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PPARγ activation blocks the FVIIa-induced inflammatory response in primary human macrophages. Differentiated macrophages were treated with GW1929 (24 h, 600 nM), washed and then incubated in the absence or in the presence of FVIIa (10 nM) for further 24 h. Total RNA was extracted and MMP-2 (a), IL-8 (b), and MCP-1 (c) mRNA levels were measured by Q-PCR and normalized to those of cyclophilin. Secretion of MCP-1 was measured by ELISA in culture medium (d). Results are expressed as the mean value ± SD of triplicate determinations, representative of three independent experiments. Statistically significant differences are indicated ( p ∗ < 0.05 , p ∗ ∗ < 0.01 , and p ∗ ∗ ∗ < 0.001 ).
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Tissue factor (TF) is the initiator of the blood coagulation cascade after interaction with the activated factor VII (FVIIa). Moreover, the TF/FVIIa complex also activates intracellular signalling pathways leading to the production of inflammatory cytokines. The TF/FVIIa complex is inhibited by the tissue factor pathway inhibitor-1 (TFPI-1). Peroxi...
Citations
... The plasma concentration of tissue factor pathway inhibitor type 1 (TFPI-1)-free antigen has been reported to exhibit a circadian variation in healthy participants, but not in tetraplegic subjects; TFPI-1 is produced in vascular endothelium abrogates the extrinsic pathway of coagulation by directly inhibiting coagulation factor Xa and activated factor VII (FVIIa)-tissue factor (TF) complex [71]. An opposite rhythm has been reported relative to the plasma concentrations of TFPI-free antigen and melatonin in healthy participants, but not within the tetraplegic individuals. ...
Severe COVID-19 is associated with the dynamic changes in coagulation parameters. Coagulopathy is considered as a major extra-pulmonary risk factor for severity and mortality of COVID-19; patients with elevated levels of coagulation biomarkers have poorer in-hospital outcomes. Oxidative stress, alterations in the activity of cytochrome P450 enzymes, development of the cytokine storm and inflammation, endothelial dysfunction, angiotensin-converting enzyme 2 (ACE2) enzyme malfunction and renin–angiotensin system (RAS) imbalance are among other mechanisms suggested to be involved in the coagulopathy induced by severe acute respiratory syndrome coronavirus (SARS-CoV-2). The activity and function of coagulation factors are reported to have a circadian component. Melatonin, a multipotential neurohormone secreted by the pineal gland exclusively at night, regulates the cytokine system and the coagulation cascade in infections such as those caused by coronaviruses. Herein, we review the mechanisms and beneficial effects of melatonin against coagulopathy induced by SARS-CoV-2 infection.
... Macrophages play crucial roles in the pathogenesis of atherosclerosis by controlling inflammation and cholesterol trafficking, and they are mainly associated with unstable, lipid-rich and thin capped plaques, where they contribute to the highly inflammatory and pro-thrombotic milieu with high levels of TF and non-matching levels of TFPI [4][5][6]57]. Similar to ADTRP, PPAR-activation up-regulates TFPI expression in monocytes/macrophages both in vitro and in vivo, a process that could control the inflammatory and pro-thrombotic effects of TF-dependent pathway activation [58]. In turn, TFPI can regulate macrophage differentiation, inhibit proliferation, and prevent foam cells formation [59]. ...
The novel protein ADTRP, identified and described by us in 2011, is androgen-inducible and regulates the expression and activity of Tissue Factor Pathway Inhibitor, the major inhibitor of the Tissue Factor-dependent pathway of coagulation on endothelial cells. Single-nucleotide polymorphisms in ADTRP associate with coronary artery disease and myocardial infarction, and deep vein thrombosis/venous thromboembolism. Some athero-protective effects of androgen could exert through up-regulation of ADTRP expression. We discovered a critical role of ADTRP in vascular development and vessel integrity and function, manifested through Wnt signaling-dependent regulation of matrix metalloproteinase-9. ADTRP also hydrolyses fatty acid esters of hydroxy-fatty acids, which have anti-diabetic and anti-inflammatory effects and can control metabolic disorders. Here we summarize and analyze the knowledge on ADTRP and try to decipher its functions in health and disease.
... Several coagulation-regulatory proteins have anti-inflammatory properties, e.g., thrombomodulin [182][183][184][185][186][187], endothelial protein C receptor (EPCR) [188], ectonucleoside triphosphate diphosphohydrolase-1 (CD39) [189][190][191], and tissue factor pathway inhibitor (TFPI) [192,193]. The N-terminal lectin-like domain of thrombomodulin was reported to possess direct anti-inflammatory activity and to suppress complement activation [182]. ...
... Hemeoxygenase-1 (HO-1) anti-inflammatory, anti-apoptotic [14,[172][173][174][175][176][177][178] A20 (tumor necrosis factor-α-induced protein) anti-inflammatory, anti-apoptotic [179][180][181] Thrombomodulin (TBM) anticoagulation, anti-inflammatory [182][183][184][185][186][187] Endothelial protein C receptor (EPCR) anticoagulation, anti-inflammatory [188] Ectonucleoside triphosphate diphosphohydrolase-1 (CD39) anticoagulation, anti-inflammatory [189][190][191] Tissue factor pathway inhibitor (TFPI) anticoagulation, anti-inflammatory [192,193] elicits activated protein C-dependent and -independent anti-inflammatory effects [188]. CD39 is a major vascular nucleoside triphosphate diphosphohydrolase, and converts adenosine triphosphate (ATP), and adenosine diphosphate (ADP) to adenosine. ...
