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Aldirawi M, Ghanbari P, Mietkowska M, März S, Odenthal-Schnittler M, Franz J, Wegner J, Currie S, Kipcke JP, Taha M, Giglmaier M, Blanque A, Schillers H, Raz E, Vestweber D, Rottner K, Schnittler H. A specific role for endothelial EPLIN-isoform-regulated actin dynamics in neutrophil transmigration. Sci Rep 2025; 15:15698. [PMID: 40325158 PMCID: PMC12053001 DOI: 10.1038/s41598-025-98192-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 04/09/2025] [Indexed: 05/07/2025] Open
Abstract
Proinflammatory cytokines such as TNF-α or IL-1β activate the endothelium promoting leukocyte transendothelial migration (TEM) via expression of cell adhesion molecules (CAM) and cause actin remodelling. However, the function of endothelial actin remodelling in TEM remains elusive, despite its involvement in the formation of docking structures, diapedesis pores and pore resealing. Here, we establish EPLIN-isoforms, EPLIN-β and EPLIN-α, as differential regulators of TNF-α-inducedactin-remodelling significantly affecting TEM. We find EPLIN-β-induced stress fiber formation upon TNF-α-treatment weakens endothelial junctions, upregulates junctional dynamics and facilitates intercellular gaps for TEM. Increased junctional dynamics involves branched actin filaments under the control of EPLIN-α, including docking structure formation and transmigratory pore closure. We further establish by EPLIN deletion and re-expression studies that EPLIN-α-mediated termination of branched actin filaments maintains TNF-α-induced junctional dynamics and intercellular gaps facilitating TEM. These findings highlight the critical role of TNF-α-induced differential actin dynamics, controlled by EPLIN isoforms, in TEM. These results also offer a wider understanding of inflammation-induced TEM by incorporating altered junctional dynamics alongside upregulation of cell adhesion molecules.
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Affiliation(s)
- Mohammed Aldirawi
- Institute of Anatomy and Vascular Biology, University Münster, Vesaliusweg 2-4, Münster, Germany
| | - Parisa Ghanbari
- Institute of Anatomy and Vascular Biology, University Münster, Vesaliusweg 2-4, Münster, Germany
- Max Planck Institute for Molecular Biomedicine, Röntgenstraße 20, Münster, Germany
| | - Magdalena Mietkowska
- Division of Molecular Cell Biology, Zoological Institute, Technische Universität Braunschweig, Spielmannstrasse 7, 38106, Braunschweig, Germany
- Molecular Cell Biology Group, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124, Braunschweig, Germany
| | - Sigrid März
- Institute of Anatomy and Vascular Biology, University Münster, Vesaliusweg 2-4, Münster, Germany
| | - Maria Odenthal-Schnittler
- Max Planck Institute for Molecular Biomedicine, Röntgenstraße 20, Münster, Germany
- Institute of Neuropathology, University of Münster, Pottkamp 2, 48149, Münster, Germany
| | - Jonas Franz
- Institute of Anatomy and Vascular Biology, University Münster, Vesaliusweg 2-4, Münster, Germany
- Max Planck Institute for Molecular Biomedicine, Röntgenstraße 20, Münster, Germany
- Institute of Neuropathology, University of Münster, Pottkamp 2, 48149, Münster, Germany
| | - Julian Wegner
- Institute of Cell Biology, Center for Molecular Biology of Inflammation, 48149, Münster, Germany
| | - Silke Currie
- Max Planck Institute for Molecular Biomedicine, Röntgenstraße 20, Münster, Germany
| | - Jan Philip Kipcke
- Institute of Anatomy and Vascular Biology, University Münster, Vesaliusweg 2-4, Münster, Germany
- Max Planck Institute for Molecular Biomedicine, Röntgenstraße 20, Münster, Germany
- Institute of Neuropathology, University of Münster, Pottkamp 2, 48149, Münster, Germany
| | - Muna Taha
- Institute of Anatomy and Vascular Biology, University Münster, Vesaliusweg 2-4, Münster, Germany
| | - Marcus Giglmaier
- Institute of Aerodynamics and Fluid Mechanics, Technical University of Munich, Boltzmannstr. 15, 85748, Garching, Germany
| | - Anja Blanque
- Institute of Physiology, University Münster, Robert-Koch Strasse 27a, 48149, Münster, Germany
| | - Hermann Schillers
- Institute of Physiology, University Münster, Robert-Koch Strasse 27a, 48149, Münster, Germany
| | - Erez Raz
- Institute of Cell Biology, Center for Molecular Biology of Inflammation, 48149, Münster, Germany
| | - Dietmar Vestweber
- Max Planck Institute for Molecular Biomedicine, Röntgenstraße 20, Münster, Germany
| | - Klemens Rottner
- Division of Molecular Cell Biology, Zoological Institute, Technische Universität Braunschweig, Spielmannstrasse 7, 38106, Braunschweig, Germany
- Molecular Cell Biology Group, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124, Braunschweig, Germany
| | - Hans Schnittler
- Institute of Anatomy and Vascular Biology, University Münster, Vesaliusweg 2-4, Münster, Germany.
- Max Planck Institute for Molecular Biomedicine, Röntgenstraße 20, Münster, Germany.
- Institute of Neuropathology, University of Münster, Pottkamp 2, 48149, Münster, Germany.
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Liu M, Chen R, Zheng Z, Xu S, Hou C, Ding Y, Zhang M, Bao M, He B, Li S. Mechanisms of inflammatory microenvironment formation in cardiometabolic diseases: molecular and cellular perspectives. Front Cardiovasc Med 2025; 11:1529903. [PMID: 39877020 PMCID: PMC11772298 DOI: 10.3389/fcvm.2024.1529903] [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: 11/18/2024] [Accepted: 12/26/2024] [Indexed: 01/31/2025] Open
Abstract
Cardiometabolic diseases (CMD) are leading causes of death and disability worldwide, with complex pathophysiological mechanisms in which inflammation plays a crucial role. This review aims to elucidate the molecular and cellular mechanisms within the inflammatory microenvironment of atherosclerosis, hypertension and diabetic cardiomyopathy. In atherosclerosis, oxidized low-density lipoprotein (ox-LDL) and pro-inflammatory cytokines such as Interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-α) activate immune cells contributing to foam cell formation and arterial wall thickening. Hypertension involves the activation of the renin-angiotensin system (RAS) alongside oxidative stress-induced endothelial dysfunction and local inflammation mediated by T cells. In diabetic cardiomyopathy, a high-glucose environment leads to the accumulation of advanced glycation end products (AGEs), activating the Receptor for Advanced Glycation Endproducts (RAGE) and triggering inflammatory responses that further damage cardiac and microvascular function. In summary, the inflammatory mechanisms in different types of metabolic cardiovascular diseases are complex and diverse; understanding these mechanisms deeply will aid in developing more effective individualized treatment strategies.
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Affiliation(s)
- Menghua Liu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Rumeng Chen
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Zhiwei Zheng
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Shuling Xu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Chunyan Hou
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Yining Ding
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Mengling Zhang
- School of Stomatology, Changsha Medical University, Changsha, China
| | - Meihua Bao
- Hunan key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, School of Pharmaceutical Science, Changsha Medical University, Changsha, China
| | - Binsheng He
- Hunan key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, School of Pharmaceutical Science, Changsha Medical University, Changsha, China
| | - Sen Li
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
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Jia T, He J, Miao C, Long Y, Dong Q, Guo J, Chen W, Hou Z. Inadequate soft tissue coverage and bone loss/comminution are the typical risk factors of surgical site infection in open fractures of the hand: A nomogram prediction model. PLoS One 2025; 20:e0313832. [PMID: 39775544 PMCID: PMC11709289 DOI: 10.1371/journal.pone.0313832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 11/01/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Different from other parts of long bone fractures, surgical site infections (SSI) often occurs in open fractures of the hand (OFH) due to the anatomical characteristics and injury mechanisms. Our aim of the study is to investigate the particular risk factors of SSI after emergency surgery in OFH and develop a prediction nomogram model. METHODS In our traumatic center, patients with OFH not less than 18 years old were retrieved between October 2020 and April 2024. We excluded patients with other fractures, non-traumatic fractures or surgery before admission. The data of these patients were processed by univariate and multivariate analysis using SPSS (24.0) in order to identify the independent risk factors for SSI. Based on the predictors, the nomogram was constructed and validated by R software (R 4.1.0). RESULTS The incidence of SSI was 6.96% (43/618). Body mass index (BMI), albumin (ALB), neutrophils (NEU), inadequate soft tissue coverage, and bone loss/comminution were identified as the independent risk factors of post-operative SSI in OFH and enrolled in the prediction nomogram model. The nomogram exhibited a high level of discrimination, with an area under the curve of 0.856 (95%CI 0.790-0.921) in the training group and 0.931 (95%CI 0.848-1.000) in the test group. Hosmer-Lemeshow (H-L) test revealed optimal consistency between the probability of prediction model and the actual probability (training group: X2 = 5.706, P = 0.680; test group: X2 = 3.886, P = 0.867). The calibration curve of both groups demonstrated excellent consistency. Decision curve analysis (DCA) showed favorable applicability of the prediction model. CONCLUSIONS Inadequate soft tissue coverage, serum ALB level, NEU level, bone loss/comminution and BMI were the independent risk factors for post-operative SSI in OFH. The nomogram of this predictors can be used as an effective tool to predict SSI risk in OFH.
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Affiliation(s)
- Tianyang Jia
- Sixth Department of Orthopedics Surgery, Handan Central Hospital, Handan, Hebei, China
- Department of Orthopaedic Surgery, Hebei Medical University Third Hospital, Shijiazhuang, China
| | - Jinglan He
- Department of Orthopaedic Surgery, Hebei Medical University Third Hospital, Shijiazhuang, China
| | - Cunliang Miao
- Sixth Department of Orthopedics Surgery, Handan Central Hospital, Handan, Hebei, China
| | - Yubin Long
- Department of Orthopaedic Surgery, Hebei Medical University Third Hospital, Shijiazhuang, China
| | - Qi Dong
- Department of Orthopaedic Surgery, Hebei Medical University Third Hospital, Shijiazhuang, China
| | - Jialiang Guo
- Department of Orthopaedic Surgery, Hebei Medical University Third Hospital, Shijiazhuang, China
| | - Wei Chen
- Department of Orthopaedic Surgery, Hebei Medical University Third Hospital, Shijiazhuang, China
- Engineering Research Center of Orthopedic Minimally Invasive Intelligent Equipment, Ministry of Education, China
- Key Laboratory of Biomechanics of Hebei Province, Shijiazhuang, China
- NHC Key Laboratory of Intelligent Orthopeadic Equipment, Shijiazhuang, China
| | - Zhiyong Hou
- Department of Orthopaedic Surgery, Hebei Medical University Third Hospital, Shijiazhuang, China
- Engineering Research Center of Orthopedic Minimally Invasive Intelligent Equipment, Ministry of Education, China
- Key Laboratory of Biomechanics of Hebei Province, Shijiazhuang, China
- NHC Key Laboratory of Intelligent Orthopeadic Equipment, Shijiazhuang, China
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Galtung N, Stein V, Prpic M, Boyraz B, Ulke J, Kurz S, Dernedde J, Diehl-Wiesenecker E, Bauer W, Kappert K. EARLY ANALYSIS OF ENDOTHELIAL MARKERS TO PREDICT SEPSIS IN THE EMERGENCY DEPARTMENT. Shock 2025; 63:72-79. [PMID: 39405404 DOI: 10.1097/shk.0000000000002482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2024]
Abstract
ABSTRACT Background: Acute infections and sepsis are a leading cause of death. These patients are primarily encountered at the emergency department (ED), where early assessment for sepsis is necessary to improve outcome. In sepsis, the inflammatory response causes several characteristic pathophysiological changes, including a dysregulated and generalized activation of the endothelium. This study aimed to analyze endothelial markers released to the blood as diagnostic biomarkers for acute infection and sepsis in the ED, as smaller studies have previously shown promising results in other settings. Methods : Serum samples from n = 312 adult patients with suspected acute infections at presentation to the ED were utilized. Patients' courses of disease and outcomes were assessed by clinical adjudication. E-selectin, P-selectin, ICAM-1, and VCAM-1 were measured by ELISAs. The accuracy of each marker for predicting bacterial infection, sepsis, and in-hospital mortality was evaluated. Results : For sepsis, E-selectin and ICAM-1 both showed an area under the receiver operating characteristic (AUROC) of 0.62, lower than procalcitonin with 0.77 (both P < 0.01) and lactate with 0.73 ( P = 0.030 and 0.046, respectively), but similar to CRP with 0.60 ( P = 0.758 and 0.876, respectively). For 28-day in-hospital mortality among patients with infection, ICAM-1 performed best with an AUROC of 0.75. Conclusions : Despite promising results in small studies and specific cohorts, particularly in intensive care units, this large-scale evaluation of four endothelial biomarkers highlights their limited diagnostic utility in a broader inclusion setup design at the earliest possible time point of evaluation.
