- Anti-neoplastic effects of aprotinin on human breast cancer cell lines: In vitro study. [Journal Article]
- ACAdv Clin Exp Med 2018 Nov 05
- CONCLUSIONS: Aprotinin significantly inhibited the growth of human breast cancer cell lines MDA-MB-231, SK-BR-3 and MCF-7, and normal fibroblast cell line HDF-1. The growth inhibitory effect was more dominant in cancer cell lines. Inhibition of local invasion by aprotinin was significant only in the case of MDA-MB-231. Future molecular studies could shed further lights on mechanisms underlying antineoplastic effects of aprotinin and its potential therapeutic effects.
- Use of antifibrinolytics in pediatric cardiac surgery: where are we now? [Journal Article]
- PAPaediatr Anaesth 2018 Oct 26
- Fibrinolytic activation is a major and preventable source of bleeding in neonates and children undergoing cardiac surgery with CPB. Based on the existing literature (adult and pediatric; cardiac and ...
Fibrinolytic activation is a major and preventable source of bleeding in neonates and children undergoing cardiac surgery with CPB. Based on the existing literature (adult and pediatric; cardiac and non-cardiac), prophylactic administration of antifibrinolytic agents can help reduce fibrinolytic activation, and consequently reduces perioperative bleeding and the requirement for blood product transfusion. Due to the increased risk of renal failure and mortality reported in adults undergoing cardiac surgery, aprotinin should not be considered as a safe option in neonates and children. Further well-designed studies would be required before the prophylactic administration of aprotinin could be considered in pediatric cardiac surgery. The lysine analogs, TXA and EACA, should be considered as safe and effective antifibrinolytic agents, but high doses should not be recommended in order to avoid the increased risk of clinical seizures. Despite the recent advances made in our understanding of the pharmacokinetics of TXA and EACA, the optimal plasmatic concentration to be targeted remains unknown. Further studies are therefore urgently needed to better define the optimal dose regimen to be used in neonates and children. In the meantime, the dose regimen published in the most recent PK studies can be used (Table 1). Based on the existing literature, a TXA loading dose of 30 mg/kg followed by a continuous infusion of 10 mg/kg/h can be used in children < 1 year of age, while loading dose of 10 mg/kg followed by a continuous infusion of 10 mg/kg/h can be used afterwards. For EACA, a loading dose 40 mg/kg followed by a 30 mg/kg/h infusion is recommended. In the absence of prospective validation, those dose schemes should be considered as 'expert opinion'. Although no studies have assessed the effect of massive bleeding and transfusion on the plasmatic concentrations of the lysine analogs, additional boluses might be considered in the presence of bleeding and/or when signs of fibrinolytic activations are observed on viscoelastic hemostatic assays. This article is protected by copyright. All rights reserved.
- Correction to: The role of fibrinolysis inhibition in engineered vascular networks derived from endothelial cells and adipose-derived stem cells. [Published Erratum]
- SCStem Cell Res Ther 2018 Oct 07; 9(1):261
- The original article  contains numerous value errors in the graphs in Fig. 2b regarding the markers describing the values for total tubule length and mean tubule length without aprotinin at 2.5 mg...
The original article  contains numerous value errors in the graphs in Fig. 2b regarding the markers describing the values for total tubule length and mean tubule length without aprotinin at 2.5 mg/ml concentration of fibrinogen. The corrected version of this figure can be viewed ahead.
- Calculation Algorithm Reduces Protamine Doses Without Increasing Blood Loss or the Transfusion Rate in Cardiac Surgery: Results of a Randomized Controlled Trial. [Journal Article]
- JCJ Cardiothorac Vasc Anesth 2018 Aug 03
- CONCLUSIONS: Use of the HeProCalc algorithm reduced protamine dosage and the protamine/heparin ratio after cardiopulmonary bypass compared with conventional dosage based on weight without significant effect on postoperative blood loss or the transfusion rate.
- Aprotinin interacts with substrate-binding site of human dipeptidyl peptidase III. [Journal Article]
- JBJ Biomol Struct Dyn 2018 Sep 08; :1-38
- Human dipeptidyl peptidase III (hDPP III) is a zinc-exopeptidase of the family M49 involved in final steps of intracellular protein degradation and in cytoprotective pathway Keap1-Nrf2. Biochemical a...
