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Gong T, Fan X, Wu M, Chen Z, Xia Z. Post-transcriptional regulation of diabetic wound healing by junctional adhesion molecule A/miR-106b axis. Burns 2025; 51:107527. [PMID: 40359641 DOI: 10.1016/j.burns.2025.107527] [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: 11/24/2024] [Revised: 04/25/2025] [Accepted: 05/03/2025] [Indexed: 05/15/2025]
Abstract
BACKGROUND Despite advancements in molecular science and biomaterial technology, the mechanisms underlying the impaired healing of diabetic wounds remain unclear. In this study, we investigated the post-transcriptional regulation of diabetic wound healing using JAM-A. METHODS Mouse wound models, hematoxylin and eosin staining analysis, and scratch wound assays were used to investigate the effects of JAM-A 3'-UTR on the re-epithelialization of diabetic wounds, whereas RNA pulldown, microRNA-seq, and bioinformatics analyses were performed to identify key miRNA players and predict their target genes. In situ hybridization, immunohistochemistry, western blotting, and polymerase chain reaction (PCR) were used to confirm the alternative splicing of JAM-A 3'-UTR in diabetic conditions. CCK-8 proliferation assays, scratch wound assays, PCR, western blotting, and dual-luciferase assays were performed to study the changes in cell proliferation and migration induced by miR-106b-5p modification and confirm the target gene. RESULTS JAM-A 3'-UTR accelerated re-epithelialization in diabetic mouse wounds. Shortened splicing was found in the 3'-UTR of JAM-A under diabetic conditions, leading to the excessive release of miR-106b-5p while the promoter of miR-106b was activated. Furthermore, upregulated miR-106b-5p over-activated cell proliferation and inhibited cell migration in diabetic wound keratinocytes by suppressing the target gene PTEN/TIAM1 and regulating the AKT and RAC1 pathways, thereby impairing wound re-epithelialization. CONCLUSIONS We identified alternative splicing of JAM-A 3'-UTR in diabetic conditions, which caused the excessive release of miR-106b. Upregulation of miR-106b reduced the expression of its target genes, PTEN and TIAM1, which led to hyperactive proliferation and impaired migration of keratinocytes, thereby dysregulating wound re-epithelialization.
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Affiliation(s)
- Teng Gong
- Burn & Wound Repair Department, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, Fujian 350001, China; Fujian Burn Institute, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, Fujian 350001, China; Fujian Burn Medical Center, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, Fujian 350001, China; Fujian Provincial Key Laboratory of Burn and Trauma, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, Fujian 350001, China
| | - Xiaoming Fan
- Department of Burn Surgery, the First Affiliated Hospital of Naval Medical University, No. 168 Changhai Road, Shanghai 200082, China; Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, No. 168 Changhai Road, Shanghai 200082, China
| | - Minjuan Wu
- Department of Histology and Embryology, Naval Medical University, No. 800 Xiangyin Road, Shanghai 200082, China.
| | - Zhaohong Chen
- Burn & Wound Repair Department, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, Fujian 350001, China; Fujian Burn Institute, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, Fujian 350001, China; Fujian Burn Medical Center, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, Fujian 350001, China; Fujian Provincial Key Laboratory of Burn and Trauma, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, Fujian 350001, China.
| | - Zhaofan Xia
- Burn & Wound Repair Department, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, Fujian 350001, China; Fujian Burn Institute, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, Fujian 350001, China; Fujian Burn Medical Center, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, Fujian 350001, China; Fujian Provincial Key Laboratory of Burn and Trauma, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, Fujian 350001, China; Department of Burn Surgery, the First Affiliated Hospital of Naval Medical University, No. 168 Changhai Road, Shanghai 200082, China; Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, No. 168 Changhai Road, Shanghai 200082, China.
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Shen Y, Nakajima H, Zhu J, Wu W. Integrin β2 regulates titanium particle‑induced inflammation in macrophages: In vitro aseptic loosening model. Mol Med Rep 2025; 31:25. [PMID: 39540364 DOI: 10.3892/mmr.2024.13390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Accepted: 09/27/2024] [Indexed: 11/16/2024] Open
Abstract
Aseptic loosening is a major complication of joint replacement surgery, characterized by periprosthetic osteolysis and chronic inflammation at the bone‑implant interface. Cells release chemokines, cytokines and other pro‑inflammatory substances that perpetuate inflammation reactions, while other particle‑stimulated macrophages promote osteoclastic bone resorption and impair bone formation. The present study investigated integrin and inflammatory cytokine expression patterns in RAW 264.7 cells treated with titanium (Ti) particles to elucidate the role of integrins in Ti particle‑mediated inflammatory osteolysis. Assessment was performed by reverse transcription‑quantitative PCR, western blotting, confocal immunofluorescence, flow cytometry and enzyme‑linked immunosorbent assays. Cell migration was evaluated by wound healing assay. It was found that Ti particles significantly induced integrin expression in RAW 264.7 cells, including upregulation of integrins β2 (CD18), aL (CD11a), aM (CD11b) and aX (CD11c). Ti particles also enhanced the expression of Toll‑like receptors (TLRs; TLR1, TLR2, TLR3 and TLR4) and triggered the release of inflammatory cytokines such as tumor necrosis factor α, interleukin (IL)‑1β, IL‑8 and IL‑12. Proteomics showed higher expression and activity levels of TLR2 and TLR4, along with their downstream signaling adaptors myeloid differentiation primary response protein 88 (MyD88) and Mal/TIR‑domain‑containing adapter protein (TIRAP), following Ti treatment. Additionally, Ti treatment significantly enhanced the migration rate of RAW 264.7 cells. The present findings indicated that Ti particles regulate the inflammatory response of RAW 264.7 cells in an in vitro aseptic loosening model by activating the TLR/TIRAP/MyD88 signaling pathway.
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Affiliation(s)
- Yue Shen
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310000, P.R. China
| | - Haruna Nakajima
- Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113‑8654, Japan
| | - Junfeng Zhu
- Department of Orthopedics Surgery, Suichang Branch of The Second Affiliated Hospital, Zhejiang University School of Medicine (Suichang County People's Hospital in Zhejiang), Lishui, Zhejiang 323300, P.R. China
| | - Weigang Wu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310000, P.R. China
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Wang D, Mao L, Li K, Wang L, Wang Y, Yang L. sJAM-C as a Potential Biomarker for Coronary Artery Stenosis: Insights from a Clinical Study in Coronary Heart Disease Patients. Diabetes Metab Syndr Obes 2024; 17:4857-4865. [PMID: 39726644 PMCID: PMC11669540 DOI: 10.2147/dmso.s478526] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 11/23/2024] [Indexed: 12/28/2024] Open
Abstract
Purpose Coronary artery stenosis caused by atherogenesis is a major pathological link in coronary heart disease (CHD), which is a leading cause of global morbidity and mortality. Junctional adhesion molecule C (JAM-C) presents more and more association with atherosclerosis. However, no studies have shown the relationship between soluble JAM-C (sJAM-C) and the degree of coronary artery stenosis. This study aimed to analyze the effect of sJAM-C on coronary artery stenosis and to verify whether sJAM-C could be a biomarker for coronary artery stenosis. Patients and Methods The participants registered at the Beijing Luhe Hospital, Capital Medical University in the cross-sectional study. A total of 121 patients without coronary stenosis and 408 patients with coronary artery stenosis were enrolled after matching age and sex. Demographic information, medication history, and laboratory data were collected. The level of serum sJAM-C was detected by enzyme-linked immunosorbent assay (ELISA) kits. We used the logistic regression model to evaluate the association between sJAM-C and coronary artery stenosis. Furthermore, the receiver operating characteristic (ROC) curve and area under curve (AUC) were used to evaluate the diagnostic value of sJAM-C on coronary artery stenosis. Results The serum level of sJAM-C was remarkably higher in patients with coronary artery stenosis than those without stenosis (p < 0.0001). Logistic regression models showed that there were positive association between serum sJAM-C level and coronary artery stenosis after adjustment, with corresponding ORs were 3.088 (95% CI 1.922-4.960, p < 0.0001). And the ROC curve revealed a sensitivity of 65.7% and specificity of 60.3% with AUC of 0.676 (95% CI 0.622-0.730) for the diagnosis of coronary artery stenosis with serum sJAM-C at a cut-off value of 18.1 pg/mL, indicating a certain diagnostic value. Conclusion In summary, higher serum sJAM-C level was possibly associated with the more severe coronary artery stenosis. Additionally, sJAM-C demonstrates a certain diagnostic value of coronary artery stenosis. These findings suggest sJAM-C may be a biomarker for coronary artery stenosis.
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Affiliation(s)
- Di Wang
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, People’s Republic of China
| | - Lin Mao
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, People’s Republic of China
| | - Kun Li
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, People’s Republic of China
| | - Lu Wang
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, People’s Republic of China
| | - Yan Wang
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, People’s Republic of China
| | - Longyan Yang
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, People’s Republic of China
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Gwozdzinski L, Pieniazek A, Gwozdzinski K. The Roles of Oxidative Stress and Red Blood Cells in the Pathology of the Varicose Vein. Int J Mol Sci 2024; 25:13400. [PMID: 39769165 PMCID: PMC11678264 DOI: 10.3390/ijms252413400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 11/25/2024] [Accepted: 12/10/2024] [Indexed: 01/11/2025] Open
Abstract
This review discusses sources of reactive oxygen species, enzymatic antioxidant systems, and low molecular weight antioxidants. We present the pathology of varicose veins (VVs), including factors such as hypoxia, inflammation, dysfunctional endothelial cells, risk factors in varicose veins, the role of RBCs in venous thrombus formation, the influence of reactive oxygen species (ROS) and RBCs on VV pathology, and the role of hemoglobin in the damage of particles and macromolecules in VVs. This review discusses the production of ROS, enzymatic and nonenzymatic antioxidants, the pathogenesis of varicose veins as a pathology based on hypoxia, inflammation, and oxidative stress, as well as the participation of red blood cells in the pathology of varicose veins.
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Affiliation(s)
- Lukasz Gwozdzinski
- Department of Pharmacology and Toxicology, Medical University of Lodz, 90-752 Lodz, Poland
| | - Anna Pieniazek
- Department of Oncobiology and Epigenetics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland; (A.P.); (K.G.)
| | - Krzysztof Gwozdzinski
- Department of Oncobiology and Epigenetics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland; (A.P.); (K.G.)
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Han H, Lee S, Gao G, Yi HG, Paek SH, Jang J. Cerebrovascular-Specific Extracellular Matrix Bioink Promotes Blood-Brain Barrier Properties. Biomater Res 2024; 28:0115. [PMID: 39641002 PMCID: PMC11617618 DOI: 10.34133/bmr.0115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 10/14/2024] [Accepted: 11/11/2024] [Indexed: 12/07/2024] Open
Abstract
Chronic neuroinflammation is a principal cause of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. The blood-brain barrier predominantly comprises endothelial cells, and their intercellular communication with pericytes and other cell types regulates neuroinflammation. Here, we develop a tubular, perfusable model of human cerebrovascular tissues to study neurodegenerative diseases using cerebrovascular-specific extracellular matrix bioink, derived from a complementary blend of brain- and blood-vessel-derived extracellular matrices. The endothelial cells and pericytes in the bioprinted constructs spontaneously self-assemble into a dual-layered structure, closely mimicking the anatomy of the blood-brain barrier. Moreover, the mature cerebrovascular tissue shows physiological barrier functions and neuroinflammatory responses, indicating its potential for developing models of neuroinflammation-related pathologies. Collectively, our study demonstrates that furnishing a cerebrovascular-specific microenvironment can guide the cells to have native-like anatomical relevance and functional recapitulation in vitro.
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Affiliation(s)
- Hohyeon Han
- Division of Interdisciplinary Bioscience and Bioengineering,
Pohang University of Science and Technology (POSTECH), Pohang 37666, Republic of Korea
| | - Sooyeon Lee
- Department of Convergence IT Engineering,
POSTECH, Pohang 37666, Republic of Korea
| | - Ge Gao
- School of Medical Technology,
Beijing Institute of Technology, Beijing 100081, China
| | - Hee-Gyeong Yi
- Department of Convergence Biosystems Engineering, College of Agriculture and Life Sciences,
Chonnam National University, Gwangju 61186, Republic of Korea
| | - Sun Ha Paek
- Department of Neurosurgery, Cancer Research Institute, Hypoxia Ischemia Disease Institute,
Seoul National University, Seoul 03080, Republic of Korea
- Advanced Institutes of Convergence Technology,
Seoul National University, Suwon-si, Republic of Korea
| | - Jinah Jang
- Division of Interdisciplinary Bioscience and Bioengineering,
Pohang University of Science and Technology (POSTECH), Pohang 37666, Republic of Korea
- Department of Convergence IT Engineering,
POSTECH, Pohang 37666, Republic of Korea
- Department of Mechanical Engineering,
Pohang University of Science and Technology, Pohang 37673, Republic of Korea
- Institute of Convergence Science,
Yonsei University, Seoul 03722, Republic of Korea
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Jiang B, Yang D, Peng H. Environmental toxins and reproductive health: unraveling the effects on Sertoli cells and the blood-testis barrier in animals†. Biol Reprod 2024; 111:977-986. [PMID: 39180724 DOI: 10.1093/biolre/ioae126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 08/14/2024] [Accepted: 08/23/2024] [Indexed: 08/26/2024] Open
Abstract
Environmental pollution is an inevitable ecological issue accompanying the process of socialization, with increasing attention to its impacts on individual organisms and ecological chains. The reproductive system, responsible for transmitting genetic material in animals, is one of the most sensitive systems to environmental toxins. Research reveals that Sertoli cells are the primary target cells for the action of environmental toxins. Different environmental toxins mostly affect the blood-testis barrier and lead to male reproductive disorders by disrupting Sertoli cells. Therefore, this article provides an in-depth exploration of the toxic mechanisms of various types of environmental toxins on the male testes. It reveals the dynamic processes of tight junctions in the blood-testis barrier affected by environmental toxins and their specific roles in the reconstruction process.