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Affiliation(s)
- Noa Galtung
- Department of Emergency Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Vanessa Stein
- Institute of Diagnostic Laboratory Medicine, Clinical Chemistry, and Pathobiochemistry, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Monika Prpic
- Institute of Diagnostic Laboratory Medicine, Clinical Chemistry, and Pathobiochemistry, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Burak Boyraz
- Institute of Diagnostic Laboratory Medicine, Clinical Chemistry, and Pathobiochemistry, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Jannis Ulke
- Institute of Diagnostic Laboratory Medicine, Clinical Chemistry, and Pathobiochemistry, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Stephan Kurz
- Department of Cardiothoracic and Vascular Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Jens Dernedde
- Institute of Diagnostic Laboratory Medicine, Clinical Chemistry, and Pathobiochemistry, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Eva Diehl-Wiesenecker
- Department of Emergency Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Wolfgang Bauer
- Department of Emergency Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Kai Kappert
- Institute of Diagnostic Laboratory Medicine, Clinical Chemistry, and Pathobiochemistry, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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Salian VS, Tang X, Thompson KJ, Curan GL, Lowe VJ, Li L, Kalari KR, Kandimalla KK. Molecular Mechanisms Underlying Amyloid Beta Peptide Mediated Upregulation of Vascular Cell Adhesion Molecule-1 in Alzheimer Disease. J Pharmacol Exp Ther 2024; 391:430-440. [PMID: 39455283 PMCID: PMC11585316 DOI: 10.1124/jpet.124.002280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 09/30/2024] [Accepted: 10/08/2024] [Indexed: 10/28/2024] Open
Abstract
Amyloid β(Aβ) deposition and neurofibrillary tangles are widely considered the primary pathological hallmarks of familial and sporadic forms of Alzheimer disease (AD). However, cerebrovascular inflammation, which is prevalent in 70% of AD patients, is emerging as another core feature of AD pathology. In our current work, we investigated the hypothesis that Aβ42 exposure drives an increase in vascular cell adhesion molecule-1 (VCAM-1) expression, a cerebrovascular inflammatory marker expressed on the blood-brain barrier (BBB) endothelium in humans and murine models. We have demonstrated that the inflammation signaling pathway is upregulated in AD patient brains, and VCAM-1 expression is increased in AD patients compared with healthy controls. Furthermore, dynamic SPEC/CT imaging in APP,PS1 transgenic mice (a mouse model that overexpresses Aβ42) demonstrated VCAM-1 upregulation at the BBB. Although there is a strong association between Aβ42 exposure and an increase in VCAM-1 expression, the underlying mechanisms remain partially understood. Molecular mechanisms driving VCAM-1 expression at the BBB were investigated in polarized human cerebral microvascular endothelial cell monolayers. Moreover, by employing reverse-phase protein array assays and immunocytochemistry we demonstrated that Aβ42 increases VCAM-1 expression via the Src/p38/MEK signaling pathway. Therefore, targeting the Src/p38/MEK pathway may help modulate VCAM-1 expression at the BBB and help mitigate cerebrovascular inflammation in Alzheimer disease. SIGNIFICANCE STATEMENT: Although considered a core pathological feature of Alzheimer disease, molecular pathways leading to cerebrovascular inflammation remain only partially understood. Moreover, clinical diagnostic methods for detecting cerebrovascular inflammation are underdeveloped. This study demonstrated the detection of VCAM-1 using radio-iodinated VCAM-1 antibody and single-photon emission computed tomography/computed tomography imaging. Additionally, exposure to Aβ42 increases VCAM-1 expression on the blood-brain barrier endothelium via the Src/p38/MEK pathway. These findings are expected to aid in the development of diagnostic and therapeutic approaches for addressing cerebrovascular inflammation in AD.
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Affiliation(s)
- Vrishali S Salian
- Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (V.S.S., K.K.K.); Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota (G.L.C., V.J.L.); Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota (X.T., K.J.T., K.R.K.); and Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (L.L.)
| | - Xiaojia Tang
- Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (V.S.S., K.K.K.); Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota (G.L.C., V.J.L.); Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota (X.T., K.J.T., K.R.K.); and Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (L.L.)
| | - Kevin J Thompson
- Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (V.S.S., K.K.K.); Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota (G.L.C., V.J.L.); Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota (X.T., K.J.T., K.R.K.); and Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (L.L.)
| | - Geoffry L Curan
- Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (V.S.S., K.K.K.); Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota (G.L.C., V.J.L.); Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota (X.T., K.J.T., K.R.K.); and Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (L.L.)
| | - Val J Lowe
- Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (V.S.S., K.K.K.); Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota (G.L.C., V.J.L.); Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota (X.T., K.J.T., K.R.K.); and Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (L.L.)
| | - Ling Li
- Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (V.S.S., K.K.K.); Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota (G.L.C., V.J.L.); Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota (X.T., K.J.T., K.R.K.); and Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (L.L.)
| | - Krishna R Kalari
- Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (V.S.S., K.K.K.); Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota (G.L.C., V.J.L.); Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota (X.T., K.J.T., K.R.K.); and Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (L.L.)
| | - Karunya K Kandimalla
- Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (V.S.S., K.K.K.); Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota (G.L.C., V.J.L.); Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota (X.T., K.J.T., K.R.K.); and Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (L.L.)
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Wu J, Fan C, Kabir AU, Krchma K, Kim M, Kwon Y, Xing X, Wang T, Choi K. Baf155 controls hematopoietic differentiation and regeneration through chromatin priming. Cell Rep 2024; 43:114558. [PMID: 39088321 PMCID: PMC11465209 DOI: 10.1016/j.celrep.2024.114558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 05/06/2024] [Accepted: 07/14/2024] [Indexed: 08/03/2024] Open
Abstract
Chromatin priming promotes cell-type-specific gene expression, lineage differentiation, and development. The mechanism of chromatin priming has not been fully understood. Here, we report that mouse hematopoietic stem and progenitor cells (HSPCs) lacking the Baf155 subunit of the BAF (BRG1/BRM-associated factor) chromatin remodeling complex produce a significantly reduced number of mature blood cells, leading to a failure of hematopoietic regeneration upon transplantation and 5-fluorouracil (5-FU) injury. Baf155-deficient HSPCs generate particularly fewer neutrophils, B cells, and CD8+ T cells at homeostasis, supporting a more immune-suppressive tumor microenvironment and enhanced tumor growth. Single-nucleus multiomics analysis reveals that Baf155-deficient HSPCs fail to establish accessible chromatin in selected regions that are enriched for putative enhancers and binding motifs of hematopoietic lineage transcription factors. Our study provides a fundamental mechanistic understanding of the role of Baf155 in hematopoietic lineage chromatin priming and the functional consequences of Baf155 deficiency in regeneration and tumor immunity.
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Affiliation(s)
- Jun Wu
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Changxu Fan
- Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA; Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Ashraf Ul Kabir
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Karen Krchma
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Minseo Kim
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Yoojung Kwon
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Xiaoyun Xing
- Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA; Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Ting Wang
- Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA; Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Kyunghee Choi
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
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Christopoulos G, Christopoulou V, Stamatiou K, Babionitakis A, Routsias JG. Association Between Soluble Cell Adhesion Molecules (sP-Selectin, sE-Selectin, and sICAM-1) and Antibodies Against the Antigens of Proteus mirabilis in Rheumatoid Arthritis Patients. Cureus 2024; 16:e64942. [PMID: 39156359 PMCID: PMC11330672 DOI: 10.7759/cureus.64942] [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] [Accepted: 07/19/2024] [Indexed: 08/20/2024] Open
Abstract
Objective The purpose of this study was to examine the association between the serum concentration of soluble cell adhesion molecules (CAMs) and antibodies against antigens of Proteus mirabilis (P. mirabilis) in rheumatoid arthritis (RA) patients, taking into consideration the implication of P. mirabilis in the etiopathogenesis of RA. Methods The serum levels of soluble P-selectin (sP-selectin), soluble E-selectin (sE-selectin), and soluble intercellular adhesion molecule-1 (sICAM-1) were determined by sandwich enzyme-linked immunosorbent assay (ELISA) in 59 RA patients and 36 healthy controls. Using the same ELISA method, the serum levels of class-specific antibodies against hemolysin (HpmB), urease C (UreC), and urease F (UreF) enzymes of P. mirabilis were also measured. Results In this study, increased levels of sP-selectin and sICAM-1 were observed in RA patients, while the levels of sE-selectin were increased in comparison with healthy controls but did not present a statistically significant difference. Moreover, increased levels of antibodies against HpmB, UreC, and UreF of P. mirabilis were found. Additionally, it was observed that the sE-selectin levels presented a significant correlation with IgG antibodies against the UreF antigen (there is no corresponding antigen in human tissue) in all the RA patients. A statistically significant correlation was observed between levels of soluble CAMs and antibodies against P. mirabilis in the different subgroups. Conclusion The observed correlation between soluble CAMs and antibodies against antigens of P. mirabilis, specifically in the subgroup of biologic therapy, indicates that P. mirabilis exists and provokes refractory in the treatment of RA.
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Affiliation(s)
| | - Vasiliki Christopoulou
- Department of Internal Medicine - Propaedeutic, Attikon University Hospital, Athens, GRC
| | | | - Andreas Babionitakis
- Department of Pathophysiology, Medical School National & Kapodistrian University of Athens, Athens, GRC
| | - John G Routsias
- Department of Microbiology, Medical School National & Kapodistrian University of Athens, Athens, GRC
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Hsu B, Wang C, Lai Y, Kuo C, Lin Y. Association of endothelial dysfunction and peripheral arterial disease with sarcopenia in chronic kidney disease. J Cachexia Sarcopenia Muscle 2024; 15:1199-1208. [PMID: 38644163 PMCID: PMC11154745 DOI: 10.1002/jcsm.13471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 12/21/2023] [Accepted: 03/19/2024] [Indexed: 04/23/2024] Open
Abstract
BACKGROUND Endothelial dysfunction and peripheral arterial disease (PAD), which disturb skeletal muscle microperfusion, are highly prevalent in patients with chronic kidney disease (CKD). We evaluated the association of endothelial dysfunction and PAD with sarcopenia in patients with non-dialysis CKD. METHODS This cross-sectional study included 420 patients with stages 3-5 non-dialysis CKD aged 69.0 ± 11.8 years. Skeletal muscle index (skeletal muscle mass/height2), handgrip strength, 6-m gait speed and strength of hip flexion and knee extension were measured. Sarcopenia was defined according to the Asian Working Group for Sarcopenia 2019. Endothelial dysfunction and PAD were assessed using the vascular reactivity index (VRI) and ankle-brachial index (ABI), respectively. A VRI < 1.0 was classified as poor endothelial function, and an ABI < 0.9 was defined as PAD. Additionally, endothelial and inflammatory biomarkers, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), asymmetric dimethylarginine, endothelin-1 (ET-1) and interleukin-6, were measured in a subgroup of 262 patients. RESULTS Among the participants, 103 (24.5%) were classified as having sarcopenia. Compared with patients without sarcopenia, those with sarcopenia had significantly lower ABI (1.04 ± 0.16 vs. 1.08 ± 0.15, P = 0.028 for the right ABI; 1.01 ± 0.16 vs. 1.06 ± 0.16, P = 0.002 for the left ABI) and VRI (0.83 ± 0.57 vs. 1.08 ± 0.56, P < 0.001) and had higher serum levels of ICAM-1 (P < 0.001), VCAM-1 (P = 0.003) and ET-1 (P = 0.037). Multivariate logistic regression revealed that, beyond age and body mass index, the average ABI (odds ratio [OR]: 0.81/0.1 increase; 95% confidence interval [CI]: 0.67-0.98; P = 0.032) and VRI (OR: 0.93/0.1 increase; 95% CI: 0.88-0.98; P = 0.010) were independently associated with sarcopenia. Among the endothelial biomarkers measured, ICAM-1 (OR: 2.47/1-SD increase; 95% CI: 1.62-3.75) and VCAM-1 (OR: 1.91/1-SD increase; 95% CI: 1.27-2.87) were independent predictors of sarcopenia. Group stratification based on the cut-offs of VRI and ABI showed that those with both poor VRI and ABI had the greatest risk for sarcopenia (OR: 4.22; 95% CI: 1.69-10.49), compared with those with normal VRI and ABI. CONCLUSIONS Endothelial dysfunction and PAD are independently associated with sarcopenia in patients with stages 3-5 CKD, suggesting the dominant role of vascular dysfunction in sarcopenia.
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Affiliation(s)
- Bang‐Gee Hsu
- Division of NephrologyHualien Tzu Chi Hospital, Buddhist Tzu Chi Medical FoundationHualienTaiwan
- School of MedicineTzu Chi UniversityHualienTaiwan
| | - Chih‐Hsien Wang
- Division of NephrologyHualien Tzu Chi Hospital, Buddhist Tzu Chi Medical FoundationHualienTaiwan
- School of MedicineTzu Chi UniversityHualienTaiwan
| | - Yu‐Hsien Lai
- Division of NephrologyHualien Tzu Chi Hospital, Buddhist Tzu Chi Medical FoundationHualienTaiwan
- School of MedicineTzu Chi UniversityHualienTaiwan
| | - Chiu‐Huang Kuo
- Division of NephrologyHualien Tzu Chi Hospital, Buddhist Tzu Chi Medical FoundationHualienTaiwan
- School of Post‐baccalaureate Chinese MedicineTzu Chi UniversityHualienTaiwan
| | - Yu‐Li Lin
- Division of NephrologyHualien Tzu Chi Hospital, Buddhist Tzu Chi Medical FoundationHualienTaiwan
- School of MedicineTzu Chi UniversityHualienTaiwan
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9
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Gingell L, Hrinczenko B. Characterizing the Immature Immunophenotype of Sickle Cell Disease Monocytes. Cureus 2024; 16:e60703. [PMID: 38899253 PMCID: PMC11186669 DOI: 10.7759/cureus.60703] [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] [Accepted: 05/20/2024] [Indexed: 06/21/2024] Open
Abstract
Sickle cell disease (SCD) is marked by episodic vaso-occlusive crisis (VOC). Recurrent VOC creates a pro-inflammatory state that induces phenotypic alterations in innate immune cells. Monocytes are of particular interest to VOC pathophysiology because they are especially malleable to inflammatory signaling. Indeed, inflammatory disease states such as chronic obstructive pulmonary disease (COPD), obesity and atherosclerosis are known to influence monocyte development and alter monocyte subpopulations. In this study, we describe SCD monocyte subsets by performing immunophenotypic flow cytometric, enzymatic, and morphologic analysis on peripheral blood. Herein, we add to the growing body of evidence suggesting aberrant monocyte populations underpin VOC pathophysiology. We found that SCD monocytes possess an immature phenotype as demonstrated by 1) decreased CD4 positivity (p < .01), 2) low α-naphthyl butyrate esterase (ANBE) expression, and 3) naïve morphologic features. We additionally found an increase in CD14+CD16-CD4- monocytes (p < .01), a subset associated with the impaired immune response of post-trauma patients. Interestingly, we also found a large proportion of CD14+CD4-HLA-DR- monocytes which, under normal circumstances, are exclusively found in neonates (p < .01). Finally, we report an increase in nonclassical monocytes (CD14dimCD16+), a subset recently shown to have a critical role in prevention and recovery from VOC.
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Affiliation(s)
- Luke Gingell
- Medical School, Michigan State University, Grand Rapids, USA
| | - Borys Hrinczenko
- Hematology/Oncology, Michigan State University, East Lansing, USA
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10
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Haynes ME, Sullivan DP, Muller WA. Neutrophil Infiltration and Function in the Pathogenesis of Inflammatory Airspace Disease. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:628-636. [PMID: 38309429 PMCID: PMC11074974 DOI: 10.1016/j.ajpath.2023.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 12/07/2023] [Accepted: 12/21/2023] [Indexed: 02/05/2024]
Abstract
Neutrophils are an important cell type often considered the body's first responders to inflammatory insult or damage. They are recruited to the tissue of the lungs in patients with inflammatory airspace diseases and have unique and complex functions that range from helpful to harmful. The uniqueness of these functions is due to the heterogeneity of the inflammatory cascade and retention in the vasculature. Neutrophils are known to marginate, or remain stagnant, in the lungs even in nondisease conditions. This review discusses the ways in which the recruitment, presence, and function of neutrophils in the airspace of the lungs are unique from those of other tissues, and the complex effects of neutrophils on pathogenesis. Inflammatory mediators produced by neutrophils, such as neutrophil elastase, proresolving mediators, and neutrophil extracellular traps, dramatically affect the outcomes of patients with disease of the lungs.
