vascular compartment to the target tissue as well as their chemotactic processes and illuminates crucial neutrophil immune properties at the site of the lesion. The review is focused on the formation of chemotactic gradients in interaction with the extracellular matrix (ECM) and the influence of the ECM on PMN function. In addition, our review summarizes current knowledge about the phenomenon of bidirectional and reverse PMN migration, neutrophil microtubules, and the microtubule organizing center in PMN migration. As a conclusive feature, we review and discuss new findings about neutrophil behavior in cancer environment and tumor tissue.
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Affiliation(s)
- Richard Felix Kraus
- Department of Anesthesiology, University Medical Center Regensburg, Regensburg, Germany
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The role of neutrophils in rheumatic disease-associated vascular inflammation. Nat Rev Rheumatol 2022; 18:158-170. [PMID: 35039664 DOI: 10.1038/s41584-021-00738-4] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/10/2021] [Indexed: 12/13/2022]
Abstract
Vascular pathologies underpin and intertwine autoimmune rheumatic diseases and cardiovascular conditions, and atherosclerosis is increasingly recognized as the leading cause of morbidity in conditions such as systemic lupus erythematosus (SLE), rheumatoid arthritis and antineutrophil cytoplasmic antibody-associated vasculitis. Neutrophils, important cells in the innate immune system, exert their functional effects in tissues via a variety of mechanisms, including the generation of neutrophil extracellular traps and the production of reactive oxygen species. Neutrophils have been implicated in the pathogenesis of several rheumatic diseases, and can also intimately interact with the vascular system, either through modulating endothelial barriers at the blood-vessel interface, or through associations with platelets. Emerging data suggest that neutrophils also have an important role maintaining homeostasis in individual organs and can protect the vascular system. Furthermore, studies using high-dimensional omics technologies have advanced our understanding of neutrophil diversity, and immature neutrophils are receiving new attention in rheumatic diseases including SLE and systemic vasculitis. Developments in genomic, imaging and organoid technologies are beginning to enable more in-depth investigations into the pathophysiology of vascular inflammation in rheumatic diseases, making now a good time to re-examine the full scope of roles of neutrophils in these processes.
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