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Affiliation(s)
- Biao Jiang
- School of Tropical Agriculture and Forestry, Hainan University, Haikou, Hainan 570228, P.R. China
| | - Diqi Yang
- School of Tropical Agriculture and Forestry, Hainan University, Haikou, Hainan 570228, P.R. China
| | - Hui Peng
- School of Tropical Agriculture and Forestry, Hainan University, Haikou, Hainan 570228, P.R. China
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Liebing E, Krug SM, Neurath MF, Siegmund B, Becker C. Wall of Resilience: How the Intestinal Epithelium Prevents Inflammatory Onslaught in the Gut. Cell Mol Gastroenterol Hepatol 2024; 19:101423. [PMID: 39461590 PMCID: PMC11720114 DOI: 10.1016/j.jcmgh.2024.101423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 10/17/2024] [Accepted: 10/18/2024] [Indexed: 10/29/2024]
Abstract
The intestinal epithelium forms the boundary between the intestinal immune system in the lamina propria and the outside world, the intestinal lumen, which contains a diverse array of microbial and environmental antigens. Composed of specialized cells, this epithelial monolayer has an exceptional turnover rate. Differentiated epithelial cells are released into the intestinal lumen within a few days, at the villus tip, a process that requires strict regulation. Dysfunction of the epithelial barrier increases the intestinal permeability and paves the way for luminal antigens to pass into the intestinal serosa. Stem cells at the bottom of Lieberkühn crypts provide a constant supply of mature epithelial cells. Differentiated intestinal epithelial cells exhibit a diverse array of mechanisms that enable communication with surrounding cells, fortification against microorganisms, and orchestration of nutrient absorption and hormonal balance. Furthermore, tight junctions regulate paracellular permeability properties, and their disruption can lead to an impairment of the intestinal barrier, allowing inflammation to develop or further progress. Intestinal epithelial cells provide a communication platform through which they maintain homeostasis with a spectrum of entities including immune cells, neuronal cells, and connective tissue cells. This homeostasis can be disrupted in disease, such as inflammatory bowel disease. Patients suffering from inflammatory bowel disease show an impaired gut barrier, dysregulated cellular communication, and aberrant proliferation and demise of cells. This review summarizes the individual cellular and molecular mechanisms pivotal for upholding the integrity of the intestinal epithelial barrier and shows how these can be disrupted in diseases, such as inflammatory bowel disease.
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Affiliation(s)
- Eva Liebing
- Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Susanne M Krug
- Clinical Physiology/Nutritional Medicine, Charité-Universitätsmedizin Berlin corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Markus F Neurath
- Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Britta Siegmund
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Christoph Becker
- Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Deutsches Zentrum Immuntherapie, Erlangen, Germany.
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Szkopek D, Mendel M, Kinsner M, Fotschki B, Juśkiewicz J, Kozłowski K, Matusevičius P, Konieczka P. Interaction Between Peroxisome Proliferator-Activated Receptors and Cannabidiol in the Gut of Chickens Applied to Different Challenge Conditions. Int J Mol Sci 2024; 25:11398. [PMID: 39518951 PMCID: PMC11547005 DOI: 10.3390/ijms252111398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 10/16/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are important targets for cannabidiol (CBD), which mediate many of its biological actions. The hypothesis of the present research assumed that PPARs affect the gut response to different challenge factors in chickens (C. perfringens vs. lipopolysaccharides (LPS) from E. coli), and that CBD can mediate the pathways of this response. The study proved that CBD and the challenge factors significantly affect the expression level of PPARα (p = 0.001) and selected genes determining gut barrier function. A positive correlation was demonstrated between PPARs and genes involved in the formation of tight junctions, immune, and oxidative stress responses in chickens. Dietary supplementation with CBD actively mediated the expression rate of PPARs, but the mechanism of interaction between CBD and PPARs was different depending on the stress factor used. The addition of CBD to the birds' diets did not contribute to reducing intestinal permeability under induced stress conditions nor cause stress, as indicated by the absence of elevated blood cortisol and endotoxin levels. CBD also supported the mechanisms of protecting intestinal cells from the cytotoxic effects in a C. perfringens challenge through the levels of genes involved in oxidative stress. This study indicates the importance of research toward understanding the mechanisms of PPARs as a target for enhancing intestinal barrier function, provides new results on the biological action of CBD in chickens, and shows a constant PPAR association with the jejunum mucosa of birds.
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Affiliation(s)
- Dominika Szkopek
- Department of Animal Nutrition, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Instytucka 3, 05-110 Jabłonna, Poland;
| | - Marta Mendel
- Division of Pharmacology and Toxicology, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Ciszewskiego 8, 02-786 Warsaw, Poland;
| | - Misza Kinsner
- Department of Animal Nutrition, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Instytucka 3, 05-110 Jabłonna, Poland;
| | - Bartosz Fotschki
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Tuwima 10, 10-748 Olsztyn, Poland; (B.F.); (J.J.)
| | - Jerzy Juśkiewicz
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Tuwima 10, 10-748 Olsztyn, Poland; (B.F.); (J.J.)
| | - Krzysztof Kozłowski
- Department of Poultry Science and Apiculture, University of Warmia and Mazury in Olsztyn, Oczapowskiego 5, 10-719 Olsztyn, Poland;
| | - Paulius Matusevičius
- Department of Animal Nutrition, Lithuanian University of Health Sciences, Tilzes 18, LT-47181 Kaunas, Lithuania;
| | - Paweł Konieczka
- Department of Animal Nutrition, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Instytucka 3, 05-110 Jabłonna, Poland;
- Department of Poultry Science and Apiculture, University of Warmia and Mazury in Olsztyn, Oczapowskiego 5, 10-719 Olsztyn, Poland;
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Berve K, Michel J, Tietz S, Blatti C, Ivan D, Enzmann G, Lyck R, Deutsch U, Locatelli G, Engelhardt B. Junctional adhesion molecule-A deficient mice are protected from severe experimental autoimmune encephalomyelitis. Eur J Immunol 2024; 54:e2350761. [PMID: 38566526 DOI: 10.1002/eji.202350761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 03/11/2024] [Accepted: 03/12/2024] [Indexed: 04/04/2024]
Abstract
In multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), early pathological features include immune cell infiltration into the central nervous system (CNS) and blood-brain barrier (BBB) disruption. We investigated the role of junctional adhesion molecule-A (JAM-A), a tight junction protein, in active EAE (aEAE) pathogenesis. Our study confirms JAM-A expression at the blood-brain barrier and its luminal redistribution during aEAE. JAM-A deficient (JAM-A-/-) C57BL/6J mice exhibited milder aEAE, unrelated to myelin oligodendrocyte glycoprotein-specific CD4+ T-cell priming. While JAM-A absence influenced macrophage behavior on primary mouse brain microvascular endothelial cells (pMBMECs) under flow in vitro, it did not impact T-cell extravasation across primary mouse brain microvascular endothelial cells. At aEAE onset, we observed reduced lymphocyte and CCR2+ macrophage infiltration into the spinal cord of JAM-A-/- mice compared to control littermates. This correlated with increased CD3+ T-cell accumulation in spinal cord perivascular spaces and brain leptomeninges, suggesting JAM-A absence leads to T-cell trapping in central nervous system border compartments. In summary, JAM-A plays a role in immune cell infiltration and clinical disease progression in aEAE.
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Affiliation(s)
- Kristina Berve
- Theodor Kocher Institute, University of Bern, Bern, Switzerland
| | - Julia Michel
- Theodor Kocher Institute, University of Bern, Bern, Switzerland
| | - Silvia Tietz
- Theodor Kocher Institute, University of Bern, Bern, Switzerland
| | - Claudia Blatti
- Theodor Kocher Institute, University of Bern, Bern, Switzerland
| | - Daniela Ivan
- Theodor Kocher Institute, University of Bern, Bern, Switzerland
| | - Gaby Enzmann
- Theodor Kocher Institute, University of Bern, Bern, Switzerland
| | - Ruth Lyck
- Theodor Kocher Institute, University of Bern, Bern, Switzerland
| | - Urban Deutsch
- Theodor Kocher Institute, University of Bern, Bern, Switzerland
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Ozgür B, Puris E, Brachner A, Appelt-Menzel A, Oerter S, Balzer V, Holst MR, Christiansen RF, Hyldig K, Buckley ST, Kristensen M, Auriola S, Jensen A, Fricker G, Nielsen MS, Neuhaus W, Brodin B. Characterization of an iPSC-based barrier model for blood-brain barrier investigations using the SBAD0201 stem cell line. Fluids Barriers CNS 2023; 20:96. [PMID: 38115090 PMCID: PMC10731806 DOI: 10.1186/s12987-023-00501-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 12/07/2023] [Indexed: 12/21/2023] Open
Abstract
BACKGROUND Blood-brain barrier (BBB) models based on primary murine, bovine, and porcine brain capillary endothelial cell cultures have long been regarded as robust models with appropriate properties to examine the functional transport of small molecules. However, species differences sometimes complicate translating results from these models to human settings. During the last decade, brain capillary endothelial-like cells (BCECs) have been generated from stem cell sources to model the human BBB in vitro. The aim of the present study was to establish and characterize a human BBB model using human induced pluripotent stem cell (hiPSC)-derived BCECs from the hIPSC line SBAD0201. METHODS The model was evaluated using transcriptomics, proteomics, immunocytochemistry, transendothelial electrical resistance (TEER) measurements, and, finally, transport assays to assess the functionality of selected transporters and receptor (GLUT-1, LAT-1, P-gp and LRP-1). RESULTS The resulting BBB model displayed an average TEER of 5474 ± 167 Ω·cm2 and cell monolayer formation with claudin-5, ZO-1, and occludin expression in the tight junction zones. The cell monolayers expressed the typical BBB markers VE-cadherin, VWF, and PECAM-1. Transcriptomics and quantitative targeted absolute proteomics analyses revealed that solute carrier (SLC) transporters were found in high abundance, while the expression of efflux transporters was relatively low. Transport assays using GLUT-1, LAT-1, and LRP-1 substrates and inhibitors confirmed the functional activities of these transporters and receptors in the model. A transport assay suggested that P-gp was not functionally expressed in the model, albeit antibody staining revealed that P-gp was localized at the luminal membrane. CONCLUSIONS In conclusion, the novel SBAD0201-derived BBB model formed tight monolayers and was proven useful for studies investigating GLUT-1, LAT-1, and LRP-1 mediated transport across the BBB. However, the model did not express functional P-gp and thus is not suitable for the performance of drug efflux P-gp reletated studies.
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Affiliation(s)
- Burak Ozgür
- Department of Pharmacy, University of Copenhagen, Universitetsparken 2, Copenhagen, DK-2100, Denmark
- Biotherapeutic Discovery, H. Lundbeck A/S, Valby, DK-2500, Denmark
| | - Elena Puris
- Institute of Pharmacy and Molecular Biotechnology, Ruprecht-Karls-University, Heidelberg, Germany
| | - Andreas Brachner
- AIT - Austrian Institute of Technology GmbH, Vienna, 1210, Austria
| | - Antje Appelt-Menzel
- Chair Tissue Engineering and Regenerative Medicine (TERM), University Hospital Würzburg, 97070, Würzburg, Germany
- Fraunhofer Institute for Silicate Research ISC, Translational Center Regenerative Therapies (TLC-RT) Röntgenring 11, 97070, Würzburg, Germany
| | - Sabrina Oerter
- Chair Tissue Engineering and Regenerative Medicine (TERM), University Hospital Würzburg, 97070, Würzburg, Germany
- Fraunhofer Institute for Silicate Research ISC, Translational Center Regenerative Therapies (TLC-RT) Röntgenring 11, 97070, Würzburg, Germany
| | - Viktor Balzer
- Institute of Pharmacy and Molecular Biotechnology, Ruprecht-Karls-University, Heidelberg, Germany
| | | | | | - Kathrine Hyldig
- Biotherapeutic Discovery, H. Lundbeck A/S, Valby, DK-2500, Denmark
- Department of Biomedicine, Aarhus University, Aarhus, DK-8000, Denmark
| | - Stephen T Buckley
- Global Research Technologies, Novo Nordisk A/S, Måløv, DK-2760, Denmark
| | - Mie Kristensen
- Department of Pharmacy, University of Copenhagen, Universitetsparken 2, Copenhagen, DK-2100, Denmark
| | - Seppo Auriola
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Allan Jensen
- Biotherapeutic Discovery, H. Lundbeck A/S, Valby, DK-2500, Denmark
| | - Gert Fricker
- Institute of Pharmacy and Molecular Biotechnology, Ruprecht-Karls-University, Heidelberg, Germany
| | | | - Winfried Neuhaus
- AIT - Austrian Institute of Technology GmbH, Vienna, 1210, Austria
- Department of Medicine, Faculty of Medicine and Dentistry, Danube Private University, Krems, 3500, Austria
| | - Birger Brodin
- Department of Pharmacy, University of Copenhagen, Universitetsparken 2, Copenhagen, DK-2100, Denmark.
