Abstract
Aims
Neutrophils have both detrimental and beneficial effects in myocardial infarction (MI), but little is known about the underlying pathways. S100A8/A9 is a pro-inflammatory alarmin ...abundantly expressed in neutrophils that is rapidly released in the myocardium and circulation after myocardial ischaemia. We investigated the role of S100A8/A9 in the innate immune response to MI.
Methods and results
In 524 patients with acute coronary syndrome (ACS), we found that high plasma S100A8/A9 at the time of the acute event was associated with lower left ventricular ejection fraction (EF) at 1-year and increased hospitalization for heart failure (HF) during follow-up. In wild-type C57BL/6 mice with MI induced by permanent coronary artery ligation, treatment with the S100A9 blocker ABR-238901 during the inflammatory phase of the immune response inhibited haematopoietic stem cell proliferation and myeloid cell egression from the bone marrow. The treatment reduced the numbers of neutrophils and monocytes/macrophages in the myocardium, promoted an anti-inflammatory environment, and significantly improved cardiac function compared with MI controls. To mimic the clinical scenario, we further confirmed the effects of the treatment in a mouse model of ischaemia/reperfusion. Compared with untreated mice, 3-day ABR-238901 treatment significantly improved left ventricular EF (48% vs. 35%, P = 0.002) and cardiac output (15.7 vs. 11.1 mL/min, P = 0.002) by Day 21 post-MI.
Conclusion
Short-term S100A9 blockade inhibits inflammation and improves cardiac function in murine models of MI. As an excessive S100A8/A9 release is linked to incident HF, S100A9 blockade might represent a feasible strategy to improve prognosis in ACS patients.
Nuclear receptor Nur77, also known as NR4A1, TR3, or NGFI-B, is expressed in human atherosclerotic lesions in macrophages, endothelial cells, T cells and smooth muscle cells. Macrophages play a ...critical role in atherosclerosis and the function of Nur77 in lesion macrophages has not yet been investigated.
This study aims to delineate the function of Nur77 in macrophages and to assess the effect of bone marrow-specific deficiency of Nur77 on atherosclerosis.
We investigated Nur77 in macrophage polarization using bone marrow-derived macrophages (BMM) from wild-type and Nur77-knockout (Nur77(-/-)) mice. Nur77(-/-) BMM exhibit changed expression of M2-specific markers and an inflammatory M1-phenotype with enhanced expression of interleukin-12, IFNγ, and SDF-1α and increased NO synthesis in (non)-stimulated Nur77(-/-) BMM cells. SDF-1α expression in nonstimulated Nur77(-/-) BMM is repressed by Nur77 and the chemoattractive activity of Nur77(-/-) BMM is abolished by SDF-1α inhibiting antibodies. Furthermore, Nur77(-/-) mice show enhanced thioglycollate-elicited migration of macrophages and B cells. The effect of bone marrow-specific deficiency of Nur77 on atherosclerosis was studied in low density lipoprotein receptor-deficient (Ldlr(-/-)) mice. Ldlr(-/-) mice with a Nur77(-/-)-deficient bone marrow transplant developed 2.1-fold larger atherosclerotic lesions than wild-type bone marrow-transplanted mice. These lesions contain more macrophages, T cells, smooth muscle cells and larger necrotic cores. SDF-1α expression is higher in lesions of Nur77(-/-)-transplanted mice, which may explain the observed aggravation of lesion formation.
In conclusion, in bone marrow-derived cells the nuclear receptor Nur77 has an anti-inflammatory function, represses SDF-1α expression and inhibits atherosclerosis.
Inflammatory bowel disease is characterized by chronic intestinal inflammation. Azathioprine and its metabolite 6-mercaptopurine (6-MP) are effective immunosuppressive drugs that are widely used in ...patients with inflammatory bowel disease. However, established understanding of their immunosuppressive mechanism is limited. Azathioprine and 6-MP have been shown to affect small GTPase Rac1 in T cells and endothelial cells, whereas the effect on macrophages and gut epithelial cells is unknown.
Macrophages (RAW cells) and gut epithelial cells (Caco-2 cells) were activated by cytokines and the effect on Rac1 signaling was assessed in the presence or absence of 6-MP.
Rac1 is activated in macrophages and epithelial cells, and treatment with 6-MP resulted in Rac1 inhibition. In macrophages, interferon-γ induced downstream signaling through c-Jun-N-terminal Kinase (JNK) resulting in inducible nitric oxide synthase (iNOS) expression. iNOS expression was reduced by 6-MP in a Rac1-dependent manner. In epithelial cells, 6-MP efficiently inhibited tumor necrosis factor-α-induced expression of the chemokines CCL2 and interleukin-8, although only interleukin-8 expression was inhibited in a Rac1-dependent manner. In addition, activation of the transcription factor STAT3 was suppressed in a Rac1-dependent fashion by 6-MP, resulting in reduced proliferation of the epithelial cells due to diminished cyclin D1 expression.
These data demonstrate that 6-MP affects macrophages and gut epithelial cells beneficially, in addition to T cells and endothelial cells. Furthermore, mechanistic insight is provided to support development of Rac1-specific inhibitors for clinical use in inflammatory bowel disease.
