Elevated level of circulatory sTLT1 induces inflammation through SYK/MEK/ERK signalling in coronary artery disease.
TL;DR: Results clearly demonstrate that sTLT1 is clinically related to the risk factors of CAD and shows that binding of s TLT1 with macrophage membrane receptor, FcɣR1 initiates inflammatory signals in macrophages suggesting its critical role in thrombus development and atherosclerosis.
Abstract: The role of inflammation in all phases of atherosclerotic process is well established and soluble TREM-like transcript 1 (sTLT1) is reported to be associated with chronic inflammation. Yet, no information is available about the involvement of sTLT1 in atherosclerotic cardiovascular disease. Present study was undertaken to determine the pathophysiological significance of sTLT1 in atherosclerosis by employing an observational study on human subjects (n=117) followed by experiments in human macrophages and atherosclerotic apolipoprotein E (apoE)-/- mice. Plasma level of sTLT1 was found to be significantly (P<0.05) higher in clinical (2342 ± 184 pg/ml) and subclinical cases (1773 ± 118 pg/ml) than healthy controls (461 ± 57 pg/ml). Moreover, statistical analyses further indicated that sTLT1 was not only associated with common risk factors for Coronary Artery Disease (CAD) in both clinical and subclinical groups but also strongly correlated with disease severity. Ex vivo studies on macrophages showed that sTLT1 interacts with Fcɣ receptor I (FcɣRI) to activate spleen tyrosine kinase (SYK)-mediated downstream MAP kinase signalling cascade to activate nuclear factor-κ B (NF-kB). Activation of NF-kB induces secretion of tumour necrosis factor-α (TNF-α) from macrophage cells that plays pivotal role in governing the persistence of chronic inflammation. Atherosclerotic apoE-/- mice also showed high levels of sTLT1 and TNF-α in nearly occluded aortic stage indicating the contribution of sTLT1 in inflammation. Our results clearly demonstrate that sTLT1 is clinically related to the risk factors of CAD. We also showed that binding of sTLT1 with macrophage membrane receptor, FcɣR1 initiates inflammatory signals in macrophages suggesting its critical role in thrombus development and atherosclerosis.
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TL;DR: Wang et al. as discussed by the authors investigated the effect of trimetazidine on myocardial cells and explored its effect on the ERK signaling pathway in rats with myocardious infarction.
Abstract: Objective. To study the protective effect of trimetazidine on myocardial cells in rats with myocardial infarction and explore its effect on ERK signaling pathway. Methods. 40 SD rats were randomly divided into the sham operation group, model group, low-dose group, and high-dose group (intra-abdominal injection of trimetazidine 5 mg/kg and 10 mg/kg, respectively), construction of rat myocardial infarction model by coronary artery left anterior descending artery ligation. 7 days after surgery, the survival rate and cardiac function of each group of rats were recorded. The myocardial infarct size was detected by TTC staining. The apoptosis level of rat cardiomyocytes was detected by TUNEL staining. The content of ROS in rat cardiomyocytes was detected by DCFH-DA. Western-blot was used to detection of Caspase-3, Bcl-2/Bax, and ERK signaling pathway-related proteins in myocardial tissue. Results. Compared with the model group, the survival rate of the rats in the low-dose group and the high-dose group was significantly increased ( ), the cardiac function was significantly improved ( ), the myocardial infarct size was significantly decreased ( ), the level of apoptosis was significantly decreased ( ), the content of ROS in cardiomyocytes was significantly decreased ( ), the protein expression of Caspase-3 and NF-κB in cardiomyocytes was significantly decreased ( ), and the expression of Bcl-2/Bax and p-ERK were significantly increased ( ). Conclusion. Trimetazidine can activate ERK signaling pathway in cardiomyocytes of rats with myocardial infarction, increase the expression of p-ERK, decrease the content of ROS in cardiomyocytes, decrease the expression of apoptotic proteins, reduce myocardial infarct size, improve cardiac function, and increase myocardial function.
