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Unfractionated heparin (UFH) is a widely used anticoagulant that possess numerous properties including anti-inflammatory, anti-viral, anti-angiogenesis, and anti-metastatic effects. The effect of this drug was evaluated on the podocyte, an important actor of the glomerular filtration. Using a functional approach, we demonstrate that heparin treatment leads to a functional podocyte perturbation characterized by the increase of podocyte monolayer permeability. This effect is enhanced with time of exposure. Proteomic study reveals that heparin down regulate focal adhesion and cytoskeletal protein expressions as well as the synthesis of glomerular basement membrane components. This study clearly demonstrates that UFH may affect podocyte function by altering cytoskeleton organization, cell-cell contacts and cell attachment., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Anti-blood coagulation rodenticides, such as warfarin, have been used all over the world. They inhibit vitamin K epoxide reductase (VKOR), which is necessary for producing several blood clotting factors. This inhibition by rodenticides results in lethal hemorrhage in rodents. However, heavy usage of these agents has led to the appearance of rodenticide-resistant rats. There are two major mechanisms underlying this resistance, i.e., mutation of the target enzyme of warfarin, VKOR, and enhanced metabolism of warfarin. However, there have been few studies regarding the hepatic metabolism of warfarin, which should be related to resistance. To investigate warfarin metabolism in resistant rats, in situ liver perfusion of warfarin was performed with resistant black rats (Rattus rattus) from Tokyo, Japan. Liver perfusion is an in situ methodology that can reveal hepatic function specifically with natural composition of the liver. The results indicated enhanced hepatic warfarin hydroxylation activity compared with sensitive black rats. On the other hand, in an in vitro microsomal warfarin metabolism assay to investigate kinetic parameters of cytochrome P450, which plays a major role in warfarin hydroxylation, the V max of resistant rats was slightly but significantly higher compared to the results obtained in the in situ study. These results indicated that another factor like electron donators may also contribute to the enhanced metabolism in addition to high expression of cytochrome P450., (Copyright © 2018. Published by Elsevier Inc.)

Usage of anticoagulant rodenticides (ARs) is an integral component of modern agriculture and is essential for the control of commensal rodent populations. However, the extensive deployment of ARs has led to widespread exposure of a range of non-target predatory birds and mammals to some compounds, in particular the second-generation anticoagulant rodenticides (SGARs). As a result, there has been considerable effort placed into devising voluntary best practice guidelines that increase the efficacy of rodent control and reduce the risk of non-target exposure. Currently, there is limited published information on actual practice amongst users or implementation of best practice. We assessed the behaviour of a typical group of users using an on-farm questionnaire survey. Most baited for rodents every year using SGARs. Most respondents were apparently aware of the risks of non-target exposure and adhered to some of the best practice recommendations but total compliance was rare. Our questionnaire revealed that users of first generation anticoagulant rodenticides rarely protected or checked bait stations, and so took little effort to prevent primary exposure of non-targets. Users almost never searched for and removed poisoned carcasses and many baited for prolonged periods or permanently. These factors are all likely to enhance the likelihood of primary and secondary exposure of non-target species., (Copyright © 2010. Published by Elsevier Ltd.)

Cranial neural tube defects occur when heparin is added to the culture media of postimplantation rat embryos undergoing organogenesis in vitro. Timed-exposure studies were undertaken to determine whether the defects caused by heparin were the result of defective folding and fusion of the neural folds, or due to reopening of a closed neural tube. Experiments were also undertaken to elucidate whether the in vitro toxicity of heparin was due to an effect of heparin at the level of the culture medium, at the level of the visceral yolk sac, or at the level of the embryo proper. Heparin was found to cause defective folding and closure of the neural folds at between 9.5 and 10.5 days' gestation. Neural tube defects did not occur when embryos were cultured in media prepared using a culture medium depleted of heparin ligands by heparin-agarose affinity chromatography. However, studies with [G-(3)H]heparin demonstrated visceral yolk sac uptake and transfer of the radiolabel to the embryo proper. In addition, microinjection of heparin directly into the amniotic cavity of early head-fold embryo explants resulted in cranial neural tube defects similar to those caused by the addition of heparin to culture medium. These data indicate that heparin causes closure defects of cranial neurulation, primarily by an effect at the tissue level of the embryo proper., (Copyright 2000 Academic Press.)

Coumarin is a known hepatotoxicant in laboratory animals, particularly rats. However, the mouse lung was identified as a major target organ in a chronic bioassay, with an oral gavage dosage of 200 mg/kg coumarin increasing the incidence of alveolar/bronchiolar adenomas and carcinomas. The purpose of the present work was to determine whether coumarin was acutely toxic in the mouse and rat lung. Male and female B6C3F1 mice were dosed orally by gavage with coumarin at 0, 10, 20, 50, 100, 150, and 200 mg/kg and lung toxicity was determined 24 h later by histological evaluation. The results indicated that coumarin dosages >/= 150 mg/kg caused selective injury to Clara cells in the distal bronchiolar epithelium. The time course of this injury was studied from 6 h to 7 days after a single dosage of coumarin (200 mg/kg). At 12 h after dosing, Clara cell swelling was apparent along with the onset of necrosis and bronchiolar epithelial disorganization. At 24-48 h, necrotic Clara cells were observed sloughed into the lumens of the terminal bronchioles, with concomitant thinning of the epithelium and flattening of the remaining ciliated cells. By 72-96 h, there was epithelial hypertrophy and hyperplasia, and by 7 days after dosing, the Clara cells had regenerated and the bronchiolar epithelial architecture appeared nearly normal. Unlike the mouse, oral administration of coumarin (200 mg/kg) caused severe hepatotoxicity in male F344 rats, seen histologically as centrilobular necrosis and associated with increases, up to 140-fold, in serum ALT, AST, and SDH levels. Clara cell toxicity was not observed in the distal bronchioles of treated rats. However, in the upper airways, coumarin treatment produced generalized epithelial necrosis involving both ciliated and nonciliated cells. 3,4-Dihydrocoumarin (DHC), which is not a mouse lung carcinogen, did not cause Clara cell injury when dosed to mice at 800 mg/kg. This finding suggests, because DHC lacks a 3,4-double bond, that bioactivation of coumarin to a 3,4-epoxide intermediate may contribute to mouse lung Clara cell toxicity. Collectively, the results indicate that coumarin is a Clara cell toxicant and establish the mouse lung as a target organ for coumarin toxicity. These new findings lay the foundation for studies to determine the mechanisms of coumarin-induced toxicity and carcincogenicity and to define the relevance of these effects to humans., (Copyright 1998 Academic Press.)