- The role of fibrinolysis inhibition in engineered vascular networks derived from endothelial cells and adipose-derived stem cells. [Journal Article]
- SCStem Cell Res Ther 2018 Feb 12; 9(1):35
- CONCLUSIONS: Taken together, our data reveal a critical role of fibrinolysis inhibition in in vitro cell-mediated vascularisation of fibrin scaffolds.
- ALBUMINURIA IN KIDNEY TRANSPLANT RECIPIENTS IS ASSOCIATED WITH INCREASED URINARY SERINE PROTEASES AND ACTIVATION OF THE EPITHELIAL SODIUM CHANNEL. [Journal Article]
- AJAm J Physiol Renal Physiol 2018 Jan 24
- Albuminuria predicts adverse renal outcome in kidney transplant recipients. The present study addressed the hypothesis that albuminuria is associated with increased urine serine proteases with the ab...
Albuminuria predicts adverse renal outcome in kidney transplant recipients. The present study addressed the hypothesis that albuminuria is associated with increased urine serine proteases with the ability to activate the epithelial sodium channel (ENaC) and with greater extracellular volume and higher blood pressure. In a cross-sectional design, kidney transplant recipients with (n=18) and without (n=19) albuminuria were included for office blood pressure measurements, estimation of volume status by bioimpedance, and collection of spot urine and plasma samples. Urine was analyzed for serine proteases and for ability to activate ENaC current in vitro. Urine exosome protein was immunoblotted for prostasin and γ-ENaC protein. In present study it was found, that compared to non-albuminuria (8.8 mg/g creatinine), albuminuric (1722mg/g creatinine) kidney transplant recipients had a higher systolic and diastolic blood pressure, despite receiving significantly more antihypertensives, and a greater urinary total plasminogen, active plasmin, active urokinase-type plasminogen activator and prostasin protein abundance which correlated significantly with u-albumin. Fluid overload correlated with systolic blood pressure, urinary albumin/creatinine and plasminogen/creatinine. Urine from albuminuric kidney transplant recipients evoked a greater amiloride- and aprotinin-sensitive inward current in single collecting duct cells (murine cell line M1). γENaC subunits at 50 and 75 kDa showed increased abundance in urine exosomes from albuminuric kidney transplant recipients when compared to controls. These findings show, that albuminuria in kidney transplant recipients is associated with hypertension, ability of urine to proteolytically activate ENaC current and increased abundance of γENaC. ENaC activity could contribute to hypertension and adverse outcome in posttransplant proteinuria.
- Activated protein C suppresses osteoclast differentiation via endothelial protein C receptor, protease-activated receptor-1, sphingosine 1-phosphate receptor, and apolipoprotein E receptor 2. [Journal Article]
- TRThromb Res 2018 Jan 03; 163:30-40
- CONCLUSIONS: APC suppresses human osteoclast differentiation mainly by inhibiting the formation of multinucleated cells via EPCR, PAR-1, S1P receptor, and ApoER2 in a manner that depends on APC protease activity.
- Biochemical characterization of unusual cysteine protease of P. falciparum, metacaspase-2 (MCA-2). [Journal Article]
- MBMol Biochem Parasitol 2018 Jan 06; 220:28-41
- Earlier studies on Plasmodium apoptosis revealed the presence of proteases with caspases like- activity, which are known as "metacaspases". Although this family of cysteine proteases is structurally ...
Earlier studies on Plasmodium apoptosis revealed the presence of proteases with caspases like- activity, which are known as "metacaspases". Although this family of cysteine proteases is structurally similar to caspases with Cys-His dyad but their evolutionary significance and functional relevance remains largely unknown. These proteases are considered to be an important target against malaria due to their absence in humans. In this report, we have biochemically characterized metacaspase-2 (PfMCA-2) of P.falciparum. Enzymatic assay showed that PfMCA-2 efficiently cleaved arginine/lysine specific peptide, but not caspase-specific substrate. Consistently, PfMCA-2 activity was sensitive to effector caspases inhibitor, Z-FA-FMK, and mildly inhibited by aprotinin and E-64. However, general caspase inhibitors such as Z-VAD-FMK and Z-DEVD-FMK had no effect on PfMCA-2 activity. Z-FA-FMK inhibits parasite growth with an IC50value of 2.7 μM along with the notable morphological changes. PfMCA-2 specifically expressed in schizonts and gametocyte stages and there was a notable depletion of PfMCA-2 expression in Z-FA-FMK treated schizonts and gametocytes stages of parasite. Notably, PfMCA-2 cleaves a phylogenetically conserved protein, TSN (Tudor staphylococcal nuclease) and the proteolysis of PfTSN did not occur after treatment with the Z-FA-FMK. The production of large amount of reactive oxygen species in presence of Z-FA-FMK caused oxidative stress which in turn leads to loss of cell viability. The oxidative stress further generates positive feedback for the occurrence of cell death in term of phosphatidylserine externalization and DNA fragmentation in vitro.
- Blood and Blood Product Conservation: Results of Strategies to Improve Clinical Outcomes in Open Heart Surgery Patients at a Tertiary Hospital. [Journal Article]
- JEJ Extra Corpor Technol 2017; 49(4):273-282
- Blood product usage is a quality outcome for patients undergoing cardiac surgery. To address an increase in blood product usage since the discontinuation of aprotinin, blood conservation strategies w...
