| 1. |
- Bennion, Douglas M, et al.
(author)
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Protective effects of the angiotensin II AT2 receptor agonist compound 21 in ischemic stroke : a nose-to-brain delivery approach.
- 2018
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In: Clinical Science. - 0143-5221 .- 1470-8736. ; 132:5, s. 581-593
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Journal article (peer-reviewed)abstract
- Significant neuroprotective effects of angiotensin II type 2 (AT2) receptor (AT2 receptor) agonists in ischemic stroke have been previously demonstrated in multiple studies. However, the routes of agonist application used in these pre-clinical studies, direct intracerebroventricular (ICV) and systemic administration, are unsuitable for translation into humans; in the latter case because AT2 receptor agonists are blood-brain barrier (BBB) impermeable. To circumvent this problem, in the current study we utilized the nose-to-brain (N2B) route of administration to bypass the BBB and deliver the selective AT2 receptor agonist Compound 21 (C21) to naïve rats or rats that had undergone endothelin 1 (ET-1)-induced ischemic stroke. The results obtained from the present study indicated that C21 applied N2B entered the cerebral cortex and striatum within 30 min in amounts that are therapeutically relevant (8.4-9 nM), regardless of whether BBB was intact or disintegrated. C21 was first applied N2B at 1.5 h after stroke indeed provided neuroprotection, as evidenced by a highly significant, 57% reduction in cerebral infarct size and significant improvements in Bederson and Garcia neurological scores. N2B-administered C21 did not affect blood pressure or heart rate. Thus, these data provide proof-of-principle for the idea that N2B application of an AT2 receptor agonist can exert neuroprotective actions when administered following ischemic stroke. Since N2B delivery of other agents has been shown to be effective in certain human central nervous system diseases, the N2B application of AT2 receptor agonists may become a viable mode of delivering these neuroprotective agents for human ischemic stroke patients
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| 2. |
- Bergqvist, Anders, et al.
(author)
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Alveolar T-helper type-2 immunity in atopic asthma is associated with poor clinical control
- 2015
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In: Clinical Science. - 1470-8736. ; 128:1, s. 47-56
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Journal article (peer-reviewed)abstract
- Real-world evaluation studies have shown that many patients with asthma remain symptomatic despite treatment with inhaled corticosteroids (ICSs). As conventional ICSs have poor access to the peripheral airways, the aim of the present paper was to study the relationship between peripheral airway inflammation and clinical control in allergic asthma. Consequently, bronchial and transbronchial biopsies were obtained from patients with poorly controlled asthma [n=12, asthma control test (ACT) score < 20], patients with well-controlled asthma (n= 12, ACT score >= 20) and healthy controls (n= 8). Tissue sections were immunostained to assess multiple leucocyte populations. To determine the degree of T-helper type-2 (Th2) immunity, the logarithmic value of the ratio between Th2 cells/mm(2) and Th1 cells/mm(2) was used as a surrogate score for Th2-skewed immunity. In the bronchi, the leucocyte infiltration pattern and the Th2-score were similar between patients with well-controlled asthma and those with poorly controlled asthma. In contrast, in the alveolar parenchyma, the expression of T-helper cells was significantly higher in patients with poorly controlled asthma than in patients with well-controlled asthma (P < 0.01). Furthermore, the alveolar Th2-score was significantly higher in patients with poorly controlled asthma (median 0.4) than in the controlled patients (median -0.10, P < 0.05). In addition, in contrast with bronchial Th2-score, the alveolar Th2-score correlated significantly with ACT score (r(s)=-0.62, P < 0.01) in the pooled asthma group. Collectively, our data reveal an alveolar Th2-skewed inflammation, specifically in asthmatic patients who are poorly controlled with ICSs, and suggest that pharmacological targeting of the peripheral airways may be beneficial in this large patient category.
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| 3. |
- Che, K. F., et al.
(author)
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The neutrophil-mobilizing cytokine interleukin-26 in the airways of long-term tobacco smokers
- 2018
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In: Clinical Science. - : Portland Press Ltd.. - 0143-5221 .- 1470-8736. ; 132:9, s. 959-983
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Journal article (peer-reviewed)abstract
- Long-term tobacco smokers with chronic obstructive pulmonary disease (COPD) or chronic bronchitis display an excessive accumulation of neutrophils in the airways; an inflammation that responds poorly to established therapy. Thus, there is a need to identify new molecular targets for the development of effective therapy. Here, we hypothesized that the neutrophil-mobilizing cytokine interleukin (IL)-26 (IL-26) is involved in airway inflammation amongst long-term tobacco smokers with or without COPD, chronic bronchitis or colonization by pathogenic bacteria. By analyzing bronchoalveolar lavage (BAL), bronchail wash (BW) and induced sputum (IS) samples, we found increased extracellular IL-26 protein in the airways of long-term smokers in vivo without further increase amongst those with clinically stable COPD. In human alveolar macrophages (AM) in vitro, the exposure to water-soluble tobacco smoke components (WTC) enhanced IL-26 gene and protein. In this cell model, the same exposure increased gene expression of the IL-26 receptor complex (IL10R2 and IL20R1) and nuclear factor kappa B (NF-kappa B); a proven regulator of IL-26 production. In the same cell model, recombinant human IL-26 in vitro caused a concentration-dependent increase in the gene expression of NF-kappa B and several pro-inflammatory cytokines. In the long-term smokers, we also observed that extracellular IL-26 protein in BAL samples correlates with measures of lung function, tobacco load, and several markers of neutrophil accumulation. Extracellular IL-26 was further increased in long-term smokers with exacerbations of COPD (IS samples), with chronic bronchitis (BAL samples) or with colonization by pathogenic bacteria (IS and BW samples). Thus, IL-26 in the airways emerges as a promising target for improving the understanding of the pathogenic mechanisms behind several pulmonary morbidities in long-term tobacco smokers.
