Rationale A prothrombotic state and increased platelet reactivity are common in pathophysiological conditions associated with oxidative stress and infections. Such conditions are associated with an appearance of altered-self ligands in circulation that can be recognized by Toll-like receptors (TLR). Platelets express a number of TLR, including TLR9, however, the role of TLR in platelet function and thrombosis is poorly understood. Objective To investigate the biological activities of carboxy(alkylpyrrole) protein adducts (CAPs), an altered self-ligand generated in oxidative stress, on platelet function and thrombosis. Methods and Results In this study we show that CAPs represent novel unconventional ligands for TLR9. Furthermore, using human and murine platelets, we demonstrate that CAPs promote platelet activation, granule secretion, and aggregation in vitro and thrombosis in vivo via the TLR9/MyD88 pathway. Platelet activation by TLR9 ligands induces IRAK1 and AKT phosphorylation, and is Src kinase dependent. Physiological platelet agonists act synergistically with TLR9 ligands by inducing TLR9 expression on the platelet surface. Conclusions Our study demonstrates that platelet TLR9 is a functional platelet receptor that links oxidative stress, innate immunity, and thrombosis.
Recent studies have suggested that inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (statins) can play a role in protection against vascular risk, which is independent of cholesterol reduction. It could act by inhibiting the synthesis of isoprenoids (farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP)), which are respectively essential for membrane attachment and biological activity of GTPases Ras and RhoA. This study demonstrates that a statin (cerivastatin) inhibits angiogenesis. This effect was due to a decrease in endothelial cell locomotion which was reversed by GGPP. It was mainly related to delocalization of RhoA from cell membrane to cytoplasm, responsible for the disorganization of actin stress fibers. Furthermore, a decrease in MMP-2 secretion, involved in cell invasion, was also observed. This effect is rather due to Ras inhibition as it was reversed by FPP. This antiangiogenic activity could explain the beneficial effect of statins on atherosclerosis and on cancer prevention as shown by clinical studies. ß
Stem cell factor (SCF), erythropoietin (Epo), and GATA-1 play an essential role(s) in erythroid development. We examined how these proteins interact functionally in G1E cells, a GATA-1 ؊ erythroblast line that proliferates in an SCF-dependent fashion and, upon restoration of GATA-1 function, undergoes GATA-1 proliferation arrest and Epo-dependent terminal maturation. We show that SCF-induced cell cycle progression is mediated via activation of the Src kinase/c-Myc pathway. Restoration of GATA-1 activity induced G 1 cell cycle arrest coincident with repression of c-Kit and its downstream effectors Vav1, Rac1, and Akt. Sustained expression of each of these individual signaling components inhibited GATA-1-induced cell cycle arrest to various degrees but had no effects on the expression of GATA-1-regulated erythroid maturation markers. Chromatin immunoprecipitation analysis revealed that GATA-1 occupies a defined Kit gene regulatory element in vivo, suggesting a direct mechanism for gene repression. Hence, in addition to its well-established function as an activator of erythroid genes, GATA-1 also participates in a distinct genetic program that inhibits cell proliferation by repressing the expression of multiple components of the c-Kit signaling axis. Our findings reveal a novel aspect of molecular cross talk between essential transcriptional and cytokine signaling components of hematopoietic development.Receptor tyrosine kinases (RTKs) trigger a multitude of cellular events, including proliferation, survival, differentiation, and migration. These functions are modulated in hematopoietic stem and progenitor cells by the essential RTK c-Kit (8,11,43). The expression of c-Kit is downregulated as progenitors mature to their respective lineages, with the exception of mast cells, which rely on c-Kit for survival, proliferation, and function throughout their life span (20). Unrestrained c-Kit activity contributes to several neoplastic disorders, including gastrointestinal stromal tumors (GIST), mastocytosis, and leukemia (5,12,21,37,46,55). In GIST, somatic kinase-activating Kit mutations result in malignant transformation. In the hematopoietic system, similar activating Kit mutations occur in stem/ progenitor cells and mast cells, causing mastocytosis and acute myelogenous leukemia, respectively (45, 54).Mutant mice without c-Kit (dominant white spotting, or W, mutants) demonstrate severe deficiencies in erythroid development with reduced CFU-erythroid progenitors in the fetal liver and embryonic death from anemia at around day 16 of gestation (11, 57). Erythropoietin (Epo) receptor (Epo-R)-deficient mice demonstrate a similar decrease in CFU-erythroid progenitors and die of anemia between days 13 and 15 of gestation, suggesting that erythroid progenitors cannot survive, proliferate, or differentiate unless both the c-Kit and Epo-R signal transduction pathways are functional. Recent studies suggest that Epo and Epo-R interactions contribute to this process by preventing apoptosis through activation of the survival factor...
