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Nan G, Wang B, Lv X, Wang W, Luo Z, Yang G, Ding R, Wang J, Lin R, Wang H. Effects of Rhaponticum carthamoides (Willd.) Iljin on endothelial dysfunction and the inflammatory response in type 2 diabetes mellitus mice. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:156134. [PMID: 39418973 DOI: 10.1016/j.phymed.2024.156134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 09/29/2024] [Accepted: 10/06/2024] [Indexed: 10/19/2024]
Abstract
BACKGROUND Diabetes mellitus (DM) and its complications seriously threaten human life and health. Rhaponticum carthamoides (Willd.) Iljin (RC) is widely used to treat cardiovascular diseases. Previous studies reported that RC reduces blood glucose levels in rats with type 1 DM. However, the effects of RC on type 2 diabetes and vascular complications, as well as its related active components and underlying mechanisms, remain unclear. PURPOSE This study aimed to investigate the effects of RC on endothelial dysfunction and the inflammatory response in type 2 DM mice and to explore its underlying mechanism and active ingredients. STUDY DESIGN/METHODS Male C57BL/6J mice were used to establish a type 2 DM mouse model. After 12 weeks of oral administration of RC extract (60, 120, and 240 mg/kg) to mice, blood glucose and lipid levels were assessed. The morphological structures of the liver and kidney tissues were observed using hematoxylin and eosin (HE) staining, and their functions were evaluated by detecting relevant biochemical indicators in the serum. Then, aorta morphology was observed via HE staining. In addition, serum levels of markers of endothelial function and inflammatory factors were detected, and the expression of inflammatory factors and the phosphorylation levels of key proteins in the aorta were examined. Furthermore, prediction and enrichment analyses of potential targets of RC acting on diabetic vascular lesions were performed on the basis of pharmacophore matching using various databases. Then, the expression, localization and phosphorylation levels of potential targets in the aortas of DM mice treated with RC were assessed using Western blotting, immunofluorescence, and RT‒PCR. Finally, the active components of RC were identified through virtual screening, and their ability to improve endothelial cell dysfunction was verified. RESULTS RC reduced blood glucose levels and serum lipid levels of total triglyceride (TG), total cholesterol (TC), and low density lipoprotein cholesterol (LDL-c), increased high density lipoprotein cholesterol (HDL-c) levels, and improved liver and kidney function in type 2 DM mice. RC decreased endothelial cell shedding in the aortas of type 2 DM mice, increased serum nitric oxide (NO) and nitric oxide synthase (NOS) levels, and reduced soluble cluster of differentiation 40 ligand (sCD40L), tumor necrosis factor α (TNF-α), and interleukin-1β (IL-1β) levels. Further findings indicated that RC reduced the expression of aortic inflammatory factors, namely, CD40, CD40L, IL-1β, and interleukin-6 (IL-6), and increased endothelial NOS (eNOS) phosphorylation levels. Sirtuin 6 (SIRT6), protein kinase B (AKT), and eNOS were predicted to be key node targets of RC acting on DM vascular lesions, and it was confirmed that RC increased SIRT6 expression and AKT phosphorylation levels in aortic endothelial cells. 20-Hydroxyecdysone (20E), daucosterol (Dau), euscaphic acid (Eus), and syringin (Syr) were identified as active components of RC. These components protect against TNF-α-induced human umbilical vein endothelial cell (HUVEC) damage and decrease the release of lactate dehydrogenase (LDH) and IL-1β and increased the release of NO in TNF-α-induced HUVECs in a dose-dependent manner. CONCLUSION RC reduced blood glucose and lipid levels in mice with type 2 DM and protected liver and kidney function. RC promotes SIRT6 expression in endothelial cells; upregulates the NO/NOS system by increasing AKT/eNOS phosphorylation levels to regulate vascular tone factors; and reduces the levels of inflammatory factors such as CD40, TNF-α, and IL-1β to inhibit endothelial inflammatory responses. Based on these mechanisms, RC improves endothelial dysfunction.
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Affiliation(s)
- Guanjun Nan
- School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, PR China
| | - Bo Wang
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, PR China
| | - Xiaohan Lv
- Department of Pharmacy, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, PR China
| | - Weirong Wang
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, PR China
| | - Zhimin Luo
- School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, PR China
| | - Guangde Yang
- School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, PR China
| | - Rongcheng Ding
- Xinjiang Rongcheng Hake Pharmaceutical Co. Ltd, Altay region, 836500, Xinjiang, PR China
| | - Jianjiang Wang
- Xinjiang Rongcheng Hake Pharmaceutical Co. Ltd, Altay region, 836500, Xinjiang, PR China
| | - Rong Lin
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, PR China.
| | - Haichen Wang
- Department of Cardiovascular Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, PR China.
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Tian S, Wang Y, Wan J, Yang M, Fu Z. Co-stimulators CD40-CD40L, a potential immune-therapy target for atherosclerosis: A review. Medicine (Baltimore) 2024; 103:e37718. [PMID: 38579073 PMCID: PMC10994492 DOI: 10.1097/md.0000000000037718] [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: 11/02/2023] [Accepted: 03/04/2024] [Indexed: 04/07/2024] Open
Abstract
The interaction between CD40 and CD40 ligand (CD40L) a crucial co-stimulatory signal for activating adaptive immune cells, has a noteworthy role in atherosclerosis. It is well-known that atherosclerosis is linked to immune inflammation in blood vessels. In atherosclerotic lesions, there is a multitude of proinflammatory cytokines, adhesion molecules, and collagen, as well as smooth muscle cells, macrophages, and T lymphocytes, particularly the binding of CD40 and CD40L. Therefore, research on inhibiting the CD40-CD40L system to prevent atherosclerosis has been ongoing for more than 30 years. However, it's essential to note that long-term direct suppression of CD40 or CD40L could potentially result in immunosuppression, emphasizing the critical role of the CD40-CD40L system in atherosclerosis. Thus, specifically targeting the CD40-CD40L interaction on particular cell types or their downstream signaling pathways may be a robust strategy for mitigating atherosclerosis, reducing potential side effects. This review aims to summarize the potential utility of the CD40-CD40L system as a viable therapeutic target for atherosclerosis.
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Affiliation(s)
- Simeng Tian
- Department of Immunology, Basic Medicine College, Heilongjiang Provincial Key Laboratory for Infection and Immunity, Harbin Medical University, Heilongjiang Academy of Medical Science, Harbin, China
- The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yufei Wang
- Department of Neurosurgery & Nursing Teaching and Research Office, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jie Wan
- Department of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Mao Yang
- Department of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhenkun Fu
- Department of Immunology, Basic Medicine College, Heilongjiang Provincial Key Laboratory for Infection and Immunity, Harbin Medical University, Heilongjiang Academy of Medical Science, Harbin, China
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Yamakawa N, Komatsu H, Usui Y, Tsubota K, Wakabayashi Y, Goto H. Immune Mediators Profiles in the Aqueous Humor of Patients with Simple Diabetic Retinopathy. J Clin Med 2023; 12:6931. [PMID: 37959396 PMCID: PMC10650684 DOI: 10.3390/jcm12216931] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 11/02/2023] [Accepted: 11/03/2023] [Indexed: 11/15/2023] Open
Abstract
Various immune mediators identified to date are associated with the development of advanced forms of diabetic retinopathy (DR), such as proliferative DR and diabetic macular edema, although the exact pathophysiological mechanisms of early stages of DR such as simple DR remain unclear. We determined the immune mediator profile in the aqueous humor of eyes with simple DR. Fifteen eyes of fifteen patients with simple DR were studied. Twenty-two eyes of twenty-two patients with cataracts and no DR served as controls. Undiluted aqueous humor samples were collected, and a cytometric bead array was used to determine the aqueous humor concentrations of 32 immune mediators comprising 13 interleukins (IL), interferon-γ, interferon-γ-inducible protein-10 (IP-10), monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-1α, MIP-1β, regulated on activation, normal T cell expressed and secreted (RANTES), monokine induced by interferon-γ, basic fibroblast growth factor (bFGF), Fas ligand, granzyme A, granzyme B, interferon-inducible T-cell alpha chemoattractant (ITAC), fractalkine, granulocyte macrophage colony-stimulating factor, granulocyte colony-stimulating factor (G-CSF), vascular endothelial growth factor (VEGF), angiogenin, tumor necrosis factor-α, and CD40 ligand. Among the 32 immune mediators, 10 immune mediators, including bFGF, CD40 ligand, fractalkine, G-CSF, IL-6, IL-8, MIP-α, MIP-1β, and VEGF, showed significantly higher aqueous humor concentrations and the Fas ligand had significantly lower concentration (p < 0.05) in eyes with simple DR compared with control eyes. Of these 10 cytokines with significant concentration alteration, protein-protein interaction analysis revealed that 8 established an intricate interaction network. Various immune mediators may contribute to the pathogenesis of simple DR. Attention should be given to the concentrations of immune mediators in ocular fluids even in simple DR. Large-scale studies are warranted to assess whether altered aqueous humor concentrations of these 10 immune mediators are associated with an increased risk of progression to advanced stages of DR.
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Affiliation(s)
| | | | - Yoshihiko Usui
- Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan; (N.Y.); (H.K.); (K.T.); (Y.W.); (H.G.)
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Siwaponanan P, Kaewkumdee P, Sudcharee P, Udompunturak S, Chomanee N, Udol K, Pattanapanyasat K, Krittayaphong R. Increased small extracellular vesicle levels and decreased miR-126 levels associated with atrial fibrillation and coexisting diabetes mellitus. Clin Cardiol 2023; 46:1326-1336. [PMID: 37503820 PMCID: PMC10642338 DOI: 10.1002/clc.24115] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 07/17/2023] [Accepted: 07/27/2023] [Indexed: 07/29/2023] Open
Abstract
BACKGROUND Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia. Diabetes mellitus (DM) is one of the risk factors for the development of stroke and thromboembolism in patients with AF. Early identification may reduce the incidence of complications and mortality in AF patients. HYPOTHESIS AF patients with DM have different pattern of small extracellular vesicle (sEV) levels and sEV-derived microRNA (miRNA) expression compared with those without DM. METHODS We compared sEV levels and sEV-miRNA expression in plasma from AF patients with and without DM using nanoparticle tracking analysis and droplet digital polymerase chain reaction, respectively. RESULTS We observed a significant increase in total sEV levels (p = .004) and a significant decrease in sEV-miR-126 level (p = .004) in AF patients with DM. Multivariate logistic regression analysis revealed a positive association between total sEV levels and AF with DM (p = .019), and a negative association between sEV-miR-126 level and AF with DM (p = .031). The combination of clinical data, total sEVs, and sEV-miR-126 level had an area under the curve of 0.968 (p < .0001) for discriminating AF with DM, which was shown to be significantly better than clinical data analysis alone (p = .0368). CONCLUSIONS These results suggest that an increased level of total sEV and a decreased sEV-miR-126 level may play a potential role in the pathophysiology and complications of AF with DM, especially endothelial dysfunction, and can be considered as an applied biomarker for distinguishing between AF with and without DM.
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Affiliation(s)
- Panjaree Siwaponanan
- Research DepartmentSiriraj Center of Research Excellence in Microparticles and Exosomes in Disease, Faculty of Medicine Siriraj Hospital, Mahidol UniversityBangkokThailand
| | - Pontawee Kaewkumdee
- Department of MedicineDivision of Cardiology, Faculty of Medicine Siriraj Hospital, Mahidol UniversityBangkokThailand
| | - Payalak Sudcharee
- Research DepartmentSiriraj Center of Research Excellence in Microparticles and Exosomes in Disease, Faculty of Medicine Siriraj Hospital, Mahidol UniversityBangkokThailand
| | - Suthipol Udompunturak
- Research DepartmentResearch Group and Research Network Division, Faculty of Medicine Siriraj Hospital, Mahidol University BangkokThailand
| | - Nusara Chomanee
- Department of PathologyFaculty of Medicine Siriraj Hospital, Mahidol UniversityBangkokThailand
| | - Kamol Udol
- Department of Preventive and Social MedicineFaculty of Medicine Siriraj Hospital, Mahidol UniversityBangkokThailand
| | - Kovit Pattanapanyasat
- Research DepartmentSiriraj Center of Research Excellence in Microparticles and Exosomes in Disease, Faculty of Medicine Siriraj Hospital, Mahidol UniversityBangkokThailand
| | - Rungroj Krittayaphong
- Department of MedicineDivision of Cardiology, Faculty of Medicine Siriraj Hospital, Mahidol UniversityBangkokThailand
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Abu El-Asrar AM, Nawaz MI, Ahmad A, Dillemans L, Siddiquei M, Allegaert E, Gikandi PW, De Hertogh G, Opdenakker G, Struyf S. CD40 Ligand-CD40 Interaction Is an Intermediary between Inflammation and Angiogenesis in Proliferative Diabetic Retinopathy. Int J Mol Sci 2023; 24:15582. [PMID: 37958563 PMCID: PMC10648257 DOI: 10.3390/ijms242115582] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 10/18/2023] [Accepted: 10/19/2023] [Indexed: 11/15/2023] Open
Abstract
We aimed to investigate the role of the CD40-CD40 ligand (CD40L) pathway in inflammation-mediated angiogenesis in proliferative diabetic retinopathy (PDR). We analyzed vitreous fluids and epiretinal fibrovascular membranes from PDR and nondiabetic patients, cultures of human retinal microvascular endothelial cells (HRMECs) and Müller glial cells and rat retinas with ELISA, immunohistochemistry, flow cytometry and Western blot analysis. Functional tests included measurement of blood-retinal barrier breakdown, in vitro angiogenesis and assessment of monocyte-HRMEC adherence. CD40L and CD40 levels were significantly increased in PDR vitreous samples. We demonstrated CD40L and CD40 expression in vascular endothelial cells, leukocytes and myofibroblasts in epiretinal membranes. Intravitreal administration of soluble (s)CD40L in normal rats significantly increased retinal vascular permeability and induced significant upregulation of phospho-ERK1/2, VEGF, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). sCD40L induced upregulation of VEGF, MMP-9, MCP-1 and HMGB1 in cultured Müller cells and phospo-ERK1/2, p65 subunit of NF-ĸB, VCAM-1 and VEGF in cultured HRMECS. TNF-α induced significant upregulation of CD40 in HRMECs and Müller cells and VEGF induced significant upregulation of CD40 in HRMECs. sCD40L induced proliferation and migration of HRMECs. We provide experimental evidence supporting the involvement of the CD40L-CD40 pathway and how it regulates inflammatory angiogenesis in PDR.