The study of aquifers of the Lece andesite complex (LAC) and its surroundings yielded a new procedural stepwise analysis that allowed the assessment of the origin of elements, particularly in areas ...affected by both anthropogenic and natural influences. The methodology uses the mineralogical composition of the rocks, including the elements available in rocks and groundwater. This study analyzes the element ratios B/Cl−, Na+/Ca2+, Ca2+/Mg2+, HCO3−/Cl−, and Na+/Na+ + Cl−; the correlations are coupled with a statistical analysis. In addition to reevaluating the already published water content, we provide an important new dataset. The results show that the main source of the water contamination with the elements B, F, U, As, Cu, Fe, Zn, Co, and Ni is the processes occurring at the contact between the groundwaters and non-altered/altered (propylitized) andesite rocks. This is also observed in the waters extracted from crystalline schists. The results may help develop an efficient use and assessment of the qualitative water potential of the LAC reservoirs. Similarly, the results highlight the applicability of the groundwaters, facilitating their regional research and use, further encouraging new initiatives for the preservation and protection of human and animal health.
Decisions around distributing available funds among potential land consolidation projects require a thorough analysis in order to maximize the effects of land consolidation. In order to avoid ...choosing the wrong land consolidation projects, different methods can be used. Generally, there are two possible groups of methods: one based on a qualitative approach (DELPHI; SWOT) and one based on a quantitative approach (AHP, VIKOR, SAW, TOPSIS, etc.). In this research, the focus was on the sensitivity of the resulting rankings affected by varying the input data in multi-criteria analysis methods, with an emphasis on the variation in the weight and the choice of criteria. This research was motivated by the subjective character of the choice of criteria and their weighting before applying the multi-criteria analysis methods. Four methods were included (AHP, TOPSIS, VIKOR, and SAW) for the multi-criteria analysis, with three ways of defining weights (consistent, modified, or quasi-consistent and freely determined without taking consistency into account), in order to determine the influence of the different methods on the final ranking. The weights were defined only by an acceptable interval of values. The sensitivity of the methods was investigated using the differences in the obtained rankings between each method. A case study is provided on real data, and the results are discussed. The results showed a relatively small variance and possible equal rankings of projects by means of statistical analyses. This finding opens up the possibility of the valuation of projects instead of simple rankings.
The Norway spruce is one of the most important tree species in Europe. This tree species has been put under considerable pressure due to the ongoing impacts of climate change. Meanwhile, frequent ...droughts and pest outbreaks are reported as the main reason for its dieback, resulting in severe forest cover loss. Such was the case with Norway spruce forests within the Kopaonik National Park (NP) in Serbia. This study aims to quantify, spatially and temporally, forest cover loss and to evaluate the sensitivity of various vegetation indices (VIs) in detecting drought-induced response and predicting the dieback of Norway spruce due to long-lasting drought effects in the Kopaonik NP. For this purpose, we downloaded and processed a large number of Landsat 7 (ETM+), Landsat 8 (OLI), and Sentinel 2 (MSI) satellite imagery acquired from 2009 to 2022. Our results revealed that forest cover loss was mainly driven by severe drought in 2011 and 2012, which was later significantly influenced by bark beetle outbreaks. Furthermore, various VIs proved to be very useful in monitoring and predicting forest health status. In summary, the drought-induced response detected using various VIs provides valuable insights into the dynamics of forest cover change, with implications for monitoring and conservation efforts of Norway spruce forests in the Kopaonik NP.
Land consolidation (LC) is an activity that brings numerous benefits to rural areas. However, being resource demanding, the LC requires a decision on where it should be provided or where the limited ...resources should be distributed in order to maximize its effects. In order to avoid the subjective decision maker’s preferences, optimization methods for identifying the priorities are recommended. Bearing in mind that every optimization method could give different results, we proposed the utilization of multiple optimization methods for ranking the cadastral municipalities which are candidates for providing LC. In this research, the main aim was to find if it is possible to avoid the subjective decision making in cadastral municipalities (CM) as a candidate for LC ranking by utilizing the statistical approach. Additionally, in this research, the analysis was provided, varying the number of optimization criteria. In this research, two assumptions were adopted: (1) every single optimization method has the same weight, and (2) the differences between different ranks are results of random errors. After determining the average ranking of a certain cadastral municipality, its interval of ranking is calculated by using the Student’s distribution. Cadastral municipalities that belong within the interval of available resources are candidates for providing LC. In the case study, fifteen cadastral municipalities were researched, including eight and ten criteria for optimization, and results showed that there are significant differences between ranks of cadastral municipalities varying depending on the method utilized.
Azathioprine and its metabolite 6-mercaptopurine (6-MP) are well established immunosuppressive drugs. Common understanding of their immunosuppressive properties is largely limited to immune cells. ...However, in this study, the mechanism underlying the protective role of 6-MP in endothelial cell activation is investigated. Because 6-MP and its derivative 6-thioguanosine-5'-triphosphate (6-T-GTP) were shown to block activation of GTPase Rac1 in T lymphocytes, we focused on Rac1-mediated processes in endothelial cells. Indeed, 6-MP and 6-T-GTP decreased Rac1 activation in endothelial cells. As a result, the compounds inhibited TNF-α-induced downstream signaling via JNK and reduced activation of transcription factors c-Jun, activating transcription factor-2 and, in addition, NF κ-light-chain-enhancer of activated B cells (NF-κB), which led to decreased transcription of proinflammatory cytokines. Moreover, 6-MP and 6-T-GTP selectively decreased TNF-α-induced VCAM-1 but not ICAM-1 protein levels. Rac1-mediated generation of cell membrane protrusions, which form docking structures to capture leukocytes, also was reduced by 6-MP/6-T-GTP. Consequently, leukocyte transmigration was inhibited after 6-MP/6-T-GTP treatment. These data underscore the anti-inflammatory effect of 6-MP and 6-T-GTP on endothelial cells by blocking Rac1 activation. Our data provide mechanistic insight that supports development of novel Rac1-specific therapeutic approaches against chronic inflammatory diseases.
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