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| 2. |
- Edmunds, Shelley J, et al.
(författare)
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ApoAI-derived peptide increases glucose tolerance and prevents formation of atherosclerosis in mice
- 2019
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 62:7, s. 1257-1267
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Finding new treatment alternatives for individuals with diabetes with severe insulin resistance is highly desired. To identify novel mechanisms that improve glucose uptake in skeletal muscle, independently from insulin levels and signalling, we have explored the therapeutic potential of a short peptide sequence, RG54, derived from apolipoprotein A-I (ApoA-I).METHODS: INS-1E rat clonal beta cells, C2C12 rat muscle myotubes and J774 mouse macrophages were used to study the impact of RG54 peptide on glucose-stimulated insulin secretion, glucose uptake and cholesterol efflux, respectively. GTTs were carried out on diet-induced insulin-resistant and Leprdb diabetic mouse models treated with RG54 peptide, and the impact of RG54 peptide on atherosclerosis was evaluated in Apoe-/- mice. Control mice received ApoA-I protein, liraglutide or NaCl.RESULTS: The synthetic RG54 peptide induced glucose uptake in cultured muscle myotubes by a similar amount as insulin, and also primed pancreatic beta cells for improved glucose-stimulated insulin secretion. The findings were verified in diet-induced insulin-resistant and Leprdb diabetic mice, jointly confirming the physiological effect. The RG54 peptide also efficiently catalysed cholesterol efflux from macrophages and prevented the formation of atherosclerotic plaques in Apoe-/- mice.CONCLUSIONS/INTERPRETATION: The RG54 peptide exhibits good prospects for providing glucose control and reducing the risk of cardiovascular disease in individuals with severe insulin resistance.
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| 3. |
- Edsfeldt, Andreas, et al.
(författare)
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Soluble Urokinase Plasminogen Activator Receptor is Associated With Inflammation in the Vulnerable Human Atherosclerotic Plaque.
- 2012
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Ingår i: Stroke: a journal of cerebral circulation. - 1524-4628. ; 43:12, s. 3305-3312
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Tidskriftsartikel (refereegranskat)abstract
- Recently, plasma soluble urokinase plasminogen activator receptor (suPAR) has gained interest as a marker of cardiovascular risk. suPAR is released through the cleavage of urokinase plasminogen activator receptor (uPAR), which is found in monocytes, activated T-lymphocytes and endothelial cells, all involved in atherosclerosis. suPAR levels have been well studied in plasma, but no studies have focused on suPAR in human atherosclerotic plaques. The aim of this study was to determine whether suPAR measured in the plaque is associated with symptomatic plaques and plaque inflammation.
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| 4. |
- Fields, James K., et al.
(författare)
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Antibodies targeting the shared cytokine receptor IL-1 receptor accessory protein invoke distinct mechanisms to block all cytokine signaling
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Ingår i: Cell Reports. - 2211-1247.
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin-1 (IL-1)-family cytokines are potent modulators of inflammation, coordinating a vast array of immunological responses across innate and adaptive immune systems. Dysregulated IL-1-family cytokine signaling, however, is involved in a multitude of adverse health effects, such as chronic inflammatory conditions, autoimmune diseases, and cancer. Within the IL-1 family of cytokines, six—IL-1α, IL-1β, IL-33, IL-36α, IL-36β, and IL-36γ—require the IL-1 receptor accessory protein (IL-1RAcP) as their shared co-receptor. Common features of cytokine signaling include redundancy of signaling pathways, sharing of cytokines and receptors, pleiotropy of the cytokines themselves, and multifaceted immune responses. Accordingly, targeting multiple cytokines simultaneously is an emerging therapeutic strategy and can provide advantages over targeting a single cytokine pathway. Here, we show that two monoclonal antibodies, CAN10 and 3G5, which target IL-1RAcP for broad blockade of all associated cytokines, do so through distinct mechanisms and provide therapeutic opportunities for the treatment of inflammatory diseases.
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| 6. |
- Grönberg, Caitríona, et al.
(författare)
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Endarterectomy patients with elevated levels of circulating IL-16 have fewer cardiovascular events during follow-up
- 2016
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Ingår i: Cytokine. - : Elsevier BV. - 1043-4666. ; 85, s. 137-139
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose Increased interleukin 16 (IL-16) levels in carotid plaques have been associated with reduced incidence of cardiovascular (CV) events during follow-up in patients who underwent carotid endarterectomy (CEA). In the present study we aimed to determine whether high circulating levels of IL-16 also are associated with a decreased risk of CV events after CEA. Methods Patients, who had their carotid plaques surgically removed (n = 473), were followed for a mean follow-up time of 3.1 years. Plasma levels of IL-16 the day before surgery were analyzed by proximity extension assay (PEA) and associated with the occurrence of CV events during follow-up (n = 98). Results High levels of circulating IL-16 were independently associated with a decreased risk of CV events when comparing the highest versus the lowest IL-16 tertile (hazard ratio [HR] 0.47; 95% CI 0.27–0.81; P = 0.007), as well as with CV deaths (HR 0.25; 95% CI 0.09–0.70; P = 0.008). Conclusion These present findings indicate an association between IL-16 and less clinical complications of atherosclerosis in a population with known advanced carotid disease.