There is increasing evidence of a sustained state of systemic inflammation after pig-to-nonhuman primate (NHP) xenotransplantation (that has been termed systemic inflammation in xenograft recipients [SIXR]). Increases in inflammatory markers, e.g., C-reactive protein, histones, serum amyloid A, D-dimer, cytokines, chemokines, and a decrease in free triiodothyronine, have been demonstrated in the recipient NHPs. The complex interactions between inflammation, coagulation, and the immune response are well-recognized, but the role of inflammation in xenograft recipients is not fully understood. The evidence suggests that inflammation can promote the activation of coagulation and the adaptive immune response, but the exact mechanisms remain uncertain. If prolonged xenograft survival is to be achieved, anti-inflammatory strategies (e.g., the administration of anti-inflammatory agents, and/or the generation of genetically-engineered organ-source pigs that are protected from the effect of inflammation) may be necessary to prevent, control, or negate the effect of the systemic inflammation that develops in xenograft recipients. This may allow for a reduction in the intensity of exogenous immunosuppressive therapy. If immunological tolerance to a xenograft is to be obtained, then control of inflammation may be essential.
... Among the several endogenous analgesic mechanisms involved in exercise-induced hypoalgesia (Martins et al., 2013;Bobinski et al., 2015;Leung et al., 2016), Peroxisome proliferator-activated receptor gamma (PPARc) have become an important target for the treatment of pain (Napimoga et al., 2008a,b;Jia et al., 2016;Pottabathini et al., 2016). PPARc receptors are nuclear proteins that act as transcription factors activated, which upon activation by ligands (Berger and Moller, 2002) develop potential anti-inflammatory effects (Pisanu et al., 2014;Croasdell et al., 2015;Chinetti-Gbaguidi et al., 2016;Kim et al., 2017). Curiously, it was demonstrated that physical exercise increases PPARc expression in muscle tissue and immune cells due to an aerobic metabolic demand (Ristow et al., 2009;Thomas et al., 2012;Sasaki et al., 2014). ...
... Liver sinusoidal endothelial cells [22] Hepatocytes [23] Megakaryocytes [24,25] Monocytes [18] Macrophages [20] Platelets [25] F13A1 6p25.1 Cells of bone marrow and the mesenchymal lineage [26] Monocytes [18,20] Macrophages [20] Platelets [20,27] TFPI1 2q32.1 Vascular endothelial cells [28] Platelets [18] Monocytes [18] Macrophages [28] THBD 20p11.21 Vascular endothelial cells [20] Monocytes [18,20] Macrophages [20] Neutrophils [29] Dendritic cells [30] * Defined as messenger RNA presence and protein synthesis. ...
... Liver sinusoidal endothelial cells [22] Hepatocytes [23] Megakaryocytes [24,25] Monocytes [18] Macrophages [20] Platelets [25] F13A1 6p25.1 Cells of bone marrow and the mesenchymal lineage [26] Monocytes [18,20] Macrophages [20] Platelets [20,27] TFPI1 2q32.1 Vascular endothelial cells [28] Platelets [18] Monocytes [18] Macrophages [28] THBD 20p11.21 Vascular endothelial cells [20] Monocytes [18,20] Macrophages [20] Neutrophils [29] Dendritic cells [30] * Defined as messenger RNA presence and protein synthesis. ...
Ovarian cancer (OC) is the deadliest gynaecological malignancy. Identifying new prognostic biomarkers is an important research field. Haemostatic components together with leukocytes can drive cancer progression while increasing the susceptibility to venous thromboembolism (VTE) through immunothrombosis. Unravelling the underlying complex interactions offers the prospect of uncovering relevant OC prognostic biomarkers, predictors of cancer-associated thrombosis (CAT), and even potential targets for cancer therapy. Thus, this study evaluated the expression of F3, F5, F8, F13A1, TFPI1, and THBD in peripheral blood cells (PBCs) of OC patients.
Regular physical exercise has been described as a good strategy for prevention or reduction of musculoskeletal pain. The Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) has been investigated as a promising target for the control of inflammatory pain. Therefore, the aim of this study was to evaluate whether activation of PPARγ receptors is involved in the reduction of acute muscle pain by chronic exercise and, in this case, whether this process is modulated by inflammatory cytokines. To this end, Wistar rats were submitted to swimming physical training for a period of 10 weeks, 5 days per week, 40 minutes/day, in an intensity of 4% of the body mass. Muscle hyperalgesia was measured by Randall Selitto test and pro-inflammatory cytokines were quantified by ELISA. The results showed that swimming physical training prevented the onset of acute mechanical muscle hyperalgesia and the increase in muscle levels of Cytokine-induced neutrophil chemoattractant 1 (CINC-1) induced by carrageenan into gastrocnemius muscle. In addition, local pre-treatment with the selective PPARγ receptors antagonist GW9662 reversed the mechanical muscle hypoalgesia and the modulation of CINC-1 levels induced by swimming physical training. These data suggest that swimming physical training prevented the onset of acute mechanical muscle hyperalgesia by a mechanism dependent of PPARγ receptors, which seems to contribute to this process by modulation of the pro-inflammatory cytokine CINC-1, and highlight the potential of PPARγ receptors as a target to control musculoskeletal pain and to potentiate the reduction of musculoskeletal pain induced by exercise.