Human dipeptidyl peptidase III (hDPP III) is a zinc-exopeptidase of the family M49 involved in final steps of intracellular protein degradation and in cytoprotective pathway Keap1-Nrf2. Biochemical and structural properties of this enzyme have been extensively investigated, but the knowledge on its contacts with other proteins is scarce. Previously, polypeptide aprotinin was shown to be a competitive inhibitor of hDPP III hydrolytic activity. In the present study, aprotinin was first investigated as a potential substrate of hDPP III, but no degradation products were demonstrated by MALDI-TOF mass spectrometry. Subsequently, molecular details of the protein-protein interaction between aprotinin and hDPP III were studied by molecular modeling. Docking and long molecular dynamics (MD) simulations have shown that aprotinin interacts by its canonical binding epitope with the substrate binding cleft of hDPP III. Thereby, free N-terminus of aprotinin is distant from the active-site zinc. Enzyme-inhibitor complex is stabilized by intermolecular hydrogen bonding network, electrostatic and hydrophobic interactions which mostly involve constituent amino acid residues of the hDPP III substrate binding subsites S1, S1', S2, S2' and S3'. This is the first study that gives insight into aprotinin binding to an metallopeptidase.
- The mechanical and pharmacological regulation of glioblastoma cell migration in 3D matrices. [Journal Article]
- JCJ Cell Physiol 2018 Aug 21
- The invasion of glioblastoma is a complex process based on the interactions of tumor cells and the extracellular matrix. Tumors that are engineered using biomaterials are more physiologically relevan...
The invasion of glioblastoma is a complex process based on the interactions of tumor cells and the extracellular matrix. Tumors that are engineered using biomaterials are more physiologically relevant than a two-dimensional (2D) cell culture system. Matrix metalloproteinases and the plasminogen activator generated by tumor cells regulate a tumor's invasive behavior. In this study, microtumors were fabricated by encapsulating U87 glioma cells in Type I collagen and then glioma cell migration in the collagen hydrogels was investigated. Crosslinking of collagen with 8S-StarPEG increased the hydrogel viscosity and reduced the tumor cell migration speed in the hydrogels. The higher migration speed corresponded to the increased gene expression of MMP-2, MMP-9, urokinase plasminogen activator (uPA), and tissue plasminogen activator (tPA) in glioma cells grown in non-crosslinked collagen hydrogels. Inhibitors of these molecules hindered U87 and A172 cell migration in collagen hydrogels. Aprotinin and tranexamic acid did not inhibit U87 and A172 migration on the culture dish. This study demonstrated the differential effect of pharmacologic molecules on tumor cell motility in either a 2D or three-dimensional culture environment.
- Molecular modeling, biochemical characterization, and pharmacological properties of Cc3 -SPase: A platelet-aggregating thrombin-like enzyme purified from Cerastes cerastes venom. [Journal Article]
- JBJ Biochem Mol Toxicol 2018 Jul 06; :e22165
- Cc3 -SPase (30 kDa-proteinase; pI 5.98) was isolated from Cerastes cerastes venom. Its sequence of 271 residues yielded from LC-MALDI-TOF showed high degrees of homology when aligned with other prote...
Cc3 -SPase (30 kDa-proteinase; pI 5.98) was isolated from Cerastes cerastes venom. Its sequence of 271 residues yielded from LC-MALDI-TOF showed high degrees of homology when aligned with other proteinases. Cc3 -SPase cleaved natural and synthetic proteins such as casein and fibrinogen leaving fibrin clots unaffected. Cc3 -SPase was fully abolished by ion chelators, whereas aprotinin, antithrombin III (Sigma Aldrich, Saint-Louis, Missouri, USA), and heparin were ineffective. Affinity of Cc3 -SPase to benzamidine indicated the presence of an aspartate residue in the catalytic site as confirmed by three-dimensional structure consisting of 14 β-strands and four α-helices. Molecular mechanisms revealed that Cc3 -SPase is capable of promoting dysfunctional platelet aggregation via two signaling pathways mediated by the G-coupled protein receptors and αIIbβ3 integrin. Cc3 -SPase is involved in both extrinsic/intrinsic coagulation pathways in deficient plasmas by replacing defective/lacking factors FII, FVII, and FVIII but not FX. Cc3 -SPase could substitute missing factors in blood diseases related to plasma factor deficiencies.