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Affiliation(s)
- Maureen E Haynes
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - David P Sullivan
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - William A Muller
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
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11
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Zielińska A, Bryk D, Paradowska K, Siudem P, Wawer I, Wrzosek M. Anti-Atherosclerotic Properties of Aronia melanocarpa Extracts Influenced by Their Chemical Composition Associated with the Ripening Stage of the Berries. Int J Mol Sci 2024; 25:4145. [PMID: 38673738 PMCID: PMC11050415 DOI: 10.3390/ijms25084145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 04/05/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
The high content of bioactive compounds in Aronia melanocarpa fruit offers health benefits. In this study, the anti-atherosclerotic effect of Aronia extracts was assessed. The impact on the level of adhesion molecules and the inflammatory response of human umbilical vein endothelial cells (HUVECs) was shown in relation to the chemical composition and the stage of ripening of the fruits. Samples were collected between May (green, unripe) and October (red, overripe) on two farms in Poland, which differed in climate. The content of chlorogenic acids, anthocyanins, and carbohydrates in the extracts was determined using HPLC-DAD/RI. The surface expression of ICAM-1 and VCAM-1 in HUVECs was determined by flow cytometry. The mRNA levels of VCAM-1, ICAM-1, IL-6, and MCP-1 were assessed using the quantitative real-time PCR method. The farms' geographical location was associated with the quantity of active compounds in berries and their anti-atherosclerotic properties. Confirmed activity for green fruits was linked to their high chlorogenic acid content.
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Affiliation(s)
- Agnieszka Zielińska
- Department of Organic and Physical Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland; (A.Z.); (K.P.)
| | - Dorota Bryk
- Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland;
| | - Katarzyna Paradowska
- Department of Organic and Physical Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland; (A.Z.); (K.P.)
| | - Paweł Siudem
- Department of Organic and Physical Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland; (A.Z.); (K.P.)
| | - Iwona Wawer
- Department of Herbology, State University of Applied Sciences, Rynek 1, 38-400 Krosno, Poland;
| | - Małgorzata Wrzosek
- Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland;
- Centre for Preclinical Research, Medical University of Warsaw, Banacha 1b, 02-097 Warsaw, Poland
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12
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Zhang Y, Fai TG. Influence of the vessel wall geometry on the wall-induced migration of red blood cells. PLoS Comput Biol 2023; 19:e1011241. [PMID: 37459356 PMCID: PMC10374106 DOI: 10.1371/journal.pcbi.1011241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 07/27/2023] [Accepted: 06/03/2023] [Indexed: 07/28/2023] Open
Abstract
The geometry of the blood vessel wall plays a regulatory role on the motion of red blood cells (RBCs). The overall topography of the vessel wall depends on many features, among which the endothelial lining of the endothelial surface layer (ESL) is an important one. The endothelial lining of vessel walls presents a large surface area for exchanging materials between blood and tissues. The ESL plays a critical role in regulating vascular permeability, hindering leukocyte adhesion as well as inhibiting coagulation during inflammation. Changes in the ESL structure are believed to cause vascular hyperpermeability and entrap immune cells during sepsis, which could significantly alter the vessel wall geometry and disturb interactions between RBCs and the vessel wall, including the wall-induced migration of RBCs and the thickening of a cell-free layer. To investigate the influence of the vessel wall geometry particularly changed by the ESL under various pathological conditions, such as sepsis, on the motion of RBCs, we developed two models to represent the ESL using the immersed boundary method in two dimensions. In particular, we used simulations to study how the lift force and drag force on a RBC near the vessel wall vary with different wall thickness, spatial variation, and permeability associated with changes in the vessel wall geometry. We find that the spatial variation of the wall has a significant effect on the wall-induced migration of the RBC for a high permeability, and that the wall-induced migration is significantly inhibited as the vessel diameter is increased.
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Affiliation(s)
- Ying Zhang
- Department of Mathematics, Brandeis University, Waltham, Massachusetts, United States of America
| | - Thomas G Fai
- Department of Mathematics, Brandeis University, Waltham, Massachusetts, United States of America
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13
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Kim KU, Han K, Kim J, Kwon DH, Ji YW, Yi DY, Min H. The Protective Role of Exosome-Derived MicroRNAs and Proteins from Human Breast Milk against Infectious Agents. Metabolites 2023; 13:metabo13050635. [PMID: 37233676 DOI: 10.3390/metabo13050635] [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: 04/07/2023] [Revised: 04/28/2023] [Accepted: 05/06/2023] [Indexed: 05/27/2023] Open
Abstract
Human breast milk (HBM)-derived exosomes contain various biological and immunological components. However, comprehensive immune-related and antimicrobial factor analysis requires transcriptomic, proteomic, and multiple databases for functional analyses, and has yet to be conducted. Therefore, we isolated and confirmed HBM-derived exosomes by detecting specific markers and examining their morphology using western blot and transmission electron microscopy. Moreover, we implemented small RNA sequencing and liquid chromatography-mass spectrometry to investigate substances within the HBM-derived exosomes and their roles in combating pathogenic effects, identifying 208 miRNAs and 377 proteins associated with immunological pathways and diseases. Integrated omics analyses identified a connection between the exosomal substances and microbial infections. In addition, gene ontology and the Kyoto Encyclopedia of Genes and Genomes pathway analyses demonstrated that HBM-derived exosomal miRNA and proteins influence immune-related functions and pathogenic infections. Finally, protein-protein interaction analysis identified three primary proteins (ICAM1, TLR2, and FN1) associated with microbial infections mediating pro-inflammation, controlling infection, and facilitating microbial elimination. Our findings determine that HBM-derived exosomes modulate the immune system and could offer therapeutic strategies for regulating pathogenic microbial infection.
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Affiliation(s)
- Ki-Uk Kim
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Kyusun Han
- Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Jisu Kim
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Da Hyeon Kwon
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Yong Woo Ji
- Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Department of Ophthalmology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin 16995, Republic of Korea
| | - Dae Yong Yi
- Department of Pediatrics, Chung-Ang University College of Medicine, Seoul 06974, Republic of Korea
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul 06974, Republic of Korea
| | - Hyeyoung Min
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
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14
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Díaz-González CDLM. Obesity as a Risk Factor in the Appearance of Haematomas Caused by Low-Molecular-Weight Heparin: A Cross-Sectional Study. NURSING REPORTS 2023; 13:765-779. [PMID: 37218948 DOI: 10.3390/nursrep13020067] [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: 01/07/2023] [Revised: 04/27/2023] [Accepted: 04/29/2023] [Indexed: 05/24/2023] Open
Abstract
Thromboembolic disease (TED) is an important health problem in Europe due to its high morbimortality. Pharmacological prevention is achieved with low-molecular-weight heparin (LMWH), among other strategies, which are supported by a high degree of evidence in the scientific literature. According to its safety data sheet, this injection produces local injuries at a rate of 0.1-1% after administration; however, these percentages are much lower than others reported in several studies focusing on LMWH (44-88%). This high incidence of injuries might be associated with procedural or individual variables. (1) Background: Among the most frequent side effects after the administration of LMWH are pain and haematomas (HMTs), which are influenced by obesity. We aimed to determine the relationship between abdominal skinfold (ASF) value and incidence of HMTs. In addition, I sought to determine how the risk of HMT changed with each mm increase in ASF. (2) Methods: A cross-sectional descriptive study developed in the hospital unit of orthopaedic and trauma surgery was conducted over one year. All participants in the sample were classified based on their ASF and the appearance and area of HMTs were assessed after the administration of enoxaparin. The STROBE checklist was used to evaluate the study. Descriptive statistical analysis and analysis of variance of non-parametric factors were carried out. (3) Results: In a sample of 202 participants (808 Clexane injections), more than 80% presented HMTs. More than 70% of the sample was overweight and more than 50% had an ASF > 36 millimetres (mm). (4) Conclusions: An ASF over 36 mm confers a higher risk of developing HMTs: with each mm increase in the ASF, the risk increases by 4%. Participants who are overweight or obese also present a higher risk of HMT, and these conditions correlate positively with the area of the HMTs. Providing education for the self-administration of the drug after discharge and information about the probability of suffering from local injuries in a more individualised way will lead to fewer primary care nursing consultations, more adherence to the antithrombotic treatment, and, as a consequence, a decrease in TED and health costs.
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Affiliation(s)
- Candelaria de la Merced Díaz-González
- Department of Nursing, Faculty of Health Sciences, University of Las Palmas de Gran Canaria, Juan de Quesada, 30, 35001 Las Palmas de Gran Canaria, Spain
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15
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Choi A, Javius-Jones K, Hong S, Park H. Cell-Based Drug Delivery Systems with Innate Homing Capability as a Novel Nanocarrier Platform. Int J Nanomedicine 2023; 18:509-525. [PMID: 36742991 PMCID: PMC9893846 DOI: 10.2147/ijn.s394389] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 01/12/2023] [Indexed: 01/29/2023] Open
Abstract
Nanoparticle-based drug delivery systems have been designed to treat various diseases. However, many problems remain, such as inadequate tumor targeting and poor therapeutic outcomes. To overcome these obstacles, cell-based drug delivery systems have been developed. Candidates for cell-mediated drug delivery include blood cells, immune cells, and stem cells with innate tumor tropism and low immunogenicity; they act as a disguise to deliver the therapeutic payload. In drug delivery systems, therapeutic agents are encapsulated intracellularly or attached to the surface of the plasma membrane and transported to the desired site. Here, we review the pros and cons of cell-based therapies and discuss their homing mechanisms in the tumor microenvironment. In addition, different strategies to load therapeutic agents inside or on the surface of circulating cells and the current applications for a wide range of disease treatments are summarized.
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Affiliation(s)
- Anseo Choi
- School of Integrative Engineering, Chung-Ang University, Seoul, Republic of Korea
| | - Kaila Javius-Jones
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin, Madison, WI, USA
| | - Seungpyo Hong
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin, Madison, WI, USA
| | - Hansoo Park
- School of Integrative Engineering, Chung-Ang University, Seoul, Republic of Korea,Correspondence: Hansoo Park; Seungpyo Hong, School of Integrative Engineering, Chung-Ang University, Seoul, 06974, Republic of Korea, Tel +82-2 820 5804, Fax +82-2 813 8159, Email ;
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16
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Okamoto J, Wang L, Yin X, Luca F, Pique-Regi R, Helms A, Im HK, Morrison J, Wen X. Probabilistic integration of transcriptome-wide association studies and colocalization analysis identifies key molecular pathways of complex traits. Am J Hum Genet 2023; 110:44-57. [PMID: 36608684 PMCID: PMC9892769 DOI: 10.1016/j.ajhg.2022.12.002] [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: 09/01/2022] [Accepted: 12/06/2022] [Indexed: 01/07/2023] Open
Abstract
Integrative genetic association methods have shown great promise in post-GWAS (genome-wide association study) analyses, in which one of the most challenging tasks is identifying putative causal genes and uncovering molecular mechanisms of complex traits. Recent studies suggest that prevailing computational approaches, including transcriptome-wide association studies (TWASs) and colocalization analysis, are individually imperfect, but their joint usage can yield robust and powerful inference results. This paper presents INTACT, a computational framework to integrate probabilistic evidence from these distinct types of analyses and implicate putative causal genes. This procedure is flexible and can work with a wide range of existing integrative analysis approaches. It has the unique ability to quantify the uncertainty of implicated genes, enabling rigorous control of false-positive discoveries. Taking advantage of this highly desirable feature, we further propose an efficient algorithm, INTACT-GSE, for gene set enrichment analysis based on the integrated probabilistic evidence. We examine the proposed computational methods and illustrate their improved performance over the existing approaches through simulation studies. We apply the proposed methods to analyze the multi-tissue eQTL data from the GTEx project and eight large-scale complex- and molecular-trait GWAS datasets from multiple consortia and the UK Biobank. Overall, we find that the proposed methods markedly improve the existing putative gene implication methods and are particularly advantageous in evaluating and identifying key gene sets and biological pathways underlying complex traits.
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Affiliation(s)
- Jeffrey Okamoto
- Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Lijia Wang
- Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Xianyong Yin
- Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Francesca Luca
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA
| | - Roger Pique-Regi
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA
| | - Adam Helms
- University of Michigan School of Medicine, Ann Arbor, MI 48109, USA
| | - Hae Kyung Im
- Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Jean Morrison
- Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Xiaoquan Wen
- Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
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17
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E3 Ubiquitin Ligase Midline 1 Regulates Endothelial Cell ICAM-1 Expression and Neutrophil Adhesion in Abdominal Sepsis. Int J Mol Sci 2022; 24:ijms24010705. [PMID: 36614145 PMCID: PMC9821100 DOI: 10.3390/ijms24010705] [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: 04/05/2022] [Revised: 12/17/2022] [Accepted: 12/27/2022] [Indexed: 01/04/2023] Open
Abstract
Septic lung damage is associated with endothelial cell and neutrophil activation. This study examines the role of the E3 ubiquitin ligase midline 1 (Mid1) in abdominal sepsis. Mid1 expression was increased in endothelial cells derived from post-capillary venules in septic mice and TNF-α challenge increased Mid1 levels in endothelial cells in vitro. The siRNA-mediated knockdown of Mid1 decreased TNF-α-induced upregulation of ICAM-1 and neutrophil adhesion to endothelial cells. Moreover, Mid1 silencing reduced leukocyte adhesion in post-capillary venules in septic lungs in vivo. The silencing of Mid1 not only decreased Mid1 expression but also attenuated expression of ICAM-1 in lungs from septic mice. Lastly, TNF-α stimulation decreased PP2Ac levels in endothelial cells in vitro, which was reversed in endothelial cells pretreated with siRNA directed against Mid1. Thus, our novel data show that Mid1 is an important regulator of ICAM-1 expression and neutrophil adhesion in vitro and septic lung injury in vivo. A possible target of Mid1 is PP2Ac in endothelial cells. Targeting the Mid1-PP2Ac axis may be a useful way to reduce pathological lung inflammation in abdominal sepsis.