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11
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Stamp MEM, Halwes M, Nisbet D, Collins DJ. Breaking barriers: exploring mechanisms behind opening the blood-brain barrier. Fluids Barriers CNS 2023; 20:87. [PMID: 38017530 PMCID: PMC10683235 DOI: 10.1186/s12987-023-00489-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 11/13/2023] [Indexed: 11/30/2023] Open
Abstract
The blood-brain barrier (BBB) is a selectively permeable membrane that separates the bloodstream from the brain. While useful for protecting neural tissue from harmful substances, brain-related diseases are difficult to treat due to this barrier, as it also limits the efficacy of drug delivery. To address this, promising new approaches for enhancing drug delivery are based on disrupting the BBB using physical means, including optical/photothermal therapy, electrical stimulation, and acoustic/mechanical stimulation. These physical mechanisms can temporarily and locally open the BBB, allowing drugs and other substances to enter. Focused ultrasound is particularly promising, with the ability to focus energies to targeted, deep-brain regions. In this review, we examine recent advances in physical approaches for temporary BBB disruption, describing their underlying mechanisms as well as evaluating the utility of these physical approaches with regard to their potential risks and limitations. While these methods have demonstrated efficacy in disrupting the BBB, their safety, comparative efficacy, and practicality for clinical use remain an ongoing topic of research.
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Affiliation(s)
- Melanie E M Stamp
- Department of Biomedical Engineering, The University of Melbourne, Melbourne, Australia.
- Graeme Clark Institute for Biomedical Engineering, The University of Melbourne, Melbourne, Australia.
| | - Michael Halwes
- Department of Biomedical Engineering, The University of Melbourne, Melbourne, Australia
- Graeme Clark Institute for Biomedical Engineering, The University of Melbourne, Melbourne, Australia
| | - David Nisbet
- Department of Biomedical Engineering, The University of Melbourne, Melbourne, Australia
- Graeme Clark Institute for Biomedical Engineering, The University of Melbourne, Melbourne, Australia
| | - David J Collins
- Department of Biomedical Engineering, The University of Melbourne, Melbourne, Australia
- Graeme Clark Institute for Biomedical Engineering, The University of Melbourne, Melbourne, Australia
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12
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Yin B, Liu H, Tan B, Deng J, Xie S. The effects of sodium butyrate (NaB) combination with soy saponin dietary supplementation on the growth parameters, intestinal performance and immune-related genes expression of hybrid grouper (Epinephelus fuscoguttatus♀ × E. lanceolatus♂). FISH & SHELLFISH IMMUNOLOGY 2023; 141:109033. [PMID: 37640123 DOI: 10.1016/j.fsi.2023.109033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 03/06/2023] [Accepted: 08/25/2023] [Indexed: 08/31/2023]
Abstract
Soy saponins are generally known to have negative effects on growth and the intestines of aquatic animals, and appropriate levels of sodium butyrate (NaB) may provide some mitigating effects. We investigated the effects of low and high levels of soy saponin and the protective effects of NaB (based on high level of soy saponin) on growth, serum cytokines, distal intestinal histopathology, and inflammation in hybrid grouper (Epinephelus fuscoguttatus ♀ × E. lanceolatus ♂). The experiment included four groups: fishmeal group (FM, 0.00% saponin and 0.00% NaB), low saponin group (SL, 0.30% saponin and 0.00% NaB), high saponin group (SH, 1.50% saponin and 0.00% NaB) and high saponin with NaB group (SH-NaB, 1.50% saponin and 0.13% NaB). The results showed compared to FM, the final body weight (FBW) and weight gain (WG) were significantly higher and lower in SL and SH, respectively (P < 0.05). Compared to SH, the FBW and WG were significant higher in SH-NaB (P < 0.05). In the serum, compared to FM, the interferon γ (IFN-γ) and interleukin-1β (IL-1β) levels in SH were significantly increased (P < 0.05). Compared to SH, the IFN-γ level was significantly decreased in SH-NaB (P < 0.05). In the distal intestine, based on Alcian Blue-Periodic Acid-Schiff (AB-PAS) observation, the goblet cell/μm was significantly increased and decreased in the SL and SH, respectively, compared to FM. The intestinal diameter/plica height ratio in the SH was significantly higher than those in the FM, SL and SH-NaB (P < 0.05). The NO and ONOO- levels in the SH were significantly higher than that in FM and SL (P < 0.05). At the transcriptional level in the distal intestine, compared to FM, the mRNA levels of tumor necrosis factor (tnfα), il1β, interleukin-8 (il8) and ifnγ were significantly up-regulated in the SH (P < 0.05). Compared to the SH, tnfα, il8 and ifnγ were significantly down-regulated in the SH-NaB (P < 0.05). Compared to the FM, the mRNA levels of claudin3, claudin15, zo2 and zo3 were significantly up-regulated in the SL (P < 0.05). The mRNA levels of occludin, claudin3, claudin12, claudin15, zo1, zo2 and zo3 were significantly down-regulated in the SH compared to the FM (P < 0.05). Additionally, compared to the SH, the mRNA levels of occludin, claudin3, claudin12, claudin15, zo1, zo2 and zo3 were significantly up-regulated in the SH-NaB (P < 0.05). After the 7-day Vibrio parahaemolyticus challenge test, the survival was significantly higher and lower in the SL and SH, respectively, compared to FM (P < 0.05). Overall, low and high levels of soy saponins had positive and negative effects on growth, disease resistance, serum cytokines, and distal intestinal development and anti-inflammation, respectively, in hybrid grouper. NaB effectively increased disease resistance and improved distal intestinal inflammation in hybrid grouper, but the effects of NaB were mainly observed in improving distal intestinal tight junctions.
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Affiliation(s)
- Bin Yin
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524025, PR China; Aquatic Animals Precision Nutrition and High Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, Guangdong, PR China; Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, 524025, PR China; Healthy Aquaculture Key Laboratory of Sichuan Province, Tongwei Agricultural Development Co., Ltd., Chengdu, 610093, PR China
| | - Hongyu Liu
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524025, PR China; Aquatic Animals Precision Nutrition and High Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, Guangdong, PR China; Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, 524025, PR China.
| | - Beiping Tan
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524025, PR China; Aquatic Animals Precision Nutrition and High Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, Guangdong, PR China; Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, 524025, PR China
| | - Junming Deng
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524025, PR China; Aquatic Animals Precision Nutrition and High Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, Guangdong, PR China; Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, 524025, PR China
| | - Shiwei Xie
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524025, PR China; Aquatic Animals Precision Nutrition and High Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, Guangdong, PR China; Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, 524025, PR China
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13
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Immanuel J, Yun S. Vascular Inflammatory Diseases and Endothelial Phenotypes. Cells 2023; 12:1640. [PMID: 37371110 PMCID: PMC10297687 DOI: 10.3390/cells12121640] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 06/06/2023] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
The physiological functions of endothelial cells control vascular tone, permeability, inflammation, and angiogenesis, which significantly help to maintain a healthy vascular system. Several cardiovascular diseases are characterized by endothelial cell activation or dysfunction triggered by external stimuli such as disturbed flow, hypoxia, growth factors, and cytokines in response to high levels of low-density lipoprotein and cholesterol, hypertension, diabetes, aging, drugs, and smoking. Increasing evidence suggests that uncontrolled proinflammatory signaling and further alteration in endothelial cell phenotypes such as barrier disruption, increased permeability, endothelial to mesenchymal transition (EndMT), and metabolic reprogramming further induce vascular diseases, and multiple studies are focusing on finding the pathways and mechanisms involved in it. This review highlights the main proinflammatory stimuli and their effects on endothelial cell function. In order to provide a rational direction for future research, we also compiled the most recent data regarding the impact of endothelial cell dysfunction on vascular diseases and potential targets that impede the pathogenic process.
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Affiliation(s)
| | - Sanguk Yun
- Department of Biotechnology, Inje University, Gimhae-si 50834, Republic of Korea;
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14
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Gerlach GF, Imseis ZH, Cooper SL, Santos AN, O’Brien LL. Mapping of the podocin proximity-dependent proteome reveals novel components of the kidney podocyte foot process. Front Cell Dev Biol 2023; 11:1195037. [PMID: 37325559 PMCID: PMC10262054 DOI: 10.3389/fcell.2023.1195037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 05/03/2023] [Indexed: 06/17/2023] Open
Abstract
Introduction: The unique architecture of glomerular podocytes is integral to kidney filtration. Interdigitating foot processes extend from the podocyte cell body, wrap around fenestrated capillaries, and form specialized junctional complexes termed slit diaphragms to create a molecular sieve. However, the full complement of proteins which maintain foot process integrity, and how this localized proteome changes with disease, remain to be elucidated. Methods: Proximity-dependent biotin identification (BioID) enables the identification of spatially localized proteomes. To this end, we developed a novel in vivo BioID knock-in mouse model. We utilized the slit diaphragm protein podocin (Nphs2) to create a podocin-BioID fusion. Podocin-BioID localizes to the slit diaphragm, and biotin injection leads to podocyte-specific protein biotinylation. We isolated the biotinylated proteins and performed mass spectrometry to identify proximal interactors. Results and Discussion: Gene ontology analysis of 54 proteins specifically enriched in our podocin-BioID sample revealed 'cell junctions,' 'actin binding,' and 'cytoskeleton organization' as top terms. Known foot process components were identified, and we further uncovered two novel proteins: the tricellular junctional protein Ildr2 and the CDC42 and N-WASP interactor Fnbp1l. We confirmed that Ildr2 and Fnbp1l are expressed by podocytes and partially colocalize with podocin. Finally, we investigated how this proteome changes with age and uncovered a significant increase in Ildr2. This was confirmed by immunofluorescence on human kidney samples and suggests altered junctional composition may preserve podocyte integrity. Together, these assays have led to new insights into podocyte biology and support the efficacy of utilizing BioID in vivo to interrogate spatially localized proteomes in health, aging, and disease.
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Affiliation(s)
| | | | | | | | - Lori L. O’Brien
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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15
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Zhao Q, Lian J, Pang K, Wang P, Ge R, Chu Y. Prognostic significance of JAM 3 in gastric cancer: An observational study from TCGA and GEO. Medicine (Baltimore) 2023; 102:e33603. [PMID: 37115068 PMCID: PMC10145878 DOI: 10.1097/md.0000000000033603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 03/23/2023] [Accepted: 04/03/2023] [Indexed: 04/29/2023] Open
Abstract
Junctional adhesion molecule 3 (JAM3) can be used as a prognostic marker in multiple cancer types. However, the potential prognostic role of JAM3 in gastric cancer (GC) remains unclear. The purpose of this research was to gauge JAM3 expression and methylation as potential biomarkers for GC patient survival. Through bioinformatics research, we analyzed JAM3 expression, methylation, prognosis, and immune cell infiltrations. JAM3 methylation acts as a negative regulator of JAM3, leading to reduced expression of JAM3 in GC tissues relative to normal tissues. Patients with GC who expressed little JAM3 have a better chance of living a long time free of the disease, according to the Cancer Genome Atlas (TCGA) database. Through univariate and multivariate Cox regression analysis, inadequate JAM3 expression was labeled as an isolated indicator for overall survival (OS). The GSE84437 dataset was also used to confirm JAM3 prognostic role in GC, with consistent findings. A meta-analysis also found that low levels of JAM3 expression were significantly associated with longer OS. Finally, there was a strong correlation between JAM3 expression and a subset of immune cells. According to the TCGA database, low JAM3 expression could predict favorable OS and progression-free-survival (PFS) in GC patients (P < .05). The univariate and multivariate Cox regression demonstrated that low JAM3 expression was independent biomarker for OS (P < .05). Moreover, GSE84437 dataset was utilized to verify the prognostic role of JAM3 in GC, and the similar results were reached (P < .05). A meta-analysis revealed that low JAM3 expression was closely relevant to better OS. Finally, JAM3 expression exhibited a close correlation with some immune cells (P < .05). JAM3 might be a viable predictive biomarker and likely plays a crucial part in immune cell infiltration in individuals with GC.
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Affiliation(s)
- Qinfu Zhao
- Department of Gastroenterology, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong Province, China
| | - Jiayu Lian
- Digestive Endoscopy Room, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong Province, China
| | - Kai Pang
- Operation Management Section, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong Province, China
| | - Ping Wang
- Department of Gastroenterology, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong Province, China
| | - Ruiyin Ge
- Department of Gastroenterology, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong Province, China
| | - Yanliu Chu
- Department of Gastroenterology, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong Province, China
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16
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Bovari-Biri J, Garai K, Banfai K, Csongei V, Pongracz JE. miRNAs as Predictors of Barrier Integrity. BIOSENSORS 2023; 13:bios13040422. [PMID: 37185497 PMCID: PMC10136429 DOI: 10.3390/bios13040422] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 03/16/2023] [Accepted: 03/21/2023] [Indexed: 05/17/2023]
Abstract
The human body has several barriers that protect its integrity and shield it from mechanical, chemical, and microbial harm. The various barriers include the skin, intestinal and respiratory epithelia, blood-brain barrier (BBB), and immune system. In the present review, the focus is on the physical barriers that are formed by cell layers. The barrier function is influenced by the molecular microenvironment of the cells forming the barriers. The integrity of the barrier cell layers is maintained by the intricate balance of protein expression that is partly regulated by microRNAs (miRNAs) both in the intracellular space and the extracellular microenvironment. The detection of changes in miRNA patterns has become a major focus of diagnostic, prognostic, and disease progression, as well as therapy-response, markers using a great variety of detection systems in recent years. In the present review, we highlight the importance of liquid biopsies in assessing barrier integrity and challenges in differential miRNA detection.