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Affiliation(s)
- Ahmed M. Abu El-Asrar
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh 11411, Saudi Arabia; (M.I.N.); (A.A.); (M.S.); (P.W.G.); (G.O.)
- Dr. Nasser Al-Rashid Research Chair in Ophthalmology, College of Medicine, King Saud University, Riyadh 11411, Saudi Arabia
| | - Mohd I. Nawaz
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh 11411, Saudi Arabia; (M.I.N.); (A.A.); (M.S.); (P.W.G.); (G.O.)
| | - Ajmal Ahmad
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh 11411, Saudi Arabia; (M.I.N.); (A.A.); (M.S.); (P.W.G.); (G.O.)
| | - Luna Dillemans
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute, University of Leuven, 3000 Leuven, Belgium; (L.D.); (S.S.)
| | - Mairaj Siddiquei
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh 11411, Saudi Arabia; (M.I.N.); (A.A.); (M.S.); (P.W.G.); (G.O.)
| | - Eef Allegaert
- Laboratory of Histochemistry and Cytochemistry, University of Leuven, 3000 Leuven, Belgium; (E.A.); (G.D.H.)
- University Hospitals UZ Gasthuisberg, 3000 Leuven, Belgium
| | - Priscilla W. Gikandi
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh 11411, Saudi Arabia; (M.I.N.); (A.A.); (M.S.); (P.W.G.); (G.O.)
| | - Gert De Hertogh
- Laboratory of Histochemistry and Cytochemistry, University of Leuven, 3000 Leuven, Belgium; (E.A.); (G.D.H.)
- University Hospitals UZ Gasthuisberg, 3000 Leuven, Belgium
| | - Ghislain Opdenakker
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh 11411, Saudi Arabia; (M.I.N.); (A.A.); (M.S.); (P.W.G.); (G.O.)
- University Hospitals UZ Gasthuisberg, 3000 Leuven, Belgium
- Laboratory of Immunobiology, Department of Microbiology, Immunology and Transplantation, Rega Institute, University of Leuven, 3000 Leuven, Belgium
| | - Sofie Struyf
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute, University of Leuven, 3000 Leuven, Belgium; (L.D.); (S.S.)
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Vos S, Aaron R, Weng M, Daw J, Rodriguez-Rivera E, Subauste CS. CD40 Upregulation in the Retina of Patients With Diabetic Retinopathy: Association With TRAF2/TRAF6 Upregulation and Inflammatory Molecule Expression. Invest Ophthalmol Vis Sci 2023; 64:17. [PMID: 37294707 PMCID: PMC10259673 DOI: 10.1167/iovs.64.7.17] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 05/16/2023] [Indexed: 06/11/2023] Open
Abstract
Purpose CD40 is upregulated in the retinas of diabetic mice, drives pro-inflammatory molecule expression, and promotes diabetic retinopathy. The role of CD40 in diabetic retinopathy in humans is unknown. Upregulation of CD40 and its downstream signaling molecules TNF receptor associated factors (TRAFs) is a key feature of CD40-driven inflammatory disorders. We examined the expression of CD40, TRAF2, and TRAF6 as well as pro-inflammatory molecules in retinas from patients with diabetic retinopathy. Methods Posterior poles from patients with diabetic retinopathy and non-diabetic controls were stained with antibodies against von Willebrand factor (labels endothelial cells), cellular retinaldehyde-binding protein (CRALBP), or vimentin (both label Müller cells) plus antibodies against CD40, TRAF2, TRAF6, ICAM-1, CCL2, TNF-α, and/or phospho-Tyr783 phospholipase Cγ1 (PLCγ1). Sections were analyzed by confocal microscopy. Results CD40 expression was increased in endothelial and Müller cells from patients with diabetic retinopathy. CD40 was co-expressed with ICAM-1 in endothelial cells and with CCL2 in Müller cells. TNF-α was detected in retinal cells from these patients, but these cells lacked endothelial/Müller cell markers. CD40 in Müller cells from patients with diabetic retinopathy co-expressed activated phospholipase Cγ1, a molecule that induces TNF-α expression in myeloid cells in mice. CD40 upregulation in endothelial cells and Müller cells from patients with diabetic retinopathy was accompanied by TRAF2 and TRAF6 upregulation. Conclusions CD40, TRAF2, and TRAF6 are upregulated in patients with diabetic retinopathy. CD40 associates with expression of pro-inflammatory molecules. These findings suggest that CD40-TRAF signaling may promote pro-inflammatory responses in the retinas of patients with diabetic retinopathy.
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Affiliation(s)
- Sarah Vos
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States
| | - Rachel Aaron
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States
| | - Matthew Weng
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States
| | - Jad Daw
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States
| | - Emmanuel Rodriguez-Rivera
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States
| | - Carlos S. Subauste
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States
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Ahmadi J, Hosseini E, Kargar F, Ghasemzadeh M. Stable CAD patients show higher levels of platelet-borne TGF-β1 associated with a superior pro-inflammatory state than the pro-aggregatory status; Evidence highlighting the importance of platelet-derived TGF-β1 in atherosclerosis. J Thromb Thrombolysis 2023; 55:102-115. [PMID: 36352058 DOI: 10.1007/s11239-022-02729-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/28/2022] [Indexed: 11/10/2022]
Abstract
Activated platelets are involved in the atherogenic stage of atherosclerosis, while they can also progress it to atherothrombosis which may cause an ischemic state and organ failure. In general, coronary artery disease (CAD) is considered as common and severe clinical consequence of atherosclerosis, manifesting as a chronic inflammatory condition with the release of platelet mediators, among which the importance of platelet-borne TGF-β1 is not yet well understood. Hence, for the first time, this study aimed to examine platelet level of TGF-β1 (latent/mature) in CAD-patients and its association with the expression of platelet pro-inflammatory molecules. Platelet from stable CAD-patients candidate for CABG and healthy controls were subjected to flowcytometry analysis to evaluate P-selectin and CD40L expressions and PAC-1 binding. Platelet-borne and soluble TGF-β1, both mature/active and latent forms were also examined with western blotting. Higher expression levels of P-selectin and CD40L in patients with CAD than in controls were associated with comparable levels of PAC-1 binding in both groups. Platelet TGF-β1 levels were also significantly higher in patients, while their platelets showed clear bands of mature TGF-β1 that were barely visible in healthy individuals. Soluble TGF-β1 was also higher in patients. Significant correlations between mature/active TGF-β1 and platelet pro-inflammatory markers (P-selectin and CD40L) as well as common indicators of inflammation (CRP and ESR) were observed in CAD patients. In this study, given the insignificant changes in pro-aggregatory potentials in stable CAD, the pro-inflammatory state of platelets may be more involved in disease development and progression. Direct correlations between active platelet-borne TGF-β1 and pro-inflammatory markers with its presence in CAD-patients, which was almost absent in the platelets of healthy individuals, may also underscore the significant contribution of platelet-borne TGF-β1 to the pathogenesis of the disease.
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Affiliation(s)
- Javad Ahmadi
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Ehteramolsadat Hosseini
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Faranak Kargar
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Science, Tehran, Iran
| | - Mehran Ghasemzadeh
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran. .,Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Iranian Blood Transfusion Organization Building, Next to the Milad Tower, Hemmat Exp. Way, P.O.Box:14665-1157, Tehran, Iran.
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Méndez-Frausto G, Godina-González S, Rivas-Santiago CE, Nungaray-Anguiano E, Mendoza-Almanza G, Rivas-Santiago B, Galván-Tejada CE, Gonzalez-Curiel IE. Downregulation of sCD40 and sCTLA4 in Recovered COVID-19 Patients with Comorbidities. Pathogens 2022; 11:pathogens11101128. [PMID: 36297185 PMCID: PMC9608172 DOI: 10.3390/pathogens11101128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/15/2022] [Accepted: 09/26/2022] [Indexed: 11/07/2022] Open
Abstract
The aim of this study was to analyze molecules associated with regulatory immune response in unvaccinated, recovered COVID-19 patients with and without diabetes mellitus (DM) and hypertension (HTN). We determined anti-SARS-CoV-2 nucleocapsid IgG in plasma by electrochemiluminescence immunoassay. The levels of sCD40, TGF-ß, IL-10, and sCTLA-4 were assessed by ELISA in the serum of the subjects, as well as in healthy donors. We observed that only half of the subjects in the non-comorbid group produced antibodies, whereas all subjects in comorbid groups were IgG-positive for the anti-SARS-CoV-2 nucleocapsid. High levels of sCTL-4 were observed in the non-comorbid group, and the level of IL-10 was observed to increase in seropositive subjects without comorbidities. TGF-ß concentration was similar in all groups studied. Finally, sCD40 decreased in the comorbid group. In conclusion, our results suggest that comorbidities such as DM and HTN alter the production of co-stimulatory inhibitory molecules sCTLA-4 and sCD40 in subjects recovering from mild COVID-19. The alterations observed here were independent of seropositivity, suggesting an effective humoral immune response against COVID-19 separate from the levels of co-stimulatory inhibitory molecules.
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Affiliation(s)
- Gwendolyne Méndez-Frausto
- Laboratorio de Inmunotoxicología y Terapéutica Experimental, Unidad Académica de Ciencias Químicas, Universidad Autónoma de Zacatecas, Zacatecas 98160, Mexico
| | - Susana Godina-González
- Laboratorio de Biomarcadores, Unidad Académica de Ciencias Químicas, Universidad Autónoma de Zacatecas, Zacatecas 98160, Mexico
| | - César E. Rivas-Santiago
- CONACYT-Academic Unit of Chemical Sciences, Autonomous University of Zacatecas, Zacatecas 98160, Mexico
| | - Edna Nungaray-Anguiano
- Laboratorio de Inmunotoxicología y Terapéutica Experimental, Unidad Académica de Ciencias Químicas, Universidad Autónoma de Zacatecas, Zacatecas 98160, Mexico
| | - Gretel Mendoza-Almanza
- CONACYT-Academic Unit of Chemical Sciences, Autonomous University of Zacatecas, Zacatecas 98160, Mexico
| | | | - Carlos E. Galván-Tejada
- Unidad Académica de Ingeniería Eléctrica, Universidad Autónoma de Zacatecas, Zacatecas 98000, Mexico
| | - Irma E. Gonzalez-Curiel
- Laboratorio de Inmunotoxicología y Terapéutica Experimental, Unidad Académica de Ciencias Químicas, Universidad Autónoma de Zacatecas, Zacatecas 98160, Mexico
- Correspondence: ; Tel.: +52-492-1324310
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Hehenkamp P, Hoffmann M, Kummer S, Reinauer C, Döing C, Förtsch K, Enczmann J, Balz V, Mayatepek E, Meissner T, Jacobsen M, Seyfarth J. Interleukin-7-dependent nonclassical monocytes and CD40 expression are affected in children with type 1 diabetes. Eur J Immunol 2021; 51:3214-3227. [PMID: 34625948 DOI: 10.1002/eji.202149229] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 08/13/2021] [Accepted: 10/04/2021] [Indexed: 12/18/2022]
Abstract
The important role of IL-7 in the generation of self-reactive T-cells in autoimmune diseases is well established. Recent studies on autoimmunity-associated genetic polymorphisms indicated that differential IL-7 receptor (IL-7R) expression of monocytes may play a role in the underlying pathogenesis. The relevance of IL-7-mediated monocyte functions in type 1 diabetes remains elusive. In the present study, we characterized monocyte phenotype and IL-7-mediated effects in children with type 1 diabetes and healthy controls with multicolor flow cytometry and t-distributed Stochastic Neighbor-Embedded (t-SNE)-analyses. IL-7R expression of monocytes rapidly increased in vitro and was boosted through LPS. In the presence of IL-7, we detected lower monocyte IL-7R expression in type 1 diabetes patients as compared to healthy controls. This difference was most evident for the subset of nonclassical monocytes, which increased after IL-7 stimulation. t-SNE analyses revealed IL-7-dependent differences in monocyte subset distribution and expression of activation and maturation markers (i.e., HLA-DR, CD80, CD86, CD40). Notably, monocyte CD40 expression increased considerably by IL-7 and CD40/IL-7R co-expression differed between patients and controls. This study shows the unique effects of IL-7 on monocyte phenotype and functions. Lower IL-7R expression on IL-7-induced CD40high monocytes and impaired IL-7 response characterize monocytes from patients with type 1 diabetes.