5 citations
TL;DR: The cytokine IL-32 was demonstrated to have prognostic information, with an increased risk of all-cause and cardiovascular mortality for those with the A/A genotype rs28372698 of IL- 32, which could therefore be regarded as a possible biomarker for mortality risk that may be used to offer optimized cardiovascular patient handling in the future.
Abstract: One of the major causes of mortality in the western hemisphere is cardiovascular disease. Therefore, a variety of markers to identify those at risk are required. Interleukin-32 (IL-32) is a cytokin ...
2 citations
TL;DR: In this paper , the effect and mechanism of polyphyllin I (PPI) on lipid metabolism and myocardial dysfunction in coronary artery disease (CAD) was investigated.
Abstract: Polyphyllin I (PPI) is a famous traditional medicine ingredient, which has been explored in wide range of areas. Nevertheless, whether PPI exerts any functions in coronary artery disease (CAD) is still uncertified. Herein, we probed the effect and mechanism of PPI on lipid metabolism and myocardial dysfunction in myocardial cells and CAD rat model. Hypoxia/reoxygenation (H/R)‐treated H9c2 cells model was constructed for the in vitro experiments, and CAD model in vivo was established by high‐fat feeding. After management with PPI, the correlated factors of lipid metabolism and myocardial function were investigated. The apoptosis of myocardial cells was assessed by Annexin V‐FITC/PI kit and TUNEL staining. The apoptosis‐associated factors (caspase 3, cleaved caspase 3, Bax, and Bcl‐2) were tested by Western blot analysis. The MEK/ERK inhibitor was applied and the functions of MEK/ERK pathway in myocardial damage were investigated. H/R‐treated H9c2 cells model was constructed for the in vitro experiments, and CAD model in vivo was established by high‐fat feeding. After management with PPI, the correlated factors of lipid metabolism and myocardial function were investigated. The apoptosis of myocardial cells was assessed by Annexin V‐FITC/PI kit and TUNEL staining. The apoptosis‐associated factors (caspase 3, cleaved caspase 3, Bax, and Bcl‐2) were tested by Western blot analysis. The MEK/ERK inhibitor was applied and the functions of MEK/ERK pathway in myocardial damage were investigated. PPI improved lipid metabolism disorder in H/R‐induced H9c2 cells or in CAD rat model. Additionally, PPI attenuated myocardial dysfunction in CAD rats via enhancing left ventricular systolic pressure, maximum rate of change of left ventricular pressure (±dp/dtmax), and arterial blood flow (CF). The apoptosis of myocardial cells was lessened by PPI management, which was further verified by reducing Bax and cleaved caspase 3 expression. Furthermore, PD0325901 (MEK/ERK inhibitor) weakened the effect of PPI on myocardial dysfunction, lipid metabolism, and myocardial cell apoptosis in CAD rats. The research confirmed the protective effect of PPI on myocardial damage in CAD, which was regulated by MEK/ERK pathway.
1 citations
References
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TL;DR: Recent studies addressing the multifaceted roles of FcRs for IgG (FcγRs) in the immune system are discussed and how this knowledge could be translated into novel therapeutic strategies to treat human autoimmune, infectious or malignant diseases are discussed.
Abstract: In addition to their role in binding antigen, antibodies can regulate immune responses through interacting with Fc receptors (FcRs). In recent years, significant progress has been made in understanding the mechanisms that regulate the activity of IgG antibodies in vivo. In this Review, we discuss recent studies addressing the multifaceted roles of FcRs for IgG (FcgammaRs) in the immune system and how this knowledge could be translated into novel therapeutic strategies to treat human autoimmune, infectious or malignant diseases.
2,390 citations
TL;DR: In this review sample size calculation for most frequently used study designs are mentioned and for genetic and microbiological studies readers are requested to read other sources.