- Advances in the characterization of the Scorpaena plumieri cytolytic toxin (Sp-CTx). [Journal Article]
- TToxicon 2018; 150:220-227
- Proteins that account for the hemolytic activity found in scorpaeniform fish venoms are responsible for the majority of the effects observed upon envenomation, for instance, neurotoxic, cardiotoxic a...
Proteins that account for the hemolytic activity found in scorpaeniform fish venoms are responsible for the majority of the effects observed upon envenomation, for instance, neurotoxic, cardiotoxic and inflammatory effects. These multifunctional toxins, described as protein lethal factors and referred to as cytolysins, are known to be extremely labile molecules. In the present work, we endeavored to overcome this constraint by determining optimal storage conditions for Sp-CTx, the major bioactive component from the scorpionfish Scorpaena plumieri venom. This cardiotoxic hemolytic cytolysin is a large dimeric glycoprotein (subunits of ≈65 kDa) with pore-forming ability. We were able to establish storage conditions that allowed us to keep the toxin partially active for up to 60 days. Stability was achieved by storing Sp-CTx at -80 and -196 °C in the presence of glycerol 10% in a pH 7.4 solution. It was demonstrated that the hemolytic activity of Sp-CTx is calcium dependent, being abolished by EDTA and zinc ions. Furthermore, the toxin exhibited its maximal hemolytic activity at pH between 8 and 9, displaying typical N- and O- linked glycoconjugated residues (galactose (1-4) N-acetylglucosamine and sialic acid (2-3) galactose in N- and/or O-glycan complexes). The hemolytic activity of Sp-CTx was inhibited by phosphatidylglycerol and phosphatidylethanolamine, suggesting a direct electrostatic interaction lipid - toxin in the pore-formation mechanism of action of this toxin. In addition, we observed that the hemolytic activity was inhibited by increasing doses of cholesterol. Finally, we were able to show, for first time, that Sp-CTx is at least partially responsible for the pain and inflammation observed upon envenomation. However, while the edema induced by Sp-CTx was reduced by pre-treatment with aprotinin and HOE-140, pointing to the involvement of the kallikrein-kinin system in this response, these drugs had no significant effect in the toxin-induced nociception. Taken together, our results could suggest that, as has been already reported for other fish cytolysins, Sp-CTx acts mostly through lipid-dependent pore formation not only in erythrocytes but also in other cell types, which could account for the pain observed upon envenomation. We believe that the present work paves the way towards the complete characterization of fish cytolysins.
- Drug-Associated Acute Kidney Injury Identified in the United States Food and Drug Administration Adverse Event Reporting System Database. [Journal Article]
- PPharmacotherapy 2018; 38(8):785-793
- CONCLUSIONS: Acute kidney injury was a common reason for adverse event reporting in the FAERS. Most AKI reports were generated for medications not recognized as nephrotoxic according to our classification system. This report provides data on medications needing further research to determine the risk of AKI with these new potential nephrotoxins.
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- A Short Peptide Inhibitor as an Activity-Based Probe for Matriptase-2. [Journal Article]
- PPharmaceuticals (Basel) 2018 May 21; 11(2)
- Matriptase-2 is a type II transmembrane serine protease and a key regulator of systemic iron homeostasis. Since the activation mechanism and several features of the physiological role of matriptase-2...
Matriptase-2 is a type II transmembrane serine protease and a key regulator of systemic iron homeostasis. Since the activation mechanism and several features of the physiological role of matriptase-2 are not fully understood, there is strong need for analytical tools to perform tasks such as distinguishing active and inactive matriptase-2. For this purpose we present a short biotinylated peptide derivative with a chloromethyl ketone group, biotin-RQRR-CMK, as an activity-based probe for matriptase-2. Biotin-RQRR-CMK was kinetically characterized and exhibited a second-order rate constant of inactivation (kinac/Ki) of 10,800 M−1 s−1 towards the matriptase-2 activity in the supernatant of transfected human embryonic kidney (HEK) cells. Biotin-RQRR-CMK was able to label active matriptase-2, as visualized in western blot experiments. Pretreatment with aprotinin, an active-site directed inhibitor of serine proteases, protected matriptase-2 from the reaction with biotin-RQRR-CMK.