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Affiliation(s)
- Paul Hehenkamp
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany
| | - Maximilian Hoffmann
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany
| | - Sebastian Kummer
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany
| | - Christina Reinauer
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany
| | - Carsten Döing
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany
| | - Katharina Förtsch
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany
| | - Jürgen Enczmann
- Institute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, University Hospital, Duesseldorf, Germany
| | - Vera Balz
- Institute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, University Hospital, Duesseldorf, Germany
| | - Ertan Mayatepek
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany
| | - Thomas Meissner
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany
| | - Marc Jacobsen
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany
| | - Julia Seyfarth
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany
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10
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Yu JS, Daw J, Portillo JAC, Subauste CS. CD40 Expressed in Endothelial Cells Promotes Upregulation of ICAM-1 But Not Pro-Inflammatory Cytokines, NOS2 and P2X7 in the Diabetic Retina. Invest Ophthalmol Vis Sci 2021; 62:22. [PMID: 34546322 PMCID: PMC8458989 DOI: 10.1167/iovs.62.12.22] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose CD40 is an upstream inducer of inflammation in the diabetic retina. CD40 is upregulated in retinal endothelial cells in diabetes. The purpose of this study was to determine whether expression of CD40 in endothelial cells is sufficient to promote inflammatory responses in the retina of diabetic mice. Methods Transgenic mice with CD40 expression restricted to endothelial cells (Trg-CD40 EC), transgenic control mice (Trg-Ctr), B6, and CD40−/− mice were made diabetic using streptozotocin. Leukostasis was assessed using FITC-conjugated ConA. Pro-inflammatory molecule expression was examined by real-time PCR, immunohistochemistry, ELISA, or flow cytometry. Release of ATP was assessed by ATP bioluminescence. Results Diabetic B6 and Trg-CD40 EC mice exhibited increased retinal mRNA levels of ICAM-1, higher ICAM-1 expression in endothelial cells, and increased leukostasis. These responses were not detected in diabetic mice that lacked CD40 (CD40−/− and Trg-Ctr). Diabetic B6 but not Trg-CD40 EC mice upregulated TNF-α, IL-1β, and NOS2 mRNA levels. CD40 stimulation in retinal endothelial cells upregulated ICAM-1 but not TNF-α, IL-1β, or NOS2. CD40 ligation did not trigger ATP release by retinal endothelial cells or pro-inflammatory cytokine production in bystander myeloid cells. In contrast to diabetic B6 mice, diabetic Trg-CD40 EC mice did not upregulate P2X7 mRNA levels in the retina. Conclusions Endothelial cell CD40 promotes ICAM-1 upregulation and leukostasis. In contrast, endothelial cell CD40 does not lead to pro-inflammatory cytokine and NOS2 upregulation likely because it does not activate purinergic-mediated pro-inflammatory molecule expression by myeloid cells or induce expression of these pro-inflammatory molecules in endothelial cells.
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Affiliation(s)
- Jin-Sang Yu
- Division of Infectious Diseases and HIV Medicine, Dept. of Medicine, Case Western Reserve University, Cleveland, Ohio, United States
| | - Jad Daw
- Division of Infectious Diseases and HIV Medicine, Dept. of Medicine, Case Western Reserve University, Cleveland, Ohio, United States
| | - Jose-Andres C Portillo
- Division of Infectious Diseases and HIV Medicine, Dept. of Medicine, Case Western Reserve University, Cleveland, Ohio, United States
| | - Carlos S Subauste
- Division of Infectious Diseases and HIV Medicine, Dept. of Medicine, Case Western Reserve University, Cleveland, Ohio, United States.,Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States
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11
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Insights into predicting diabetic nephropathy using urinary biomarkers. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2020; 1868:140475. [DOI: 10.1016/j.bbapap.2020.140475] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 05/27/2020] [Accepted: 06/14/2020] [Indexed: 12/20/2022]
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12
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Wu SF, Noren Hooten N, Freeman DW, Mode NA, Zonderman AB, Evans MK. Extracellular vesicles in diabetes mellitus induce alterations in endothelial cell morphology and migration. J Transl Med 2020; 18:230. [PMID: 32517700 PMCID: PMC7285586 DOI: 10.1186/s12967-020-02398-6] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 06/01/2020] [Indexed: 02/08/2023] Open
Abstract
Background Inflammation-related atherosclerotic peripheral vascular disease is a major end organ complication of diabetes mellitus that results in devastating morbidity and mortality. Extracellular vesicles (EVs) are nano-sized particles that contain molecular cargo and circulate in the blood. Here, we examined EV protein cargo from diabetic individuals and whether these EVs cause functional changes in endothelial cells. Methods We quantified inflammatory protein levels in plasma-derived EVs from a longitudinal cohort of euglycemic and diabetic individuals and used in vitro endothelial cell biological assays to assess the functional effects of these EVs with samples from a cross-sectional cohort. Results We found several significant associations between EV inflammatory protein levels and diabetes status. The angiogenic factor, vascular endothelial growth factor A (VEGF-A), was associated with diabetes status in our longitudinal cohort. Those with diabetes mellitus had higher EV VEGF-A levels compared to euglycemic individuals. Additionally, EV levels of VEGF-A were significantly associated with homeostatic model assessment of insulin resistance (HOMA-IR) and β-cell function (HOMA-B). To test whether EVs with different inflammatory cargo can demonstrate different effects on endothelial cells, we performed cell migration and immunofluorescence assays. We observed that EVs from diabetic individuals increased cell lamellipodia formation and migration when compared to EVs from euglycemic individuals. Conclusions Higher levels of inflammatory proteins were found in EVs from diabetic individuals. Our data implicate EVs as playing important roles in peripheral vascular disease that occur in individuals with diabetes mellitus and suggest that EVs may serve as an informative diagnostic tool for the disease.
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Affiliation(s)
- Sharon F Wu
- Laboratory of Epidemiology and Population Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Nicole Noren Hooten
- Laboratory of Epidemiology and Population Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA
| | - David W Freeman
- Laboratory of Epidemiology and Population Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.,University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Nicolle A Mode
- Laboratory of Epidemiology and Population Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Alan B Zonderman
- Laboratory of Epidemiology and Population Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Michele K Evans
- Laboratory of Epidemiology and Population Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.
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13
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Metwalley KA, Farghaly HS, Raafat DM, Ismail AM, Saied GM. Soluble CD40 Ligand Levels in Children with Newly Diagnosed Graves’ Disease. J Clin Res Pediatr Endocrinol 2020; 12:197-201. [PMID: 31782290 PMCID: PMC7291405 DOI: 10.4274/jcrpe.galenos.2019.2019.0108] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
OBJECTIVE Soluble CD40 ligand (sCD40L) is elevated in various autoimmune disorders, which may have diagnostic and therapeutic implications. The aims of the current study were to evaluate serum sCD40L concentrations in children with newly diagnosed Graves’ disease (GD) and to correlate its levels with patients’ clinical and laboratory parameters. METHODS This study included 48 children with newly diagnosed GD and 48 healthy children. Serum thyroid-stimulating hormone (TSH) (TSH, fT4 and fT3), TSH receptor antibodies (TRAbs), high sensitivity C-reactive protein (hsCRP) and sCD40L levels and thyroid volume were measured. RESULTS Compared to control subjects, children with GD had higher thyroid volume standard deviation scores (SDS) (p=0.001), and higher levels of hsCRP (p=0.001), TRAbs (p=0.001) and sCD40L (p=0.001). Significant correlations were found between sCD40L and age (p=0.01), thyroid volume SDS (p=0.001), hsCRP (p=0.01) and TRAbs (p=0.001). In multivariate analysis, sCD40L concentrations were correlated with TRAbs [odds ratio (OR)=3.1, 95% confidence intervals (CI): 2.2-2.7, p=0.001] and thyroid volume SDS (OR=2.1, 95% CI: 1.2-2.7, p=0.001). CONCLUSION This preliminary study has evidence of high concentrations of sCD40L in children with newly diagnosed GD and a correlation between sCD40L and both TRAbs and thyroid volume, which may indicate a biologically active role for sCD40L in the pathogenesis of GD.
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Affiliation(s)
- Kotb Abbass Metwalley
- Assiut University Faculty of Medicine, Department of Pediatrics, Assiut, Egypt,* Address for Correspondence: Assiut University Faculty of Medicine, Department of Pediatrics, Assiut, Egypt Phone: +0020882368373 E-mail:
| | - Hekma Saad Farghaly
- Assiut University Faculty of Medicine, Department of Pediatrics, Assiut, Egypt
| | | | | | - Ghada Mohamed Saied
- Assiut University Faculty of Medicine, Department of Clinical Pathology, Assiut, Egypt
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14
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Dierschke SK, Toro AL, Miller WP, Sunilkumar S, Dennis MD. Diabetes enhances translation of Cd40 mRNA in murine retinal Müller glia via a 4E-BP1/2-dependent mechanism. J Biol Chem 2020; 295:10831-10841. [PMID: 32475820 DOI: 10.1074/jbc.ra120.013711] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 05/27/2020] [Indexed: 11/06/2022] Open
Abstract
Activation of the immune costimulatory molecule cluster of differentiation 40 (CD40) in Müller glia has been implicated in the initiation of diabetes-induced retinal inflammation. Results from previous studies support that CD40 protein expression is elevated in Müller glia of diabetic mice; however, the mechanisms responsible for this increase have not been explored. Here, we evaluated the hypothesis that diabetes augments translation of the Cd40 mRNA. Mice receiving thiamet G (TMG), an inhibitor of the O-GlcNAc hydrolase O-GlcNAcase, exhibited enhanced retinal protein O-GlcNAcylation and increased Cd40 mRNA translation. TMG administration also promoted Cd40 mRNA association with Müller cell-specific ribosomes isolated from the retina of RiboTag mice. Similar effects on O-GlcNAcylation and Cd40 mRNA translation were also observed in the retina of a mouse model of type 1 diabetes. In cultured cells, TMG promoted sequestration of the cap-binding protein eIF4E (eukaryotic translation in initiation factor 4E) by 4E-BP1 (eIF4E-binding protein 1) and enhanced cap-independent Cd40 mRNA translation as assessed by a bicistronic reporter that contained the 5'-UTR of the Cd40 mRNA. Ablation of 4E-BP1/2 prevented the increase in Cd40 mRNA translation in TMG-exposed cells, and expression of a 4E-BP1 variant that constitutively sequesters eIF4E promoted reporter activity. Extending on the cell culture results, we found that in contrast to WT mice, diabetic 4E-BP1/2-deficient mice did not exhibit enhanced retinal Cd40 mRNA translation and failed to up-regulate expression of the inflammatory marker nitric-oxide synthase 2. These findings support a model wherein diabetes-induced O-GlcNAcylation of 4E-BP1 promotes Cd40 mRNA translation in Müller glia.
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Affiliation(s)
- Sadie K Dierschke
- Department of Cellular and Molecular Physiology, Pennsylvania State College of Medicine, Hershey, Pennsylvania, USA
| | - Allyson L Toro
- Department of Cellular and Molecular Physiology, Pennsylvania State College of Medicine, Hershey, Pennsylvania, USA
| | - William P Miller
- Department of Cellular and Molecular Physiology, Pennsylvania State College of Medicine, Hershey, Pennsylvania, USA
| | - Siddharth Sunilkumar
- Department of Cellular and Molecular Physiology, Pennsylvania State College of Medicine, Hershey, Pennsylvania, USA
| | - Michael D Dennis
- Department of Cellular and Molecular Physiology, Pennsylvania State College of Medicine, Hershey, Pennsylvania, USA .,Department of Ophthalmology, Pennsylvania State College of Medicine, Hershey, Pennsylvania, USA
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15
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Barale C, Russo I. Influence of Cardiometabolic Risk Factors on Platelet Function. Int J Mol Sci 2020; 21:ijms21020623. [PMID: 31963572 PMCID: PMC7014042 DOI: 10.3390/ijms21020623] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 01/15/2020] [Accepted: 01/16/2020] [Indexed: 12/16/2022] Open
Abstract
Platelets are key players in the thrombotic processes. The alterations of platelet function due to the occurrence of metabolic disorders contribute to an increased trend to thrombus formation and arterial occlusion, thus playing a major role in the increased risk of atherothrombotic events in patients with cardiometabolic risk factors. Several lines of evidence strongly correlate metabolic disorders such as obesity, a classical condition of insulin resistance, dyslipidemia, and impaired glucose homeostasis with cardiovascular diseases. The presence of these clinical features together with hypertension and disturbed microhemorrheology are responsible for the prothrombotic tendency due, at least partially, to platelet hyperaggregability and hyperactivation. A number of clinical platelet markers are elevated in obese and type 2 diabetes (T2DM) patients, including the mean platelet volume, circulating levels of platelet microparticles, oxidation products, platelet-derived soluble P-selectin and CD40L, thus contributing to an intersection between obesity, inflammation, and thrombosis. In subjects with insulin resistance and T2DM some defects depend on a reduced sensitivity to mediators—such as nitric oxide and prostacyclin—playing a physiological role in the control of platelet aggregability. Furthermore, other alterations occur only in relation to hyperglycemia. In this review, the main cardiometabolic risk factors, all components of metabolic syndrome involved in the prothrombotic tendency, will be taken into account considering some of the mechanisms involved in the alterations of platelet function resulting in platelet hyperactivation.