Abstract: Calculation of exact sample size is an important part of research design. It is very important to understand that different study design need different method of sample size calculation and one formula cannot be used in all designs. In this short review we tried to educate researcher regarding various method of sample size calculation available for different study designs. In this review sample size calculation for most frequently used study designs are mentioned. For genetic and microbiological studies readers are requested to read other sources.
1,623 citations
TL;DR: It is demonstrated that ox-LDL levels show a significant positive correlation with the severity of acute coronary syndromes and that the more severe lesions also contain a significantly higher percentage of ox- LDL–positive macrophages.
Abstract: Background—There is accumulating data that acute coronary syndromes relate to recent onset activation of inflammation affecting atherosclerotic plaques. Increased blood levels of oxidized low density lipoprotein (ox-LDL) could play a role in these circumstances. Methods and Results—Ox-LDL levels were measured in 135 patients with acute myocardial infarction (AMI; n=45), unstable angina pectoris (UAP; n=45), and stable angina pectoris (SAP; n=45) and in 46 control subjects using a sandwich ELISA method. In addition, 33 atherectomy specimens obtained from a different cohort of patients with SAP (n=10) and UAP (n=23) were studied immunohistochemically for ox-LDL. In AMI patients, ox-LDL levels were significantly higher than in patients with UAP (P<0.0005) or SAP (P<0.0001) or in controls (P<0.0001) (AMI, 1.95±1.42 ng/5 μg LDL protein; UAP, 1.19±0.74 ng/5 μg LDL protein; SAP, 0.89±0.48 ng/5 μg LDL protein; control, 0.58±0.23 ng/5 μg LDL protein). Serum levels of total, HDL, and LDL cholesterol did not differ ...
817 citations
TL;DR: In advanced atherosclerotic lesions, the ratio between specialized pro-resolving mediators and pro-inflammatory lipids is strikingly low, providing a molecular explanation for the defective inflammation resolution features of these lesions.
Abstract: Atherosclerosis is a lipid-driven inflammatory disease of the arterial intima in which the balance of pro-inflammatory and inflammation-resolving mechanisms dictates the final clinical outcome. Intimal infiltration and modification of plasma-derived lipoproteins and their uptake mainly by macrophages, with ensuing formation of lipid-filled foam cells, initiate atherosclerotic lesion formation, and deficient efferocytotic removal of apoptotic cells and foam cells sustains lesion progression. Defective efferocytosis, as a sign of inadequate inflammation resolution, leads to accumulation of secondarily necrotic macrophages and foam cells and the formation of an advanced lesion with a necrotic lipid core, indicative of plaque vulnerability. Resolution of inflammation is mediated by specialized pro-resolving lipid mediators derived from omega-3 fatty acids or arachidonic acid and by relevant proteins and signalling gaseous molecules. One of the major effects of inflammation resolution mediators is phenotypic conversion of pro-inflammatory macrophages into macrophages that suppress inflammation and promote healing. In advanced atherosclerotic lesions, the ratio between specialized pro-resolving mediators and pro-inflammatory lipids (in particular leukotrienes) is strikingly low, providing a molecular explanation for the defective inflammation resolution features of these lesions. In this Review, we discuss the mechanisms of the formation of clinically dangerous atherosclerotic lesions and the potential of pro-resolving mediator therapy to inhibit this process.
712 citations
TL;DR: The most prominent FoldX commands such as free energy difference upon mutagenesis and interaction energy calculations can now be run entirely via a windowed menu system and the results are immediately shown on screen.
Abstract: Summary: A graphical user interface for the FoldX protein design program has been developed as a plugin for the YASARA molecular graphics suite. The most prominent FoldX commands such as free energy difference upon mutagenesis and interaction energy calculations can now be run entirely via a windowed menu system and the results are immediately shown on screen.
Availability and Implementation: The plugin is written in Python and is freely available for download at http://foldxyasara.switchlab.org/ and supported on Linux, MacOSX and MS Windows.
Contact:[email protected]; [email protected]; [email protected]
287 citations