| 1. |
- Källberg, Eva, et al.
(författare)
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S100A9 Interaction with TLR4 Promotes Tumor Growth
- 2012
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Ingår i: PLOS ONE. - San Francisco : Public Library of Science. - 1932-6203. ; 7:3, s. e34207-
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Tidskriftsartikel (refereegranskat)abstract
- By breeding TRAMP mice with S100A9 knock-out (S100A9(-/-)) animals and scoring the appearance of palpable tumors we observed a delayed tumor growth in animals devoid of S100A9 expression. CD11b(+) S100A9 expressing cells were not observed in normal prostate tissue from control C57BL/6 mice but were readily detected in TRAMP prostate tumors. Also, S100A9 expression was observed in association with CD68(+) macrophages in biopsies from human prostate tumors. Delayed growth of TRAMP tumors was also observed in mice lacking the S100A9 ligand TLR4. In the EL-4 lymphoma model tumor growth inhibition was observed in S100A9(-/-) and TLR4(-/-), but not in RAGE(-/-) animals lacking an alternative S100A9 receptor. When expression of immune-regulating genes was analyzed using RT-PCR the only common change observed in mice lacking S100A9 and TLR4 was a down-regulation of TGF beta expression in splenic CD11b(+) cells. Lastly, treatment of mice with a small molecule (ABR-215050) that inhibits S100A9 binding to TLR4 inhibited EL4 tumor growth. Thus, S100A9 and TLR4 appear to be involved in promoting tumor growth in two different tumor models and pharmacological inhibition of S100A9-TLR4 interactions is a novel and promising target for anti-tumor therapies.
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| 2. |
- Björkman, Per, et al.
(författare)
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Common Interactions between S100A4 and S100A9 Defined by a Novel Chemical Probe.
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:5
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Tidskriftsartikel (refereegranskat)abstract
- S100A4 and S100A9 proteins have been described as playing roles in the control of tumor growth and metastasis. We show here that a chemical probe, oxyclozanide (OX), selected for inhibiting the interaction between S100A9 and the receptor for advanced glycation end-products (RAGE) interacts with both S100A9 and S100A4. Furthermore, we show that S100A9 and S100A4 interact with RAGE and TLR4; interactions that can be inhibited by OX. Hence, S100A4 and S100A9 display similar functional elements despite their primary sequence diversity. This was further confirmed by showing that S100A4 and S100A9 dimerize both in vitro and in vivo. All of these interactions required levels of Zn(++) that are found in the extracellular space but not intracellularly. Interestingly, S100A4 and S100A9 are expressed by distinct CD11b(+) subpopulations both in healthy animals and in animals with either inflammatory disease or tumor burden. The functions of S100A9 and S100A4 described in this paper, including heterodimerization, may therefore reflect S100A9 and S100A4 that are released into the extra-cellular milieu.
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| 3. |
- Fornander, Louise, et al.
(författare)
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Airway symptoms and biological markers in nasal lavage fluid in subjects exposed to metalworking fluids
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 8:12, s. e83089-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUNDS: Occurrence of airway irritation among industrial metal workers was investigated. The aims were to study the association between exposures from water-based metal working fluids (MWF) and the health outcome among the personnel, to assess potential effects on the proteome in nasal mucous membranes, and evaluate preventive actions.METHODS: The prevalence of airway symptoms related to work were examined among 271 metalworkers exposed to MWF and 24 metal workers not exposed to MWF at the same factory. At the same time, air levels of potentially harmful substances (oil mist, morpholine, monoethanolamine, formaldehyde) generated from MWF was measured. Nasal lavage fluid was collected from 13 workers and 15 controls and protein profiles were determined by a proteomic approach.RESULTS: Airway symptoms were reported in 39% of the workers exposed to MWF although the measured levels of MWF substances in the work place air were low. Highest prevalence was found among workers handling the MWF machines but also those working in the same hall were affected. Improvement of the ventilation to reduce MWF exposure lowered the prevalence of airway problems. Protein profiling showed significantly higher levels of S100-A9 and lower levels of SPLUNC1, cystatin SN, Ig J and β2-microglobulin among workers with airway symptoms.CONCLUSIONS: This study confirms that upper airway symptoms among metal workers are a common problem and despite low levels of MWF-generated substances, effects on airway immune proteins are found. Further studies to clarify the role of specific MWF components in connection to airway inflammation and the identified biological markers are warranted.