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16
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D'Ardes D, Santilli F, Guagnano MT, Bucci M, Cipollone F. From Endothelium to Lipids, Through microRNAs and PCSK9: A Fascinating Travel Across Atherosclerosis. High Blood Press Cardiovasc Prev 2020; 27:1-8. [PMID: 31925708 DOI: 10.1007/s40292-019-00356-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 12/17/2019] [Indexed: 12/22/2022] Open
Abstract
Lipids and endothelium are pivotal players on the scene of atherosclerosis and their interaction is crucial for the establishment of the pathological processes. The endothelium is not only the border of the arterial wall: it plays a key role in regulating circulating fatty acids and lipoproteins and vice versa it is regulated by these lipidic molecules thereby promoting atherosclerosis. Inflammation is another important element in the relationship between lipids and endothelium. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been recognized as a fundamental regulator of LDL-C and anti-PCSK9 monoclonal antibodies have been approved for therapeutic use in hypercholesterolemia, with the promise to subvert the natural history of the disease. Moreover, growing experimental and clinical evidence is enlarging our understanding of the mechanisms through which this protein may facilitate the genesis of atherosclerosis, independently of its impact on lipid metabolism. In addition, environmental stimuli may affect the post-transcriptional regulation of genes through micro-RNAs, which in turn play a key role in orchestrating the crosstalk between endothelium and cholesterol. Advances in experimental research, with development of high throughput techniques, have led, over the last century, to a tremendous progress in the understanding and fine tuning of the molecular mechanisms leading to atherosclerosis. Identification of pivotal keystone molecules bridging lipid metabolism, endothelial dysfunction and atherogenesis will provide the mechanistic substrate to test valuable targets for prediction, prevention and treatment of atherosclerosis-related disease.
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Affiliation(s)
- D D'Ardes
- Department of Medicine and Aging, "G. d'Annunzio" University, Chieti, Italy
- Clinica Medica Division and European Center of Excellence on Atherosclerosis, Hypertension and Dyslipidemia "SS. Annunziata" Hospital, Chieti, Italy
| | - F Santilli
- Department of Medicine and Aging, "G. d'Annunzio" University, Chieti, Italy
| | - M T Guagnano
- Department of Medicine and Aging, "G. d'Annunzio" University, Chieti, Italy
| | - M Bucci
- Department of Medicine and Aging, "G. d'Annunzio" University, Chieti, Italy
- Clinica Medica Division and European Center of Excellence on Atherosclerosis, Hypertension and Dyslipidemia "SS. Annunziata" Hospital, Chieti, Italy
| | - F Cipollone
- Department of Medicine and Aging, "G. d'Annunzio" University, Chieti, Italy.
- Clinica Medica Division and European Center of Excellence on Atherosclerosis, Hypertension and Dyslipidemia "SS. Annunziata" Hospital, Chieti, Italy.
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17
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Subauste CS. The CD40-ATP-P2X 7 Receptor Pathway: Cell to Cell Cross-Talk to Promote Inflammation and Programmed Cell Death of Endothelial Cells. Front Immunol 2019; 10:2958. [PMID: 31921199 PMCID: PMC6928124 DOI: 10.3389/fimmu.2019.02958] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 12/02/2019] [Indexed: 12/15/2022] Open
Abstract
Extracellular adenosine 5′-triphosphate (ATP) functions not only as a neurotransmitter but is also released by non-excitable cells and mediates cell–cell communication involving glia. In pathological conditions, extracellular ATP released by astrocytes may act as a “danger” signal that activates microglia and promotes neuroinflammation. This review summarizes in vitro and in vivo studies that identified CD40 as a novel trigger of ATP release and purinergic-induced inflammation. The use of transgenic mice with expression of CD40 restricted to retinal Müller glia and a model of diabetic retinopathy (a disease where the CD40 pathway is activated) established that CD40 induces release of ATP in Müller glia and triggers in microglia/macrophages purinergic receptor-dependent inflammatory responses that drive the development of retinopathy. The CD40-ATP-P2X7 pathway not only amplifies inflammation but also induces death of retinal endothelial cells, an event key to the development of capillary degeneration and retinal ischemia. Taken together, CD40 expressed in non-hematopoietic cells is sufficient to mediate inflammation and tissue pathology as well as cause death of retinal endothelial cells. This process likely contributes to development of degenerate capillaries, a hallmark of diabetic and ischemic retinopathies. Blockade of signaling pathways downstream of CD40 operative in non-hematopoietic cells may offer a novel means of treating diabetic and ischemic retinopathies.
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Affiliation(s)
- Carlos S Subauste
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, OH, United States.,Department of Pathology, Case Western Reserve University, Cleveland, OH, United States
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18
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Athithan L, Gulsin GS, McCann GP, Levelt E. Diabetic cardiomyopathy: Pathophysiology, theories and evidence to date. World J Diabetes 2019; 10:490-510. [PMID: 31641426 PMCID: PMC6801309 DOI: 10.4239/wjd.v10.i10.490] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 09/25/2019] [Accepted: 09/25/2019] [Indexed: 02/05/2023] Open
Abstract
The prevalence of type 2 diabetes (T2D) has increased worldwide and doubled over the last two decades. It features among the top 10 causes of mortality and morbidity in the world. Cardiovascular disease is the leading cause of complications in diabetes and within this, heart failure has been shown to be the leading cause of emergency admissions in the United Kingdom. There are many hypotheses and well-evidenced mechanisms by which diabetic cardiomyopathy as an entity develops. This review aims to give an overview of these mechanisms, with particular emphasis on metabolic inflexibility. T2D is associated with inefficient substrate utilisation, an inability to increase glucose metabolism and dependence on fatty acid oxidation within the diabetic heart resulting in mitochondrial uncoupling, glucotoxicity, lipotoxicity and initially subclinical cardiac dysfunction and finally in overt heart failure. The review also gives a concise update on developments within clinical imaging, specifically cardiac magnetic resonance studies to characterise and phenotype early cardiac dysfunction in T2D. A better understanding of the pathophysiology involved provides a platform for targeted therapy in diabetes to prevent the development of early heart failure with preserved ejection fraction.
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Affiliation(s)
- Lavanya Athithan
- Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Cardiovascular Biomedical Research Centre, Glenfield Hospital, Leicester LE3 9QP, United Kingdom
| | - Gaurav S Gulsin
- Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Cardiovascular Biomedical Research Centre, Glenfield Hospital, Leicester LE3 9QP, United Kingdom
| | - Gerald P McCann
- Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Cardiovascular Biomedical Research Centre, Glenfield Hospital, Leicester LE3 9QP, United Kingdom
| | - Eylem Levelt
- Multidisciplinary Cardiovascular Research Centre and Biomedical Imaging Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LF9 7TF, United Kingdom
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19
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Kojok K, El-Kadiry AEH, Merhi Y. Role of NF-κB in Platelet Function. Int J Mol Sci 2019; 20:E4185. [PMID: 31461836 PMCID: PMC6747346 DOI: 10.3390/ijms20174185] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 08/25/2019] [Accepted: 08/26/2019] [Indexed: 01/04/2023] Open
Abstract
Platelets are megakaryocyte-derived fragments lacking nuclei and prepped to maintain primary hemostasis by initiating blood clots on injured vascular endothelia. Pathologically, platelets undergo the same physiological processes of activation, secretion, and aggregation yet with such pronouncedness that they orchestrate and make headway the progression of atherothrombotic diseases not only through clot formation but also via forcing a pro-inflammatory state. Indeed, nuclear factor-κB (NF-κB) is largely implicated in atherosclerosis and its pathological complication in atherothrombotic diseases due to its transcriptional role in maintaining pro-survival and pro-inflammatory states in vascular and blood cells. On the other hand, we know little on the functions of platelet NF-κB, which seems to function in other non-genomic ways to modulate atherothrombosis. Therein, this review will resemble a rich portfolio for NF-κB in platelets, specifically showing its implications at the levels of platelet survival and function. We will also share the knowledge thus far on the effects of active ingredients on NF-κB in general, as an extrapolative method to highlight the potential therapeutic targeting of NF-κB in coronary diseases. Finally, we will unzip a new horizon on a possible extra-platelet role of platelet NF-κB, which will better expand our knowledge on the etiology and pathophysiology of atherothrombosis.
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Affiliation(s)
- Kevin Kojok
- The Laboratory of Thrombosis and Hemostasis, Montreal Heart Institute, Research Centre, 5000 Belanger Street, Montreal, H1T 1C8, QC, Canada
- Faculty of Medicine, Université de Montréal, Montreal, H3T 1J4, QC, Canada
| | - Abed El-Hakim El-Kadiry
- The Laboratory of Thrombosis and Hemostasis, Montreal Heart Institute, Research Centre, 5000 Belanger Street, Montreal, H1T 1C8, QC, Canada
- Faculty of Medicine, Université de Montréal, Montreal, H3T 1J4, QC, Canada
| | - Yahye Merhi
- The Laboratory of Thrombosis and Hemostasis, Montreal Heart Institute, Research Centre, 5000 Belanger Street, Montreal, H1T 1C8, QC, Canada.
- Faculty of Medicine, Université de Montréal, Montreal, H3T 1J4, QC, Canada.
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20
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Falasca K, Reale M, Di Nicola M, Ucciferri C, Zecca IA, Santilli F, Pontolillo M, Liani R, D'Angelo C, Costantini E, Vecchiet J. Circulating CD40 ligand, Dickkopf-1 and P-selectin in HIV-infected patients. HIV Med 2019; 20:681-690. [PMID: 31424619 DOI: 10.1111/hiv.12789] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/04/2019] [Indexed: 11/29/2022]
Abstract
OBJECTIVES The aim of this study was to evaluate the circulating levels of CD40 ligand (CD40 L), Dickkopf-1 (DKK-1) and P-selectin, their relationships and their contributions to cardiovascular risk in subjects with HIV infection. METHODS The study population included 80 HIV-infected patients, 14 (17.5%) of whom had diabetes mellitus (DM) and 32 (40.0%) of whom had arterial hypertension (AH). The HIV-infected patients were compared with a control group with similar demographic and clinical features. CD40L, DKK-1 and P-selectin levels were measured using an enzyme-linked immunosorbent assay. RESULTS The HIV-infected patients showed higher levels of all the cardiovascular disease (CVD) markers. Both serum CD40L and DKK-1 were significantly higher in HIV-infected patients than in the HIV-negative controls (P < 0.001), while soluble P-selectin showed no significant between-group difference (P = 0.133), reflecting the role of HIV infection in CVD. In the HIV-infected group, patients with DM showed lower levels of CD40L and DKK-1 in comparison with the nondiabetic patients and patients with AH (P < 0.05, with Bonferroni correction). In contrast, patients with AH showed higher levels of CD40L and DKK-1 in comparison to patients without DM or AH (P < 0.05, with Bonferroni correction). Patients with AH showed higher levels of CD40L and DKK-1 than patients with DM (P < 0.05, with Bonferroni correction). CONCLUSIONS In this study, we found that HIV-infected patients displayed significantly higher circulating levels of both CD40L and DKK-1, which were linearly and directly correlated, when compared to HIV-negative patients. The presence of diabetes was associated with lower levels of both CD40L and DKK-1, whereas the presence of hypertension was associated with higher levels of CD40L.