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| 4. |
- Che, Karlhans Fru, et al.
(author)
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The neutrophil-mobilizing cytokine interleukin-26 in the airways of long-term tobacco smokers
- 2018
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In: Clinical Science. - 0143-5221. ; 132:9, s. 959-983
-
Journal article (peer-reviewed)abstract
- Long-term tobacco smokers with chronic obstructive pulmonary disease (COPD) or chronic bronchitis display an excessive accumulation of neutrophils in the airways; an inflammation that responds poorly to established therapy. Thus, there is a need to identify new molecular targets for the development of effective therapy. Here, we hypothesized that the neutrophil-mobilizing cytokine interleukin (IL)-26 (IL-26) is involved in airway inflammation amongst long-term tobacco smokers with or without COPD, chronic bronchitis or colonization by pathogenic bacteria. By analyzing bronchoalveolar lavage (BAL), bronchail wash (BW) and induced sputum (IS) samples, we found increased extracellular IL-26 protein in the airways of long-term smokers in vivo without further increase amongst those with clinically stable COPD. In human alveolar macrophages (AM) in vitro, the exposure to water-soluble tobacco smoke components (WTC) enhanced IL-26 gene and protein. In this cell model, the same exposure increased gene expression of the IL-26 receptor complex (IL10R2 and IL20R1) and nuclear factor κ B (NF-κB); a proven regulator of IL-26 production. In the same cell model, recombinant human IL-26 in vitro caused a concentration-dependent increase in the gene expression of NF-κB and several pro-inflammatory cytokines. In the long-term smokers, we also observed that extracellular IL-26 protein in BAL samples correlates with measures of lung function, tobacco load, and several markers of neutrophil accumulation. Extracellular IL-26 was further increased in long-term smokers with exacerbations of COPD (IS samples), with chronic bronchitis (BAL samples ) or with colonization by pathogenic bacteria (IS and BW samples). Thus, IL-26 in the airways emerges as a promising target for improving the understanding of the pathogenic mechanisms behind several pulmonary morbidities in long-term tobacco smokers.
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| 8. |
- Fred, Rikard G., et al.
(author)
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Imatinib mesylate stimulates low-density lipoprotein receptor-related protein 1-mediated ERK phosphorylation in insulin-producing cells
- 2015
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In: Clinical Science. - 0143-5221 .- 1470-8736. ; 128:1, s. 17-28
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Journal article (peer-reviewed)abstract
- Low-density lipoprotein receptor-related protein 1 (LRP1) is an endocytic and multi-functional type I cell surface membrane protein, which is known to be phosphorylated by the activated platelet-derived growth factor receptor (PDGFR). The tyrosine kinase inhibitor imatinib, which inhibits PDGFR and c-Abl, and which has previously been reported to counteract beta-cell death and diabetes, has been suggested to reduce atherosclerosis by inhibiting PDGFR-induced LRP1 phosphorylation. The aim of the present study was to study LRP1 function in beta-cells and to what extent imatinib modulates LRP1 activity. LRP1 and c-Abl gene knockdown was performed by RNAi using rat INS-1 832/13 and human EndoC1-beta H1 cells. LRP1 was also antagonized by treatment with the antagonist low-density lipoprotein receptor-related protein associated protein 1 (LRPAP1). We have used PDGF-BB, a PDGFR agonist, and apolipoprotein E (ApoE), an LRP1 agonist, to stimulate the activities of PDGFR and LRP1 respectively. Knockdown or inhibition of LRP1 resulted in increased hydrogen peroxide (H2O2)(-) or cytokine-induced cell death, and glucose-induced insulin release was lowered in LRP1-silenced cells. These results indicate that LRP1 function is necessary for beta-cell function and that LRP1 is adversely affected by challenges to beta-cell health. PDGF-BB, or the combination of PDGF-BB+ApoE, induced phosphorylation of extracellular-signal-regulated kinase (ERK), Akt and LRP1. LRP1 silencing blocked this event. Imatinib blocked phosphorylation of LRP1 by PDGFR activation but induced phosphorylation of ERK. LRP1 silencing blocked imatinib-induced phosphorylation of ERK. Sunitinib also blocked LRP1 phosphorylation in response to PDGF-BB and induced phosphorylation of ERK, but this latter event was not affected by LRP1 knockdown. siRNA-mediated knockdown of the imatinib target c-Abl resulted in an increased ERK phosphorylation at basal conditions, with no further increase in response to imatinib. Imatinib-induced cell survival of tunicamycin-treated cells was partially mediated by ERK activation. We have concluded that imatinib promotes LRP1-dependent ERK activation, possibly via inhibition of c-Abl, and that this could contribute to the pro-survival effects of imatinib on beta-cells.
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| 9. |
- Galant, Natalie J., et al.
(author)
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Transthyretin amyloidosis : an under-recognized neuropathy and cardiomyopathy
- 2017
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In: Clinical Science. - : PORTLAND PRESS LTD. - 0143-5221 .- 1470-8736. ; 131:5, s. 395-409
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Research review (peer-reviewed)abstract
- Transthyretin (TTR) amyloidosis (ATTR amyloidosis) is an underdiagnosed and important type of cardiomyopathy and/or polyneuropathy that requires increased awareness within the medical community. Raising awareness among clinicians about this type of neuropathy and lethal form of heart disease is critical for improving earlier diagnosis and the identification of patients for treatment. The following review summarizes current criteria used to diagnose both hereditary and wild-type ATTR (ATTRwt) amyloidosis, tools available to clinicians to improve diagnostic accuracy, available and newly developing therapeutics, as well as a brief biochemical and biophysical background of TTR amyloidogenesis.
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