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| 4. |
- Isaacs, John T., et al.
(författare)
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Tasquinimod Is an Allosteric Modulator of HDAC4 Survival Signaling within the Compromised Cancer Microenvironment
- 2013
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Ingår i: Cancer Research. - 1538-7445. ; 74:4, s. 1386-1399
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Tidskriftsartikel (refereegranskat)abstract
- Tasquinimod is an orally active antiangiogenic drug that is currently in phase III clinical trials for the treatment of castration-resistant prostate cancer. However, the target of this drug has remained unclear. In this study, we applied diverse strategies to identify the histone deacetylase HDAC4 as a target for the antiangiogenic activity of tasquinimod. Our comprehensive analysis revealed allosteric binding (Kd 10-30 nmol/L) to the regulatory Zn2+ binding domain of HDAC4 that locks the protein in a conformation preventing HDAC4/N-CoR/HDAC3 complex formation. This binding inhibited colocalization of N-CoR/HDAC3, thereby inhibiting deacetylation of histones and HDAC4 client transcription factors, such as HIF-1 alpha, which are bound at promoter/enhancers where epigenetic reprogramming is required for cancer cell survival and angiogenic response. Through this mechanism, tasquinimod is effective as a monotherapeutic agent against human prostate, breast, bladder, and colon tumor xenografts, where its efficacy could be further enhanced in combination with a targeted thapsigargin prodrug (G202) that selectively kills tumor endothelial cells. Together, our findings define a mechanism of action of tasquinimod and offer a perspective on how its clinical activity might be leveraged in combination with other drugs that target the tumor microenvironment. Cancer Res; 73(4); 1386-99. (C) 2012 AACR.
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| 5. |
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| 6. |
- Riva, Matteo, et al.
(författare)
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Induction of NFκB responses by the S100A9 protein is TLR4-dependent.
- 2012
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Ingår i: Immunology. - : Wiley. - 0019-2805. ; 137:2, s. 172-182
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Tidskriftsartikel (refereegranskat)abstract
- Interactions between danger and pathogen-associated molecular patterns (DAMP and PAMP) and pattern recognition receptors such as Toll-like receptors (TLRs) are critical for the regulation of the inflammatory process via activation of NFκB and cytokine secretion. In this report, we investigated the capacity of LPS-free S100A9 (DAMP) protein to activate human and mouse cells compared to lipoprotein-free LPS (PAMP). Firstly, we showed that LPS and S100A9 were able to increase NFκB activity followed by increased cytokine and nitric oxide (NO) secretion both in human THP-1 cells and mouse bone marrow-derived dendritic cells (BM-DC). Surprisingly, although S100A9 triggered a weaker cytokine response compared to LPS, we found that S100A9 more potently induced IκBα degradation and hence NFkB activation. Both the S100A9- and LPS-induced response was completely absent in TLR4 knock-out mice, while it was only slightly affected in RAGE knock-out mice. Also, we showed that LPS and S100A9 NFkB induction were strongly reduced in the presence of specific inhibitors of TLR-signaling. Chloroquine reduced S100A9 but not LPS signaling, indicating that S100A9 may need to be internalized in order to be fully active as a TLR4 inducer. This was confirmed using A488-labeled S100A9 that was internalized in THP-1 cells, showing a raise in fluorescence after 30 minutes at 37°C. Chloroquine treatment significantly reduced the fluorescence. In summary, our data indicate that both human and mouse S100A9 are TLR4 agonists. Importantly, S100A9 induced stronger NFκB activation albeit weaker cytokine secretion than LPS, suggesting that S100A9 and LPS activated NFκB in a qualitative distinct manner. © 2012 The Authors. Immunology © 2012 Blackwell Publishing Ltd, Immunology.