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| 7. |
- Grönberg, Caitriona, et al.
(författare)
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Human Carotid Plaques With High Levels of Interleukin-16 Are Associated With Reduced Risk for Cardiovascular Events.
- 2015
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Ingår i: Stroke: a journal of cerebral circulation. - 1524-4628. ; 46:10, s. 2748-2754
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin-16 (IL-16) functions as a regulator of T-cell growth and acts as an inducer of cell migration. The aim of this study was to determine whether IL-16 measured in human carotid plaques was associated with symptoms (eg, stroke, transient ischemic attack, or amaurosis fugax), markers of plaque stability, and postoperative cardiovascular events.
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| 8. |
- Grönberg, Caitriona
(författare)
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Interleukin 16 in Atherosclerosis and Cardiovascular Disease
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background and aim - The development of clinical manifectations due to an eroded or ruptured atherosclerotic plaque, or occluded vessel, are one of the major causes of death world wide. It has been known for some time that atherosclerosis develops due to retention and modification of LDL particles in the vessel wall and the subsequent triggering of the immune system. The research presented within this thesis has focused on IL-16, a signaling molecule, in the immune system.. IL-16 has shown pleiotropic functions in inflammatory diseases. IL-16 has been described to have the capacity to induce T cell unresponsivness and increase the regulatory T cell population. Regulatory T cells are known to be protective in atherosclerosis by dampening the immune responses. There has been no extensive research on the role of IL-16 in atherosclerosis disease and the clinical manifestations thereof. The aim of the collected work in this thesis was to investigate if IL-16 can induce anti-inflammatory and atherosclerosis dampening effects, if IL-16 holds potential as a biomarker for predicting future cardiovascular events, and if IL-16 is altered in an retrospective cardiovascular case-control study.Results – (I) Administration of IL-16, in an experimental model of atherosclerosis consisting of hypercholesterolemic female mice, increased anti-inflammatory factors and decreased the atherosclerotic plaque burden. Male mice, which were defective of IL-16, displayed an increased atherosclerotic burden compared to control mice. (II) Elevated levels of IL-16, in carotid plaques, from individuals with severe carotid atherosclerosis displayed associations to plaque stabilizing components (collagen, elastin and FoxP3). High levels of carotid plaque IL-16 were associated to a decreased risk of suffering from a cardiovascular event. (III) Individuals suffering from severe carotid atherosclerosis had a decreased risk of suffering from a post-operative cardiovascular event, or a cardiovascular event leading to death, if they had high levels of circulating IL-16 compared to individuals with low levels of IL-16. (IV) In a population-based prospective study four single nucleotide polymophisms (SNPs) were found to be associated with IL-16 plasma levels. High plasma levels of IL-16 were associated with an increased risk of myocardial infarction in women, compared to women with low levels of circulating IL-16. None of the SNPs were associated with an increased risk of cardiovascular events. One of the identified SNPs was associated with a decreased risk of all-cause mortality during the 20-year follow-up period. (V) In a retrospective case-control study, including individuals suffering from diabetes, IL-16 was 50% elevated in individuals whom also suffered from cardiovascular complications compared to the individuals only suffering from diabetes. Plasma levels of IL-16 were associated with surrogate markers of atherosclerosis which was further supported by SNP analysis.Conclusion - IL-16 in plasma did not display associations to a decreased risk of cardiovascular events in a prospective population-based study, rather the opposite. We have presented supporting evidence of a protective role of IL-16 in severe and experimental atherosclerosis, reinforced by the associations between high IL-16 levels and increasing amounts of stabilizing factors in the atherosclerotic plaque. We also present supporting evidence, in an experimental setting, for an anti-inflammatory role and plaque burden limiting role of IL-16. The data presented within this thesis warrants further investigation of the plaque stabilizing properties of IL-16 in severe atherosclerosis and the role of IL-16 in promoting anti-inflammatory mediators.
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| 9. |
- Grönberg, Caitríona, et al.
(författare)
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Recent advances on CD4+ T cells in atherosclerosis and its implications for therapy
- 2017
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999. ; 816, s. 58-66
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Tidskriftsartikel (refereegranskat)abstract
- Atherosclerosis is an arterial inflammatory disease and the primary cause of cardiovascular disease. T helper (Th) cells are an important part in atherosclerotic plaque as they can be either disease promoting or protective. A body of evidence points to a pro-atherosclerotic role of Th1 cells, whereas the role of Th2, Th17 and iNKT cells seems more complex and dependent on surrounding factors, including the developmental stage of the disease. Opposed to Th1 cells, there is convincing support for an anti-atherogenic role of Tregs. Recent data identify the plasticity of Th cells as an important challenge in understanding the functional role of different Th cell subsets in atherosclerosis. Much of the knowledge of Th cell function in atherosclerosis is based on findings from experimental models and translating this into human disease is challenging. Targeting Th cells and/or their specific cytokines represents an attractive option for future therapy against atherosclerosis, although the benefits and the risk of modulation of Th cells with these novel drug targets must first be carefully assessed.
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