Critical Role of TCF-1 in Repression of the IL-17 Gene

Overwhelming activation of IL-17, a gene involved in inflammation, leads to exaggerated Th17 responses associated with numerous autoimmune conditions, such as experimental autoimmune encephalomyelitis (EAE). Here we show that TCF-1 is a critical factor to repress IL-17 gene locus by chromatin modifications during T cell development. Deletion of TCF-1 resulted in increased IL-17 gene expression both in thymus and peripheral T cells, which led to enhanced Th17 differentiation. As a result, TCF-1-/- mice were susceptible to Th17-dependent EAE induction. Rag1-/- mice reconstituted with TCF-1-/- T cells were also susceptible to EAE, indicating TCF-1 is intrinsically required to repress IL-17. However, expression of wild-type TCF-1 or dominant negative TCF-1 did not interfere with Th17 differentiation in mature T cells. Furthermore, expression of TCF-1 in TCF-1-/- T cells could not restore Th17 differentiation to wild-type levels, indicating that TCF-1 cannot affect IL-17 production at the mature T cell stage. This is also supported by the normal up-regulation or activation in mature TCF-1-/- T cells of factors known to regulate Th17 differentiation, including RORγt and Stat3. We observed hyperacetylation together with trimethylation of Lys-4 at the IL-17 locus in TCF-1-/- thymocytes, two epigenetic modifications indicating an open active state of the gene. Such epigenetic modifications were preserved even when TCF-1-/- T cells migrated out of thymus. Therefore, TCF-1 mediates an active process to repress IL-17 gene expression via epigenetic modifications during T cell development. This TCF-1-mediated repression of IL-17 is critical for peripheral T cells to generate balanced immune responses

Cardiovascular dynamics in ischemic cardiomyopathy during exercise

Cardiac Dysfunction and Arrhythmia

Differentiation of Bone Marrow–Derived Endothelial Progenitor Cells Is Shifted into a Proinflammatory Phenotype by Hyperglycemia

Bone marrow (BM)-derived endothelial progenitor cells (EPC) contribute to vascular maintenance by participating in angiogenesis, re-endothelialization, and remodeling. Myeloid progenitor cells in the BM are functionally and quantitatively an important precursor pool for cells that contribute to these processes. However, these precursor pools in the BM also give rise to important effector cells of the innate immune system, such as macrophages and dendritic cells. We hypothesized that the disturbed repair responses that are being observed in diabetes mellitus are also related to an effect on functional and differentiation characteristics at the level of this bone marrow precursor pool. Indeed, we observed that bone marrow differentiation cultures for EPC, macrophages (Mph), or dendritic cells (DC) from hyperglycemic BM yielded 40% fewer EPC and 50% more Mph compared with control BM. These changes were directly related to the hemoglobin A1C levels of the donor mice. BM-derived DC numbers were not affected by hyperglycemia. The composition of the BM was not altered; in particular, the numbers of CD31+/Ly6C+ cells, which serve as common progenitors for EPC, Mph, and DC, were unaffected. In addition, BM-derived EPC from hyperglycemic mice were less angiogenic and more proinflammatory in regards to endocytosis, T-cell activation, and interleukin 12 production. HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibition by statin supplementation of the culture medium counteracted these hyperglycemia-induced changes. Our study results show that hyperglycemia alters the differentiation fate of BM precursor cells, reducing the potential to generate vascular regenerative cells and favoring the development of proinflammatory cells

Mode of action of plant-derived natural insecticides

Most of the chemical insecticides are neurotoxic, acting on targets in the central nervous system such as the membrane ion channels (DDT, pyrethroids), the enzyme acetylcholinesterase (organophosphate, carbamate), and the receptors of neurotransmitters (avermectins, neonicotinoids). The recently introduced diamide group of insecticides target the novel ryanodine receptor in the nervous system. Since pests continue to evolve resistance to compounds currently in use, new compounds with new modes of action are needed. Natural products could be a promising source for novel pest control agents. The origin of many of the important insecticide classes is traceable to a natural source as in the case of pyrethroids, avermectins, spinosads, and neonicotinoids. Although insect control agents acting on targets other than the nervous system such as insect growth regulators (e.g., azadirachtin, JH analogues, ecdysone antagonists) have been developed, due to their lack of contact toxicity, they are not quite successful, but find a place in the integrated pest management. Recent progress in understanding the biology of insect olfaction and taste offers new strategies for developing selective pest control agents. Decalesides, recently discovered natural insecticides, represent a new class of plant-derived insecticides targeting the tarsal gustatory receptors. In this chapter, we focus on the toxicity and mode of action of natural insecticides