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Affiliation(s)
- K Falasca
- Clinic of Infectious Diseases, Department of Medicine and Science of Aging, University 'G. d'Annunzio' Chieti-Pescara, Chieti, Italy
| | - M Reale
- Unit of Immunodiagnostic and Molecular Pathology, Department of Medical, Oral and Biotechnological Sciences, University 'G. d'Annunzio' Chieti-Pescara, Chieti, Italy
| | - M Di Nicola
- Laboratory of Biostatistics, Department of Medical, Oral and Biotechnological Sciences, University 'G. d'Annunzio' Chieti-Pescara, Chieti, Italy
| | - C Ucciferri
- Clinic of Infectious Diseases, Department of Medicine and Science of Aging, University 'G. d'Annunzio' Chieti-Pescara, Chieti, Italy.,Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy
| | - I A Zecca
- Division of Hygene, Epidemiology and Public Health, Department of Medicine and Science of Aging, University 'G. d'Annunzio' Chieti-Pescara, Chieti, Italy
| | - F Santilli
- Department of Medicine and Aging, Center of Aging Science and Translational Medicine (CESI-Met), University 'G. d'Annunzio' Chieti-Pescara, Chieti, Italy
| | - M Pontolillo
- Clinic of Infectious Diseases, Department of Medicine and Science of Aging, University 'G. d'Annunzio' Chieti-Pescara, Chieti, Italy
| | - R Liani
- Department of Medicine and Aging, Center of Aging Science and Translational Medicine (CESI-Met), University 'G. d'Annunzio' Chieti-Pescara, Chieti, Italy
| | - C D'Angelo
- Unit of Immunodiagnostic and Molecular Pathology, Department of Medical, Oral and Biotechnological Sciences, University 'G. d'Annunzio' Chieti-Pescara, Chieti, Italy
| | - E Costantini
- Unit of Immunodiagnostic and Molecular Pathology, Department of Medical, Oral and Biotechnological Sciences, University 'G. d'Annunzio' Chieti-Pescara, Chieti, Italy
| | - J Vecchiet
- Clinic of Infectious Diseases, Department of Medicine and Science of Aging, University 'G. d'Annunzio' Chieti-Pescara, Chieti, Italy
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Meyerovich K, Ortis F, Cardozo AK. The non-canonical NF-κB pathway and its contribution to β-cell failure in diabetes. J Mol Endocrinol 2018; 61:F1-F6. [PMID: 29728424 DOI: 10.1530/jme-16-0183] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 05/04/2018] [Indexed: 12/20/2022]
Abstract
The prevalence of diabetes has reached 8.8% in worldwide population and is predicted to increase up to 10.4% by 2040. Thus, there is an urgent need for the development of means to treat or prevent this major disease. Due to its role in inflammatory responses, several studies demonstrated the importance of the transcription factor nuclear factor-κB (NF-κB) in both type 1 diabetes (T1D) and type 2 diabetes (T2D). The two major NF-κB pathways are the canonical and the non-canonical. The later pathway is activated by the NF-κB-inducing kinase (NIK) that triggers p100 processing into p52, which forms with RelB its main dimer. Cytokines mediating the activation of this pathway are present in the serum of T1D and T2D patients. Conversely, limited information is available regarding the role of the alternative pathway on diabetes development and β-cell fate. In the present review, we will briefly describe the involvement of NF-κB on diabetes pathology and discuss new studies indicating an important role for the non-canonical NF-κB activation in β-cell function and survival. The non-canonical NF-κB pathway is emerging as a novel potential target for the development of therapeutic strategies to treat or prevent diabetes.
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Affiliation(s)
- Kira Meyerovich
- ULB Center for Diabetes ResearchUniversité Libre de Bruxelles (ULB), Brussels, Belgium
| | - Fernanda Ortis
- Department of Cell and Developmental BiologyUniversidade de São Paulo, São Paulo, Brazil
| | - Alessandra K Cardozo
- ULB Center for Diabetes ResearchUniversité Libre de Bruxelles (ULB), Brussels, Belgium
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Jin R, Xiao AY, Song Z, Yu S, Li J, Cui MZ, Li G. Platelet CD40 Mediates Leukocyte Recruitment and Neointima Formation after Arterial Denudation Injury in Atherosclerosis-Prone Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:252-263. [PMID: 29037856 PMCID: PMC5745524 DOI: 10.1016/j.ajpath.2017.09.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Revised: 09/06/2017] [Accepted: 09/21/2017] [Indexed: 12/31/2022]
Abstract
The role of platelets in the development of thrombosis and abrupt closure after angioplasty is well recognized. However, the direct impact of platelets on neointima formation after arterial injury remains undetermined. Herein, we show that neointima formation after carotid artery wire injury reduces markedly in CD40-/- apolipoprotein E-deficient (apoE-/-) mice but only slightly in CD40 ligand-/-apoE-/- mice, compared with apoE-/- mice. Wild-type and CD40-deficient platelets were isolated from blood of apoE-/- and CD40-/-apoE-/- mice, respectively. The i.v. injection of thrombin-activated platelets into CD40-/-apoE-/- mice was performed every 5 days, starting at 2 days before wire injury. Injection of wild-type platelets promoted neointima formation, which was associated with increased inflammation by stimulating leukocyte recruitment via up-regulation of circulating platelet surface P-selectin expression and the formation of platelet-leukocyte aggregates. It was also associated with further promoting the luminal deposition of platelet-derived regulated on activation normal T cell expressed and secreted/chemokine (C-C motif) ligand 5 and expression of monocyte chemoattractant protein-1 and vascular cell adhesion molecule 1 in wire-injured carotid arteries. Remarkably, all these inflammatory actions by activated platelets were abrogated by lack of CD40 on injected platelets. Moreover, injection of wild-type platelets inhibited endothelial recovery in wire-injured carotid arteries, but this effect was also abrogated by lack of CD40 on injected platelets. Results suggest that platelet CD40 plays a pivotal role in neointima formation after arterial injury and might represent an attractive target to prevent restenosis after vascular interventions.
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Affiliation(s)
- Rong Jin
- Department of Neurosurgery, Louisiana State University Health Sciences Center, Shreveport, Louisiana; Department of Neurosurgery, the Pennsylvania State University College of Medicine, Hershey, Pennsylvania
| | - Adam Y Xiao
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana
| | - Zifang Song
- Department of Neurosurgery, the Pennsylvania State University College of Medicine, Hershey, Pennsylvania
| | - Shiyong Yu
- Department of Neurosurgery, the Pennsylvania State University College of Medicine, Hershey, Pennsylvania
| | - Jarvis Li
- Caddo Magnet High School, Shreveport, Louisiana
| | - Mei-Zhen Cui
- Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee
| | - Guohong Li
- Department of Neurosurgery, Louisiana State University Health Sciences Center, Shreveport, Louisiana; Department of Neurosurgery, the Pennsylvania State University College of Medicine, Hershey, Pennsylvania; Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana.
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Morange PE, Alessi MC. Thrombosis in central obesity and metabolic syndrome: Mechanisms and epidemiology. Thromb Haemost 2017; 110:669-80. [DOI: 10.1160/th13-01-0075] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Accepted: 04/20/2013] [Indexed: 12/19/2022]
Abstract
summaryCentral obesity is a key feature of the metabolic syndrome (metS), a multiplex risk factor for subsequent development of type 2 diabetes and cardiovascular disease. Many metabolic alterations closely related to this condition exert effects on platelets and vascular cells. A procoagulant and hypofibrinolytic state has been identified, mainly underlain by inflammation, oxidative stress, dyslipidaemia, and ectopic fat that accompany central obesity. In support of these data, central obesity independently predisposes not only to atherothrombosis but also to venous thrombosis.
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Gerdes N, Zirlik A. Co-stimulatory molecules in and beyond co-stimulation – tipping the balance in atherosclerosis? Thromb Haemost 2017; 106:804-13. [DOI: 10.1160/th11-09-0605] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Accepted: 09/28/2011] [Indexed: 12/23/2022]
Abstract
SummaryA plethora of basic laboratory and clinical studies has uncovered the chronic inflammatory nature of atherosclerosis. The adaptive immune system with its front-runner, the T cell, drives the atherogenic process at all stages. T cell function is dependent on and controlled by a variety of either co-stimulatory or co-inhibitory signals. In addition, many of these proteins enfold T cell-independent pro-atherogenic functions on a variety of cell types. Accordingly they represent potential targets for immune- modulatory and/or anti-inflammatory therapy of atherosclerosis. This review focuses on the diverse role of co-stimulatory molecules of the B7 and tumour necrosis factor (TNF)-superfamily and their downstream signalling effectors in atherosclerosis. In particular, the contribution of CD28/CD80/CD86/CTLA4, ICOS/ICOSL, PD-1/PDL-1/2, TRAF, CD40/CD154, OX40/OX40L, CD137/CD137L, CD70/CD27, GITR/GITRL, and LIGHT to arterial disease is reviewed. Finally, the potential for a therapeutic exploitation of these molecules in the treatment of atherosclerosis is discussed.
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Abrey Recalde MJ, Alvarez RS, Alberto F, Mejias MP, Ramos MV, Fernandez Brando RJ, Bruballa AC, Exeni RA, Alconcher L, Ibarra CA, Amaral MM, Palermo MS. Soluble CD40 Ligand and Oxidative Response Are Reciprocally Stimulated during Shiga Toxin-Associated Hemolytic Uremic Syndrome. Toxins (Basel) 2017; 9:toxins9110331. [PMID: 29068360 PMCID: PMC5705951 DOI: 10.3390/toxins9110331] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 09/29/2017] [Accepted: 10/15/2017] [Indexed: 01/01/2023] Open
Abstract
Shiga toxin (Stx), produced by Escherichia coli, is the main pathogenic factor of diarrhea-associated hemolytic uremic syndrome (HUS), which is characterized by the obstruction of renal microvasculature by platelet-fibrin thrombi. It is well known that the oxidative imbalance generated by Stx induces platelet activation, contributing to thrombus formation. Moreover, activated platelets release soluble CD40 ligand (sCD40L), which in turn contributes to oxidative imbalance, triggering the release of reactive oxidative species (ROS) on various cellular types. The aim of this work was to determine if the interaction between the oxidative response and platelet-derived sCD40L, as consequence of Stx-induced endothelium damage, participates in the pathogenic mechanism during HUS. Activated human glomerular endothelial cells (HGEC) by Stx2 induced platelets to adhere to them. Although platelet adhesion did not contribute to endothelial damage, high levels of sCD40L were released to the medium. The release of sCD40L by activated platelets was inhibited by antioxidant treatment. Furthermore, we found increased levels of sCD40L in plasma from HUS patients, which were also able to trigger the respiratory burst in monocytes in a sCD40L-dependent manner. Thus, we concluded that platelet-derived sCD40L and the oxidative response are reciprocally stimulated during Stx2-associated HUS. This process may contribute to the evolution of glomerular occlusion and the microangiopathic lesions.
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Affiliation(s)
- Maria J Abrey Recalde
- Laboratorio de Patogénesis e Inmunología de Procesos Infecciosos, Instituto de Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas-Academia Nacional de Medicina, 1425 Buenos Aires, Argentina.
| | - Romina S Alvarez
- Laboratorio de Fisiopatogenia, Departamento de Fisiología, Instituto de Fisiología y Biofísica "Bernardo Houssay", Facultad de Medicina-Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de Buenos Aires, 1121 Buenos Aires, Argentina.
| | - Fabiana Alberto
- División Trombosis, Instituto de investigaciones Hematológicas "Mariano R. Castex", Academia Nacional de Medicina, 1425 Buenos Aires, Argentina.
| | - Maria P Mejias
- Laboratorio de Patogénesis e Inmunología de Procesos Infecciosos, Instituto de Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas-Academia Nacional de Medicina, 1425 Buenos Aires, Argentina.
| | - Maria V Ramos
- Laboratorio de Patogénesis e Inmunología de Procesos Infecciosos, Instituto de Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas-Academia Nacional de Medicina, 1425 Buenos Aires, Argentina.
| | - Romina J Fernandez Brando
- Laboratorio de Patogénesis e Inmunología de Procesos Infecciosos, Instituto de Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas-Academia Nacional de Medicina, 1425 Buenos Aires, Argentina.
| | - Andrea C Bruballa
- Laboratorio de Patogénesis e Inmunología de Procesos Infecciosos, Instituto de Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas-Academia Nacional de Medicina, 1425 Buenos Aires, Argentina.
| | - Ramon A Exeni
- Departamento de Nefrología, Hospital Municipal del Niño, San Justo, B1754FUD Provincia de Buenos Aires, Argentina.
| | - Laura Alconcher
- Unidad de Nefrourología Infantil. Hospital Interzonal General Dr. José Penna, Bahía Blanca, 8000 Provincia de Buenos Aires, Argentina.
| | - Cristina A Ibarra
- Laboratorio de Fisiopatogenia, Departamento de Fisiología, Instituto de Fisiología y Biofísica "Bernardo Houssay", Facultad de Medicina-Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de Buenos Aires, 1121 Buenos Aires, Argentina.
| | - María M Amaral
- Laboratorio de Fisiopatogenia, Departamento de Fisiología, Instituto de Fisiología y Biofísica "Bernardo Houssay", Facultad de Medicina-Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de Buenos Aires, 1121 Buenos Aires, Argentina.
| | - Marina S Palermo
- Laboratorio de Patogénesis e Inmunología de Procesos Infecciosos, Instituto de Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas-Academia Nacional de Medicina, 1425 Buenos Aires, Argentina.
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Subauste CS. CD40, a Novel Inducer of Purinergic Signaling: Implications to the Pathogenesis of Experimental Diabetic Retinopathy. Vision (Basel) 2017; 1:vision1030020. [PMID: 31740645 PMCID: PMC6835793 DOI: 10.3390/vision1030020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 08/08/2017] [Accepted: 08/09/2017] [Indexed: 11/16/2022] Open
Abstract
Diabetic retinopathy is a leading complication of diabetes. Death of capillary cells with resulting capillary degeneration is a central feature of this disease. Chronic low-grade inflammation has been linked to the development of retinal capillary degeneration in diabetes. CD40 is an upstream inducer of a broad range of inflammatory responses in the diabetic retina and is required for death of retinal capillary cells. Recent studies uncovered CD40 as a novel inducer of purinergic signaling and identified the CD40-ATP-P2X7 pathway as having a key role in the induction of inflammation in the diabetic retina and programmed cell death of retinal endothelial cells.