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Affiliation(s)
- Judit Bovari-Biri
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Pecs, 2 Rokus Str, H-7624 Pecs, Hungary
- Szentagothai Research Centre, University of Pecs, 20 Ifjusag Str, H-7624 Pecs, Hungary
| | - Kitti Garai
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Pecs, 2 Rokus Str, H-7624 Pecs, Hungary
- Szentagothai Research Centre, University of Pecs, 20 Ifjusag Str, H-7624 Pecs, Hungary
| | - Krisztina Banfai
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Pecs, 2 Rokus Str, H-7624 Pecs, Hungary
- Szentagothai Research Centre, University of Pecs, 20 Ifjusag Str, H-7624 Pecs, Hungary
| | - Veronika Csongei
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Pecs, 2 Rokus Str, H-7624 Pecs, Hungary
- Szentagothai Research Centre, University of Pecs, 20 Ifjusag Str, H-7624 Pecs, Hungary
| | - Judit E Pongracz
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Pecs, 2 Rokus Str, H-7624 Pecs, Hungary
- Szentagothai Research Centre, University of Pecs, 20 Ifjusag Str, H-7624 Pecs, Hungary
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17
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Caetano MAF, Castelucci P. Role of short chain fatty acids in gut health and possible therapeutic approaches in inflammatory bowel diseases. World J Clin Cases 2022; 10:9985-10003. [PMID: 36246826 PMCID: PMC9561599 DOI: 10.12998/wjcc.v10.i28.9985] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 08/02/2022] [Accepted: 08/25/2022] [Indexed: 02/05/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) are characterized by inflammation in the gastrointestinal tract and include Ulcerative Colitis and Crohn's Disease. These diseases are costly to health services, substantially reduce patients' quality of life, and can lead to complications such as cancer and even death. Symptoms include abdominal pain, stool bleeding, diarrhea, and weight loss. The treatment of these diseases is symptomatic, seeking disease remission. The intestine is colonized by several microorganisms, such as fungi, viruses, and bacteria, which constitute the intestinal microbiota (IM). IM bacteria promotes dietary fibers fermentation and produces short-chain fatty acids (SCFAs) that exert several beneficial effects on intestinal health. SCFAs can bind to G protein-coupled receptors, such as GPR41 and GPR43, promoting improvements in the intestinal barrier, anti-inflammatory, and antioxidant effects. Thus, SCFAs could be a therapeutic tool for IBDs. However, the mechanisms involved in these beneficial effects of SCFAs remain poorly understood. Therefore, this paper aims to provide a review addressing the main aspects of IBDs, and a more detailed sight of SCFAs, focusing on the main effects on different aspects of the intestine with an emphasis on IBDs.
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Affiliation(s)
| | - Patricia Castelucci
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508900, SP, Brazil
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18
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Arrojo ML, Oliveira KK, Bettim BB, Kowalski LP, Carraro DM, Meira ITJE, Torrezan GT, Lourenço SV, Coutinho-Camillo CM. Tight junction gene expression in salivary gland tumors. Pathol Res Pract 2022; 238:154113. [PMID: 36099718 DOI: 10.1016/j.prp.2022.154113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 08/29/2022] [Accepted: 08/31/2022] [Indexed: 11/18/2022]
Abstract
Salivary gland neoplasms comprise a heterogeneous group of lesions with multiple histological subtypes, each with distinct growth patterns, resulting in a spectrum of tumor-specific prognoses; pleomorphic adenoma (PA) and mucoepidermoid carcinoma (MEC) are the most common representatives of these neoplasms. Many studies have associated specific profiles of membrane and adhesion molecules in salivary gland tissues; these profiles appear to be relevant in tumor biology as well as be interpreted as fingerprints for tumor classification, diagnostic prognostic and therapeutic targets. One of these membrane molecule complexes are the tight junctions, composed by various proteins, in which claudins are protagonists. The aim of this study was to evaluate the expressions of genes that encode tight junction proteins (CLDN-1, -3, -4, -5, -7, and -11, occludin [OCLN], zonula occludens [TJP1, TJP2, and TJP3] and junctional adhesion molecule A [F11R]) in MEC and PA using real time RT-PCR. We observed high expression of CLDN-1 and -7 and low expression of CLDN-3, -11 and TJP2 in MEC compared to PA. PA samples demonstrated high OCLN expression when compared to MEC. CRTC1::MAML2 fusion was detected in 12 of 20 (60.0%) MEC samples and was associated with CLDN7 expression, while the absence of fusion was associated with high histological grade. Increased CLDN5 expression was associated with submandibular gland tumors. This study demonstrated differential expressions of genes encoding tight junction constituent proteins and their associations with tumor characteristics, suggesting their potential future role as diagnostic and prognostic markers.
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Affiliation(s)
- Maria Luiza Arrojo
- International Research Center, A.C.Camargo Cancer Center, São Paulo, Brazil
| | | | | | - Luiz Paulo Kowalski
- Department of Head and Neck Surgery and Otorhinolaryngology, A.C.Camargo Cancer Center, São Paulo, Brazil
| | - Dirce Maria Carraro
- Clinical and Functional Genomics Group, International Research Center A.C.Camargo Cancer Center, São Paulo, Brazil
| | - Isabella Tanus Job E Meira
- Clinical and Functional Genomics Group, International Research Center A.C.Camargo Cancer Center, São Paulo, Brazil
| | - Giovana Tardin Torrezan
- Clinical and Functional Genomics Group, International Research Center A.C.Camargo Cancer Center, São Paulo, Brazil
| | - Silvia Vanessa Lourenço
- Department of General Pathology, Dental School, University of São Paulo, São Paulo, SP, Brazil
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19
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Day-Walsh PE, Keeble B, Pirabagar G, Fountain SJ, Kroon PA. Transcriptional and Post-Translational Regulation of Junctional Adhesion Molecule-B (JAM-B) in Leukocytes under Inflammatory Stimuli. Int J Mol Sci 2022; 23:ijms23158646. [PMID: 35955781 PMCID: PMC9369439 DOI: 10.3390/ijms23158646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/27/2022] [Accepted: 07/28/2022] [Indexed: 11/16/2022] Open
Abstract
Junctional adhesion molecules (JAMs; comprising JAM-A, -B and -C) act as receptors for viruses, mediate cell permeability, facilitate leukocyte migration during sterile and non-sterile inflammation and are important for the maintenance of epithelial barrier integrity. As such, they are implicated in the development of both communicable and non-communicable chronic diseases. Here, we investigated the expression and regulation of JAM-B in leukocytes under pathogen- and host-derived inflammatory stimuli using immunoassays, qPCR and pharmacological inhibitors of inflammatory signalling pathways. We show that JAM-B is expressed at both the mRNA and protein level in leukocytes. JAM-B protein is localised to the cytoplasm, Golgi apparatus and in the nucleus around ring-shaped structures. We also provide evidence that JAM-B nuclear localisation occurs via the classical importin-α/β pathway, which is likely mediated through JAM-B protein nuclear localisation signals (NLS) and export signals (NES). In addition, we provide evidence that under both pathogen- and host-derived inflammatory stimuli, JAM-B transcription is regulated via the NF-κB-dependent pathways, whereas at the post-translational level JAM-B is regulated by ubiquitin-proteosome pathways. Anaphase-promoting ubiquitin ligase complex (APC/C) and herpes simplex virus-associated ubiquitin-specific protease (HAUSP/USP) were identified as candidates for JAM-B ubiquitination and de-ubiquitination, respectively. The expression and regulation of JAM-B in leukocytes reported here is a novel observation and contrasts with previous reports. The data reported here suggest that JAM-B expression in leukocytes is under the control of common inflammatory pathways.
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Affiliation(s)
- Priscilla E. Day-Walsh
- Quadram Institute Bioscience, Food Innovation & Health Programme, Norwich Research Park, Rosalind Franklin Road, Norwich NR4 7UQ, UK; (P.E.D.-W.); (B.K.); (G.P.)
| | - Bryony Keeble
- Quadram Institute Bioscience, Food Innovation & Health Programme, Norwich Research Park, Rosalind Franklin Road, Norwich NR4 7UQ, UK; (P.E.D.-W.); (B.K.); (G.P.)
| | - Gothai Pirabagar
- Quadram Institute Bioscience, Food Innovation & Health Programme, Norwich Research Park, Rosalind Franklin Road, Norwich NR4 7UQ, UK; (P.E.D.-W.); (B.K.); (G.P.)
| | - Samuel J. Fountain
- School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK;
| | - Paul A. Kroon
- Quadram Institute Bioscience, Food Innovation & Health Programme, Norwich Research Park, Rosalind Franklin Road, Norwich NR4 7UQ, UK; (P.E.D.-W.); (B.K.); (G.P.)
- Correspondence:
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20
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Pseudomonas aeruginosa Alters Critical Lung Epithelial Cell Functions through Activation of ADAM17. Cells 2022; 11:cells11152303. [PMID: 35892600 PMCID: PMC9331763 DOI: 10.3390/cells11152303] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/22/2022] [Accepted: 07/23/2022] [Indexed: 02/01/2023] Open
Abstract
Severe epithelial dysfunction is one major hallmark throughout the pathophysiological progress of bacterial pneumonia. Junctional and cellular adhesion molecules (e.g., JAMA-A, ICAM-1), cytokines (e.g., TNFα), and growth factors (e.g., TGFα), controlling proper lung barrier function and leukocyte recruitment, are proteolytically cleaved and released into the extracellular space through a disintegrin and metalloproteinase (ADAM) 17. In cell-based assays, we could show that the protein expression, maturation, and activation of ADAM17 is upregulated upon infection of lung epithelial cells with Pseudomonas aeruginosa and Exotoxin A (ExoA), without any impact of infection by Streptococcus pneumoniae. The characterization of released extracellular vesicles/exosomes and the comparison to heat-inactivated bacteria revealed that this increase occurred in a cell-associated and toxin-dependent manner. Pharmacological targeting and gene silencing of ADAM17 showed that its activation during infection with Pseudomonas aeruginosa was critical for the cleavage of junctional adhesion molecule A (JAM-A) and epithelial cell survival, both modulating barrier integrity, epithelial regeneration, leukocyte adhesion and transepithelial migration. Thus, site-specific targeting of ADAM17 or blockage of the activating toxins may constitute a novel anti-infective therapeutic option in Pseudomonas aeruginosa lung infection preventing severe epithelial and organ dysfunctions and stimulating future translational studies.
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21
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Wang J, Chen X. Junctional Adhesion Molecules: Potential Proteins in Atherosclerosis. Front Cardiovasc Med 2022; 9:888818. [PMID: 35872908 PMCID: PMC9302484 DOI: 10.3389/fcvm.2022.888818] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 06/21/2022] [Indexed: 11/13/2022] Open
Abstract
Junctional adhesion molecules (JAMs) are cell-cell adhesion molecules of the immunoglobulin superfamily and are involved in the regulation of diverse atherosclerosis-related processes such as endothelial barrier maintenance, leucocytes transendothelial migration, and angiogenesis. To combine and further broaden related results, this review concluded the recent progress in the roles of JAMs and predicted future studies of JAMs in the development of atherosclerosis.
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Affiliation(s)
- Junqi Wang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoping Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Xiaoping Chen,
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22
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Beck LA, Cork MJ, Amagai M, De Benedetto A, Kabashima K, Hamilton JD, Rossi AB. Type 2 Inflammation Contributes to Skin Barrier Dysfunction in Atopic Dermatitis. JID INNOVATIONS 2022; 2:100131. [PMID: 36059592 PMCID: PMC9428921 DOI: 10.1016/j.xjidi.2022.100131] [Citation(s) in RCA: 115] [Impact Index Per Article: 38.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 01/04/2022] [Accepted: 01/06/2022] [Indexed: 01/02/2023] Open
Abstract
Skin barrier dysfunction, a defining feature of atopic dermatitis (AD), arises from multiple interacting systems. In AD, skin inflammation is caused by host-environment interactions involving keratinocytes as well as tissue-resident immune cells such as type 2 innate lymphoid cells, basophils, mast cells, and T helper type 2 cells, which produce type 2 cytokines, including IL-4, IL-5, IL-13, and IL-31. Type 2 inflammation broadly impacts the expression of genes relevant for barrier function, such as intracellular structural proteins, extracellular lipids, and junctional proteins, and enhances Staphylococcus aureus skin colonization. Systemic anti‒type 2 inflammation therapies may improve dysfunctional skin barrier in AD.
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Key Words
- AD, atopic dermatitis
- AMP, antimicrobial peptide
- CLDN, claudin
- FFA, free fatty acid
- ILC2, type 2 innate lymphoid cell
- Jaki, Jak inhibitor
- K, keratin
- KC, keratinocyte
- MMP, matrix metalloproteinase
- NMF, natural moisturizing factor
- PAR, protease-activated receptor
- PDE-4, phosphodiesterase-4
- SC, stratum corneum
- SG, stratum granulosum
- TCI, topical calcineurin inhibitor
- TCS, topical corticosteroid
- TEWL, transepidermal water loss
- TJ, tight junction
- TLR, toll-like receptor
- TNF-α, tumor necrosis factor alpha
- TYK, tyrosine kinase
- Th, T helper
- ZO, zona occludens
- hBD, human β-defensin
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Affiliation(s)
- Lisa A. Beck
- Department of Dermatology, University of Rochester Medical Center, Rochester, New York, USA,Correspondence: Lisa A. Beck, Department of Dermatology, University of Rochester Medical Center, 601 Elmwood Ave, Box 697, Rochester, New York 14642, USA.
| | - Michael J. Cork
- Sheffield Dermatology Research, Department of Infection, Immunity and Cardiovascular Disease (IICD), The University of Sheffield, The Medical School, Sheffield, United Kingdom
| | - Masayuki Amagai
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan,Laboratory for Skin Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Anna De Benedetto
- Department of Dermatology, University of Rochester Medical Center, Rochester, New York, USA
| | - Kenji Kabashima
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto University, Kyoto, Japan
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23
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Inczefi O, Bacsur P, Resál T, Keresztes C, Molnár T. The Influence of Nutrition on Intestinal Permeability and the Microbiome in Health and Disease. Front Nutr 2022; 9:718710. [PMID: 35548572 PMCID: PMC9082752 DOI: 10.3389/fnut.2022.718710] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 02/22/2022] [Indexed: 01/09/2023] Open
Abstract
The leakage of the intestinal barrier and the disruption of the gut microbiome are increasingly recognized as key factors in different pathophysiological conditions, such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), chronic liver diseases, obesity, diabetes mellitus, types of cancer, and neuropsychiatric disorders. In this study, the mechanisms leading to dysbiosis and "leaky gut" are reviewed, and a short summary of the current knowledge regarding different diseases is provided. The simplest way to restore intestinal permeability and the microbiota could be ideal nutrition. Further therapeutic options are also available, such as the administration of probiotics or postbiotics or fecal microbiota transplantation.