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18
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Yakovlev S, Strickland DK, Medved L. Current View on the Molecular Mechanisms Underlying Fibrin(ogen)-Dependent Inflammation. Thromb Haemost 2022; 122:1858-1868. [PMID: 35896433 PMCID: PMC10680782 DOI: 10.1055/a-1910-4538] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
Abstract
Numerous studies have revealed the involvement of fibrinogen in the inflammatory response. To explain the molecular mechanisms underlying fibrinogen-dependent inflammation, two bridging mechanisms have been proposed in which fibrin(ogen) bridges leukocytes to endothelial cells. The first mechanism suggests that bridging occurs via the interaction of fibrinogen with the leukocyte receptor Mac-1 and the endothelial receptor ICAM-1 (intercellular adhesion molecule-1), which promotes leukocyte transmigration and enhances inflammation. The second mechanism includes bridging of leukocytes to the endothelium by fibrin degradation product E1 fragment through its interaction with leukocyte receptor CD11c and endothelial VE-cadherin to promote leukocyte transmigration. The role of E1 in promoting inflammation is inhibited by the fibrin-derived β15-42 fragment, and this has been suggested to result from its ability to compete for the E1-VE-cadherin interaction and to trigger signaling pathways through the src kinase Fyn. Our recent study revealed that the β15-42 fragment is ineffective in inhibiting the E1- or fibrin-VE-cadherin interaction, leaving the proposed signaling mechanism as the only viable explanation for the inhibitory function of β15-42. We have discovered that fibrin interacts with the very-low-density lipoprotein (VLDL) receptor, and this interaction triggers a signaling pathway that promotes leukocyte transmigration through inhibition of the src kinase Fyn. This pathway is inhibited by another pathway induced by the interaction of β15-42 with a putative endothelial receptor. In this review, we briefly describe the previously proposed molecular mechanisms underlying fibrin-dependent inflammation and their advantages/disadvantages and summarize our recent studies of the novel VLDL receptor-dependent pathway of leukocyte transmigration which plays an important role in fibrin-dependent inflammation.
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Affiliation(s)
- Sergiy Yakovlev
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland, United States
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, United States
| | - Dudley K. Strickland
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland, United States
- Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland, United States
- Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, United States
| | - Leonid Medved
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland, United States
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, United States
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19
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Shafiey SI, Abo-Saif AA, Abo-Youssef AM, Mohamed WR. Protective effects of rivaroxaban against cisplatin-induced testicular damage in rats: Impact on oxidative stress, coagulation, and p-NF-κB/VCAM-1 signaling. Food Chem Toxicol 2022; 169:113419. [PMID: 36122812 DOI: 10.1016/j.fct.2022.113419] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 08/16/2022] [Accepted: 09/06/2022] [Indexed: 11/18/2022]
Abstract
Coagulation is a main pathway in various diseases pathogenesis including testicular damage. This study evaluated rivaroxaban (RVX) protective effects in testicular impairment by cisplatin (CP). Rats were randomly allocated into five groups: Control, RVX (7 mg/kg/day), CP (10 mg/kg), RVX 5 mg + CP and RVX 7 mg + CP. Serum testosterone and testicular ALT, AST, and ALP were assessed. Testicular oxidative stress and antioxidant parameters and inflammatory indicators including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were assessed. qRT-PCR was used to determine mRNA expression of 3β-hydroxysteroid dehydrogenase (3β-HSD), 17β-hydroxysteroid dehydrogenase (17β-HSD), and steroidogenic acute regulatory protein (stAR). Protein expressions of p-Nuclear factor kappa B (p- NF-κB) and vascular cell adhesion protein-1 (VCAM-1) were analyzed by Western blot analysis. Tissue factor (TF) expression was immunohistochemically analyzed. Results revealed that RVX significantly increased serum testosterone and sperm count while significantly reduced IL-1β and TNF-α. It significantly decreased tissue MDA and NO contents while increased SOD and GPx. In addition, RVX attenuated CP-induced histopathological aberrations and normalized TF. It also decreased the VCAM-1 and p-NF-κB expression and showed strong expression of 3β-HSD, 17β-HSD, and stAR, indicating improvement of steroidogenesis. In conclusion, RVX counteracted testicular damage by CP via suppressing oxidative stress, inflammation, and coagulation and downregulating p-NF-κB/VCAM-1 signaling.
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Affiliation(s)
- Sara I Shafiey
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, 62514, Egypt
| | - Ali A Abo-Saif
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, 62514, Egypt
| | - Amira M Abo-Youssef
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt
| | - Wafaa R Mohamed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt.
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20
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Asong-Fontem N, Panisello-Rosello A, Beghdadi N, Lopez A, Rosello-Catafau J, Adam R. Pre-Ischemic Hypothermic Oxygenated Perfusion Alleviates Protective Molecular Markers of Ischemia-Reperfusion Injury in Rat Liver. Transplant Proc 2022; 54:1954-1969. [PMID: 35961798 DOI: 10.1016/j.transproceed.2022.05.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 04/26/2022] [Accepted: 05/22/2022] [Indexed: 11/16/2022]
Abstract
To expand the pool of organs, hypothermic oxygenated perfusion (HOPE), one of the most promising perfusion protocols, is currently performed after cold storage (CS) at transplant centers (HOPE-END). We investigated a new timing for HOPE, hypothesizing that performing HOPE before CS (HOPE-PRE) could boost mitochondrial protection allowing the graft to better cope with the accumulation of oxidative stress during CS. We analyzed liver injuries at 3 different levels. Histologic analysis demonstrated that, compared to classical CS (CTRL), the HOPE-PRE group showed significantly less ischemic necrosis compared to CTRL vs HOPE-END. From a biochemical standpoint, transaminases were lower after 2 hours of reperfusion in the CTRL vs HOPE-PRE group, which marked decreased liver injury. qPCR analysis on 37 genes involved in ischemia-reperfusion injury revealed protection in HOPE-PRE and HOPE-END compared to CTRL mediated through similar pathways. However, the CTRL vs HOPE-PRE group demonstrated an increased transcriptional level for protective genes compared to the CTRL vs HOPE-END group. This study provides insights on novel biomarkers that could be used in the clinic to better characterize graft quality improving transplantation outcomes.
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Affiliation(s)
- Njikem Asong-Fontem
- Université Paris-Saclay, Faculté de Médecine, Unité Chronothérapie, Cancers et Transplantation, Kremlin-Bicêtre, France.
| | - Arnau Panisello-Rosello
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Catalonia, Spain
| | - Nassiba Beghdadi
- Université Paris-Saclay, Faculté de Médecine, Unité Chronothérapie, Cancers et Transplantation, Kremlin-Bicêtre, France; Center Hépato-Biliaire, APHP Hôpital Universitaire Paul Brousse, Villejuif, France
| | - Alexandre Lopez
- Université Paris-Saclay, Faculté de Médecine, Unité Chronothérapie, Cancers et Transplantation, Kremlin-Bicêtre, France
| | - Joan Rosello-Catafau
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Catalonia, Spain
| | - René Adam
- Université Paris-Saclay, Faculté de Médecine, Unité Chronothérapie, Cancers et Transplantation, Kremlin-Bicêtre, France; Center Hépato-Biliaire, APHP Hôpital Universitaire Paul Brousse, Villejuif, France
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21
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Motkowski R, Alifier M, Abramowicz P, Konstantynowicz J, Mikołuć B, Stasiak-Barmuta A. Innate and Acquired Cellular Immunity in Children with Familial Hypercholesterolemia Treated with Simvastatin. J Clin Med 2022; 11:2924. [PMID: 35629051 PMCID: PMC9147505 DOI: 10.3390/jcm11102924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 05/17/2022] [Accepted: 05/19/2022] [Indexed: 12/03/2022] Open
Abstract
The aim of this cross-sectional study was to assess the influence of simvastatin treatment in children with familial hypercholesterolemia (FH) on parameters of cellular immunity. Twenty-six children with FH were included, of which thirteen were treated with 10 mg simvastatin for at least 26 weeks, and thirteen were age- and sex-matched with a low-cholesterol diet only. Total WBC count and lipid profile were measured. Flow cytometry was used to identify lymphocyte subsets and determine the expression of adhesion molecules (AM) and toll-like receptors (TLRs) on leukocytes. No differences were found in the basic values of peripheral blood count and subpopulations of lymphocytes between groups. The percentage of granulocytes with the expression of AM was higher in those treated with statins. The TLR-2 expression on granulocytes and monocytes showed higher values, whereas the TLR-4 expression was lower on lymphocytes and granulocytes in simvastatin-treated children. Treatment with simvastatin in children with FH is not associated with alterations in the amounts of granulocytes and monocytes. There is no association between statin treatment and the pattern of peripheral blood lymphocyte subpopulations. The role of AM and TLRs needs further investigation, given the effect of statins on the innate immunity may be important for their efficacy and safety during growth.
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Affiliation(s)
- Radosław Motkowski
- Department of Pediatrics, Rheumatology, Immunology and Metabolic Bone Diseases, Medical University of Bialystok, 15-274 Bialystok, Poland
| | - Marek Alifier
- Department of Clinical Immunology, Medical University of Bialystok, 15-274 Bialystok, Poland
| | - Paweł Abramowicz
- Department of Pediatrics, Rheumatology, Immunology and Metabolic Bone Diseases, Medical University of Bialystok, 15-274 Bialystok, Poland
| | - Jerzy Konstantynowicz
- Department of Pediatrics, Rheumatology, Immunology and Metabolic Bone Diseases, Medical University of Bialystok, 15-274 Bialystok, Poland
| | - Bożena Mikołuć
- Department of Pediatrics, Rheumatology, Immunology and Metabolic Bone Diseases, Medical University of Bialystok, 15-274 Bialystok, Poland
| | - Anna Stasiak-Barmuta
- Department of Clinical Immunology, Medical University of Bialystok, 15-274 Bialystok, Poland
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22
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Lee SY, Kim S, Han K, Woong Choi J, Byung Chae H, Yeon Choi D, Min Lee S, Kyun Park M, Mun S, Koo JW. Microarray analysis of lipopolysaccharide-induced endotoxemia in the cochlea. Gene 2022; 823:146347. [PMID: 35227853 DOI: 10.1016/j.gene.2022.146347] [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: 09/29/2021] [Revised: 02/06/2022] [Accepted: 02/15/2022] [Indexed: 11/24/2022]
Abstract
Lipopolysaccharide (LPS)-induced endotoxemia alters intracochlear homeostasis and potentiates aminoglycoside-induced ototoxicity. However, the pathological mechanisms in the cochlea following systemic LPS-induced inflammation are unclear. In this study, three groups of mice received intraperitoneal injections [group A, saline control (n = 10); group B, 1 mg/kg LPS (n = 10); group C, 10 mg/kg LPS (n = 10)]. After 24 h, gene expression in cochlea samples was analyzed using DNA microarrays covering 28,853 genes in a duplicate manner. A total of 505 differentially expressed genes (DEGs) (≥2.0-fold change; p < 0.05) were identified. Interferon- and chemotaxis-related genes, including gbp2, gbp5, cxcl10, and Rnf125, were dose-dependently upregulated by LPS-induced endotoxemia. These results were verified by RT-qPCR. Upregulated DEGs were associated with inflammation, positive regulation of immune responses, and regulation of cell adhesion, while downregulated ones were associated with chemical synaptic transmission and the synaptic vesicle cycle. Protein-protein interaction included four functional clusters associated with interleukin-4, -10, and -13 and G protein-coupled receptor (GPCR) ligand binding; activation of matrix metalloproteinases and collagen degradation; recruitment of amyloid A proteins; and neutrophil degranulation. The findings of this study provide an additional basis on changes in the expression of genes in the cochlea in response to LPS-induced endotoxemia.
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Affiliation(s)
- Sang-Yeon Lee
- Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea; Sensory Organ Research Institute, Seoul National University Medical Research Center, South Korea
| | - Songmi Kim
- Center for Bio-Medical Engineering Core Facility, Dankook University, Cheonan 31116, South Korea; Department of Microbiology, College of Science and Technology, Dankook University, Cheonan 31116, South Korea
| | - Kyudong Han
- Center for Bio-Medical Engineering Core Facility, Dankook University, Cheonan 31116, South Korea; Department of Microbiology, College of Science and Technology, Dankook University, Cheonan 31116, South Korea
| | - Jin Woong Choi
- Department of Otorhinolaryngology-Head and Neck Surgery, Chungnam National University, College of Medicine, Daejeon, South Korea
| | - Ho Byung Chae
- Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea
| | - Da Yeon Choi
- Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea
| | - So Min Lee
- Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea
| | - Moo Kyun Park
- Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea
| | - Seyoung Mun
- Center for Bio-Medical Engineering Core Facility, Dankook University, Cheonan 31116, South Korea; Department of Nanobiomedical Science & BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, South Korea.
| | - Ja-Won Koo
- Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea; Sensory Organ Research Institute, Seoul National University Medical Research Center, South Korea.
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23
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Imabayashi H, Miyake A, Chiba K. Establishment of a suitable combination of serological markers to diagnose surgical site infection following spine surgery: A novel surgical site infection scoring system. J Orthop Sci 2022; 27:569-573. [PMID: 33947607 DOI: 10.1016/j.jos.2021.02.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 02/25/2021] [Accepted: 02/28/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND The accuracy rates of several effective serological markers of surgical site infection following spine surgery are unclear. We aimed to verify the accuracy of each significant marker and identify the most suitable and effective combination of these markers for the diagnosis of surgical site infection following spine surgery. METHODS This retrospective study enrolled 329 patients who underwent spine surgery for causes other than infectious spondylitis, including 9 patients with surgical site infection. Complete blood cell count, differential counts, and C-reactive protein levels were measured preoperatively and postoperatively (days 2 and 7). Serological data were compared among non-surgical site infection and surgical site infection cases. Cutoff values for items presenting significant differences were determined using receiver operating characteristic curves. Ratios in each serological factor at each time-point were compared. Combinations of these factors on postoperative day 7 and ratio items were investigated to determine the most suitable combination comprising the least number of items. RESULTS Significant differences were noted among four factors on postoperative day 7, except for the lymphocyte count. For the ratio items, significant differences were observed among 6 items. The combination of these ten markers was examined; each factor was assigned 1 point. The most suitable combination comprising 4 items, including neutrophil count, neutrophil-to-lymphocyte ratio, lymphocyte count ratio, and C-reactive protein ratio, presented an AUC of 0.95, with a cutoff value, sensitivity, and specificity of 3 points, 0.89, and 0.92, respectively. CONCLUSION The combination of four markers is the most suitable criterion for the surgical site infection scoring system following spine surgery, where scores of ≥3 points strongly indicate surgical site infection. This criterion may be a strong tool for detecting surgical site infection.