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Affiliation(s)
- Carlos S. Subauste
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; ; Tel.: +1-216-368-2785
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
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Aarts SABM, Seijkens TTP, Kusters PJH, van der Pol SMA, Zarzycka B, Heijnen PDAM, Beckers L, den Toom M, Gijbels MJJ, Boon L, Weber C, de Vries HE, Nicolaes GAF, Dijkstra CD, Kooij G, Lutgens E. Inhibition of CD40-TRAF6 interactions by the small molecule inhibitor 6877002 reduces neuroinflammation. J Neuroinflammation 2017; 14:105. [PMID: 28494768 PMCID: PMC5427621 DOI: 10.1186/s12974-017-0875-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Accepted: 04/26/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The influx of leukocytes into the central nervous system (CNS) is a key hallmark of the chronic neuro-inflammatory disease multiple sclerosis (MS). Strategies that aim to inhibit leukocyte migration across the blood-brain barrier (BBB) are therefore regarded as promising therapeutic approaches to combat MS. As the CD40L-CD40 dyad signals via TNF receptor-associated factor 6 (TRAF6) in myeloid cells to induce inflammation and leukocyte trafficking, we explored the hypothesis that specific inhibition of CD40-TRAF6 interactions can ameliorate neuro-inflammation. METHODS Human monocytes were treated with a small molecule inhibitor (SMI) of CD40-TRAF6 interactions (6877002), and migration capacity across human brain endothelial cells was measured. To test the therapeutic potential of the CD40-TRAF6-blocking SMI under neuro-inflammatory conditions in vivo, Lewis rats and C57BL/6J mice were subjected to acute experimental autoimmune encephalomyelitis (EAE) and treated with SMI 6877002 for 6 days (rats) or 3 weeks (mice). RESULTS We here show that a SMI of CD40-TRAF6 interactions (6877002) strongly and dose-dependently reduces trans-endothelial migration of human monocytes. Moreover, upon SMI treatment, monocytes displayed a decreased production of ROS, tumor necrosis factor (TNF), and interleukin (IL)-6, whereas the production of the anti-inflammatory cytokine IL-10 was increased. Disease severity of EAE was reduced upon SMI treatment in rats, but not in mice. However, a significant reduction in monocyte-derived macrophages, but not in T cells, that had infiltrated the CNS was eminent in both models. CONCLUSIONS Together, our results indicate that SMI-mediated inhibition of the CD40-TRAF6 pathway skews human monocytes towards anti-inflammatory cells with reduced trans-endothelial migration capacity, and is able to reduce CNS-infiltrated monocyte-derived macrophages during neuro-inflammation, but minimally ameliorates EAE disease severity. We therefore conclude that SMI-mediated inhibition of the CD40-TRAF6 pathway may represent a beneficial treatment strategy to reduce monocyte recruitment and macrophage activation in the CNS and has the potential to be used as a co-treatment to combat MS.
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Affiliation(s)
- Suzanne A. B. M. Aarts
- Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
| | - Tom T. P. Seijkens
- Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
| | - Pascal J. H. Kusters
- Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
| | - Susanne M. A. van der Pol
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands
| | - Barbara Zarzycka
- Department of Biochemistry, University of Maastricht, 6200 MD Maastricht, The Netherlands
| | - Priscilla D. A. M. Heijnen
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands
| | - Linda Beckers
- Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
| | - Myrthe den Toom
- Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
| | - Marion J. J. Gijbels
- Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
- Department of Pathology and Department of Molecular Genetics, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, Maastricht, The Netherlands
| | - Louis Boon
- Bioceros, 3584 CM Utrecht, The Netherlands
| | - Christian Weber
- Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilians University (LMU), Pettenkoferstraße 9, 80336 Munich, Germany
| | - Helga E. de Vries
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands
| | - Gerry A. F. Nicolaes
- Department of Biochemistry, University of Maastricht, 6200 MD Maastricht, The Netherlands
| | - Christine D. Dijkstra
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands
| | - Gijs Kooij
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands
| | - Esther Lutgens
- Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
- Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilians University (LMU), Pettenkoferstraße 9, 80336 Munich, Germany
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Foks AC, Kuiper J. Immune checkpoint proteins: exploring their therapeutic potential to regulate atherosclerosis. Br J Pharmacol 2017; 174:3940-3955. [PMID: 28369782 DOI: 10.1111/bph.13802] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 02/17/2017] [Accepted: 03/15/2017] [Indexed: 12/23/2022] Open
Abstract
The immune system provides a large variety of immune checkpoint proteins, which involve both costimulatory and inhibitory proteins. Costimulatory proteins can promote cell survival, cell cycle progression and differentiation to effector and memory cells, whereas inhibitory proteins terminate these processes to halt ongoing inflammation. Immune checkpoint proteins play a pivotal role in atherosclerosis by regulating the activation and proliferation of various immune and non-immune cells, such as T-cells, macrophages and platelets. Upon activation within the atherosclerotic lesions or in secondary lymphoid organs, these cells produce large amounts of pro-atherogenic cytokines that contribute to the growth and destabilization of lesions, which can result in rupture of the lesion causing acute coronary syndromes, such as a myocardial infarction. Given the presence and regulatory capacity of immune checkpoint proteins in the circulation and atherosclerotic lesions of cardiovascular patients, modulation of these proteins by, for example, the use of monoclonal antibodies, offers unique opportunities to regulate pro-inflammatory immune responses in atherosclerosis. In this review, we highlight the latest advances on the role of immune checkpoint proteins, such as OX40-OX40L, CTLA-4 and TIM proteins, in atherosclerosis and discuss their therapeutic potential as promising immunotherapies to treat or prevent cardiovascular disease. LINKED ARTICLES This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc.
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Affiliation(s)
- A C Foks
- Division of Biopharmaceutics, LACDR, Leiden University, Leiden, The Netherlands
| | - J Kuiper
- Division of Biopharmaceutics, LACDR, Leiden University, Leiden, The Netherlands
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Morin SO, Poggi M, Alessi MC, Landrier JF, Nunès JA. Modulation of T Cell Activation in Obesity. Antioxid Redox Signal 2017; 26:489-500. [PMID: 27225042 DOI: 10.1089/ars.2016.6746] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
SIGNIFICANCE Immune T cells are present in adipose tissues (AT), and the stoichiometry of the different T cell subsets is altered during diet-induced obesity (DIO). T cells contribute to the early steps of AT inflammation during DIO. Recent Advances: Many factors could potentially be responsible for this altered pro-inflammatory versus anti-inflammatory T cell balance. CRITICAL ISSUES T cells are potentially activated in AT, which vitamin D might contribute to, as will be discussed in this article. In addition, we will review the different possible contributors to T cell activation in AT, such as the CD28 and CD154 T cell costimulatory molecules in AT. FUTURE DIRECTIONS The potential antigen presentation capacities of adipocytes should be further investigated. Moreover, the properties of these AT resident (or migrating to AT) T cells must be further assessed. Antioxid. Redox Signal. 26, 489-500.
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Affiliation(s)
- Stéphanie O Morin
- 1 Inserm, U1068, Centre de Recherche en Cancérologie de Marseille , Marseille, France .,2 Institut Paoli-Calmettes , Marseille, France .,3 CNRS, UMR7258, Centre de Recherche en Cancérologie de Marseille , Marseille, France .,4 Aix-Marseille Université , UM105, Marseille, France
| | - Marjorie Poggi
- 5 Inserm U1062 , Marseille, France .,6 Inra , UMR1260, Marseille, France .,7 Aix-Marseille Université , Nutrition Obésité Risques Thrombotiques, Marseille, France
| | - Marie-Christine Alessi
- 5 Inserm U1062 , Marseille, France .,6 Inra , UMR1260, Marseille, France .,7 Aix-Marseille Université , Nutrition Obésité Risques Thrombotiques, Marseille, France
| | - Jean-François Landrier
- 5 Inserm U1062 , Marseille, France .,6 Inra , UMR1260, Marseille, France .,7 Aix-Marseille Université , Nutrition Obésité Risques Thrombotiques, Marseille, France
| | - Jacques A Nunès
- 1 Inserm, U1068, Centre de Recherche en Cancérologie de Marseille , Marseille, France .,2 Institut Paoli-Calmettes , Marseille, France .,3 CNRS, UMR7258, Centre de Recherche en Cancérologie de Marseille , Marseille, France .,4 Aix-Marseille Université , UM105, Marseille, France
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Qian L, Ma L, Wu G, Yu Q, Lin H, Ying Q, Wen D, Gao C. G004, a synthetic sulfonylurea compound, exerts anti-atherosclerosis effects by targeting SIRT1 in ApoE −/− mice. Vascul Pharmacol 2017; 89:49-57. [DOI: 10.1016/j.vph.2016.12.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 11/29/2016] [Accepted: 12/31/2016] [Indexed: 01/08/2023]
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Zirlik A, Lutgens E. An inflammatory link in atherosclerosis and obesity. Co-stimulatory molecules. Hamostaseologie 2016. [PMID: 26225729 DOI: 10.5482/hamo-14-12-0079] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Atherosclerosis and obesity-induced metabolic dysfunction are lipid-driven inflammatory pathologies responsible for a major part of cardiovascular complications. Immune cell activation as well as interactions between the different immune cells is dependent on and controlled by a variety of co-stimulatory signals. These co-stimulatory signals can either aggravate or ameliorate the disease depending on the stage of the disease, the cell-types involved and the signal transduction cascades initiated. This review focuses on the diverse roles of the most established co-stimulatory molecules of the B7 and Tumor Necrosis Factor Receptor (TNFR) families, ie the CD28/CTLA4-CD80/CD86 and CD40L/CD40 dyads in the pathogenesis of atherosclerosis and obesity. In addition, we will explore their potential as therapeutic targets in both atherosclerosis and obesity.
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Affiliation(s)
- A Zirlik
- Prof. Andreas Zirlik, Atherogenesis Research Group, Heart Center Freiburg University, Cardiology and Angiology I, University of Freiburg, Germany, E-mail:
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Rusu C, Racasan S, Moldovan D, Kacso IM, Potra A, Bondor CI, Patiu IM, Vladutiu D, Caprioara MG. Soluble CD40 ligand in haemodialysis patients: survival impact and cardiovascular prognostic role. Biomarkers 2016; 22:232-238. [PMID: 27295448 DOI: 10.1080/1354750x.2016.1201531] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
CONTEXT Soluble CD40 ligand (sCD40l) can predict cardiovascular events (CVE) and mortality in haemodialysis (HD) patients (short-, medium-term follow-up studies). OBJECTIVE To evaluate the relationship between sCD40l and survival, CVE and mortality in HD patients on long-term follow-up. METHODS We registered 46 HD patients' baseline characteristics, mortality and CVE for 108 months. RESULTS SCD40l correlated positively with C-reactive protein, was higher in survivors, but had no impact on survival and was not predictive for CVE or CV mortality. CONCLUSION The levels of sCD40l have no influence on survival or CVE and mortality in HD patients in a long-term follow-up.
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Affiliation(s)
- Crina Rusu
- a Department of Nephrology , University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca , Romania
| | | | - Diana Moldovan
- a Department of Nephrology , University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca , Romania
| | - Ina Maria Kacso
- a Department of Nephrology , University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca , Romania
| | - Alina Potra
- a Department of Nephrology , University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca , Romania
| | - Cosmina Ioana Bondor
- c Department of Statistics , University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca , Romania
| | | | - Dan Vladutiu
- a Department of Nephrology , University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca , Romania
| | - Mirela Gherman Caprioara
- a Department of Nephrology , University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca , Romania
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Chao TH, Chen IC, Li YH, Lee PT, Tseng SY. Plasma Levels of Proprotein Convertase Subtilisin/Kexin Type 9 Are Elevated in Patients With Peripheral Artery Disease and Associated With Metabolic Disorders and Dysfunction in Circulating Progenitor Cells. J Am Heart Assoc 2016; 5:JAHA.116.003497. [PMID: 27207972 PMCID: PMC4889209 DOI: 10.1161/jaha.116.003497] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in cholesterol homeostasis, inflammation, and oxidative stress. This study investigated the association of plasma PCSK9 levels with the presence and severity of peripheral artery disease (PAD) and with parameters of endothelial homeostasis. METHODS AND RESULTS A post hoc analysis of 2 randomized trials (115 patients, 44 with PAD and 71 without atherosclerotic disease) was conducted. Patients with PAD had significantly higher plasma PCSK9 levels than those without (471.6±29.6 versus 302.4±16.1 ng/mL, P<0.001). Parameters for glucose homeostasis, endothelial progenitor cell functions, apoptotic circulating endothelial cell counts, and plasma levels of vascular endothelial growth factor-A165 and oxidized low-density lipoprotein were correlated with PCSK9 concentration. By multivariable linear regression analysis, presence of PAD, plasma glucose or hemoglobin A1c levels, apoptotic circulating endothelial cell counts, and vascular endothelial growth factor-A165 concentration were found to be associated with PCSK9 levels after multivariable adjustment. Patients with extensive involvement of PAD or with severe PAD had significantly higher PCSK9 levels than those without PAD. Computed tomographic angiography showed that the numbers of chronic total occlusion sites and vessels involved were positively associated with PCSK9 levels in patients with PAD (r=0.40, P=0.01, and r=0.36, P=0.02, respectively). CONCLUSION PCSK9 levels were significantly higher in patients with PAD, especially those with advanced PAD. Further large-scale studies examining the effect of PCSK9-targeting therapies or the modification of PCSK9 levels on cardiovascular outcomes in this clinical setting are warranted. CLINICAL TRIAL REGISTRATION Cohort 1: URL: ClinicalTrials.gov. Unique identifier: NCT01952756; cohort 2: URL: ClinicalTrials.gov. Unique identifier: NCT02194686.