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Affiliation(s)
- Orsolya Inczefi
- Department of Gastroenterology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Péter Bacsur
- Department of Gastroenterology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Tamás Resál
- Department of Gastroenterology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Csilla Keresztes
- Department for Medical Communication and Translation Studies, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Tamás Molnár
- Department of Gastroenterology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary,*Correspondence: Tamás Molnár,
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24
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Li Y, Peng L, Cao X, Yang K, Wang Z, Xiao Y, Xiao H, Qian C, Liu H. The Long Non-Coding RNA HOXC-AS3 Promotes Glioma Progression by Sponging miR-216 to Regulate F11R Expression. Front Oncol 2022; 12:845009. [PMID: 35402226 PMCID: PMC8984117 DOI: 10.3389/fonc.2022.845009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 03/01/2022] [Indexed: 11/24/2022] Open
Abstract
HOXC cluster antisense RNA 3 (HOXC-AS3) is a long noncoding RNA (lncRNA) that plays a crucial role in various tumors; nevertheless, its role in glioma and its mechanism have not been completely elucidated. In this research, we discovered that HOXC-AS3 was over-expression in glioma cells and tissues and was associated with prognosis. Next, we determined that HOXC-AS3 targeted miR-216 as a sponge and that the F11 receptor (F11R) was the target of miR-216 by online databases analysis, qRT–PCR, and luciferase reporter assay. In addition, the rescue experiments confirmed that HOXC-AS3 regulated the expression of F11R by competitively binding miR-216 and functioning as a competing endogenous RNA (ceRNA). The intracranial glioblastoma mouse model suggested that HOXC-AS3 could promote glioma malignant progression in vivo. In summary, our study shows that the HOXC-AS3/miR-216/F11R axis plays an important role in the malignant progression of glioma, and may provide new ideas for the treatment of glioma.
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Affiliation(s)
- Yongshuai Li
- Department of Neurosurgery, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China
| | - Lu Peng
- Department of Clinical Laboratory, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China
| | - Xianwen Cao
- Department of Neurosurgery, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China
| | - Kun Yang
- Department of Neurosurgery, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China
| | - Zhen Wang
- Department of Neurosurgery, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China
| | - Yong Xiao
- Department of Neurosurgery, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China
| | - Hong Xiao
- Department of Neuro-Psychiatric Institute, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China
| | - Chunfa Qian
- Department of Neurosurgery, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China
- *Correspondence: Chunfa Qian, ; Hongyi Liu,
| | - Hongyi Liu
- Department of Neurosurgery, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China
- *Correspondence: Chunfa Qian, ; Hongyi Liu,
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25
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Wang J, Liu H. The Roles of Junctional Adhesion Molecules (JAMs) in Cell Migration. Front Cell Dev Biol 2022; 10:843671. [PMID: 35356274 PMCID: PMC8959349 DOI: 10.3389/fcell.2022.843671] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Accepted: 02/10/2022] [Indexed: 01/15/2023] Open
Abstract
The review briefly summarizes the role of the family of adhesion molecules, JAMs (junctional adhesion molecules), in various cell migration, covering germ cells, epithelial cells, endothelial cells, several leukocytes, and different cancer cells. These functions affect multiple diseases, including reproductive diseases, inflammation-related diseases, cardiovascular diseases, and cancers. JAMs bind to both similar and dissimilar proteins and take both similar and dissimilar effects on different cells. Concluding relevant results provides a reference to further research.
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Affiliation(s)
- Junqi Wang
- Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China
| | - Han Liu
- Department of Pharmacy, People’s Hospital of Longhua, Shenzhen, China
- *Correspondence: Han Liu,
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26
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Amatruda M, Chapouly C, Woo V, Safavi F, Zhang J, Dai D, Therattil A, Moon C, Villavicencio J, Gordon A, Parkos C, Horng S. Astrocytic junctional adhesion molecule-A regulates T cell entry past the glia limitans to promote central nervous system autoimmune attack. Brain Commun 2022; 4:fcac044. [PMID: 35265839 PMCID: PMC8899531 DOI: 10.1093/braincomms/fcac044] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 10/05/2021] [Accepted: 02/16/2022] [Indexed: 11/15/2022] Open
Abstract
Contact-mediated interactions between the astrocytic endfeet and infiltrating immune cells within the perivascular space are underexplored, yet represent potential regulatory check-points against CNS autoimmune disease and disability. Reactive astrocytes upregulate junctional adhesion molecule-A, an immunoglobulin-like cell surface receptor that binds to T cells via its ligand, the integrin, lymphocyte function-associated antigen-1. Here, we tested the role of astrocytic junctional adhesion molecule-A in regulating CNS autoinflammatory disease. In cell co-cultures, we found that junctional adhesion molecule-A-mediated signalling between astrocytes and T cells increases levels of matrix metalloproteinase-2, C–C motif chemokine ligand 2 and granulocyte-macrophage colony-stimulating factor, pro-inflammatory factors driving lymphocyte entry and pathogenicity in multiple sclerosis and experimental autoimmune encephalomyelitis, an animal model of CNS autoimmune disease. In experimental autoimmune encephalomyelitis, mice with astrocyte-specific JAM-A deletion (mGFAP:CreJAM-Afl/fl) exhibit decreased levels of matrix metalloproteinase-2, reduced ability of T cells to infiltrate the CNS parenchyma from the perivascular spaces and a milder histopathological and clinical course of disease compared with wild-type controls (JAM-Afl/fl). Treatment of wild-type mice with intraperitoneal injection of soluble junctional adhesion molecule-A blocking peptide decreases the severity of experimental autoimmune encephalomyelitis, highlighting the potential of contact-mediated astrocyte–immune cell signalling as a novel translational target against neuroinflammatory disease.
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Affiliation(s)
| | | | - Viola Woo
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Farinaz Safavi
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Joy Zhang
- University of Virginia School of Medicine, Charlottesville, VA, USA
| | - David Dai
- Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | | | - Chang Moon
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jorge Villavicencio
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Alexandra Gordon
- Miller School of Medicine at University of Miami, Miami, FL, USA
| | - Charles Parkos
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Sam Horng
- Correspondence to: Sam Horng, MD, PhD Icahn School of Medicine at Mount Sinai Icahn 10-20A, 1468 Madison Avenue New York NY, 10029, USA E-mail:
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27
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Takeuchi H, Nakamura E, Yamaga S, Amano A. Porphyromonas gingivalis Infection Induces Lipopolysaccharide and Peptidoglycan Penetration Through Gingival Epithelium. FRONTIERS IN ORAL HEALTH 2022; 3:845002. [PMID: 35211692 PMCID: PMC8861192 DOI: 10.3389/froh.2022.845002] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 01/14/2022] [Indexed: 12/04/2022] Open
Abstract
Periodontal diseases initiate on epithelial surfaces of the subgingival compartment, while the gingival epithelium functions as an epithelial barrier against microbial infection and orchestrates immune responses. Porphyromonas gingivalis is a major pathogen of periodontal diseases and has an ability to penetrate the epithelial barrier. To assess the molecular basis of gingival epithelial barrier dysfunction associated with P. gingivalis, we newly developed a three-dimensional multilayered tissue model of gingival epithelium with gene manipulation. Using this novel approach, P. gingivalis gingipains including Arg- or Lys-specific cysteine proteases were found to specifically degrade junctional adhesion molecule 1 and coxsackievirus and adenovirus receptor in the tissue model, leading to increased permeability for lipopolysaccharide, peptidoglycan, and gingipains. This review summarizes the strategy used by P. gingivalis to disable the epithelial barrier by disrupting specific junctional adhesion molecules.
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Affiliation(s)
- Hiroki Takeuchi
- Department of Preventive Dentistry, Osaka University Dental Hospital, Suita, Japan
- *Correspondence: Hiroki Takeuchi
| | - Eriko Nakamura
- Department of Preventive Dentistry, Graduate School of Dentistry, Osaka University, Suita, Japan
| | - Shunsuke Yamaga
- Department of Preventive Dentistry, Graduate School of Dentistry, Osaka University, Suita, Japan
| | - Atsuo Amano
- Department of Preventive Dentistry, Graduate School of Dentistry, Osaka University, Suita, Japan
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28
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Tian Y, Fopiano KA, Buncha V, Lang L, Rudic RD, Filosa JA, Dou H, Bagi Z. Aging-induced impaired endothelial wall shear stress mechanosensing causes arterial remodeling via JAM-A/F11R shedding by ADAM17. GeroScience 2022; 44:349-369. [PMID: 34718985 PMCID: PMC8810930 DOI: 10.1007/s11357-021-00476-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 10/08/2021] [Indexed: 11/25/2022] Open
Abstract
Physiological and pathological vascular remodeling is uniquely driven by mechanical forces from blood flow in which wall shear stress (WSS) mechanosensing by the vascular endothelium plays a pivotal role. This study aimed to determine the novel role for a disintegrin and metalloproteinase 17 (ADAM17) in impaired WSS mechanosensing, which was hypothesized to contribute to aging-associated abnormal vascular remodeling. Without changes in arterial blood pressure and blood flow rate, skeletal muscle resistance arteries of aged mice (30-month-old vs. 12-week-old) exhibited impaired WSS mechanosensing and displayed inward hypertrophic arterial remodeling. These vascular changes were recapitulated by in vivo confined, AAV9-mediated overexpression of ADAM17 in the resistance arteries of young mice. An aging-related increase in ADAM17 expression reduced the endothelial junction level of its cleavage substrate, junctional adhesion molecule-A/F11 receptor (JAM-A/F11R). In cultured endothelial cells subjected to steady WSS ADAM17 activation or JAM-A/F11R knockdown inhibited WSS mechanosensing. The ADAM17-activation induced, impaired WSS mechanosensing was normalized by overexpression of ADAM17 cleavage resistant, mutated JAM-AV232Y both in cultured endothelial cells and in resistance arteries of aged mice, in vivo. These data demonstrate a novel role for ADAM17 in JAM-A/F11R cleavage-mediated impaired endothelial WSS mechanosensing and subsequently developed abnormal arterial remodeling in aging. ADAM17 could prove to be a key regulator of WSS mechanosensing, whereby it can also play a role in pathological vascular remodeling in diseases.
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Affiliation(s)
- Yanna Tian
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Katie Anne Fopiano
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Vadym Buncha
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Liwei Lang
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - R Daniel Rudic
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Jessica A Filosa
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Huijuan Dou
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
- Department of Medicine, Columbia University Medical Center, New York, NY, 10032, USA
| | - Zsolt Bagi
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
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29
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Pseudomonas aeruginosa Triggered Exosomal Release of ADAM10 Mediates Proteolytic Cleavage in Trans. Int J Mol Sci 2022; 23:ijms23031259. [PMID: 35163191 PMCID: PMC8835980 DOI: 10.3390/ijms23031259] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/18/2022] [Accepted: 01/20/2022] [Indexed: 02/05/2023] Open
Abstract
Pneumonia is a life-threatening disease often caused by infection with Streptococcus pneumoniae and Pseudomonas aeruginosa. Many of the mediators (e.g., TNF, IL-6R) and junction molecules (e.g., E-cadherin) orchestrating inflammatory cell recruitment and loss of barrier integrity are proteolytically cleaved through a disintegrin and metalloproteinases (ADAMs). We could show by Western blot, surface expression analysis and measurement of proteolytic activity in cell-based assays, that ADAM10 in epithelial cells is upregulated and activated upon infection with Pseudomonas aeruginosa and Exotoxin A (ExoA), but not upon infection with Streptococcus pneumoniae. Targeting ADAM10 by pharmacological inhibition or gene silencing, we demonstrated that this activation was critical for cleavage of E-cadherin and modulated permeability and epithelial integrity. Stimulation with heat-inactivated bacteria revealed that the activation was based on the toxin repertoire rather than the interaction with the bacterial particle itself. Furthermore, calcium imaging experiments showed that the ExoA action was based on the induction of calcium influx. Investigating the extracellular vesicles and their proteolytic activity, we could show that Pseudomonas aeruginosa triggered exosomal release of ADAM10 and proteolytic cleavage in trans. This newly described mechanism could constitute an essential mechanism causing systemic inflammation in patients suffering from Pseudomonas aeruginosa-induced pneumonia stimulating future translational studies.
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30
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Mendoza C, Nagidi SH, Collett K, Mckell J, Mizrachi D. Calcium regulates the interplay between the tight junction and epithelial adherens junction at the plasma membrane. FEBS Lett 2022; 596:219-231. [PMID: 34882783 DOI: 10.1002/1873-3468.14252] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 11/05/2021] [Accepted: 12/05/2021] [Indexed: 01/15/2023]
Abstract
The apical junctional complex (AJC) is a membrane protein ultrastructure that regulates cell adhesion and homeostasis. The tight junction (TJ) and the adherens junction (AJ) are substructures of the AJC. The interplay between TJ and AJ membrane proteins to assemble the AJC remains unclear. We employed synthetic biology strategies to express the basic membrane elements of a simple AJC-the adhesive extracellular domains of junctional adhesion molecule A (JAM-A), epithelial cadherin, claudin 1, and occludin-to study their interactions. Our results suggest that calcium concentration fluctuations and JAM-A, acting as an interface molecule between the TJ and AJ, orchestrate their interplay. Calcium affects the secondary structure, oligomerization, and binding affinity of homotypic and heterotypic interactions of TJ and AJ components, thus acting as a molecular switch influencing AJC dynamics.