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| 7. |
- Rydén, Mireille, et al.
(författare)
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Carotenoid levels in plasma : can dietary intake and inflammation explain variability?
- 2011
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Konferensbidrag (refereegranskat)abstract
- Purpose: Low plasma levels of carotenoids and low dietary intake of carotenoids are both linked to increased cardiovascular risk. The supply of carotenoids depends on dietary sources. However, it has also been shown that inflammation may have major influence on plasma carotenoids. The aim of this study was to examine the association of plasma carotenoids with dietary intake of carotenoids and a panel of inflammatory markers including matrix metalloproteinase (MMP)-9.Methods: A population-based cohort consisting of 285 Swedish men and women (45-69 years) was studied. Fruit and vegetable consumption was estimated from a validated 92-item semi-quantitative food-frequency questionnaire. Plasma levels of C-reactive protein, interleukin (IL)-6, IL-8, myeloperoxidase and MMP-9 were determined as were plasma concentrations of 5 major carotenoids: lutein, β-crypthoxanthine, lycopen, α-carotene and β-carotene.Result: Lower plasma levels of lipid-adjusted carotenoids (low vs top tertile) were significantly associated with higher age, male sex, higher body mass index (BMI), higher systolic and diastolic blood pressure, higher IL-6 and MMP-9 levels and lower intake of carotenoid-rich food. Low dietary intake of carotenoids was related to male sex, smoking and low plasma carotenoids. After adjustment for age, sex, BMI, blood pressure, physical activity, smoking, dietary intake, IL-6 and MMP-9, plasma carotenoids remained associated with age (Beta= -0.17, p<0.01), sex (Beta=0.19, p<0.01), BMI (Beta= -0.19, p<0.01), dietary intake (Beta=0.21, p<0.01) and MMP-9 (Beta= -0.13, p<0.05). However, these associations differed among individual carotenoids, e.g. the correlation to MMP-9 was restricted to α-carotene (Beta= -0.13, p<0.05) and the correlation to sex was restricted to α-carotene (Beta=0.23, p<0.001) and β-carotene (Beta=0.18, p<0.01).Conclusion: In this population-based study, plasma carotenoids reflected dietary intake of carotenoids but to a minor extent. Also, levels of inflammatory markers explained very little of the variability in plasma carotenoids. Instead, age, sex and BMI independently influenced the levels of carotenoids. In cardiovascular risk management, we need to better understand the potential determinants of carotenoid levels in plasma.
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| 8. |
- Rydén, Mireille, et al.
(författare)
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Effects of Simvastatin on carotenoid status in plasma
- 2010
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- BACKGROUND AND AIMS: Carotenoids are potent antioxidants mainly transported in the low density lipoprotein (LDL) fraction. They may also influence the immune response and inverse associations with inflammatory markers have been reported. We investigated whether simvastatin, by exerting both lipid-lowering and anti-inflammatory effects, altered the carotenoid status in plasma. METHODS AND RESULTS: A randomized, double-blind, placebo-controlled study design was applied. Eighty volunteers with mild to moderate hypercholesterolemia received either simvastatin 40 mg or placebo for 6 weeks. Lipids, oxidized LDL (ox-LDL), C-reactive protein (CRP), interleukin (IL)-6, oxygenated carotenoids (lutein, zeaxanthin, beta-cryptoxanthin) and hydrocarbon carotenoids (alpha-carotene, beta-carotene, lycopene) were measured in plasma. Simvastatin use was associated with significant reductions in total cholesterol, LDL, ox-LDL and CRP. Simvastatin therapy also resulted in reduced plasma levels of both oxygenated and hydrocarbon carotenoids. However, when adjusted for lipids, all carotenoids except beta-cryptoxanthin showed significant increases after simvastatin therapy. Both crude and lipid-adjusted carotenoids were inversely correlated with CRP and IL-6 in plasma but the change in carotenoid status during simvastatin therapy was not specifically related to any changes in inflammatory markers. CONCLUSIONS: To summarize, the change in carotenoid status during simvastatin therapy was mainly attributed to the lowering of cholesterol and not to the suppression of inflammatory activity. After adjustment for lipids, the levels of lutein, lycopene, alpha-carotene and beta-carotene were significantly increased by simvastatin suggesting an increased ratio of carotenoids per particle.
