Fibrinogen Gamma\u27 Inhibits Thrombin-Induced Platelet Activation

Fibrinogen gamma\u27 (Y\u27) is a minor isoform of fibrinogen, a plasma protein that contains an altered Y chain due to an insertion sequence of 20 amino acids. The fibrinogen Y\u27 chain binds to thrombin with high affinity at a positively charged surface or exosite II, mainly through its interactions at residues 410-427. Several recent studies have shown that binding of fibrinogen Y\u27 inhibits thrombin induced platelet aggregation and the presence of fibrinogen Y\u27 changes clot architecture. Fibrinogen Y\u27 peptide has been shown to affect thrombin interaction with platelet receptors, mainly binding of thrombin to GpIb-α, and it prevents thrombin cleavage of protease activated receptor PAR-1. This study investigated the inhibitory effect of fibrinogen Y\u27 peptide on thrombin- induced dense granule release and intraplatelet calcium mobilization which indicates platelets activation. My study have shown that the fibrinogen Y\u27 peptide inhibits thrombin- induced dense granule release and calcium mobilization in platelets. In summary, fibrinogen Y\u27 peptide binds to thrombin and inhibits the platelet response to thrombin. Thus, this study may help in assessing the effects of fibrinogen Y\u27 and indicate the potential of fibrinogen Y\u27 as an antithrombotic therapeutic agent

Sdhd ablation promotes thyroid tumorigenesis by inducing a stem-like phenotype.

Mutations in genes encoding enzymes in the tricarboxylic acid cycle (TCA, also known as the Krebs cycle) have been implicated as causative genetic lesions in a number of human cancers, including renal cell cancers, glioblastomas and pheochromocytomas. In recent studies, missense mutations in the succinate dehydrogenase (SDH) complex have also been proposed to cause differentiated thyroid cancer. In order to gain mechanistic insight into this process, we generated mice lacking the SDH subunit D (Sdhd) in the thyroid. We report that these mice develop enlarged thyroid glands with follicle hypercellularity and increased proliferation. In vitro, human thyroid cell lines with knockdown of SDHD exhibit an enhanced migratory capability, despite no change in proliferative capacity. Interestingly, these cells acquire stem-like features which are also observed in the mouse tumors. The stem-like characteristics are reversed by α-ketoglutarate, suggesting that SDH-associated tumorigenesis results from dedifferentiation driven by an imbalance in cellular metabolites of the TCA cycle. The results of this study reveal a metabolic vulnerability for potential future treatment of SDH-associated neoplasia