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Affiliation(s)
- Ting-Hsing Chao
- Department of Internal Medicine, National Cheng Kung University College of Medicine and Hospital, Tainan, Taiwan
| | - I-Chih Chen
- Department of Internal Medicine, Tainan Municipal Hospital, Tainan, Taiwan
| | - Yi-Heng Li
- Department of Internal Medicine, National Cheng Kung University College of Medicine and Hospital, Tainan, Taiwan
| | - Po-Tseng Lee
- Department of Internal Medicine, National Cheng Kung University College of Medicine and Hospital, Tainan, Taiwan
| | - Shih-Ya Tseng
- Department of Biological Science, National Sun Yat-Sen University, Kaohsiung, Taiwan
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Lee SI, Patel M, Jones CM, Narendran P. Cardiovascular disease and type 1 diabetes: prevalence, prediction and management in an ageing population. Ther Adv Chronic Dis 2015; 6:347-74. [PMID: 26568811 DOI: 10.1177/2040622315598502] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Cardiovascular disease (CVD) is a major cause of mortality in type 1 diabetes mellitus (T1D). However, evidence of its risks and management is often extrapolated from studies in type 2 diabetic (T2D) patients or the general population. This approach is unsatisfactory given that the underlying pathology, demographics and natural history of the disease differ between T1D and T2D. Furthermore, with a rising life expectancy, a greater number of T1D patients are exposed to the cardiovascular (CV) risk factors associated with an ageing population. The aim of this review is to examine the existing literature around CVD in T1D. We pay particular attention to CVD prevalence, how well we manage risk, potential biomarkers, and whether the studies included the older aged patients (defined as aged over 65). We also discuss approaches to the management of CV risk in the older aged. The available data suggest a significant CVD burden in patients with T1D and poor management of CV risk factors. This is underpinned by a poor evidence base for therapeutic management of CV risk specifically for patients with T1D, and in the most relevant population - the older aged patients. We would suggest that important areas remain to be addressed, particularly exploring the risks and benefits of therapeutic approaches to CVD management in the older aged.
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Affiliation(s)
- Siang Ing Lee
- School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, UK
| | - Mitesh Patel
- School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, UK
| | - Christopher M Jones
- School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, UK
| | - Parth Narendran
- Institute of Biomedical Research, The Medical School, University of Birmingham, Edgbaston B15 2TT, UK
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Cornelius DC, Castillo J, Porter J, Amaral LM, Campbell N, Paige A, Thomas AJ, Harmon A, Cunningham MW, Wallace K, Herse F, Wallukat G, Dechend R, LaMarca B. Blockade of CD40 ligand for intercellular communication reduces hypertension, placental oxidative stress, and AT1-AA in response to adoptive transfer of CD4+ T lymphocytes from RUPP rats. Am J Physiol Regul Integr Comp Physiol 2015; 309:R1243-50. [PMID: 26310940 PMCID: PMC4666934 DOI: 10.1152/ajpregu.00273.2015] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Accepted: 08/24/2015] [Indexed: 12/21/2022]
Abstract
Preeclampsia (PE) is associated with altered immune activation during pregnancy. We have previously shown that adoptive transfer of CD4(+) T cells from the reduced uterine perfusion pressure (RUPP) rat model of PE increases blood pressure, oxidative stress (ROS), and inflammation in normal pregnant recipient rats. The objective of this study was to determine if blockade of communication via the CD40-CD40 ligand (CD40L) interaction between placental ischemia-induced CD4(+) T cells with endogenous normal pregnant (NP) cells would improve pathophysiology that was previously observed in NP recipient rats of RUPP CD4(+) T cells. Splenic CD4(+) T lymphocytes were magnetically separated, incubated with 2.5 μg/ml anti-CD40 ligand (αCD40L) overnight, and transferred into NP rats on day 12 of gestation (NP+RUPP CD4(+) T+anti-CD40L). On day 19 of gestation, blood pressure (MAP), blood, and tissues were collected. MAP was 99 ± 2 in NP (n = 13), 116 ± 4 in NP+RUPP CD4(+) T cells (n = 7; P < 0.01); MAP only increased to 104 ± 2 in NP+RUPP CD4(+) T cells+CD40L (n = 24) (P < 0.05 vs. NP+RUPP CD4(+) T cells). Mechanisms of hypertension in response to RUPP CD4(+) T cells include endothelin-1 (ET-1), ROS, and angiotensin II type I receptor (AT1-AA) were analyzed. Inhibition of CD40L binding reduced placental ET-1 to 2.3-fold above NP rats and normalized placental ROS from 318.6 ± 89 in NP+RUPP CD4(+) T cells (P < 0.05) to 118.7 ± 24 in NP+RUPP CD4(+) T+anti-CD40L (P < 0.05). AT1-AA was also normalized with inhibition of CD40L. These data suggest that placental ischemia-induced T-cell communication via the CD40L is one important mechanism leading to much of the pathophysiology of PE.
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Affiliation(s)
- Denise C Cornelius
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Javier Castillo
- Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Justin Porter
- Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Lorena M Amaral
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Nathan Campbell
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Adrienne Paige
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Alexia J Thomas
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Ashlyn Harmon
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Mark W Cunningham
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Kedra Wallace
- Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Florian Herse
- Experimental and Clinical Research Center, Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany; and
| | - Gerd Wallukat
- Experimental and Clinical Research Center, Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany; and
| | - Ralf Dechend
- Experimental and Clinical Research Center, Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany; and HELIOS-Klinikum, Berlin, Germany
| | - Babbette LaMarca
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi; Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, Mississippi;
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Groen B, van der Wijk AE, van den Berg PP, Lefrandt JD, van den Berg G, Sollie KM, de Vos P, Links TP, Faas MM. Immunological Adaptations to Pregnancy in Women with Type 1 Diabetes. Sci Rep 2015; 5:13618. [PMID: 26391604 PMCID: PMC4585728 DOI: 10.1038/srep13618] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Accepted: 07/21/2015] [Indexed: 12/16/2022] Open
Abstract
Despite adequate glycemic control, pregnancy outcome of women with type 1 diabetes (T1D) is still unfavorable as compared to healthy women. In a rat-model of T1D under normoglycemic conditions, adverse pregnancy outcome was also observed, which was associated with aberrant immunological adaptations to pregnancy. Because similar processes may occur in women with T1D we studied the systemic immune response in non-pregnant and pregnant women with and without T1D. The systemic immune response was assessed by using flow cytometry to evaluate the number and activational status of subpopulations of lymphocytes, Natural Killer cells and monocytes in peripheral blood of non-pregnant and pregnant women with and without T1D. An increased white blood cell count, an increased Th1/Th2 ratio, increased Natural Killer cell expression of CD335 and enhanced activation of intermediate and non-classical monocytes was observed in pregnant women with T1D vs. healthy pregnant women. Also, the pregnancy outcome (i.e. incidence of preterm delivery and macrosomia) of women with T1D was unfavorable as compared to healthy women. This study showed that in T1D, the immunological adaptations to pregnancy are disturbed. In addition to hyperglycemia, these different immunological adaptations may be responsible for the greater frequency of complications in pregnant women with T1D.
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Affiliation(s)
- Bart Groen
- Department of Endocrinology, University of Groningen, University Medical Center Groningen, 9700 RB, the Netherlands.,Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen, 9700 RB, the Netherlands
| | - Anne-Eva van der Wijk
- Department of Pathology and Medical Biology, Div. of Medical Biology, University of Groningen, University Medical Center Groningen, 9700 RB, the Netherlands
| | - Paul P van den Berg
- Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen, 9700 RB, the Netherlands
| | - Joop D Lefrandt
- Department of Internal Medicine, University of Groningen, University Medical Center Groningen, 9700 RB, the Netherlands
| | - Gerrit van den Berg
- Department of Endocrinology, University of Groningen, University Medical Center Groningen, 9700 RB, the Netherlands
| | - Krystina M Sollie
- Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen, 9700 RB, the Netherlands
| | - Paul de Vos
- Department of Pathology and Medical Biology, Div. of Medical Biology, University of Groningen, University Medical Center Groningen, 9700 RB, the Netherlands
| | - Thera P Links
- Department of Endocrinology, University of Groningen, University Medical Center Groningen, 9700 RB, the Netherlands
| | - Marijke M Faas
- Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen, 9700 RB, the Netherlands.,Department of Pathology and Medical Biology, Div. of Medical Biology, University of Groningen, University Medical Center Groningen, 9700 RB, the Netherlands
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Yuan M, Fu H, Ren L, Wang H, Guo W. Soluble CD40 ligand promotes macrophage foam cell formation in the etiology of atherosclerosis. Cardiology 2015; 131:1-12. [PMID: 25825037 DOI: 10.1159/000374105] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Accepted: 01/08/2015] [Indexed: 11/19/2022]
Abstract
OBJECTIVE High levels of soluble CD40 ligand (sCD40L) in the circulation have been suggested as an important indicator of cardiovascular diseases such as atherosclerosis and acute coronary syndromes. In the present study, we explored the role of sCD40L in the formation of foam cells. METHODS Lipid deposition and foam cell formation was measured by high-performance liquid chromatography and Nile Red staining, respectively. Gene expressions were detected by quantitative real-time PCR and Western blot analysis. The interaction between CD40 and sCD40L were blocked by CD40 small interfering RNA or anti-CD40 antibody. RESULTS sCD40L significantly increased lipid deposition and foam cell formation associated with upregulation of scavenger receptor type A and CD36. Additionally, sCD40L increased adipocyte enhancer-binding protein 1 and cholesterol efflux, and activated NF-κB in macrophages. sCD40L promoted foam cell formation via CD40 ligation and disruption of the ligation between CD40 and CD40L either by small interfering RNA or by a blocking anti-CD40 antibody apparently inhibiting foam cell formation in response to sCD40L. CONCLUSION Our data suggests a novel insight into the role of sCD40L in foam cell formation during atherosclerosis, which further confirms the importance of sCD40L in atherosclerosis and as a target for the treatment of this disease.
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Affiliation(s)
- Ming Yuan
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
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de Ferranti SD, de Boer IH, Fonseca V, Fox CS, Golden SH, Lavie CJ, Magge SN, Marx N, McGuire DK, Orchard TJ, Zinman B, Eckel RH. Type 1 diabetes mellitus and cardiovascular disease: a scientific statement from the American Heart Association and American Diabetes Association. Diabetes Care 2014; 37:2843-63. [PMID: 25114297 PMCID: PMC4170130 DOI: 10.2337/dc14-1720] [Citation(s) in RCA: 268] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
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40
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Portillo JAC, Greene JA, Okenka G, Miao Y, Sheibani N, Kern TS, Subauste CS. CD40 promotes the development of early diabetic retinopathy in mice. Diabetologia 2014; 57:2222-31. [PMID: 25015056 PMCID: PMC4291184 DOI: 10.1007/s00125-014-3321-x] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Accepted: 06/09/2014] [Indexed: 11/26/2022]
Abstract
AIMS/HYPOTHESIS Microangiopathy is a leading complication of diabetes that commonly affects the retina. Degenerate capillaries are a central feature of diabetic retinopathy. An inflammatory process has been linked to the development of diabetic retinopathy but its regulation is incompletely understood. Cluster of differentiation (CD) 40 is a member of the TNF receptor superfamily that promotes the development of certain inflammatory disorders. The role of CD40 in diabetic microangiopathy is unknown. METHODS B6 and Cd40−/− mice were administered streptozotocin to induce diabetes. Leucostasis was assessed using fluorescein isothiocyanate-conjugated concanavalin A. Retinal Icam1 and Cd40 mRNA levels were examined using real-time PCR. Protein nitration was assessed by immunohistochemistry. Histopathology was examined in the retinal vasculature. CD40 expression was assessed by flow cytometry and immunohistochemistry. Intercellular adhesion molecule 1 (ICAM-1) and nitric oxide synthase 2 (NOS2) were examined by immunoblot and/or flow cytometry. Nitric oxide production was examined by immunoblot and Griess reaction. RESULTS In mouse models of diabetes, Cd40−/− mice exhibited reduced retinal leucostasis and did not develop capillary degeneration in comparison with B6 mice. Diabetic Cd40−/− mice had diminished ICAM-1 upregulation and decreased protein nitration. Cd40 mRNA levels were increased in the retinas of diabetic B6 mice compared with non-diabetic controls. CD40 expression increased in retinal Müller cells, endothelial cells and microglia of diabetic animals. CD40 stimulation upregulated ICAM-1 in retinal endothelial cells and Müller cells. CD40 ligation upregulated NOS2 and nitric oxide production by Müller cells. CONCLUSIONS/INTERPRETATION CD40-deficient mice were protected fromthe development of diabetic retinopathy. These mice exhibited diminished inflammatory responses linked to diabetic retinopathy. CD40 stimulation of retinal cells triggered these pro-inflammatory responses.