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Affiliation(s)
- Hideaki Imabayashi
- Department of Orthopedic Surgery, Saiseikai Central Hospital, Mita 1-4-17, Minato-ku, Tokyo, 108-0073, Japan.
| | - Atsushi Miyake
- Orthopedic Department, National Defense College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
| | - Kazuhiro Chiba
- Orthopedic Department, National Defense College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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24
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Rocco E, Grimaldi MC, Maino A, Cappannoli L, Pedicino D, Liuzzo G, Biasucci LM. Advances and Challenges in Biomarkers Use for Coronary Microvascular Dysfunction: From Bench to Clinical Practice. J Clin Med 2022; 11:2055. [PMID: 35407662 PMCID: PMC8999821 DOI: 10.3390/jcm11072055] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 03/27/2022] [Accepted: 04/02/2022] [Indexed: 02/01/2023] Open
Abstract
Coronary microvascular dysfunction (CMD) is related to a broad variety of clinical scenarios in which cardiac microvasculature is morphologically and functionally affected, and it is associated with impaired responses to vasoactive stimuli. Although the prevalence of CMD involves about half of all patients with chronic coronary syndromes and more than 20% of those with acute coronary syndrome, the diagnosis of CMD is often missed, leading to the underestimation of its clinical importance. The established and validated techniques for the measurement of coronary microvascular function are invasive and expensive. An ideal method to assess endothelial dysfunction should be accurate, non-invasive, cost-effective and accessible. There are varieties of biomarkers available, potentially involved in microvascular disease, but none have been extensively validated in this heterogeneous clinical population. The investigation of potential biomarkers linked to microvascular dysfunction might improve the assessment of the diagnosis, risk stratification, disease progression and therapy response. This review article offers an update about traditional and novel potential biomarkers linked to CMD.
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Affiliation(s)
- Erica Rocco
- Department of Medical-Surgical Sciences and Biotechnologies, Cardiology Unit, ICOT Hospital, Sapienza University of Rome, 04110 Latina, Italy;
| | - Maria Chiara Grimaldi
- Department of Cardiovascular and Pneumological Sciences, Catholic University of the Sacred Heart, 00168 Rome, Italy; (A.M.); (L.C.); (D.P.); (G.L.); (L.M.B.)
- Department of Cardiovascular Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Alessandro Maino
- Department of Cardiovascular and Pneumological Sciences, Catholic University of the Sacred Heart, 00168 Rome, Italy; (A.M.); (L.C.); (D.P.); (G.L.); (L.M.B.)
| | - Luigi Cappannoli
- Department of Cardiovascular and Pneumological Sciences, Catholic University of the Sacred Heart, 00168 Rome, Italy; (A.M.); (L.C.); (D.P.); (G.L.); (L.M.B.)
| | - Daniela Pedicino
- Department of Cardiovascular and Pneumological Sciences, Catholic University of the Sacred Heart, 00168 Rome, Italy; (A.M.); (L.C.); (D.P.); (G.L.); (L.M.B.)
- Department of Cardiovascular Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Giovanna Liuzzo
- Department of Cardiovascular and Pneumological Sciences, Catholic University of the Sacred Heart, 00168 Rome, Italy; (A.M.); (L.C.); (D.P.); (G.L.); (L.M.B.)
- Department of Cardiovascular Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Luigi Marzio Biasucci
- Department of Cardiovascular and Pneumological Sciences, Catholic University of the Sacred Heart, 00168 Rome, Italy; (A.M.); (L.C.); (D.P.); (G.L.); (L.M.B.)
- Department of Cardiovascular Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
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25
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Khademi Z, Heravi MM. Applications of Claisen condensations in total synthesis of natural products. An old reaction, a new perspective. Tetrahedron 2022. [DOI: 10.1016/j.tet.2021.132573] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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26
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Seyyar SA, Tıskaoğlu NS, Gürbostan G, Pekpak E, Sayglı O. Increased Endothelial Cell Density in Childhood Patients With Thalassemia Major. Eye Contact Lens 2021; 47:660-663. [PMID: 34173366 DOI: 10.1097/icl.0000000000000806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/19/2021] [Indexed: 11/26/2022]
Abstract
PURPOSE We aimed to compare specular microscopy, biometric, refractive, and anterior segment topographic parameters in children with thalassemia major (TM) with normal children of the same age. MATERIAL METHOD This cross-sectional study included 55 eyes of 55 patients with TM and 63 eyes of 63 age-sex-matched healthy children; all patients with TM were receiving treatment with blood transfusions every 3 to 4 weeks and an oral iron chelator deferasirox (DFX) (ICL670) tablet. A comprehensive ophthalmic examination was performed, including refraction (spherical equivalent), best-corrected visual acuity, slit-lamp bio microscopy, specular examination, optical biometry, intraocular pressure, anterior segment topography, and fundus examination. RESULTS Endothelial cell density (ECD) was 3,138 in the TM group and 2,996 in the control group (P=0.003). The mean central corneal thickness was significantly thinner in the TM group (P=0.010). Flat keratometry (K1) was 43.5 D in the study group and 42.9 D in the control group (P=0.039). The mean anterior chamber depth (ACD) was shallower in the TM group (P=0.004); axial length (AL) was significantly shorter in the TM group (P=0.002). CONCLUSION This study shows that there are differences in ECD, AL, keratometry values, ACD, and anterior segment parameters of pediatric patients with TM compared with healthy controls.
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Affiliation(s)
- Sevim Ayca Seyyar
- Ophthalmology Department (S.A.S.), Kocaeli Derince Education and Research Hospital; Ophthalmology Department (N.S.T.), Ersin Arslan Education and Research Hospital; and Ophthalmology Department (G.G., E.P., O.S.), Gaziantep University Hospital
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27
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Tkáčová Z, Bhide K, Mochnáčová E, Petroušková P, Hruškovicová J, Kulkarni A, Bhide M. Comprehensive Mapping of the Cell Response to Borrelia bavariensis in the Brain Microvascular Endothelial Cells in vitro Using RNA-Seq. Front Microbiol 2021; 12:760627. [PMID: 34819924 PMCID: PMC8606740 DOI: 10.3389/fmicb.2021.760627] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 10/11/2021] [Indexed: 12/01/2022] Open
Abstract
Borrelia bavariensis can invade the central nervous system (CNS) by crossing the blood-brain barrier (BBB). It is predicted that B. bavariensis evokes numerous signaling cascades in the human brain microvascular endothelial cells (hBMECs) and exploits them to traverse across the BBB. The complete picture of signaling events in hBMECs induced by B. bavariensis remains uncovered. Using RNA sequencing, we mapped 11,398 genes and identified 295 differentially expressed genes (DEGs, 251 upregulated genes and 44 downregulated genes) in B. bavariensis challenged hBMECs. The results obtained from RNA-seq were validated with qPCR. Gene ontology analysis revealed the participation of DEGs in a number of biological processes like cell communication, organization of the extracellular matrix, vesicle-mediated transport, cell response triggered by pattern recognition receptors, antigen processing via MHC class I, cellular stress, metabolism, signal transduction, etc. The expression of several non-protein coding genes was also evoked. In this manuscript, we discuss in detail the correlation between several signaling cascades elicited and the translocation of BBB by B. bavariensis. The data revealed here may contribute to a better understanding of the mechanisms employed by B. bavariensis to cross the BBB.
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Affiliation(s)
- Zuzana Tkáčová
- Laboratory of Biomedical Microbiology and Immunology, The University of Veterinary Medicine and Pharmacy, Kosice, Slovakia
| | - Katarína Bhide
- Laboratory of Biomedical Microbiology and Immunology, The University of Veterinary Medicine and Pharmacy, Kosice, Slovakia
| | - Evelina Mochnáčová
- Laboratory of Biomedical Microbiology and Immunology, The University of Veterinary Medicine and Pharmacy, Kosice, Slovakia
| | - Patrícia Petroušková
- Laboratory of Biomedical Microbiology and Immunology, The University of Veterinary Medicine and Pharmacy, Kosice, Slovakia
| | - Jana Hruškovicová
- Laboratory of Biomedical Microbiology and Immunology, The University of Veterinary Medicine and Pharmacy, Kosice, Slovakia
| | - Amod Kulkarni
- Laboratory of Biomedical Microbiology and Immunology, The University of Veterinary Medicine and Pharmacy, Kosice, Slovakia.,Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Mangesh Bhide
- Laboratory of Biomedical Microbiology and Immunology, The University of Veterinary Medicine and Pharmacy, Kosice, Slovakia.,Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia
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28
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Kumar A, Bhatia M. Role of Hydrogen Sulfide, Substance P and Adhesion Molecules in Acute Pancreatitis. Int J Mol Sci 2021; 22:12136. [PMID: 34830018 PMCID: PMC8622943 DOI: 10.3390/ijms222212136] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/03/2021] [Accepted: 11/05/2021] [Indexed: 01/02/2023] Open
Abstract
Inflammation is a natural response to tissue injury. Uncontrolled inflammatory response leads to inflammatory disease. Acute pancreatitis is one of the main reasons for hospitalization amongst gastrointestinal disorders worldwide. It has been demonstrated that endogenous hydrogen sulfide (H2S), a gasotransmitter and substance P, a neuropeptide, are involved in the inflammatory process in acute pancreatitis. Cell adhesion molecules (CAM) are key players in inflammatory disease. Immunoglobulin (Ig) gene superfamily, selectins, and integrins are involved at different steps of leukocyte migration from blood to the site of injury. When the endothelial cells get activated, the CAMs are upregulated which leads to them interacting with leukocytes. This review summarizes our current understanding of the roles H2S, substance P and adhesion molecules play in acute pancreatitis.
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Affiliation(s)
| | - Madhav Bhatia
- Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand;
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29
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Kim YS, Lee YG, Park HS, Cho RK, Lee HJ. Comparison of Gene Expression of Inflammation- and Fibrosis-Related Factors Between the Anterior and Posterior Capsule in Patients With Rotator Cuff Tear and Shoulder Stiffness. Orthop J Sports Med 2021; 9:23259671211032543. [PMID: 34660822 PMCID: PMC8511928 DOI: 10.1177/23259671211032543] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 03/24/2021] [Indexed: 11/16/2022] Open
Abstract
Background Arthroscopic capsular release is an effective treatment for refractory shoulder stiffness, yet there are no basic studies that can explain the extent of the release. Purpose This study aimed to compare the genetic expression of inflammation- and fibrosis-related factors between the anterior and posterior capsules in patients with shoulder stiffness and rotator cuff tear. Study Design Descriptive laboratory study. Methods Enrolled in this study were 35 patients who underwent arthroscopic capsular release for shoulder stiffness along with the rotator cuff repair. Anterior and posterior glenohumeral joint capsular tissues were obtained during the capsular release. For the control tissue, anterior capsule was obtained from 40 patients without stiffness who underwent arthroscopic rotator cuff repair. The gene expression of collagen types I and III, fibronectin, extracellular matrix, basic fibroblast growth factor, transforming growth factor-β, connective tissue growth factor, matrix metalloproteinase (MMP)-1, MMP-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, TIMP-2, intercellular adhesion molecule 1, interleukin 1, and tumor necrotizing factor-α were analyzed using real-time reverse transcription polymerase chain reaction. Differences in gene expression between the anterior capsule, the posterior capsule, and the control tissue were compared with the Kruskal-Wallis test. Results The expression levels of collagen types I and III were significantly higher in the anterior capsule with stiffness com (pared with both the posterior capsule with stiffness (P = .010 for both) and the control (P = .038 and .010, respectively). The levels of fibronectin, MMP-2, and MMP-9 in the anterior capsule were significantly higher than in both the posterior capsule (P = .013, .003, and .006, respectively) and the control (P = .014, .003, and .005, respectively). Conclusion Genetic analysis of the shoulder capsule revealed that more fibrogenic processes occur in the anterior capsule compared with the posterior capsule in patients with shoulder stiffness. Clinical Relevance Capsular release for shoulder stiffness should be more focused on the anterior capsule than on the posterior capsule.
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Affiliation(s)
- Yang-Soo Kim
- Department of Orthopedic Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yun-Gyoung Lee
- Department of Orthopedic Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hyung-Seok Park
- Department of Orthopedic Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ryu-Kyoung Cho
- Department of Orthopedic Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hyo-Jin Lee
- Department of Orthopedic Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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30
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Begenisic T, Pavese C, Aiachini B, Nardone A, Rossi D. Dynamics of biomarkers across the stages of traumatic spinal cord injury - implications for neural plasticity and repair. Restor Neurol Neurosci 2021; 39:339-366. [PMID: 34657853 DOI: 10.3233/rnn-211169] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Traumatic spinal cord injury (SCI) is a complex medical condition causing significant physical disability and psychological distress. While the adult spinal cord is characterized by poor regenerative potential, some recovery of neurological function is still possible through activation of neural plasticity mechanisms. We still have limited knowledge about the activation of these mechanisms in the different stages after human SCI. OBJECTIVE In this review, we discuss the potential role of biomarkers of SCI as indicators of the plasticity mechanisms at work during the different phases of SCI. METHODS An extensive review of literature related to SCI pathophysiology, neural plasticity and humoral biomarkers was conducted by consulting the PubMed database. Research and review articles from SCI animal models and SCI clinical trials published in English until January 2021 were reviewed. The selection of candidates for humoral biomarkers of plasticity after SCI was based on the following criteria: 1) strong evidence supporting involvement in neural plasticity (mandatory); 2) evidence supporting altered expression after SCI (optional). RESULTS Based on selected findings, we identified two main groups of potential humoral biomarkers of neural plasticity after SCI: 1) neurotrophic factors including: Brain derived neurotrophic factor (BDNF), Nerve growth factor (NGF), Neurotrofin-3 (NT-3), and Insulin-like growth factor 1 (IGF-1); 2) other factors including: Tumor necrosis factor-alpha (TNF-α), Matrix Metalloproteinases (MMPs), and MicroRNAs (miRNAs). Plasticity changes associated with these biomarkers often can be both adaptive (promoting functional improvement) and maladaptive. This dual role seems to be influenced by their concentrations and time-window during SCI. CONCLUSIONS Further studies of dynamics of biomarkers across the stages of SCI are necessary to elucidate the way in which they reflect the remodeling of neural pathways. A better knowledge about the mechanisms underlying plasticity could guide the selection of more appropriate therapeutic strategies to enhance positive spinal network reorganization.
