Discovery of DS-1093a: An oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of renal anemia.

Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We discovered DS44470011 in our previous study, which showed potent in vitro activity and in vivo efficacy based on HIF-PHD inhibition. However, DS44470011 was also found to exert genotoxic effects.

Fibrinolytic potential of DS-1040, a novel orally available inhibitor of activated thrombin-activatable fibrinolysis inhibitor (TAFIa).

An activated thrombin-activatable fibrinolysis inhibitor (TAFIa) attenuates fibrinolysis by removing C-terminal lysine/arginine residues from partially degraded fibrin. We have identified a novel low-molecular-weight inhibitor of TAFIa, DS-1040, to be potentially useful for treating thrombotic diseases. In this study, we investigated its in vitro pharmacological profile and in vivo effects in animal models of microthrombosis and bleeding.

Tissue-type plasminogen activator transgenic rats for evaluating inhibitors of the activated form of thrombin-activatable fibrinolysis inhibitor.

: No rodent models are currently available for evaluating inhibitors of the activated form of thrombin-activatable fibrinolysis inhibitor (TAFIa) without exogenous supplementation of tissue-type plasminogen activator (tPA). Characterization of tPA transgenic rats as a tool for the nonclinical evaluation of TAFIa inhibitors is the objective of the current study. tPA transgenic rats were subjected to rat models of tissue-factor-induced thromboembolism, FeCl3-induced deep vein thrombosis (DVT) and arterial thrombosis, and tail bleeding.

Correction to: Generation and characterization of tissue-type plasminogen activator transgenic rats.

In the original publication of the article, the sentence in "Result" section have been incorrectly published as: "Three lines of tPA Tg rats were generated and analyzed by Southern blotting to confirm the presence of the transgene in genomic DNA. When rat DNA was digested with EcoRI and hybridized to the tPA probe described in "Materials and methods", a 1.0 kb band was detected (Fig.

Generation and characterization of tissue-type plasminogen activator transgenic rats.

To address a species difference in the responsiveness to human recombinant tissue-type plasminogen activator (rt-PA) between rats and humans, tPA transgenic (Tg) rats were generated and characterized. In the rats, transcriptional regulation of tPA was designed under the control of the endogenous tPA promoter. There were no significant differences in hematological parameters between the tPA Tg and non Tg rats.

Targeting Oxygen-Sensing Prolyl Hydroxylase for Metformin-Associated Lactic Acidosis Treatment.

Metformin is one of the most widely used therapeutics for type 2 diabetes mellitus and also has anticancer and antiaging properties. However, it is known to induce metformin-associated lactic acidosis (MALA), a severe medical condition with poor prognosis, especially in individuals with renal dysfunction. Inhibition of prolyl hydroxylase (PHD) is known to activate the transcription factor hypoxia-inducible factor (HIF) that increases lactate efflux as a result of enhanced glycolysis, but it also enhances gluconeogenesis from lactate in the liver that contributes to reducing circulating lactate levels.

Fibronectin promotes proplatelet formation in the human megakaryocytic cell line UT-7/TPO.

We investigated PPF (proplatelet formation) in the human megakaryocytic cell line UT-7/TPO in vitro and signal transduction pathways responsible for PPF. The megakaryocytic cell lines are useful for studying megakaryocyte biology, although PPF is induced only in the presence of phorbol ester. TPO (thrombopoietin) stimulates megakaryocyte proliferation and differentiation; however, no PPF occurred in the megakaryocytic cell lines, even after the addition of TPO.

Transgenic mice overexpressing soluble osteoclast differentiation factor (sODF) exhibit severe osteoporosis.

Osteoclast differentiation factor, ODF, also called RANKL, TRANCE, or OPGL, is a key molecule for osteoclast differentiation and activation, and is thought to act as a membrane-associated molecule in bone remodeling. Recent study suggested that soluble ODF (sODF) released from T cells also has some roles in bone resorption. To investigate the physiological and pathological function of sODF, we generated two types of transgenic mice overexpressing sODF.