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de Ferranti SD, de Boer IH, Fonseca V, Fox CS, Golden SH, Lavie CJ, Magge SN, Marx N, McGuire DK, Orchard TJ, Zinman B, Eckel RH. Type 1 diabetes mellitus and cardiovascular disease: a scientific statement from the American Heart Association and American Diabetes Association. Circulation 2014; 130:1110-30. [PMID: 25114208 DOI: 10.1161/cir.0000000000000034] [Citation(s) in RCA: 239] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Obulesu M, Jhansilakshmi M. Neuroinflammation in Alzheimer's disease: an understanding of physiology and pathology. Int J Neurosci 2013; 124:227-35. [DOI: 10.3109/00207454.2013.831852] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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43
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Zhang B, Wu T, Chen M, Zhou Y, Yi D, Guo R. The CD40/CD40L system: a new therapeutic target for disease. Immunol Lett 2013; 153:58-61. [PMID: 23892087 DOI: 10.1016/j.imlet.2013.07.005] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2013] [Revised: 07/13/2013] [Accepted: 07/17/2013] [Indexed: 12/14/2022]
Abstract
The role of CD40/CD40 ligand (CD40L) interactions in atherothrombosis, in the response of the immune system to pathogens and in thrombosis is now widely accepted. A role for CD40-CD40L interactions has been identified in atherosclerosis (AS), and such interactions are known to destabilize atherosclerotic plaques by inducing the expression of cytokines, chemokines, growth factors, matrix metalloproteinases and pro-coagulant factors. CD40/CD40L interactions have also been implicated in immune system disorders. Recent studies have suggested that CD40/CD40L interactions regulate oxidative stress and affect various signaling pathways in both the immunological and the cardiovascular systems. Here, we discuss the current drugs that target the CD40/CD40L system, as understanding the roles and regulations of CD40/CD40L-mediated signal pathways by these drugs could facilitate the development of therapeutics that target diverse diseases.
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Affiliation(s)
- Bikui Zhang
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
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Moresco RN, Sangoi MB, De Carvalho JAM, Tatsch E, Bochi GV. Diabetic nephropathy: traditional to proteomic markers. Clin Chim Acta 2013; 421:17-30. [PMID: 23485645 DOI: 10.1016/j.cca.2013.02.019] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Revised: 02/06/2013] [Accepted: 02/09/2013] [Indexed: 01/11/2023]
Abstract
Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes and it is defined as a rise in the urinary albumin excretion (UAE) rate and abnormal renal function. Currently, changes in albuminuria are considered a hallmark of onset or progression of DN. However, some patients with diabetes have advanced renal pathological changes and progressive kidney function decline even if urinary albumin levels are in the normal range, indicating that albuminuria is not the perfect marker for the early detection of DN. The present article provides an overview of the literature reporting some relevant biomarkers that have been found to be associated with DN and that potentially may be used to predict the onset and/or monitor the progression of nephropathy. In particular, biomarkers of renal damage, inflammation, and oxidative stress may be useful tools for detection at an early stage or prediction of DN. Proteomic-based biomarker discovery represents a novel strategy to improve diagnosis, prognosis and treatment of DN; however, proteomics-based approaches are not yet available in most of the clinical chemistry laboratories. The use of a panel with a combination of biomarkers instead of urinary albumin alone seems to be an interesting approach for early detection of DN, including markers of glomerular damage (e.g., albumin), tubular damage (e.g., NAG and KIM-1), inflammation (e.g., TNF-α) and oxidative stress (e.g., 8-OHdG) because these mechanisms contribute to the development and outcomes of this disease.
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Affiliation(s)
- Rafael N Moresco
- Laboratório de Pesquisa em Bioquímica Clínica, Departamento de Análises Clínicas e Toxicológicas, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil.
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45
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Diabetes Mellitus. Platelets 2013. [DOI: 10.1016/b978-0-12-387837-3.00035-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2023]
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El-Asrar MA, Adly AA, Ismail EA. Soluble CD40L in children and adolescents with type 1 diabetes: relation to microvascular complications and glycemic control. Pediatr Diabetes 2012; 13:616-24. [PMID: 22702645 DOI: 10.1111/j.1399-5448.2012.00881.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2012] [Revised: 04/09/2012] [Accepted: 04/17/2012] [Indexed: 12/28/2022] Open
Abstract
CD40-soluble CD40 ligand (sCD40L) interactions might constitute an important mediator for vascular inflammation that initiates diabetic microangiopathy. Little is known about the relation between sCD40L and glycemic control. Therefore, this study aimed to evaluate sCD40L levels in patients with type 1 diabetes and its relation to microvascular complications and metabolic control. Sixty patients with type 1 diabetes were compared with 30 healthy control subjects. Detailed medical history, thorough clinical examination, and laboratory assessment of high-sensitivity C-reactive protein, glycemic control, and the presence of microvascular complications were performed. Measurement of serum sCD40L levels was done using enzyme-linked immunosorbent assay. Patients were divided into two groups according to the presence of microvascular complications. Serum sCD40L levels were significantly elevated in patients with type 1 diabetes in both groups compared with healthy controls (p < 0.001). Patients with microvascular complications had higher serum sCD40L concentrations than non-complicated cases (median, 13 000 vs. 450 pg/mL; p < 0.001). Serum sCD40L cutoff value of 530 pg/mL was able to differentiate complicated from non-complicated cases (p < 0.001). Patients with microalbuminuria or peripheral neuropathy showed higher levels of sCD40L when compared with patients without these complications (p < 0.05). Serum sCD40L levels were positively correlated with hemoglobin A1c and urinary albumin excretion (p < 0.001). We suggest that serum sCD40L levels are elevated in type 1 diabetes, particularly in patients with microvascular complications and a significant correlation with glycemic control exists. Therefore, measurement of serum sCD40L levels in poorly controlled patients would help to identify those at high risk of developing microvascular complications.
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Panichi V, Scatena A, Migliori M, Marchetti V, Paoletti S, Beati S. Biomarkers of chronic inflammatory state in uremia and cardiovascular disease. Int J Inflam 2012; 2012:360147. [PMID: 22701810 PMCID: PMC3373120 DOI: 10.1155/2012/360147] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2012] [Revised: 04/05/2012] [Accepted: 04/17/2012] [Indexed: 11/17/2022] Open
Abstract
Cardiovascular disease is the leading cause of death in the general population; traditional risk factors seem inadequate to explain completely the remarkable prevalence of cardiovascular mortality and morbidity observed in the uremic population. A role for chronic inflammation has been well established in the development of atherosclerotic disease, and, on the basis of these observations, atherosclerosis might be considered an inflammatory disease. Inflammation has been implicated in the etiology of coronary artery disease in the general population, and traditional inflammatory biomarkers such as C-reactive protein (CRP) and interleukin-6 (IL-6) have been shown to predict cardiovascular events in both symptomatic and asymptomatic individuals as well as those in the uremic population. Later on, new nontraditional markers were related to the risk of cardiovascular morbidity and mortality in general and in uremic population. As a consequence of the expanding research base and availability of assays, the number of inflammatory marker tests ordered by clinicians for cardiovascular disease (CVD) risk prediction has grown rapidly and several commercial assays have become available. So, up to now we can consider that several new nontraditional markers as CD40-CD40 ligand system and pentraxin-3 seem to be significant features of cardiovascular disease in general and in ESRD population.
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Affiliation(s)
- Vincenzo Panichi
- Nephrology and Dialysis Unit, Versilia Hospital, Via Aurelia 335, 55034 Lido di Camaiore, Italy
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Yamamoto K, Itoh M, Okamura T, Kimura M, Yokoyama A, Yoshino Y, Makino M, Hayakawa N, Suzuki A. Relative levels of the inflammatory cytokine TNFα and the soluble CD40 ligand profile in serum correlate with the thyrotoxic activity of Graves' disease. Thyroid 2012; 22:516-21. [PMID: 22512415 DOI: 10.1089/thy.2011.0222] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
BACKGROUND Interactions between CD40 and its ligand (CD40L) have important roles in T-cell-dependent activation of B cells, which may be related to the thyrotoxic activity of Graves' disease (GD). Soluble forms of CD40 ligand (sCD40L) are released from activated T cells and platelets, and several types of inflammatory cytokines are increased in patients with hyperthyroid GD. The aim of this study was to assess sCD40L and other cytokines as clinical indicators of disease activity or as possible markers of remission in GD. METHODS Serum levels of sCD40L, interleukin 18 (IL-18), tumor necrosis factor-alpha (TNFα), and TNFα receptors 1 and 2 (TNFR1 and TNFR2) were investigated in patients with active GD (GD-A), intractable GD (GD-IT), inactive GD (GD-IA), GD in remission (GD-R), and Hashimoto's thyroiditis (HT), and in control subjects (CON). RESULTS Serum concentrations of sCD40L were higher in the GD-A and GD-IT groups than in the HT and CON groups. Similarly, serum concentrations of IL-18, which induces Th1 cytokines, such as interferon-γ, were higher in the GD-A and GD-IT groups than in all other groups. Serum levels of TNFR1 and TNFR2 were also significantly higher in the GD-A than in all other groups. The mean serum concentration of TNFα was higher in the GD-R compared with the GD-A and GD-IT groups, although the difference was not significant. Serum sCD40L concentrations in the GD-R group were lower than in the GD-A and GD-IT groups. Finally, the ratio of serum TNFα to sCD40L was higher in the GD-R group than in the GD-A and GD-IT groups. This is the first report that serum sCD40L is increased in active GD, and that the serum TNFα:sCD40L ratio is a marker for remission in GD. CONCLUSIONS Our results suggest that not only thyrotoxicosis, but also the activity of the immunoreaction presenting as anti-thyrotropin receptor antibodies (TRAb) titer in GD, affects inflammatory cytokine serum profiles. Serum profiles of cytokines vary in patients with GD depending on disease activity. An elevated serum TNFα:sCD40L ratio indicates declining disease activity and reflects a shift from Th2 to Th1 dominance, suggesting that suppression of sCD40L or increased production of TNFα is required to initiate or maintain remission of GD.
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Affiliation(s)
- Keiko Yamamoto
- Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan
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Giannini S, Falcinelli E, Bury L, Guglielmini G, Rossi R, Momi S, Gresele P. Interaction with damaged vessel wall in vivo in humans induces platelets to express CD40L resulting in endothelial activation with no effect of aspirin intake. Am J Physiol Heart Circ Physiol 2011; 300:H2072-9. [PMID: 21378140 DOI: 10.1152/ajpheart.00467.2010] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Activated platelets express CD40L on their plasma membrane and release the soluble fragment sCD40L. The interaction between platelet surface CD40L and endothelial cell CD40 leads to the activation of endothelium contributing to atherothrombosis. Few studies have directly demonstrated an increased expression of platelet CD40L in conditions of in vivo platelet activation in humans, and no data are available on its relevance for endothelial activation. We aimed to assess whether platelets activated in vivo at a localized site of vascular injury in humans express CD40L and release sCD40L, whether the level of platelet CD40L expression attained in vivo is sufficient to induce endothelial activation, and whether platelet CD40L expression is inhibited by aspirin intake. We used the skin-bleeding-time test as a model to study the interaction between platelets and a damaged vessel wall by measuring CD40L in the blood emerging from a skin wound in vivo in healthy volunteers. In some experiments, shed blood was analyzed before and 1 h after the intake of 500 mg of aspirin. Platelets from the bleeding-time blood express CD40L and release soluble sCD40L, in a time-dependent way. In vivo platelet CD40L expression was mild but sufficient to induce VCAM-1 expression and IL-8 secretion in coincubation experiments with cultured human endothelial cells. Moreover, platelets recovered from the bleeding-time blood activated endothelial cells; an anti-CD40L antibody blocked this effect. On the contrary, the amount of sCD40L released by activated platelets at a localized site of vascular injury did not reach the concentrations required to induce endothelial cell activation. Soluble monocyte chemoattractant protein-1, a marker of endothelium activation, was increased in shed blood and correlated with platelet CD40L expression. Aspirin intake did not inhibit CD40L expression by platelets in vivo. We concluded that CD40L expressed by platelets in vivo in humans upon contact with a damaged vessel wall activates endothelium; aspirin treatment does not inhibit this mechanism.
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Affiliation(s)
- Silvia Giannini
- Div. of Internal and Cardiovascular Medicine, Dept. of Internal Medicine, Univ. of Perugia, Via E. dal Pozzo, 06126 Perugia, Italy
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Desideri G, Panichi V, Paoletti S, Grassi D, Bigazzi R, Beati S, Bernabini G, Rosati A, Ferri C, Taddei S, Ghiadoni L. Soluble CD40 ligand is predictive of combined cardiovascular morbidity and mortality in patients on haemodialysis at a relatively short-term follow-up. Nephrol Dial Transplant 2011; 26:2983-8. [DOI: 10.1093/ndt/gfq823] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
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