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Affiliation(s)
- Tatjana Begenisic
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
| | - Chiara Pavese
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy.,Neurorehabilitation and Spinal Units, ICS Maugeri SPA SB, Institute of Pavia, IRCCS, Pavia, Italy
| | - Beatrice Aiachini
- Neurorehabilitation and Spinal Units, ICS Maugeri SPA SB, Institute of Pavia, IRCCS, Pavia, Italy
| | - Antonio Nardone
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy.,Neurorehabilitation and Spinal Units, ICS Maugeri SPA SB, Institute of Pavia, IRCCS, Pavia, Italy
| | - Daniela Rossi
- Laboratory for Research on Neurodegenerative Disorders, ICS Maugeri SPA SB, Institute of Pavia, IRCCS, Pavia, Italy
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Immunohistochemistry in the Postmortem Diagnosis of Sepsis: A Systematic Review. Appl Immunohistochem Mol Morphol 2021; 28:571-578. [PMID: 31290786 DOI: 10.1097/pai.0000000000000790] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
It is not uncommon for the forensic pathologist to question whether a deceased person had experienced sepsis that could have either been the cause of or contributed to the person's death. Often, the missing typical pathologic factors or lack of clinical and circumstantial information on the death render the autopsy of a sepsis-related death a difficult task for the forensic pathologist. Several authors emphasize on how an immunohistochemical analysis could help in diagnosing death related to sepsis. The research we carried out analyzes the main scientific studies in the literature, primarily the tracing of 21 immunohistochemical antigens evaluated to help diagnose death related to sepsis. The purpose of this review was to analyze and summarize the markers studied until now and to consider the limitations of immunohistochemistry that currently exist with regard to this particular field of forensic pathology. Immunohistochemistry provided interesting and promising results, but further studies are needed in order for them to be confirmed, so that they may be applied in standard forensic practice.
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Sultan W, Sapkota A, Khurshid H, Qureshi IA, Jahan N, Went TR, Dominic JL, Win M, Kannan A, Tara A, Ruo SW, Alfonso M. Statins' Effect on Cognitive Outcome After Traumatic Brain Injury: A Systematic Review. Cureus 2021; 13:e16953. [PMID: 34405076 PMCID: PMC8352842 DOI: 10.7759/cureus.16953] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 08/06/2021] [Indexed: 11/05/2022] Open
Abstract
Traumatic brain injury (TBI), also known as the "Silent Epidemic," is a growing devastating global health problem estimated to affect millions of individuals yearly worldwide with little public recognition, leading to many individuals living with a TBI-related disability. TBI has been associated with up to five times increase in the risk of dementia among multiple neurologic complications compared with the general population. Several therapies, including statins, have been tried and showed promising benefits for TBI patients. In this systematic review, we evaluated the recent literature that tested the role of statins on neurological and cognitive outcomes such as Alzheimer's Disease and non-Alzheimer's dementia in survivors of TBI with various severities. We conducted a systematic search on PubMed, PubMed Central, MEDLINE, and Google Scholar. MeSH terms and keywords were used to search for full-text randomized clinical trials (RCTs), cross-sectional, case-control, cohort studies, systematic reviews, and animal studies published in English. Inclusion and exclusion criteria were applied, and the articles were subjected to quality appraisal by two reviewers. Our data search retrieved 4948 nonduplicate records. A total of 18 studies were included - nine human studies, and nine animal laboratory trials - after meeting inclusion, eligibility, and quality assessment criteria. Simvastatin was the most tested statin, and the oral route of administration was the most used. Eight human studies showed a significant neuroprotective effect and improvement in the cognitive outcomes, including dementia. Four randomized clinical trials with 296 patients showed that statins play a neuroprotective role and improve cognitive outcomes through different mechanisms, especially their anti-inflammatory effect; they were shown to lower tumor necrosis factor (TNF)-α and C-reactive protein (CRP) levels. Also, they decreased axonal injury and cortical thickness changes. In addition, four cohort studies compared a total of 867.953 patients. One study showed a decrease in mortality in statin-treated patients (p=0.05). Another study showed a reduction in the incidence of Alzheimer's disease and related dementias (RR, 0.77; 95% CI, 0.73-0.81), while one study showed a decreased risk of dementia after concussions by 6.13% (p=0.001). On the other hand, one cohort study showed no significant difference with the use of statins. In eight animal trials, statins showed a significant neuroprotective effect, improved cognitive outcomes, and neurological functions. Different molecular and cellular mechanisms were suggested, including anti-inflammatory effects, promoting angiogenesis, neurogenesis, increasing cerebral blood flow, neurite outgrowth, promoting the proliferation and differentiation of neural stem cells, and reducing axonal injury. On the contrary, one study showed no benefit and actual adverse effect on the cognitive outcome. Most of the studies showed promising neuroprotective effects of statins in TBI patients. Cognitive outcomes, especially dementia, were improved. However, the optimal therapeutic protocol is still unknown. Thus, statins are candidates for more advanced studies to test their efficacy in preventing cognitive decline in patients with TBI.
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Affiliation(s)
- Waleed Sultan
- Medicine, California Institute of Behavioral Neurosciences & Psychology (CIBNP), Fairfield, USA
| | - Alisha Sapkota
- Psychiatry, California Institute of Behavioral Neurosciences & Psychology (CIBNP), Fairfield, USA
| | - Hajra Khurshid
- Psychiatry, California Institute of Behavioral Neurosciences & Psychology (CIBNP), Fairfield, USA
| | - Israa A Qureshi
- Medicine, California Institute of Behavioral Neurosciences & Psychology (CIBNP), Fairfield, USA
| | - Nasrin Jahan
- Psychiatry, California Institute of Behavioral Neurosciences & Psychology (CIBNP), Fairfield, USA
| | - Terry R Went
- Medicine, California Institute of Behavioral Neurosciences & Psychology (CIBNP), Fairfield, USA
| | - Jerry Lorren Dominic
- General Surgery, California Institute of Behavioral Neurosciences & Psychology (CIBNP), Fairfield, USA
| | - Myat Win
- General Surgery, California Institute of Behavioral Neurosciences & Psychology (CIBNP), Fairfield, USA
| | - Amudhan Kannan
- General Surgery, California Institute of Behavioral Neurosciences & Psychology (CIBNP), Fairfield, USA
| | - Anjli Tara
- General Surgery, California Institute of Behavioral Neurosciences & Psychology (CIBNP), Fairfield, USA
| | - Sheila W Ruo
- General Surgery, California Institute of Behavioral Neurosciences & Psychology (CIBNP), Fairfield, USA
| | - Michael Alfonso
- Medicine, California Institute of Behavioral Neurosciences & Psychology (CIBNP), Fairfield, USA
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Circulating levels of cell adhesion molecules and risk of cardiovascular events in obstructive sleep apnea. PLoS One 2021; 16:e0255306. [PMID: 34329349 PMCID: PMC8323915 DOI: 10.1371/journal.pone.0255306] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 07/13/2021] [Indexed: 11/25/2022] Open
Abstract
Background Obstructive sleep apnea (OSA) patients are at increased risk of cardiovascular disease (CVD). Cell adhesion molecules (CAM) are increased in OSA and CAM are also implicated in the development of CVD. Research question Do CAM (ICAM-1, VCAM-1 and E-selectin) have prognostic value in identifying risk of cardiovascular events in OSA? Study design and methods Patients with suspected OSA referred for a polysomnogram provided a fasting blood sample. Plasma levels of ICAM-1, VCAM-1 and E-selectin were determined by multiplex Luminex Assay (Milliporesigma ON, Canada). Cardiovascular events were determined by deterministic linkage to provincial health databases. Results 418 patients were included in the analysis. Mostly male (68.2%), mean age of 50.7 yrs, median AHI 16.5 events/hour, and mean BMI of 31.7 kg/m2. 36 cardiovascular events occurred in 8-yrs of follow up. Higher levels of ICAM-1 were associated with developing CVD (HR = 3.65 95% CI 1.40–9.53, 2nd and 3rd tertiles vs. 1st tertile), including in patients with OSA (HR = 3.1 95% CI 1.16–8.25). E-selectin was significantly associated with cardiovascular events in patients with moderate to severe OSA (HR = 3.31 95% CI 0.94–11.72, 2nd and 3rd tertiles vs. 1st tertile) but not in patients without moderate to severe OSA (HR = 0.67 95% CI 0.19–2.38), p-value for interaction = 0.07. Interpretation In a suspected OSA cohort, patients with higher levels of ICAM-1 (>816 ng/ml) were significantly more likely to experience a cardiovascular event within 8 years after PSG. In moderate to severe OSA patients, a higher E-selectin (>36.4 ng/ml) was significantly associated with cardiovascular events.
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Kisucká A, Bimbová K, Bačová M, Gálik J, Lukáčová N. Activation of Neuroprotective Microglia and Astrocytes at the Lesion Site and in the Adjacent Segments Is Crucial for Spontaneous Locomotor Recovery after Spinal Cord Injury. Cells 2021; 10:1943. [PMID: 34440711 PMCID: PMC8394075 DOI: 10.3390/cells10081943] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/16/2021] [Accepted: 07/29/2021] [Indexed: 12/27/2022] Open
Abstract
Microglia and astrocytes play an important role in the regulation of immune responses under various pathological conditions. To detect environmental cues associated with the transformation of reactive microglia (M1) and astrocytes (A1) into their polarization states (anti-inflammatory M2 and A2 phenotypes), we studied time-dependent gene expression in naive and injured spinal cord. The relationship between astrocytes and microglia and their polarization states were studied in a rat model after Th9 compression (40 g/15 min) in acute and subacute stages at the lesion site, and both cranially and caudally. The gene expression of microglia/macrophages and M1 microglia was strongly up-regulated at the lesion site and caudally one week after SCI, and attenuated after two weeks post-SCI. GFAP and S100B, and A1 astrocytes were profoundly expressed predominantly two weeks post-SCI at lesion site and cranially. Gene expression of anti-inflammatory M2a microglia (CD206, CHICHI, IL1rn, Arg-1), M2c microglia (TGF-β, SOCS3, IL4R α) and A2 astrocytes (Tgm1, Ptx3, CD109) was greatly activated at the lesion site one week post-SCI. In addition, we observed positive correlation between neurological outcome and expression of M2a, M2c, and A2 markers. Our findings indicate that the first week post-injury is critical for modulation of reactive microglia/astrocytes into their neuroprotective phenotypes.
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Affiliation(s)
| | | | | | | | - Nadežda Lukáčová
- Institute of Neurobiology of Biomedical Research Centre of Slovak Academy of Sciences, Soltesovej 4, 040 01 Kosice, Slovakia; (A.K.); (K.B.); (M.B.); (J.G.)
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35
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Dahou S, Smahi MCE, Nouari W, Dahmani Z, Benmansour S, Ysmail-Dahlouk L, Miliani M, Yebdri F, Fakir N, Laoufi MY, Chaib-Draa M, Tourabi A, Aribi M. L-Threoascorbic acid treatment promotes S. aureus-infected primary human endothelial cells survival and function, as well as intracellular bacterial killing, and immunomodulates the release of IL-1β and soluble ICAM-1. Int Immunopharmacol 2021; 95:107476. [PMID: 33676147 DOI: 10.1016/j.intimp.2021.107476] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 02/02/2021] [Accepted: 02/03/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Vitamin C (ascorbic acid, AscH2) has been shown to enhance immunity. Here, we studied its immunomodulatory effect on human endothelial cells (ECs) during S. aureus infection. MATERIALS AND METHODS The ex vivo effects of AscH2 were performed on primary human umbilical vein endothelial cells (HUVECs) infected or not with S. aureus. RESULTS AscH2 treatment induced a marked downregulation of nitric oxide (NO) production and a moderate upregulation of arginase activity in S. aureus-infected HUVECs (respectively, p < 0.05 and p > 0.05). Although the upregulated release levels of soluble intercellular adhesion molecular 1 (sICAM-1/sCD54) and sE-selectin (sCD62E) molecules were not significantly different between treated and untreated S. aureus-infected HUVECs, AscH2 treatment induced reversing effect on sICAM-1 release when comparing to uninfected control HUVECs. Moreover, AscH2 treatment appears to have a significant effect on preventing HUVEC necrosis induced by S. aureus infection (p < 0.05). Furthermore, AscH2 treatment induced a significant upregulation of cell protective redox biomarker in S. aureus-infected, as shown by superoxide dismutase (SOD) activity (p < 0.05), but not by catalase activity (p > 0.05). Additionally, S. aureus infection markedly downregulated total bound calcium ions (bCa2+) levels as compared to control HUVECs, whereas, AscH2 treatment induced a slight upregulation of bCa2+ levels in infected HUVECs as compared to infected and untreated HUVECs (p > 0.05). On the other hand, AscH2 treatment downregulated increased total cellular cholesterol content (tccCHOL) levels in HUVECs induced by S. aureus infection (p < 0.05). In addition, AscH2 treatment markedly reversed S. aureus effect on upregulation of intracellular glucose (iGLU) levels within infected HUVECs (p < 0.05). Moreover, AscH2 treatment significantly downregulated S. aureus growth (p < 0.05), and significantly upregulated bacterial internalization and intracellular killing by HUVECs (p < 0.05), as well as their cell cycle activation (p < 0.01). Finally, AscH2 treatment has a slight effect on the production of interleukin 6 (IL-6), but induced a marked downregulation of that of IL-1β in S. aureus-infected HUVECs (respectively, p > 0.05, and p < 0.05). CONCLUSIONS Our outcomes demonstrated that, during S. aureus infection, AscH2 treatment promotes human ECs survival and function, as well as prevents inflammatory response exacerbation, while inducing bactericidal activity.
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Affiliation(s)
- Sara Dahou
- Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria
| | - Mohammed Chems-Eddine Smahi
- Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria; Neonatal Department of Specialized Maternal and Child Hospital of Tlemcen, 13000, Tlemcen, Algeria
| | - Wafa Nouari
- Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria
| | - Zoheir Dahmani
- Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria
| | - Souheila Benmansour
- Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria; Neonatal Department of Specialized Maternal and Child Hospital of Tlemcen, 13000, Tlemcen, Algeria
| | - Lamia Ysmail-Dahlouk
- Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria
| | - Maroua Miliani
- Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria
| | - Fadela Yebdri
- Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria
| | - Nassima Fakir
- Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria
| | - Mohammed Yassine Laoufi
- Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria; Neonatal Department of Specialized Maternal and Child Hospital of Tlemcen, 13000, Tlemcen, Algeria
| | - Mouad Chaib-Draa
- Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria
| | - Amina Tourabi
- Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria
| | - Mourad Aribi
- Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria.