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Affiliation(s)
- Christopher Mendoza
- Department of Physiology and Developmental Biology, College of Life Sciences, Brigham Young University, Provo, UT, USA
| | - Sai Harsha Nagidi
- Department of Molecular Microbiology, College of Life Sciences, Brigham Young University, Provo, UT, USA
| | - Kjetil Collett
- Department of Physiology and Developmental Biology, College of Life Sciences, Brigham Young University, Provo, UT, USA
| | - Jacob Mckell
- Department of Physiology and Developmental Biology, College of Life Sciences, Brigham Young University, Provo, UT, USA
| | - Dario Mizrachi
- Department of Physiology and Developmental Biology, College of Life Sciences, Brigham Young University, Provo, UT, USA
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31
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Deng L, Petrek H, Tu MJ, Batra N, Yu AX, Yu AM. Bioengineered miR-124-3p prodrug selectively alters the proteome of human carcinoma cells to control multiple cellular components and lung metastasis in vivo. Acta Pharm Sin B 2021; 11:3950-3965. [PMID: 35024318 PMCID: PMC8727917 DOI: 10.1016/j.apsb.2021.07.027] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 07/05/2021] [Accepted: 07/07/2021] [Indexed: 02/07/2023] Open
Abstract
With the understanding of microRNA (miRNA or miR) functions in tumor initiation, progression, and metastasis, efforts are underway to develop new miRNA-based therapies. Very recently, we demonstrated effectiveness of a novel humanized bioengineered miR-124-3p prodrug in controlling spontaneous lung metastasis in mouse models. This study was to investigate the molecular and cellular mechanisms by which miR-124-3p controls tumor metastasis. Proteomics study identified a set of proteins selectively and significantly downregulated by bioengineered miR-124-3p in A549 cells, which were assembled into multiple cellular components critical for metastatic potential. Among them, plectin (PLEC) was verified as a new direct target for miR-124-3p that links cytoskeleton components and junctions. In miR-124-3p-treated lung cancer and osteosarcoma cells, protein levels of vimentin, talin 1 (TLN1), integrin beta-1 (ITGB1), IQ motif containing GTPase activating protein 1 (IQGAP1), cadherin 2 or N-cadherin (CDH2), and junctional adhesion molecule A (F11R or JAMA or JAM1) decreased, causing remodeling of cytoskeletons and disruption of cell-cell junctions. Furthermore, miR-124-3p sharply suppressed the formation of focal adhesion plaques, leading to reduced cell adhesion capacity. Additionally, efficacy and safety of biologic miR-124-3p therapy was established in an aggressive experimental metastasis mouse model in vivo. These results connect miR-124-3p-PLEC signaling to other elements in the control of cytoskeleton, cell junctions, and adhesion essential for cancer cell invasion and extravasation towards metastasis, and support the promise of miR-124 therapy.
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Affiliation(s)
- Linglong Deng
- Department of Orthopaedic Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan 430072, China
- Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA
| | - Hannah Petrek
- Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA
| | - Mei-Juan Tu
- Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA
| | - Neelu Batra
- Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA
| | - Ai-Xi Yu
- Department of Orthopaedic Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan 430072, China
| | - Ai-Ming Yu
- Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA
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32
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Ruysseveldt E, Martens K, Steelant B. Airway Basal Cells, Protectors of Epithelial Walls in Health and Respiratory Diseases. FRONTIERS IN ALLERGY 2021; 2:787128. [PMID: 35387001 PMCID: PMC8974818 DOI: 10.3389/falgy.2021.787128] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 10/25/2021] [Indexed: 01/02/2023] Open
Abstract
The airway epithelium provides a critical barrier to the outside environment. When its integrity is impaired, epithelial cells and residing immune cells collaborate to exclude pathogens and to heal tissue damage. Healing is achieved through tissue-specific stem cells: the airway basal cells. Positioned near the basal membrane, airway basal cells sense and respond to changes in tissue health by initiating a pro-inflammatory response and tissue repair via complex crosstalks with nearby fibroblasts and specialized immune cells. In addition, basal cells have the capacity to learn from previous encounters with the environment. Inflammation can indeed imprint a certain memory on basal cells by epigenetic changes so that sensitized tissues may respond differently to future assaults and the epithelium becomes better equipped to respond faster and more robustly to barrier defects. This memory can, however, be lost in diseased states. In this review, we discuss airway basal cells in respiratory diseases, the communication network between airway basal cells and tissue-resident and/or recruited immune cells, and how basal cell adaptation to environmental triggers occurs.
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Affiliation(s)
- Emma Ruysseveldt
- Allergy and Clinical Immunology Research Unit, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Katleen Martens
- Allergy and Clinical Immunology Research Unit, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Bioscience Engineering, University of Antwerp, Antwerp, Belgium
| | - Brecht Steelant
- Allergy and Clinical Immunology Research Unit, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Head and Neck Surgery, Department of Otorhinolaryngology, University of Crete School of Medicine, Heraklion, Greece
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Yemanyi F, Bora K, Blomfield AK, Wang Z, Chen J. Wnt Signaling in Inner Blood-Retinal Barrier Maintenance. Int J Mol Sci 2021; 22:11877. [PMID: 34769308 PMCID: PMC8584977 DOI: 10.3390/ijms222111877] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 10/28/2021] [Accepted: 10/29/2021] [Indexed: 12/14/2022] Open
Abstract
The retina is a light-sensing ocular tissue that sends information to the brain to enable vision. The blood-retinal barrier (BRB) contributes to maintaining homeostasis in the retinal microenvironment by selectively regulating flux of molecules between systemic circulation and the retina. Maintaining such physiological balance is fundamental to visual function by facilitating the delivery of nutrients and oxygen and for protection from blood-borne toxins. The inner BRB (iBRB), composed mostly of inner retinal vasculature, controls substance exchange mainly via transportation processes between (paracellular) and through (transcellular) the retinal microvascular endothelium. Disruption of iBRB, characterized by retinal edema, is observed in many eye diseases and disturbs the physiological quiescence in the retina's extracellular space, resulting in vision loss. Consequently, understanding the mechanisms of iBRB formation, maintenance, and breakdown is pivotal to discovering potential targets to restore function to compromised physiological barriers. These unraveled targets can also inform potential drug delivery strategies across the BRB and the blood-brain barrier into retinas and brain tissues, respectively. This review summarizes mechanistic insights into the development and maintenance of iBRB in health and disease, with a specific focus on the Wnt signaling pathway and its regulatory role in both paracellular and transcellular transport across the retinal vascular endothelium.
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Affiliation(s)
| | | | | | | | - Jing Chen
- Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (F.Y.); (K.B.); (A.K.B.); (Z.W.)
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Alizadeh A, Akbari P, Garssen J, Fink-Gremmels J, Braber S. Epithelial integrity, junctional complexes, and biomarkers associated with intestinal functions. Tissue Barriers 2021; 10:1996830. [PMID: 34719339 PMCID: PMC9359365 DOI: 10.1080/21688370.2021.1996830] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
An intact intestinal barrier is crucial for immune homeostasis and its impairment activates the immune system and may result in chronic inflammation. The epithelial cells of the intestinal barrier are connected by tight junctions, which form an anastomosing network sealing adjacent epithelial cells. Tight junctions are composed of transmembrane and cytoplasmic scaffolding proteins. Transmembrane tight junction proteins at the apical-lateral membrane of the cell consist of occludin, claudins, junctional adhesion molecules, and tricellulin. Cytoplasmic scaffolding proteins, including zonula occludens, cingulin and afadin, provide a direct link between transmembrane tight junction proteins and the intracellular cytoskeleton. Each individual component of the tight junction network closely interacts with each other to form an efficient intestinal barrier. This review aims to describe the molecular structure of intestinal epithelial tight junction proteins and to characterize their organization and interaction. Moreover, clinically important biomarkers associated with impairment of gastrointestinal integrity are discussed.
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Affiliation(s)
- Arash Alizadeh
- Division of Pharmacology and Toxicology, Department of Basic Science, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
| | - Peyman Akbari
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Johan Garssen
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.,Department of Immunology, Danone Nutricia Research, Utrecht, The Netherlands
| | - Johanna Fink-Gremmels
- Institute for Risk Assessment Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Saskia Braber
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
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Mertowska P, Mertowski S, Wojnicka J, Korona-Głowniak I, Grywalska E, Błażewicz A, Załuska W. A Link between Chronic Kidney Disease and Gut Microbiota in Immunological and Nutritional Aspects. Nutrients 2021; 13:3637. [PMID: 34684638 PMCID: PMC8540836 DOI: 10.3390/nu13103637] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/14/2021] [Accepted: 10/15/2021] [Indexed: 02/07/2023] Open
Abstract
Chronic kidney disease (CKD) is generally progressive and irreversible, structural or functional renal impairment for 3 or more months affecting multiple metabolic pathways. Recently, the composition, dynamics, and stability of a patient's microbiota has been noted to play a significant role during disease onset or progression. Increasing urea concentration during CKD can lead to an acceleration of the process of kidney injury leading to alterations in the intestinal microbiota that can increase the production of gut-derived toxins and alter the intestinal epithelial barrier. A detailed analysis of the relationship between the role of intestinal microbiota and the development of inflammation within the symbiotic and dysbiotic intestinal microbiota showed significant changes in kidney dysfunction. Several recent studies have determined that dietary factors can significantly influence the activation of immune cells and their mediators. Moreover, dietary changes can profoundly affect the balance of gut microbiota. The aim of this review is to present the importance and factors influencing the differentiation of the human microbiota in the progression of kidney diseases, such as CKD, IgA nephropathy, idiopatic nephropathy, and diabetic kidney disease, with particular emphasis on the role of the immune system. Moreover, the effects of nutrients, bioactive compounds on the immune system in development of chronic kidney disease were reviewed.
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Affiliation(s)
- Paulina Mertowska
- Department of Experimental Immunology, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland; (P.M.); (S.M.); (E.G.)
| | - Sebastian Mertowski
- Department of Experimental Immunology, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland; (P.M.); (S.M.); (E.G.)
| | - Julia Wojnicka
- Department of Pathobiochemistry and Interdisciplinary Applications of Ion Chromatography, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (J.W.); (A.B.)
| | - Izabela Korona-Głowniak
- Department of Pharmaceutical Microbiology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland
| | - Ewelina Grywalska
- Department of Experimental Immunology, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland; (P.M.); (S.M.); (E.G.)
| | - Anna Błażewicz
- Department of Pathobiochemistry and Interdisciplinary Applications of Ion Chromatography, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (J.W.); (A.B.)
| | - Wojciech Załuska
- Department of Nephrology, Medical University of Lublin, 8 Jaczewskiego Street, 20-954 Lublin, Poland;
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Panwar S, Sharma S, Tripathi P. Role of Barrier Integrity and Dysfunctions in Maintaining the Healthy Gut and Their Health Outcomes. Front Physiol 2021; 12:715611. [PMID: 34630140 PMCID: PMC8497706 DOI: 10.3389/fphys.2021.715611] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 08/27/2021] [Indexed: 01/08/2023] Open
Abstract
Mucosal surface layers are the critical borders throughout epithelial membranes. These epithelial cells segregate luminal material from external environments. However, mucosal linings are also accountable for absorbing nutrients and requiring specific barrier permeability. These functional acts positioned the mucosal epithelium at the epicenter of communications concerning the mucosal immune coordination and foreign materials, such as dietary antigens and microbial metabolites. Current innovations have revealed that external stimuli can trigger several mechanisms regulated by intestinal mucosal barrier system. Crucial constituents of this epithelial boundary are physical intercellular structures known as tight junctions (TJs). TJs are composed of different types transmembrane proteins linked with cytoplasmic adaptors which helps in attachment to the adjacent cells. Disruption of this barrier has direct influence on healthy or diseased condition, as barrier dysfunctions have been interrelated with the initiation of inflammation, and pathogenic effects following metabolic complications. In this review we focus and overview the TJs structure, function and the diseases which are able to influence TJs during onset of disease. We also highlighted and discuss the role of phytochemicals evidenced to enhance the membrane permeability and integrity through restoring TJs levels.
