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Article ; Online: Extracellular Vesicles from Red Blood Cells and Their Evolving Roles in Health, Coagulopathy and Therapy.

Thangaraju, Kiruphagaran / Neerukonda, Sabari Nath / Katneni, Upendra / Buehler, Paul W

International journal of molecular sciences

2020 Volume 22, Issue 1

Abstract: Red blood cells (RBCs) release extracellular vesicles (EVs) including both endosome-derived exosomes and plasma-membrane-derived microvesicles (MVs). RBC-derived EVs (RBCEVs) are secreted during erythropoiesis, physiological cellular aging, disease ... ...

Abstract	Red blood cells (RBCs) release extracellular vesicles (EVs) including both endosome-derived exosomes and plasma-membrane-derived microvesicles (MVs). RBC-derived EVs (RBCEVs) are secreted during erythropoiesis, physiological cellular aging, disease conditions, and in response to environmental stressors. RBCEVs are enriched in various bioactive molecules that facilitate cell to cell communication and can act as markers of disease. RBCEVs contribute towards physiological adaptive responses to hypoxia as well as pathophysiological progression of diabetes and genetic non-malignant hematologic disease. Moreover, a considerable number of studies focus on the role of EVs from stored RBCs and have evaluated post transfusion consequences associated with their exposure. Interestingly, RBCEVs are important contributors toward coagulopathy in hematological disorders, thus representing a unique evolving area of study that can provide insights into molecular mechanisms that contribute toward dysregulated hemostasis associated with several disease conditions. Relevant work to this point provides a foundation on which to build further studies focused on unraveling the potential roles of RBCEVs in health and disease. In this review, we provide an analysis and summary of RBCEVs biogenesis, composition, and their biological function with a special emphasis on RBCEV pathophysiological contribution to coagulopathy. Further, we consider potential therapeutic applications of RBCEVs.
MeSH term(s)	Biological Transport ; Biomarkers/metabolism ; Blood Coagulation Disorders/etiology ; Blood Coagulation Disorders/metabolism ; Blood Coagulation Disorders/therapy ; Cell Communication ; Cell-Derived Microparticles/metabolism ; Disease Management ; Disease Susceptibility ; Erythrocytes/metabolism ; Extracellular Vesicles/metabolism ; Gene Expression Profiling ; Homeostasis ; Humans ; Nitric Oxide/metabolism ; Oxidation-Reduction
Chemical Substances	Biomarkers ; Nitric Oxide (31C4KY9ESH)
Language	English
Publishing date	2020-12-25
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22010153
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Article ; Online: The Molecular Size of Bioengineered Oxygen Carriers Determines Tissue Oxygenation in a Hypercholesterolemia Guinea Pig Model of Hemorrhagic Shock and Resuscitation.

Lamb, Derek R / Greenfield, Alisyn / Thangaraju, Kiruphagaran / Setua, Saini / Eiker, Gena / Wang, Qihong / Vahedi, Amid / Khan, Mohd Asim / Yahya, Ahmad / Cabrales, Pedro / Palmer, Andre F / Buehler, Paul W

Molecular pharmaceutics

2023 Volume 20, Issue 11, Page(s) 5739–5752

Abstract: Polymerized human hemoglobin (PolyhHb) has shown promise in preclinical hemorrhagic shock settings. Different synthetic and purification schemes can control the size of PolyhHbs, yet research is lacking on the impact of polymerized hemoglobin size on ... ...