Age-related macular degeneration (AMD) is a major cause of blindness in the developed world. Oxidative stress and inflammation are implicated in AMD, but precise mechanisms remain poorly defined. Carboxyethylpyrrole (CEP) is an AMD-associated lipid peroxidation product. We previously demonstrated that mice immunized with CEP-modified albumin developed AMD-like degenerative changes in the outer retina. Here, we examined the kinetics of lesion development in immunized mice and the presence of macrophages within the interphotoreceptor matrix (IPM), between the retinal pigment epithelium and photoreceptor outer segments. We observed a significant and time-dependent increase in the number of macrophages in immunized mice relative to young age-matched controls prior to overt pathology. These changes were more pronounced in BALB/c mice than in C57BL/6 mice. Importantly, IPM-infiltrating macrophages were polarized toward the M1 phenotype but only in immunized mice. Moreover, when Ccr2-deficient mice were immunized, macrophages were not present in the IPM and no retinal lesions were observed, suggesting a deleterious role for these cells in our model. This work provides mechanistic evidence linking immune responses against oxidative damage with the presence of proinflammatory macrophages at sites of future AMD and experimentally demonstrates that manipulating immunity may be a target for modulating the development of AMD.
Mixed‐anion perovskite CH3NH3PbI(3−x)(BF4)x has been developed and optimized to enable a highly efficient hole‐conductor‐free fully printable mesoscopic solar cell. The employment of BF4− in hybrid organic–inorganic halide perovskite significantly improves its optical and electric properties, such as light harvesting ability, carrier concentration, and conductivity, leading to an enhanced power conversion efficiency of 13.24%.
The basic-leucine zipper (bZIP) domain-containing transcription factors (TFs) function as key regulators of cellular growth and differentiation in eukaryotic organisms including fungi. We have previously identified MoAp1 and MoAtf1 as bZIP TFs in Magnaporthe oryzae and demonstrated that they regulate the oxidative stress response and are critical in conidiogenesis and pathogenicity. Studies of bZIP proteins could provide a novel strategy for controlling rice blast, but a systematic examination of the bZIP proteins has not been carried out. Here, we identified 19 additional bZIP TFs and characterized their functions. We found that the majority of these TFs exhibit active functions, most notably, in conidiogenesis. We showed that MoHac1 regulates the endoplasmic reticulum (ER)-stress response through a conserved unfolded protein response (UPR) pathway, MoMetR controls amino acid metabolism to govern growth and differentiation, and MoBzip10 governs appressorium function and invasive hyphal growth. Moreover, MoBzip5 participates in appressorium formation through a pathway distinct from that MoBzip10, and MoMeaB appears to exert a regulatory role through nutrient uptake and nitrogen utilization. Collectively, our results provide insights into shared and specific functions associated with each of these TFs and link the regulatory roles to the fungal growth, conidiation, appressorium formation, host penetration, and pathogenicity.
Abstract-Cerivastatin is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. It inhibits the biosynthesis of cholesterol and its precursors: farnesyl pyrophosphate and geranylgeranyl pyrophosphate (GGPP), which are involved in Ras and RhoA cell signaling, respectively. Statins induce greater protection against vascular risk than that expected by cholesterol reduction. Therefore, cerivastatin could protect plaque against rupture, an important cause of ischemic events. In this study, the effect of cerivastatin was tested on angiogenesis because it participates in plaque progression and plaque destabilization. Cerivastatin inhibits in vitro the microvascular endothelial cell proliferation induced by growth factors, whereas it has no effect on unstimulated cells. This growth arrest occurs at the G 1 /S phase and is related to the increase of the cyclin-dependent kinase inhibitor p21 Waf1/Cip1 . These effects are reversed by GGPP, suggesting that the inhibitory effect of cerivastatin is related to RhoA inactivation. This mechanism was confirmed by RhoA delocalization from cell membrane to cytoplasm and actin fiber depolymerization, which are also prevented by GGPP. It was also shown that RhoA-dependent inhibition of cell proliferation is mediated by the inhibition of focal adhesion kinase and Akt activations. Moreover, cerivastatin inhibits in vivo angiogenesis in matrigel and chick chorioallantoic membrane models. These results demonstrate the antiangiogenic activity of statins and suggest that it may contribute to their therapeutic benefits in the progression and acute manifestations of atherosclerosis.
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