Blood product usage is a quality outcome for patients undergoing cardiac surgery. To address an increase in blood product usage since the discontinuation of aprotinin, blood conservation strategies were initiated at a tertiary hospital in Oakland, CA. Improving transfusion rates for open heart surgery patients requiring Cardiopulmonary bypass (CPB) involved multiple departments in coordination. Specific changes to conserve blood product usage included advanced CPB technology upgrades, and precise individualized heparin dose response titration assay for heparin and protamine management. Retrospective analysis of blood product usage pre-implementation, post-CPB changes and post-Hemostasis Management System (HMS) implementation was done to determine the effectiveness of the blood conservation strategies. Statistically significant decrease in packed red blood cells, fresh frozen plasma, cryoprecipitate, and platelet usage over the stepped implementation of both technologies was observed. New oxygenator and centrifugal pump technologies reduced active circuitry volume and caused less damage to blood cells. Individualizing heparin and protamine dosing to a patient using the HMS led to transfusion reductions as well. Overall trends toward reductions in hospital length of stay and intensive care unit stay, and as a result, blood product cost and total hospitalization cost are positive over the period of implementation of both CPB circuit changes and HMS implementation. Although they are multifactorial in nature, these trends provide positive enforcement to the changes implemented.
- Targeted Imaging of Brain Tumors with a Framework Nucleic Acid Probe. [Journal Article]
- AAACS Appl Mater Interfaces 2018 Jan 31; 10(4):3414-3420
- Development of agents for delivering drugs and imaging probes across the blood-brain barrier (BBB) remains a major challenge. In this study, we designed a biocompatible framework nucleic acid (FNA)-b...
Development of agents for delivering drugs and imaging probes across the blood-brain barrier (BBB) remains a major challenge. In this study, we designed a biocompatible framework nucleic acid (FNA)-based imaging probe for brain tumor-targeting. We employed a typical type of FNAs, tetrahedral DNA nanostructures (TDNs), as the building block, which were modified with angiopep-2 (ANG), a 19-mer peptide derived from human Kunitz domain of aprotinin. This probe exhibited high binding efficiency with low-density lipoprotein receptor-related protein-1 (LRP-1) of BBB and glioma. We found that ANG-functionalized TDNs (ANG-TDNs) stayed intact for at least 12 h in serum, and that ANG modification effectively enhanced cellular uptake of TDNs in brain capillary endothelial cells and Uppsala 87 malignant glioma (U87MG) cells. Remarkably, studies in both in vitro and in vivo models revealed that ANG-TDNs could cross the BBB. Especially, in vivo imaging showed strong fluorescent signals in U87MG human glioblastoma xenograft in nude mice. This study establishes that the FNA-based platform provides a new theranostic tool for the study and therapy of brain tumors.
- Fibrin hydrogels as a xenofree and rapidly degradable support for transplantation of retinal pigment epithelium monolayers. [Journal Article]
- ABActa Biomater 2018; 67:134-146
- Recent phase 1 trials of embryonic stem cell and induced pluripotent stem cell (iPSCs) derived RPE transplants for the treatment of macular degeneration have demonstrated the relative safety of this ...
Recent phase 1 trials of embryonic stem cell and induced pluripotent stem cell (iPSCs) derived RPE transplants for the treatment of macular degeneration have demonstrated the relative safety of this process. However, there is concern over clumping, thickening, folding, and wrinkling of the transplanted RPE. To deliver a flat RPE monolayer, current phase 1 trials are testing synthetic substrates for RPE transplantation. These substrates, however, cause localized inflammation and fibrosis in animal models due to long degradation times. Here we describe the use of thin fibrin hydrogels as a support material for the transplantation of RPE. Fibrin was formed into a mechanically rigid support that allow for easy manipulation with standard surgical instruments. Using fibrinolytic enzymes, fibrin hydrogels were degraded on the scale of hours. The rate of degradation could be controlled by varying the fibrinolytic enzyme concentration used. RPE cells degraded fibrin spontaneously. To preserve the fibrin support during differentiation of iPSCs to RPE, media was supplemented with the protease inhibitor aprotinin. iPSC-RPE on fibrin gels remained viable, generated monolayers with characteristic cobblestone appearance and dark pigmentation, and expressed mRNA and protein markers characteristic of RPE in the eye. Following differentiation of the cells, addition of fibrinolytic enzymes fully and rapidly degraded the fibrin support leaving behind an intact, viable iPSC-RPE monolayer. In conclusion, human fibrin hydrogels provide a xeno-free support on which iPSCs can be differentiated to RPE cells for transplant which can be rapidly degraded under controlled conditions using fibrinolytic enzymes without adverse effects to the cells.
- Effectiveness and Safety of Aprotinin Use in Thoracic Aortic Surgery. [Journal Article]
- JCJ Cardiothorac Vasc Anesth 2018; 32(1):170-177
- CONCLUSIONS: The use of aprotinin demonstrated a limited effect in reducing postoperative bleeding and prevention of major bleeding events. Aprotinin did not adversely affect early outcomes and long-term survival.
- Nonsurgical Strategies to Reduce Mortality in Patients Undergoing Cardiac Surgery: An Updated Consensus Process. [Journal Article]
- JCJ Cardiothorac Vasc Anesth 2018; 32(1):225-235
- CONCLUSIONS: This updated consensus process identified 11 nonsurgical interventions with possible survival implications for patients undergoing cardiac surgery. This list of interventions may help cardiac anesthesiologists and intensivists worldwide in their daily clinical practice and can contribute to direct future research in the field.
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- Efficacy, Reliability, and Safety of Completely Autologous Fibrin Glue in Neurosurgical Procedures: Single-Center Retrospective Large-Number Case Study. [Journal Article]
- WNWorld Neurosurg 2018; 109:e819-e828
- CONCLUSIONS: CAFG effectively provides hemostatic, adhesive, and safety performance. The timing and three-dimensional shape of CAFG-soaked oxidized regenerated cellulose and/or polyglycolic acid sheets solidification can be controlled with slow fibrin formation. The cost to prepare CAFG is similar compared with Com-FG products, and it can therefore be easily used at most institutions.