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Affiliation(s)
- Shruti Panwar
- Infection and Immunology, Translational Health Science and Technology Institute, National Capital Region (NCR) Biotech Science Cluster, Faridabad, India
| | - Sapna Sharma
- Gene Regulation Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
| | - Prabhanshu Tripathi
- Food Drug and Chemical Toxicology Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Toxicology Research, Lucknow, India
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Takeuchi H, Yamaga S, Sasaki N, Kuboniwa M, Matsusaki M, Amano A. Porphyromonas gingivalis induces penetration of lipopolysaccharide and peptidoglycan through the gingival epithelium via degradation of coxsackievirus and adenovirus receptor. Cell Microbiol 2021; 23:e13388. [PMID: 34448537 DOI: 10.1111/cmi.13388] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/13/2021] [Accepted: 08/22/2021] [Indexed: 11/28/2022]
Abstract
Porphyromonas gingivalis is a major pathogen of human periodontitis and dysregulates innate immunity at the gingival epithelial surface. We previously reported that the bacterium specifically degrades junctional adhesion molecule 1 (JAM1), causing gingival epithelial barrier breakdown. However, the functions of other JAM family protein(s) in epithelial barrier dysregulation caused by P. gingivalis are not fully understood. The present results show that gingipains, Arg-specific or Lys-specific cysteine proteases produced by P. gingivalis, specifically degrade coxsackievirus and adenovirus receptor (CXADR), a JAM family protein, at R145 and K235 in gingival epithelial cells. In contrast, a gingipain-deficient P. gingivalis strain was found to be impaired in regard to degradation of CXADR. Furthermore, knockdown of CXADR in artificial gingival epithelium increased permeability to dextran 40 kDa, lipopolysaccharide and peptidoglycan, whereas overexpression of CXADR in a gingival epithelial tissue model prevented penetration by those agents following P. gingivalis infection. Together, these results suggest that P. gingivalis gingipains breach the stratified squamous epithelium barrier by degrading CXADR as well as JAM1, which allows for efficient transfer of bacterial virulence factors into subepithelial tissues. TAKEAWAYS: P. gingivalis, a periodontal pathogen, degraded coxsackievirus and adenovirus receptor (CXADR), a JAM family protein, in gingival epithelial tissues. P. gingivalis gingipains, cysteine proteases, degraded CXADR at R145 and K235. CXADR degradation by P. gingivalis caused increased permeability to lipopolysaccharide and peptidoglycan through gingival epithelial tissues.
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Affiliation(s)
- Hiroki Takeuchi
- Department of Preventive Dentistry, Graduate School of Dentistry, Osaka University, Osaka, Japan
| | - Shunsuke Yamaga
- Department of Preventive Dentistry, Graduate School of Dentistry, Osaka University, Osaka, Japan
| | - Naoko Sasaki
- Joint Research Laboratory (TOPPAN) for Advanced Cell Regulatory Chemistry, Graduate School of Engineering, Osaka University, Osaka, Japan
| | - Masae Kuboniwa
- Department of Preventive Dentistry, Graduate School of Dentistry, Osaka University, Osaka, Japan
| | - Michiya Matsusaki
- Joint Research Laboratory (TOPPAN) for Advanced Cell Regulatory Chemistry, Graduate School of Engineering, Osaka University, Osaka, Japan.,Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Osaka, Japan
| | - Atsuo Amano
- Department of Preventive Dentistry, Graduate School of Dentistry, Osaka University, Osaka, Japan
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38
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Eom DS, Patterson LB, Bostic RR, Parichy DM. Immunoglobulin superfamily receptor Junctional adhesion molecule 3 (Jam3) requirement for melanophore survival and patterning during formation of zebrafish stripes. Dev Biol 2021; 476:314-327. [PMID: 33933422 PMCID: PMC10069301 DOI: 10.1016/j.ydbio.2021.04.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/03/2021] [Accepted: 04/22/2021] [Indexed: 12/14/2022]
Abstract
Adhesive interactions are essential for tissue patterning and morphogenesis yet difficult to study owing to functional redundancies across genes and gene families. A useful system in which to dissect roles for cell adhesion and adhesion-dependent signaling is the pattern formed by pigment cells in skin of adult zebrafish, in which stripes represent the arrangement of neural crest derived melanophores, cells homologous to melanocytes. In a forward genetic screen for adult pattern defects, we isolated the pissarro (psr) mutant, having a variegated phenotype of spots, as well as defects in adult fin and lens. We show that psr corresponds to junctional adhesion protein 3b (jam3b) encoding a zebrafish orthologue of the two immunoglobulin-like domain receptor JAM3 (JAM-C), known for roles in adhesion and signaling in other developing tissues, and for promoting metastatic behavior of human and murine melanoma cells. We found that zebrafish jam3b is expressed post-embryonically in a variety of cells including melanophores, and that jam3b mutants have defects in melanophore survival. Jam3b supported aggregation of cells in vitro and was required autonomously by melanophores for an adherent phenotype in vivo. Genetic analyses further indicated both overlapping and non-overlapping functions with the related receptor, Immunoglobulin superfamily 11 (Igsf11) and Kit receptor tyrosine kinase. These findings suggest a model for Jam3b function in zebrafish melanophores and hint at the complexity of adhesive interactions underlying pattern formation.
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Affiliation(s)
- Dae Seok Eom
- Department of Biology, University of Virginia, Charlottesville, VA, USA.
| | | | - Raegan R Bostic
- Department of Biology, University of Virginia, Charlottesville, VA, USA; Department of Cell Biology, University of Virginia, Charlottesville, VA, USA
| | - David M Parichy
- Department of Biology, University of Virginia, Charlottesville, VA, USA; Department of Cell Biology, University of Virginia, Charlottesville, VA, USA.
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Fernandez-Cantos MV, Garcia-Morena D, Iannone V, El-Nezami H, Kolehmainen M, Kuipers OP. Role of microbiota and related metabolites in gastrointestinal tract barrier function in NAFLD. Tissue Barriers 2021; 9:1879719. [PMID: 34280073 PMCID: PMC8489918 DOI: 10.1080/21688370.2021.1879719] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 01/13/2021] [Accepted: 01/18/2021] [Indexed: 11/06/2022] Open
Abstract
The Gastrointestinal (GI) tract is composed of four main barriers: microbiological, chemical, physical and immunological. These barriers play important roles in maintaining GI tract homeostasis. In the crosstalk between these barriers, microbiota and related metabolites have been shown to influence GI tract barrier integrity, and alterations of the gut microbiome might lead to an increase in intestinal permeability. As a consequence, translocation of bacteria and their products into the circulatory system increases, reaching proximal and distal tissues, such as the liver. One of the most prevalent chronic liver diseases, Nonalcoholic Fatty Liver Disease (NAFLD), has been associated with an altered gut microbiota and barrier integrity. However, the causal link between them has not been fully elucidated yet. In this review, we aim to highlight relevant bacterial taxa and their related metabolites affecting the GI tract barriers in the context of NAFLD, discussing their implications in gut homeostasis and in disease.
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Affiliation(s)
- Maria Victoria Fernandez-Cantos
- Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands
| | - Diego Garcia-Morena
- Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands
| | - Valeria Iannone
- Institute of Public Health and Clinical Nutrition, Department of Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Hani El-Nezami
- Molecular and Cell Biology Division, School of Biological Sciences, University of Hong Kong, Hong Kong SAR
| | - Marjukka Kolehmainen
- Institute of Public Health and Clinical Nutrition, Department of Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Oscar P. Kuipers
- Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands
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Mendoza C, Nagidi SH, Mizrachi D. Molecular Characterization of the Extracellular Domain of Human Junctional Adhesion Proteins. Int J Mol Sci 2021; 22:ijms22073482. [PMID: 33801758 PMCID: PMC8037251 DOI: 10.3390/ijms22073482] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 03/24/2021] [Accepted: 03/25/2021] [Indexed: 12/22/2022] Open
Abstract
The junction adhesion molecule (JAM) family of proteins play central roles in the tight junction (TJ) structure and function. In contrast to claudins (CLDN) and occludin (OCLN), the other membrane proteins of the TJ, whose structure is that of a 4α-helix bundle, JAMs are members of the immunoglobulin superfamily. The JAM family is composed of four members: A, B, C and 4. The crystal structure of the extracellular domain of JAM-A continues to be used as a template to model the secondary and tertiary structure of the other members of the family. In this article, we have expressed the extracellular domains of JAMs fused with maltose-binding protein (MBP). This strategy enabled the work presented here, since JAM-B, JAM-C and JAM4 are more difficult targets due to their more hydrophobic nature. Our results indicate that each member of the JAM family has a unique tertiary structure in spite of having similar secondary structures. Surface plasmon resonance (SPR) revealed that heterotypic interactions among JAM family members can be greatly favored compared to homotypic interactions. We employ the well characterized epithelial cadherin (E-CAD) as a means to evaluate the adhesive properties of JAMs. We present strong evidence that suggests that homotypic or heterotypic interactions among JAMs are stronger than that of E-CADs.
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Affiliation(s)
- Christopher Mendoza
- Department of Physiology and Developmental Biology, College of Life Sciences, Brigham Young University, Provo, UT 84602, USA;
| | - Sai Harsha Nagidi
- Department of Molecular Microbiology, College of Life Sciences, Brigham Young University, Provo, UT 84602, USA;
| | - Dario Mizrachi
- Department of Physiology and Developmental Biology, College of Life Sciences, Brigham Young University, Provo, UT 84602, USA;
- Correspondence:
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Development of a Novel Weighted Ranking Method for Immunohistochemical Quantification of a Heterogeneously Expressed Protein in Gastro-Esophageal Cancers. Cancers (Basel) 2021; 13:cancers13061286. [PMID: 33805812 PMCID: PMC7998246 DOI: 10.3390/cancers13061286] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 03/06/2021] [Accepted: 03/10/2021] [Indexed: 11/29/2022] Open
Abstract
Simple Summary High levels of the protein Junctional Adhesion Molecule-A (JAM-A) have been linked with aggressive disease in patients with several different cancers. However, its distribution is often non-uniform (heterogeneous) across tumors, and can be difficult to quantify. JAM-A has also been linked with high levels of HER2 (an important oncogene) in breast tumors, and the development of resistance to HER2-targeted drugs in those patients. Since gastro-esophageal (GE) cancers are often high in HER2 and have also been approved for HER2-targeted drugs, the aim of this study was to investigate if levels of JAM-A and HER2 are linked in GE cancer. JAM-A was expressed very heterogeneously across miniaturized tissue sections called tissue microarrays (TMAs) of GE cancer patients. In this model, therefore, there was no correlation between JAM-A and HER2 expression. However, when we used larger tissue sections and developed a scoring system to account for heterogeneity, a significant correlation between JAM-A and HER2 levels emerged. This work illustrates the importance of taking intra-tumor heterogeneity into account, particularly in an era when analysis of protein levels by this method is increasingly used to select patients for targeted cancer drugs. Abstract High expression of Junctional Adhesion Molecule-A (JAM-A) has been linked with poor prognosis in several cancers, including breast cancers overexpressing the human epidermal growth factor receptor-2 (HER2). Furthermore, JAM-A expression has been linked with regulating that of HER2, and associated with the development of resistance to HER2-targeted therapies in breast cancer patients. The purpose of this study was to establish a potential relationship between JAM-A and HER2 in HER2-overexpressing gastro-esophageal (GE) cancers. Interrogation of gene expression datasets revealed that high JAM-A mRNA expression was associated with poorer survival in HER2-positive gastric cancer patients. However, high intra-tumoral heterogeneity of JAM-A protein expression was noted upon immunohistochemical scoring of a GE cancer tissue microarray (TMA), precluding a simple confirmation of any relationship between JAM-A and HER2 at protein level. However, in a test-set of 25 full-face GE cancer tissue sections, a novel weighted ranking system proved effective in capturing JAM-A intra-tumoral heterogeneity and confirming statistically significant correlations between JAM-A/HER2 expression. Given the growing importance of immunohistochemistry in stratifying cancer patients for the receipt of new targeted therapies, this may sound a cautionary note against over-relying on cancer TMAs in biomarker discovery studies of heterogeneously expressed proteins. It also highlights a timely need to develop validated mechanisms of capturing intra-tumoral heterogeneity to aid in future biomarker/therapeutic target development for the benefit of cancer patients.
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Kim J, Cooper JA. Junctional Localization of Septin 2 Is Required for Organization of Junctional Proteins in Static Endothelial Monolayers. Arterioscler Thromb Vasc Biol 2021; 41:346-359. [PMID: 33147991 PMCID: PMC7769918 DOI: 10.1161/atvbaha.120.315472] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 10/20/2020] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Septin 2 is localized at junctions in human microvascular endothelial monolayers. The junctional localization of septin 2 is necessary for organization of cell-cell adhesion proteins of endothelial cells. Approach and Results: Septin 2 was depleted at junctions by suppression of expression using shRNA, treatment with inflammatory cytokine, TNF (tumor necrosis factor)-α, and ectopic overexpression of septin 2 phosphatidylinositol 4,5-bisphosphate binding mutant defect in interaction with plasma membrane. Under those conditions, organizations and expression levels of various junctional proteins were analyzed. Confocal images of immunofluorescence staining showed substantial disorganization of adherens junctional proteins, nectin-2 and afadin, TJP (tight junction protein), ZO (zonula occludens)-1, and intercellular adhesion protein, PECAM-1 (platelet-endothelial cell adhesion molecule-1). Immunoblots for those proteins did not show significant changes in expression except for nectin-2 that highly increased in expression. Significant differential gene expression profiles and biological pathway analysis by septin 2 suppression and by TNF-α treatment using RNA-seq showed common overlapping pathways. The commonalities in expression may be consistent with the similar effects on the overall organization of cell-cell adhesion proteins. CONCLUSIONS Localization of septin 2 at cell junctions are required for the arrangement of junctional proteins and the integrity of the barrier formed by endothelial monolayers.
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Affiliation(s)
- Joanna Kim
- Department of Biochemistry & Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO, USA
| | - John A. Cooper
- Department of Biochemistry & Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO, USA
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Role of tight junctions in the epithelial-to-mesenchymal transition of cancer cells. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2020; 1863:183503. [PMID: 33189716 DOI: 10.1016/j.bbamem.2020.183503] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 10/20/2020] [Accepted: 10/21/2020] [Indexed: 12/15/2022]
Abstract
The epithelial-mesenchymal transition (EMT) is an essential step in cancer progression. Epithelial cells possess several types of cell-cell junctions, and tight junctions are known to play important roles in maintaining the epithelial program. EMT is characterized by a loss of epithelial markers, including E-cadherin and tight junction proteins. Somewhat surprisingly, the evidence is accumulating that upregulated expression of tight junction proteins plays an important role in the EMT of cancer cells. Tight junctions have distinct tissue-specific and cancer-specific regulatory mechanisms, enabling them to play different roles in EMT. Tight junctions and related signaling pathways are attractive targets for cancer treatments; signal transduction inhibitors and monoclonal antibodies for tight junction proteins may be used to suppress EMT, invasion, and metastasis. Here we review the role of bicellular and tricellular tight junction proteins during EMT. Further investigation of regulatory mechanisms of tight junctions during EMT in cancer cells will inform the development of biomarkers for predicting prognosis as well as novel therapies.