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Notarnicola A, Barsotti S, Näsman L, Tang Q, Holmqvist M, Lundberg IE, Antovic A. Evaluation of risk factors and biomarkers related to arterial and venous thrombotic events in idiopathic inflammatory myopathies. Scand J Rheumatol 2021; 50:390-397. [PMID: 33622160 DOI: 10.1080/03009742.2020.1861647] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Objectives: This study aimed to assess the contribution of traditional/disease-related risk factors and biomarkers linked to arterial and venous thrombotic events (TEs) in patients with idiopathic inflammatory myopathies (IIMs).Method: The occurrence of arterial and/or venous TEs at the time of or after IIM diagnosis was retrospectively evaluated in a cohort of 253 patients with IIMs, resulting in a final population of 246 IIM patients, 51 with reported TE (cases) and 195 without a history of TE (comparators). Information on disease characteristics and traditional risk factors for arterial and venous TE (essential hypertension, diabetes, dyslipidaemia, smoking, malignancy) was retrieved. Serum levels of anti-phospholipid antibodies (aPLs) and adhesion molecules were analysed at the time of IIM diagnosis and at the time of the TE in cases.Results: One in five IIM patients (21%) had experienced a TE, arterial TE in 22 and venous TE in 29 patients, with a peak prevalence within 5 years after diagnosis. Among traditional/disease-related risk factors, only older age was associated with both arterial and venous TEs, after adjusting for other covariates. Low serum levels of e-selectin were associated with higher odds of developing a TE, without specific association with either arterial or venous TEs. Only 6% of IIM patients had aPLs, with no significant difference between cases and comparators.Conclusions: An increased risk of both venous and arterial TEs should be considered in IIM patients, particularly close to diagnosis and in elderly people. Low serum levels of e-selectin may predict TE in IIM patients, but the underlying biological mechanism is not known.
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Affiliation(s)
- A Notarnicola
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Division of Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - S Barsotti
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - L Näsman
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Division of Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - Q Tang
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Division of Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - M Holmqvist
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Division of Rheumatology, Karolinska University Hospital, Stockholm, Sweden.,Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - I E Lundberg
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Division of Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - A Antovic
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Division of Rheumatology, Karolinska University Hospital, Stockholm, Sweden
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van Steen AC, van der Meer WJ, Hoefer IE, van Buul JD. Actin remodelling of the endothelium during transendothelial migration of leukocytes. Atherosclerosis 2020; 315:102-110. [DOI: 10.1016/j.atherosclerosis.2020.06.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 05/29/2020] [Accepted: 06/03/2020] [Indexed: 12/30/2022]
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Shi JH, Luo L, Chen XL, Pan YP, Zhang Z, Fang H, Chen Y, Chen WD, Cao Q. Real-world cost-effectiveness associated with infliximab maintenance therapy for moderate to severe Crohn’s disease in China. World J Gastroenterol 2020; 26:6455-6474. [PMID: 33244205 PMCID: PMC7656205 DOI: 10.3748/wjg.v26.i41.6455] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/05/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Infliximab was the first approved biologic treatment for moderate to severe Crohn’s disease (MS-CD) in China. However, the cost-effectiveness of infliximab maintenance therapy (IMT) for MS-CD relative to conventional maintenance therapy remained unclarified.
AIM To assess the cost-effectiveness of IMT for MS-CD in Chinese patients from the perspective of Chinese public insurance payer.
METHODS A cohort of MS-CD patients managed in a Chinese tertiary care hospital was created to compare IMT with conventional maintenance therapy (CMT) for clinical outcomes and direct medical costs over a 1-year observation time using conventional regression analyses. A decision-analytic model with the generated evidence was constructed to assess the cost-effectiveness of IMT relative to CMT using reimbursed medical costs.
RESULTS Based on the included 389 patients, IMT was associated with significantly higher disease remission chance [odds ratio: 4.060, P = 0.003], lower risk of developing new complications (odds ratio: 0.527, P = 0.010), higher utility value for quality of life (coefficient 0.822, P = 0.008), and lower total hospital costs related to disease management (coefficient -0.378, P = 0.008) than CMT. Base-case cost-effectiveness analysis estimated that IMT could cost Chinese health insurance payers ¥55260 to gain one quality-adjusted life year (QALY). The cost-effectiveness of IMT was mainly driven by the estimate of quality of life, treatment efficacy of maintenance therapy, mortality risk associated with active disease, and unit price of infliximab. The probability that IMT was cost-effective at a willingness-to-pay threshold of three times gross domestic product [2018 Chinese gross domestic product per capita (GDPPC)] was 86.4%.
CONCLUSION IMT significantly improved real-world health outcomes and cost the Chinese public health insurance payers less than one GDPPC to gain one QALY in Chinese MS-CD patients.
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Affiliation(s)
- Ji-Hao Shi
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Liang Luo
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Xiao-Li Chen
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Yi-Peng Pan
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Zhou Zhang
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Hao Fang
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Ying Chen
- Department of Project, Changsha Normin Health Technology Ltd, Changsha 410013, Hunan Province, China
| | - Wen-Dong Chen
- Department of HEOR, Normin Health Consulting Ltd, Toronto L5R 0E9, Ontario, Canada
| | - Qian Cao
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
- Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, Hangzhou 310016, Zhejiang Province, China
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Pourfathi M, Xin Y, Rosalino M, Cereda M, Kadlecek S, Duncan I, Profka H, Hamedani H, Siddiqui S, Ruppert K, Chatterjee S, Rizi RR. Pulmonary pyruvate metabolism as an index of inflammation and injury in a rat model of acute respiratory distress syndrome. NMR IN BIOMEDICINE 2020; 33:e4380. [PMID: 32681670 DOI: 10.1002/nbm.4380] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Revised: 06/15/2020] [Accepted: 06/29/2020] [Indexed: 06/11/2023]
Abstract
Increased pulmonary lactate production is correlated with severity of lung injury and outcome in acute respiratory distress syndrome (ARDS) patients. This study was conducted to investigate the relative contributions of inflammation and hypoxia to the lung's metabolic shift to glycolysis in an experimental animal model of ARDS using hyperpolarized (HP) 13 C MRI. Fifty-three intubated and mechanically ventilated male rats were imaged using HP 13 C MRI before, and 1, 2.5 and 4 hours after saline (sham) or hydrochloric acid (HCl; 0.5 ml/kg) instillation in the trachea, followed by protective and nonprotective mechanical ventilation (HCl-PEEP and HCl-ZEEP) or the start of moderate or severe hypoxia (Hyp90 and Hyp75 groups). Pulmonary and cardiac HP lactate-to-pyruvate ratios were compared among groups for different time points. Postmortem histology and immunofluorescence were used to assess lung injury severity and quantify the expression of innate inflammatory markers and local tissue hypoxia. HP pulmonary lactate-to-pyruvate ratio progressively increased in rats with lung injury and moderate hypoxia (HCl-ZEEP), with no significant change in pulmonary lactate-to-pyruvate ratio in noninjured but moderately hypoxic rats (Hyp90). Pulmonary lactate-to-pyruvate ratio was elevated in otherwise healthy lung tissue only in severe systemic hypoxia (Hyp75 group). ex vivo histological and immunopathological assessment further confirmed the link between elevated glycolysis and the recruitment into and presence of activated neutrophils in injured lungs. HP lactate-to-pyruvate ratio is elevated in injured lungs predominantly as a result of increased glycolysis in activated inflammatory cells, but can also increase due to severe inflammation-induced hypoxia.
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Affiliation(s)
- Mehrdad Pourfathi
- Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Yi Xin
- Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Michael Rosalino
- Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Maurizio Cereda
- Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Stephen Kadlecek
- Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Ian Duncan
- Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Harrilla Profka
- Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Hooman Hamedani
- Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Sarmad Siddiqui
- Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Kai Ruppert
- Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Shampa Chatterjee
- Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Rahim R Rizi
- Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Nikitidou O, Daskalopoulou E, Papagianni A, Vlachogiannis E, Dombros N, Liakopoulos V. The impact of OSA and CPAP treatment on cell adhesion molecules' night-morning variation. Sleep Breath 2020; 25:1301-1307. [PMID: 33104982 DOI: 10.1007/s11325-020-02232-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 09/14/2020] [Accepted: 10/16/2020] [Indexed: 11/28/2022]
Abstract
PURPOSE Obstructive sleep apnea (OSA) has been related to vascular inflammation and production of endothelial cell adhesion molecules (CAMs). We aimed to determine night-morning variation of CAMs in patients with OSA compared to controls and the effect of one-night continuous positive airway pressure (CPAP) treatment on them. METHODS Nonsmoking men went through a full-attended polysomnography (PSG) study. Participants with moderate to severe OSA went through another PSG study while being treated with CPAP. Participants who did not have OSA composed the control group. Serum levels of intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and E-selectin were measured before and after sleep on both nights. RESULTS Of 30 men, 20 had moderate to severe OSA while 10 did not. Night and morning ICAM-1 levels of patients with OSA were significantly higher than controls (p = 0.002 and p < 0.0001 respectively), while both night and morning VCAM-1 and E-selectin levels were not. Morning ICAM-1 levels of controls were significantly lower than night levels (p = 0.031), while morning ICAM-1, VCAM-1, and E-selectin levels of patients with OSA and morning VCAM-1 and E-selectin levels of controls were not. After CPAP treatment, the morning ICAM-1 levels, but not VCAM-1 levels, of patients with OSA were significantly lower than night levels (p = 0.006) and E-selectin levels showed a tendency for reduction (p = 0.06). CONCLUSIONS OSA is associated with elevated night and morning ICAM-1 levels in adult men with OSA. Even one night of CPAP treatment restores the normal night-morning variation of ICAM-1 levels and may have an effect on E-selectin levels, as well.
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Affiliation(s)
- Olga Nikitidou
- Division of Nephrology and Hypertension, 1st Department of Internal Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
| | | | - Aikaterini Papagianni
- Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | | | - Nicholas Dombros
- Division of Nephrology and Hypertension, 1st Department of Internal Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Vassilios Liakopoulos
- Division of Nephrology and Hypertension, 1st Department of Internal Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Kumar G, Dey SK, Kundu S. Functional implications of vascular endothelium in regulation of endothelial nitric oxide synthesis to control blood pressure and cardiac functions. Life Sci 2020; 259:118377. [PMID: 32898526 DOI: 10.1016/j.lfs.2020.118377] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 08/24/2020] [Accepted: 08/31/2020] [Indexed: 11/29/2022]
Abstract
The endothelium is the innermost vascular lining performing significant roles all over the human body while maintaining the blood pressure at physiological levels. Malfunction of endothelium is thus recognized as a biomarker linked with many vascular diseases including but not limited to atherosclerosis, hypertension and thrombosis. Alternatively, prevention of endothelial malfunctioning or regulating the functions of its associated physiological partners like endothelial nitric oxide synthase can prevent the associated vascular disorders which account for the highest death toll worldwide. While many anti-hypertensive drugs are available commercially, a comprehensive description of the key physiological roles of the endothelium and its regulation by endothelial nitric oxide synthase or vice versa is the need of the hour to understand its contribution in vascular homeostasis. This, in turn, will help in designing new therapeutics targeting endothelial nitric oxide synthase or its interacting partners present in the cellular pool. This review describes the central role of vascular endothelium in the regulation of endothelial nitric oxide synthase while outlining the emerging drug targets present in the vasculature with potential to treat vascular disorders including hypertension.
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Affiliation(s)
- Gaurav Kumar
- Department of Biochemistry, University of Delhi, South Campus, New Delhi 110021, India
| | - Sanjay Kumar Dey
- Department of Biochemistry, University of Delhi, South Campus, New Delhi 110021, India; Center for Advanced Biotechnology and Medicine, Rutgers University, NJ 08854, USA
| | - Suman Kundu
- Department of Biochemistry, University of Delhi, South Campus, New Delhi 110021, India.
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Öztel Z, Gazan S, Balcan E. Tunicamycin induced endoplasmic reticulum stress in the small intestine. Biotech Histochem 2020; 96:507-519. [PMID: 32962446 DOI: 10.1080/10520295.2020.1823481] [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: 10/23/2022] Open
Abstract
Because the small intestine is exposed to variety of foreign substances, it participates in host immune response. We investigated whether the expression levels of intestinal MAdCAM-1, PECAM-1 (CD31) and CAV-1 are affected by endoplasmic reticulum (ER) stress following brief treatment with tunicamycin (TN). We administered a single dose of TN intraperitoneally. Twenty-four hours later, MAdCAM-1, PECAM-1 and CAV-1 expression levels in Peyer's patches and villi were examined using immunohistochemistry (IHC), immunofluorescence (IF) and western blotting. Immunostaining of MAdCAM-1 and CAV-1 in control and TN treated Peyer's patches and villi exhibited similar staining patterns. The immunoreactivity of PECAM-1 was similar for the control and TN treated Payer's patches, whereas staining was decreased significantly in TN treated villi. Our findings suggest that short term TN treatment did not affect leukocyte movement to lymphoid compartments of the small intestine, but it altered villus architecture due to decreased PECAM-1 expression.