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| 9. |
- Rydén, Mireille, et al.
(författare)
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Effects of simvastatin on carotenoid status in plasma
- 2010
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Konferensbidrag (refereegranskat)abstract
- Purpose: Carotenoids are potent antioxidants and immunomodulators mainly transported in the low density lipoprotein (LDL) fraction. It is well known that low plasma carotenoids are associated with cardiovascular disease incidence. We investigated whether simvastatin altered the carotenoid status in plasma.Methods: A randomized double-blind study design was used. Eighty volunteers with mild to moderate hypercholesterolemia received either simvastatin 40 mg or placebo for 6 weeks. Lipids, inflammatory markers, oxygenated carotenoids (lutein, zeaxanthin, beta-cryptoxanthin) and hydrocarbon carotenoids (alphacarotene, beta-carotene and lycopene) were measured in plasma.Results: After simvastatin therapy, total cholesterol, LDL, apolipoprotein B (apo B), oxidized LDL and C-reactive protein were significantly reduced. Simvastatin therapy also resulted in significantly reduced plasma levels of all crude major carotenoids. However, after adjustment for total cholesterol, LDL or apo B, all carotenoids except beta-cryptoxanthin increased during statin therapy (see Table). The carotenoids were inversely correlated with inflammatory markers but these correlations were abolished during simvastatin therapy.Conclusions: The increase in lipid-adjusted levels of carotenoids during simvastatin therapy suggest that lipoproteins had become enriched with carotenoids. The data highlight the risk to misinterpret the carotenoid status in individuals with statin therapy if relying on absolute plasma levels.
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| 10. |
- Rydén, Mireille, et al.
(författare)
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Effects of simvastatin on carotenoid status in plasma
- 2012
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Ingår i: NMCD. Nutrition Metabolism and Cardiovascular Diseases. - : Elsevier. - 0939-4753 .- 1590-3729. ; 22:1, s. 66-71
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Carotenoids are potent antioxidants mainly transported in the low density lipoprotein (LDL) fraction. They may also influence the immune response and inverse associations with inflammatory markers have been reported. We investigated whether simvastatin, by exerting both lipid-lowering and anti-inflammatory effects, altered the carotenoid status in plasma.METHODS AND RESULTS: A randomized, double-blind, placebo-controlled study design was applied. Eighty volunteers with mild to moderate hypercholesterolemia received either simvastatin 40 mg or placebo for 6 weeks. Lipids, oxidized LDL (ox-LDL), C-reactive protein (CRP), interleukin (IL)-6, oxygenated carotenoids (lutein, zeaxanthin, beta-cryptoxanthin) and hydrocarbon carotenoids (alpha-carotene, beta-carotene, lycopene) were measured in plasma. Simvastatin use was associated with significant reductions in total cholesterol, LDL, ox-LDL and CRP. Simvastatin therapy also resulted in reduced plasma levels of both oxygenated and hydrocarbon carotenoids. However, when adjusted for lipids, all carotenoids except beta-cryptoxanthin showed significant increases after simvastatin therapy. Both crude and lipid-adjusted carotenoids were inversely correlated with CRP and IL-6 in plasma but the change in carotenoid status during simvastatin therapy was not specifically related to any changes in inflammatory markers.CONCLUSIONS: To summarize, the change in carotenoid status during simvastatin therapy was mainly attributed to the lowering of cholesterol and not to the suppression of inflammatory activity. After adjustment for lipids, the levels of lutein, lycopene, alpha-carotene and beta-carotene were significantly increased by simvastatin suggesting an increased ratio of carotenoids per particle.
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