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Khurana N, Pulsipher A, Jedrzkiewicz J, Ashby S, Pollard CE, Ghandehari H, Alt JA. Inflammation-driven vascular dysregulation in chronic rhinosinusitis. Int Forum Allergy Rhinol 2020; 11:976-983. [PMID: 33135871 DOI: 10.1002/alr.22723] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 09/24/2020] [Accepted: 10/13/2020] [Indexed: 11/11/2022]
Abstract
BACKGROUND Altered neovascularity is typically observed in chronic inflammatory diseases with overlapping pathophysiology to that observed in chronic rhinosinusitis (CRS). However, characterization of these inflammatory-induced vascular-mediated changes in CRS is limited. Understanding the underlying vascular changes in CRS will allow for strategic design and development of new drug-delivery technologies that exploit vascular permeability for increased extravasation into the target sinonasal tissues. METHODS Patients with CRS with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP) and non-CRS controls were enrolled in this prospective, observational study. The extent of angiogenesis in tissue was characterized using immunohistochemical and multiplex gene expression analyses. Vascular permeability, interendothelial junction structures, and endothelial barrier morphology were evaluated using transmission electron microscopy. RESULTS Sinonasal vascularity was increased significantly in CRSsNP and CRSwNP (p < 0.05) when compared with controls, as assessed by enumerating the platelet endothelial cell adhesion molecule (PECAM-1)-positive blood vessels. Pro-angiogenic gene expression, including PECAM1 and platelet-activating factor receptor, was elevated significantly in patients with CRSwNP when compared with controls (p < 0.05). The fenestration sizes between endothelial cells (17-280 nm) were larger in CRSwNP compared with CRSsNP (10-33 nm) patients and controls (4-12 nm). Global thinning of the endothelial cell lining was observed in CRS patients but not in controls. CONCLUSION Significant increases in vascularity, the pro-angiogenic gene, and protein expression and blood vessel morphogenesis were observed in CRS patients compared with controls. In addition, fenestration sizes between interendothelial junction structures were larger in CRS patients than in controls, suggesting inflammation-driven vascular dysregulation in CRS pathology.
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Affiliation(s)
- Nitish Khurana
- Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT.,Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT
| | - Abigail Pulsipher
- Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT.,Sinus and Skull Base Surgery Program, Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Utah, Salt Lake City, UT
| | | | - Shaelene Ashby
- Sinus and Skull Base Surgery Program, Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Utah, Salt Lake City, UT
| | - Chelsea E Pollard
- Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT.,Sinus and Skull Base Surgery Program, Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Utah, Salt Lake City, UT
| | - Hamidreza Ghandehari
- Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT.,Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT.,Sinus and Skull Base Surgery Program, Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Utah, Salt Lake City, UT.,Department of Biomedical Engineering, University of Utah, Salt Lake City, UT
| | - Jeremiah A Alt
- Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT.,Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT.,Sinus and Skull Base Surgery Program, Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Utah, Salt Lake City, UT.,Department of Biomedical Engineering, University of Utah, Salt Lake City, UT
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Chambers JM, Wingert RA. Advances in understanding vertebrate nephrogenesis. Tissue Barriers 2020; 8:1832844. [PMID: 33092489 PMCID: PMC7714473 DOI: 10.1080/21688370.2020.1832844] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 10/01/2020] [Accepted: 10/01/2020] [Indexed: 02/07/2023] Open
Abstract
The kidney is a complex organ that performs essential functions such as blood filtration and fluid homeostasis, among others. Recent years have heralded significant advancements in our knowledge of the mechanisms that control kidney formation. Here, we provide an overview of vertebrate renal development with a focus on nephrogenesis, the process of generating the epithelialized functional units of the kidney. These steps begin with intermediate mesoderm specification and proceed all the way to the terminally differentiated nephron cell, with many detailed stages in between. The establishment of nephron architecture with proper cellular barriers is vital throughout these processes. Continuously striving to gain further insights into nephrogenesis can ultimately lead to a better understanding and potential treatments for developmental maladies such as Congenital Anomalies of the Kidney and Urinary Tract (CAKUT).
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Affiliation(s)
- Joseph M. Chambers
- Department of Biological Sciences, Center for Stem Cells and Regenerative Medicine, Center for Zebrafish Research, Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN, USA
| | - Rebecca A. Wingert
- Department of Biological Sciences, Center for Stem Cells and Regenerative Medicine, Center for Zebrafish Research, Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN, USA
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46
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Pujari A, Smith AF, Hall JD, Mei P, Chau K, Nguyen DT, Sweet DT, Jiménez JM. Lymphatic Valves Separate Lymph Flow Into a Central Stream and a Slow-Moving Peri-Valvular Milieu. J Biomech Eng 2020; 142:100805. [PMID: 32766737 PMCID: PMC7477708 DOI: 10.1115/1.4048028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 07/28/2020] [Indexed: 01/09/2023]
Abstract
The lymphatic system plays a pivotal role in the transport of fats, waste, and immune cells, while also serving as a metastatic route for select cancers. Using live imaging and particle tracking, we experimentally characterized the lymph flow field distal from the inguinal lymph node in the vicinity of normal bileaflet and malformed unileaflet intraluminal valves. Particle tracking experiments demonstrated that intraluminal lymphatic valves concentrate higher velocity lymph flow in the center of the vessel, while generating adjacent perivalvular recirculation zones. The recirculation zones are characterized by extended particle residence times and low wall shear stress (WSS) magnitudes in comparison to the rest of the lymphangion. A malformed unileaflet valve skewed lymph flow toward the endothelium on the vessel wall, generating a stagnation point and a much larger recirculation zone on the opposite wall. These studies define physical consequences of bileaflet and unileaflet intraluminal lymphatic valves that affect lymph transport and the generation of a heterogeneous flow field that affects the lymphatic endothelium nonuniformly. The characterized flow fields were recreated in vitro connecting different flow environments present in the lymphangion to a lymphatic endothelial cell (LEC) pro-inflammatory phenotype. Unique and detailed insight into lymphatic flow is provided, with potential applications to a variety of diseases that affect lymph transport and drug delivery.
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Affiliation(s)
- Akshay Pujari
- Department of Mechanical and Industrial Engineering, University of Massachusetts, Amherst, MA 01003
| | - Alexander F. Smith
- Department of Mechanical and Industrial Engineering, University of Massachusetts, Amherst, MA 01003
| | - Joshua D. Hall
- Department of Mechanical and Industrial Engineering, University of Massachusetts, Amherst, MA 01003
| | - Patrick Mei
- Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, MA 01003
| | - Kin Chau
- Department of Mechanical and Industrial Engineering, University of Massachusetts, Amherst, MA 01003
| | - Duy T. Nguyen
- Department of Mechanical and Industrial Engineering, University of Massachusetts, Amherst, MA 01003
| | - Daniel T. Sweet
- Department of Medicine and Division of Cardiology, University of Pennsylvania, Philadelphia, PA 19104
| | - Juan M. Jiménez
- Department of Mechanical and Industrial Engineering, University of Massachusetts, N575 Life Sciences Laboratory,240 Thatcher Way Amherst Amherst, MA 01003; Department of Biomedical Engineering, University of Massachusetts, Amherst, MA 01003
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47
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Vandereyken M, James OJ, Swamy M. Mechanisms of activation of innate-like intraepithelial T lymphocytes. Mucosal Immunol 2020; 13:721-731. [PMID: 32415229 PMCID: PMC7434593 DOI: 10.1038/s41385-020-0294-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Revised: 04/09/2020] [Accepted: 04/11/2020] [Indexed: 02/04/2023]
Abstract
Intraepithelial T lymphocytes (T-IEL) contain subsets of innate-like T cells that evoke innate and adaptive immune responses to provide rapid protection at epithelial barrier sites. In the intestine, T-IEL express variable T cell antigen receptors (TCR), with unknown antigen specificities. Intriguingly, they also express multiple inhibitory receptors, many of which are normally found on exhausted or antigen-experienced T cells. This pattern suggests that T-IEL are antigen-experienced, yet it is not clear where, and in what context, T-IEL encounter TCR ligands. We review recent evidence indicating TCR antigens for intestinal innate-like T-IEL are found on thymic or intestinal epithelium, driving agonist selection of T-IEL. We explore the contributions of the TCR and various co-stimulatory and co-inhibitory receptors in activating T-IEL effector functions. The balance between inhibitory and activating signals may be key to keeping these highly cytotoxic, rapidly activated cells in check, and key to harnessing their immune surveillance potential.
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Affiliation(s)
- Maud Vandereyken
- MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK
| | - Olivia J James
- MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK
| | - Mahima Swamy
- MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
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Hartmann C, Schwietzer YA, Otani T, Furuse M, Ebnet K. Physiological functions of junctional adhesion molecules (JAMs) in tight junctions. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2020; 1862:183299. [DOI: 10.1016/j.bbamem.2020.183299] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 03/25/2020] [Accepted: 03/28/2020] [Indexed: 12/24/2022]
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49
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Lauko A, Mu Z, Gutmann DH, Naik UP, Lathia JD. Junctional Adhesion Molecules in Cancer: A Paradigm for the Diverse Functions of Cell-Cell Interactions in Tumor Progression. Cancer Res 2020; 80:4878-4885. [PMID: 32816855 DOI: 10.1158/0008-5472.can-20-1829] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 07/15/2020] [Accepted: 08/07/2020] [Indexed: 01/22/2023]
Abstract
Tight junction (TJ) proteins are essential for mediating interactions between adjacent cells and coordinating cellular and organ responses. Initial investigations into TJ proteins and junctional adhesion molecules (JAM) in cancer suggested a tumor-suppressive role where decreased expression led to increased metastasis. However, recent studies of the JAM family members JAM-A and JAM-C have expanded the roles of these proteins to include protumorigenic functions, including inhibition of apoptosis and promotion of proliferation, cancer stem cell biology, and epithelial-to-mesenchymal transition. JAM function by interacting with other proteins through three distinct molecular mechanisms: direct cell-cell interaction on adjacent cells, stabilization of adjacent cell surface receptors on the same cell, and interactions between JAM and cell surface receptors expressed on adjacent cells. Collectively, these diverse interactions contribute to both the pro- and antitumorigenic functions of JAM. In this review, we discuss these context-dependent functions of JAM in a variety of cancers and highlight key areas that remain poorly understood, including their potentially diverse intracellular signaling networks, their roles in the tumor microenvironment, and the consequences of posttranslational modifications on their function. These studies have implications in furthering our understanding of JAM in cancer and provide a paradigm for exploring additional roles of TJ proteins.
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Affiliation(s)
- Adam Lauko
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.,Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio.,Department of Pathology, Case Western Reserve University, Cleveland, Ohio
| | - Zhaomei Mu
- Cardeza Center for Vascular Biology, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - David H Gutmann
- Washington University School of Medicine, St. Louis, Missouri
| | - Ulhas P Naik
- Cardeza Center for Vascular Biology, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania.
| | - Justin D Lathia
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio. .,Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio.,Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.,Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio
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50
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Peligero-Cruz C, Givony T, Sebé-Pedrós A, Dobeš J, Kadouri N, Nevo S, Roncato F, Alon R, Goldfarb Y, Abramson J. IL18 signaling promotes homing of mature Tregs into the thymus. eLife 2020; 9:e58213. [PMID: 32687059 PMCID: PMC7371425 DOI: 10.7554/elife.58213] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 07/03/2020] [Indexed: 12/22/2022] Open
Abstract
Foxp3+ regulatory T cells (Tregs) are potent suppressor cells, essential for the maintenance of immune homeostasis. Most Tregs develop in the thymus and are then released into the immune periphery. However, some Tregs populate the thymus and constitute a major subset of yet poorly understood cells. Here we describe a subset of thymus recirculating IL18R+ Tregs with molecular characteristics highly reminiscent of tissue-resident effector Tregs. Moreover, we show that IL18R+ Tregs are endowed with higher capacity to populate the thymus than their IL18R- or IL18R-/- counterparts, highlighting the key role of IL18R in this process. Finally, we demonstrate that IL18 signaling is critical for the induction of the key thymus-homing chemokine receptor - CCR6 on Tregs. Collectively, this study provides a detailed characterization of the mature Treg subsets in the mouse thymus and identifies a key role of IL18 signaling in controlling the CCR6-CCL20-dependent migration of Tregs into the thymus.
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Affiliation(s)
| | - Tal Givony
- Department of Immunology, Weizmann Institute of ScienceRehovotIsrael
| | - Arnau Sebé-Pedrós
- Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST)BarcelonaSpain
- Universitat Pompeu Fabra (UPF)BarcelonaSpain
| | - Jan Dobeš
- Department of Immunology, Weizmann Institute of ScienceRehovotIsrael
| | - Noam Kadouri
- Department of Immunology, Weizmann Institute of ScienceRehovotIsrael
| | - Shir Nevo
- Department of Immunology, Weizmann Institute of ScienceRehovotIsrael
| | - Francesco Roncato
- Department of Immunology, Weizmann Institute of ScienceRehovotIsrael
| | - Ronen Alon
- Department of Immunology, Weizmann Institute of ScienceRehovotIsrael
| | - Yael Goldfarb
- Department of Immunology, Weizmann Institute of ScienceRehovotIsrael
| | - Jakub Abramson
- Department of Immunology, Weizmann Institute of ScienceRehovotIsrael
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