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Affiliation(s)
- Zübeyde Öztel
- Department of Biology, Manisa Celal Bayar University, Manisa, Turkey
| | - Sibel Gazan
- Department of Biology, Manisa Celal Bayar University, Manisa, Turkey
| | - Erdal Balcan
- Department of Biology, Manisa Celal Bayar University, Manisa, Turkey
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Kim MS, Oh DJ. Monocyte counts are negatively associated with ankle-brachial index values in non-dialysis-dependent chronic kidney disease patients. Ren Fail 2020; 42:740-747. [PMID: 32718214 PMCID: PMC7470144 DOI: 10.1080/0886022x.2020.1796704] [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] [Indexed: 11/03/2022] Open
Abstract
Our aim was to determine which leukocyte subtypes are most relevant to ankle-brachial index (ABI) values in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD). The study included 79 NDD-CKD patients aged 62.84 ± 12.09 years (63.33% men; 26.67% patients with diabetes) and 21 age-matched normal controls. According to the estimated glomerular filtration rate (eGFR) calculated by the CKD-Epidemiology Collaboration equation (CKD-EPI), we classified the study population into 2 groups (21 subjects with NDD-CKD with an eGFR 60–89 mL/min/1.73m2, 58 subjects with NDD-CKD with eGFR <60 mL/min/1.73 m2). ABI was calculated as the ratio of the ankle systolic BP divided by the arm systolic BP using an ABI-form device. An automated hematologic analyzer was used to measure total and differential leukocyte counts. Monocyte counts and monocyte-to-total leukocyte count ratios (MTR) in patients with an ABI value <1.10 were significantly higher than those in patients with an ABI value ≥1.10, respectively. Univariate analyses revealed that mean ABI values were negatively correlated with monocyte count (r= −0.341; p = 0.044), MTR (r= −0.346, p = 0.031). Multivariate linear regression analyses showed that monocyte count was negatively associated with ABI values (β ± SE = −1.825 ± 0.341, p = 0.013). The area under the curve of monocyte counts was 0.695 (95% confidence interval 0.586–0.804, p = 0.002) in predicting an ABI value <1.10. Monocyte counts are negatively associated with ABI values in patients with NDD-CKD without apparent peripheral arterial occlusive disorder (PAOD).
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Affiliation(s)
- Myung Sung Kim
- Department of Internal Medicine, Myongji Hospital, Hanyang University College of Medicine, Goyang, Korea
| | - Dong-Jin Oh
- Department of Internal Medicine, Myongji Hospital, Hanyang University College of Medicine, Goyang, Korea
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Zhang T, Zhao T, Zhang Y, Liu T, Gagnon G, Ebrahim J, Johnson J, Chu YF, Ji LL. Avenanthramide supplementation reduces eccentric exercise-induced inflammation in young men and women. J Int Soc Sports Nutr 2020; 17:41. [PMID: 32711519 PMCID: PMC7382060 DOI: 10.1186/s12970-020-00368-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 07/09/2020] [Indexed: 12/26/2022] Open
Abstract
Background Avenanthramides (AVA) are a group of di-phenolic acids found only in oats and have shown antioxidant and anti-inflammatory effects in vitro and in vivo. Eccentric muscle contraction is intimately involved in rigorous exercise that activates systemic and local inflammatory responses. The objective of the study is to evaluate whether chronic AVA supplementation could attenuate peripheral inflammatory and immunological markers in human subjects in response to an acute bout of downhill running (DR). Methods Eleven male and thirteen female subjects voluntarily participated in this double-blinded, randomized controlled study and were randomly divided into AVA-supplemented (AVA) or control (C) groups. All subjects conducted a DR protocol at − 10% grade with an intensity equivalent to 75% of their maximal heart rate. Blood samples were collected at rest and various time points (0-72 h) after DR (PRE). After an 8-week washout period, participants received two cookies daily containing either 206 mg/kg (AVA) or 0 mg/kg (C) AVA for 8 weeks. Following the oat supplementation regimen, the DR and blood sampling protocols were repeated (POST). Plasma inflammatory and immunological markers were measured using Multiplex immunoassay and muscle soreness was evaluated with pain rating scale. Results DR increased plasma creatine kinase (CK) activity (P < 0.01) during PRE, but the response was reduced at 24 and 48 h during POST vs. PRE regardless of AVA status (P < 0.05). Neutrophil respiratory burst (NRB) levels were elevated at 4 and 24 h (P < 0.05) during PRE but were significantly decreased at 0–48 h during POST vs. PRE (P < 0.05 or 0.01). Granulocyte-colony stimulating factor (G-CSF), the neutrophil stimulating cytokine, was also increased in response to DR but showed lower levels in AVA compared to C during POST vs. PRE (P < 0.05). Plasma interleukin-6 (IL-6) content showed an increase at 0 and 4 h during PRE and 0 h during POST (P < 0.01), whereas during POST there was a trend toward a lower IL-6 level in AVA vs. C (P = 0.082). Plasma levels of anti-inflammatory agent interleukin-1 receptor antagonist (IL-1Ra) showed an increase at 4 h during PRE, and was significantly elevated in AVA vs. C during POST. Both soluble vascular cell adhesion molecule-1 (sVCAM-1) and monocyte chemoattractant protein-1 (MCP-1) contents increased at 0 and 24 h post DR during PRE as well as POST sessions, however, sVCAM-1 content was lower in AVA vs. C during POST (P < 0.05) and MCP-1 levels were below resting level at 24, 48 and 72 h during POST (P < 0.05). DR increased muscle pain at all post-DR time points (P < 0.01), but the pain level was alleviated by oat supplementation at 48 and 72 h during POST regardless of AVA treatment (P < 0.05). Conclusions Oat AVA supplementation reduced circulatory inflammatory cytokines and inhibited expression of chemokines and cell adhesion molecules induced by DR. Trial registration ClinicalTrials.gov identifier: NCT02584946. Registered 23 October 2015.
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Affiliation(s)
- Tianou Zhang
- Laboratory of Exercise and Sports Nutrition (LESN), Department of Kinesiology, The University of Texas at San Antonio, San Antonio, TX, 78249, USA
| | - Tong Zhao
- Laboratory of Physiological Hygiene and Exercise Science (LPHES), School of Kinesiology, University of Minnesota-Twin Cities, Minneapolis, MN, 55455, USA
| | - Yuzi Zhang
- Laboratory of Physiological Hygiene and Exercise Science (LPHES), School of Kinesiology, University of Minnesota-Twin Cities, Minneapolis, MN, 55455, USA
| | - Tao Liu
- Laboratory of Physiological Hygiene and Exercise Science (LPHES), School of Kinesiology, University of Minnesota-Twin Cities, Minneapolis, MN, 55455, USA
| | | | | | | | - Yi-Fang Chu
- PepsiCo R&D Nutrition, Barrington, IL, 60010, USA
| | - Li Li Ji
- Laboratory of Physiological Hygiene and Exercise Science (LPHES), School of Kinesiology, University of Minnesota-Twin Cities, Minneapolis, MN, 55455, USA.
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Primed PMNs in healthy mouse and human circulation are first responders during acute inflammation. Blood Adv 2020; 3:1622-1637. [PMID: 31138591 DOI: 10.1182/bloodadvances.2018030585] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Accepted: 03/31/2019] [Indexed: 12/17/2022] Open
Abstract
Polymorphonuclear neutrophils (PMNs) are the most abundant circulating leukocytes, and the first cells recruited to sites of tissue inflammation. Using a fixation method to preserve native CD marker expression prior to immunophenotyping, we identified a distinct population of "primed for recruitment" PMNs in healthy mouse and human blood that has high expression of adhesion and activation markers compared with the bulk resting-state PMNs. In response to acute tissue inflammation, primed PMNs (pPMNs) were rapidly depleted from the circulation and recruited to the tissue. One hour after acute peritoneal insult, pPMNs became the dominant PMN population in bone marrow (BM) and blood, returning to baseline levels with resolution of inflammation. PMN priming was induced by the granulopoietic factors granulocyte-macrophage-colony-stimulating factor (GM-CSF) and granulocyte-colony-stimulating factor (G-CSF). High levels of pPMNs were observed in neutropenic mice and in pediatric neutropenic patients who were resistant to infection, highlighting an important role of this population in innate immune function.
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Mahdavi Sharif P, Jabbari P, Razi S, Keshavarz-Fathi M, Rezaei N. Importance of TNF-alpha and its alterations in the development of cancers. Cytokine 2020; 130:155066. [PMID: 32208336 DOI: 10.1016/j.cyto.2020.155066] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
TNF-alpha is involved in many physiologic and pathologic cellular pathways, including cellular proliferation, differentiation, and death, regulation of immunologic reactions to different cells and molecules, local and vascular invasion of neoplasms, and destruction of tumor vasculature. It is obvious that because of integrated functions of TNF-alpha inside different physiologic systems, it cannot be used as a single-agent therapy for neoplasms; however, long-term investigation of its different cellular pathways has led to recognition of a variety of subsequent molecules with more specific interactions, and therefore, might be suitable as prognostic and therapeutic factors for neoplasms. Here, we will review different aspects of the TNF-alpha as a cytokine involved in both physiologic functions of cells and pathologic abnormalities, most importantly, cancers.
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Affiliation(s)
- Pouya Mahdavi Sharif
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran; School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Parnian Jabbari
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Sepideh Razi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mahsa Keshavarz-Fathi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran; School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Sheffield, UK.
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Regal-McDonald K, Patel RP. Selective Recruitment of Monocyte Subsets by Endothelial N-Glycans. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 190:947-957. [PMID: 32084367 DOI: 10.1016/j.ajpath.2020.01.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 12/17/2019] [Accepted: 01/07/2020] [Indexed: 12/26/2022]
Abstract
Monocyte rolling, adhesion, and transmigration across the endothelium are mediated by specific interactions between surface adhesion molecules. This process is fundamental to innate immunity and to inflammatory disease, including atherosclerosis, where monocyte egress into the intimal space is central to formation of fatty plaques. Monocytes are a heterogeneous population of three distinct subsets of cells, all of which play different roles in atherosclerosis progression. However, it is not well understood how interactions between different monocyte subsets and the endothelium are regulated. Furthermore, it is appreciated that endothelial adhesion molecules are heavily N-glycosylated, but beyond regulating protein trafficking to the cell surface, whether and if so how these N-glycans contribute to monocyte recruitment is not known. This review discusses how changes in endothelial N-glycosylation may impact vascular and monocytic inflammation. It will also discuss how regulating N-glycoforms on the endothelial surface may allow for the recruitment of specific monocyte subsets to sites of inflammation, and how further understanding in this area may lead to the development of glyco-specific therapeutics in the treatment of cardiovascular disease.
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Affiliation(s)
- Kellie Regal-McDonald
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Rakesh P Patel
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama.
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Targeting and imaging of monocyte-derived macrophages in rat's injured artery following local delivery of liposomal quantum dots. J Control Release 2020; 318:145-157. [DOI: 10.1016/j.jconrel.2019.12.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 11/26/2019] [Accepted: 12/08/2019] [Indexed: 12/27/2022]
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Toiyama Y, Okugawa Y, Shimura T, Ide S, Yasuda H, Fujikawa H, Okita Y, Yokoe T, Hiro J, Ohi M, Kusunoki M. Neutrophil priming as a risk factor for surgical site infection in patients with colon cancer treated by laparoscopic surgery. BMC Surg 2020; 20:5. [PMID: 31906993 PMCID: PMC6945448 DOI: 10.1186/s12893-019-0674-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 12/27/2019] [Indexed: 12/21/2022] Open
Abstract
Background The purpose of this study is to identify perioperative marker predicting postoperative surgical site infection (SSI) including with anastomotic leakage (AL) in curative colon cancer patients, laparoscopically. Methods In total, 135 colon cancer patients (stage I–III) undergoing curative laparoscopic surgery between January 2004 and December 2013 were enrolled in this study. We collected data on clinicopathological factors, laboratory data on pre and postoperative day 3 (POD3) and tumor markers levels to assess the relation to surgical site infection (SSI) including with anastomotic leakage (AL). Results SSI and AL occurred in 16 cases (5.6%) and 4 cases (3%), respectively. SSI and AL were not association with clinicopathological factors. Within laboratory data and tumor markers preoperatively, high neutrophil counts were significantly associated with SSI (P < 0.05) and AL (P < 0.01), respectively. Area under curves (AUC) of SSI and AL were 0.656 and 0.854, respectively. In addition, high neutrophil counts on POD3 also were significantly associated with SSI (P < 0.01) and AL (P < 0.01), respectively. Area under curves (AUC) of SSI and AL were 0.747 and 0.832, respectively. Conclusion Neutrophil count on pre and POD3 are potentially valuable indicators of SSI including with AL in colon cancer patients undergoing curative surgery laparoscopically.
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Affiliation(s)
- Yuji Toiyama
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Tsu, Mie, 514-8507, Japan.
| | - Yoshinaga Okugawa
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Tsu, Mie, 514-8507, Japan
| | - Tadanobu Shimura
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Tsu, Mie, 514-8507, Japan
| | - Shozo Ide
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Tsu, Mie, 514-8507, Japan
| | - Hiromi Yasuda
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Tsu, Mie, 514-8507, Japan
| | - Hiroyuki Fujikawa
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Tsu, Mie, 514-8507, Japan
| | - Yoshiki Okita
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Tsu, Mie, 514-8507, Japan
| | - Takeshi Yokoe
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Tsu, Mie, 514-8507, Japan
| | - Junichiro Hiro
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Tsu, Mie, 514-8507, Japan
| | - Masaki Ohi
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Tsu, Mie, 514-8507, Japan
| | - Masato Kusunoki
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Tsu, Mie, 514-8507, Japan
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Hesh CA, Qiu Y, Lam WA. Vascularized Microfluidics and the Blood-Endothelium Interface. MICROMACHINES 2019; 11:E18. [PMID: 31878018 PMCID: PMC7019435 DOI: 10.3390/mi11010018] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 12/19/2019] [Accepted: 12/20/2019] [Indexed: 12/13/2022]
Abstract
The microvasculature is the primary conduit through which the human body transmits oxygen, nutrients, and other biological information to its peripheral tissues. It does this through bidirectional communication between the blood, consisting of plasma and non-adherent cells, and the microvascular endothelium. Current understanding of this blood-endothelium interface has been predominantly derived from a combination of reductionist two-dimensional in vitro models and biologically complex in vivo animal models, both of which recapitulate the human microvasculature to varying but limited degrees. In an effort to address these limitations, vascularized microfluidics have become a platform of increasing importance as a consequence of their ability to isolate biologically complex phenomena while also recapitulating biochemical and biophysical behaviors known to be important to the function of the blood-endothelium interface. In this review, we discuss the basic principles of vascularized microfluidic fabrication, the contribution this platform has made to our understanding of the blood-endothelium interface in both homeostasis and disease, the limitations and challenges of these vascularized microfluidics for studying this interface, and how these inform future directions.
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Affiliation(s)
- Christopher A. Hesh
- Department of Radiology & Imaging Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA;
| | - Yongzhi Qiu
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30322, USA
- Department of Pediatrics, Division of Pediatric Hematology/Oncology, Aflac Cancer Center and Blood Disorders Service of Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30322, USA
- Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA
- Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30322, USA
| | - Wilbur A. Lam
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30322, USA
- Department of Pediatrics, Division of Pediatric Hematology/Oncology, Aflac Cancer Center and Blood Disorders Service of Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30322, USA
- Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA
- Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30322, USA
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