Abstract	Polymerized human hemoglobin (PolyhHb) has shown promise in preclinical hemorrhagic shock settings. Different synthetic and purification schemes can control the size of PolyhHbs, yet research is lacking on the impact of polymerized hemoglobin size on tissue oxygenation following hemorrhage and resuscitation in specialized animal models that challenge their resuscitative capabilities. Pre-existing conditions that compromise the vasculature and end organs, such as the liver, may limit the effectiveness of resuscitation and exacerbate the toxicity of these molecules, which is an important but minimally explored therapeutic dimension. In this study, we compared the effective oxygen delivery of intermediate molecular weight PolyhHb (PolyhHb-B3; 500-750 kDa) to high molecular weight PolyhHb (PolyhHb-B4; 750 kDa-0.2 μm) for resuscitative effectiveness in guinea pig models subjected to hemorrhagic shock. We evaluated how the size of PolyhHb impacts hemodynamics and tissue oxygenation in normal guinea pigs and guinea pigs on an atherogenic diet. We observed that while PolyhHb-B3 and -B4 equivalently restore hemodynamic parameters of normal-dieted guinea pigs, high-fat-dieted guinea pigs resuscitated with PolyhHb-B4 have lower mean arterial pressures, impaired tissue oxygenation, and higher plasma lactate levels than those receiving PolyhHb-B3. We characterized the plasma of these animals following resuscitation and found that despite similar oxygen delivery kinetics, circulating PolyhHb-B3 and -B4 demonstrated a size-dependent increase in the plasma viscosity, consistent with impaired perfusion in the PolyhHb-B4 transfusion group. We conclude that intermediate-sized PolyhHbs (such as -B3) are ideal for further research given the effective resuscitation of hemorrhagic shock based on tissue oxygenation in hypercholesterolemic guinea pigs.
MeSH term(s)	Humans ; Guinea Pigs ; Animals ; Shock, Hemorrhagic/drug therapy ; Hypercholesterolemia/drug therapy ; Oxygen ; Hemodynamics ; Hemoglobins
Chemical Substances	Oxygen (S88TT14065) ; Hemoglobins
Language	English
Publishing date	2023-10-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2138405-8
ISSN	1543-8392 ; 1543-8384
ISSN (online)	1543-8392
ISSN	1543-8384
DOI	10.1021/acs.molpharmaceut.3c00611
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Article ; Online: Biophysical Analysis and Preclinical Pharmacokinetics-Pharmacodynamics of Tangential Flow Filtration Fractionated Polymerized Human Hemoglobin as a Red Blood Cell Substitute.

Greenfield, Alisyn / Lamb, Derek R / Gu, Xiangming / Thangaraju, Kiruphagaran / Setua, Saini / Yahya, Ahmad / Vahedi, Amid / Khan, Mohd Asim / Wang, Qihong / Buehler, Paul W / Palmer, Andre F

Biomacromolecules

2023 Volume 24, Issue 4, Page(s) 1855–1870

Abstract: Red blood cell (RBC) substitutes tested in late-phase clinical trials contained low-molecular-weight hemoglobin species (<500 kDa), resulting in vasoconstriction, hypertension, and oxidative tissue injury; therefore, contributing to poor clinical ... ...

Abstract	Red blood cell (RBC) substitutes tested in late-phase clinical trials contained low-molecular-weight hemoglobin species (<500 kDa), resulting in vasoconstriction, hypertension, and oxidative tissue injury; therefore, contributing to poor clinical outcomes. This work aims to improve the safety profile of the RBC substitute, polymerized human hemoglobin (PolyhHb), via in vitro and in vivo screening of PolyhHb fractionated into four molecular weight brackets (50-300 kDa [PolyhHb-B1]; 100-500 kDa [PolyhHb-B2]; 500-750 kDa [PolyhHb-B3]; and 750 kDa to 0.2 μm [PolyhHb-B4]) using a two-stage tangential flow filtration purification process. Analysis showed that PolyhHb's oxygen affinity, and haptoglobin binding kinetics decreased with increasing bracket size. A 25% blood-for-PolyhHb exchange transfusion guinea pig model suggests that hypertension and tissue extravasation decreased with increasing bracket size. PolyhHb-B3 demonstrated extended circulatory pharmacokinetics, no renal tissue distribution, no aberrant blood pressure, or cardiac conduction effects, and may therefore be appropriate material for further evaluation.
MeSH term(s)	Humans ; Animals ; Guinea Pigs ; Hemoglobins/chemistry ; Oxygen/metabolism ; Polymerization ; Blood Substitutes/pharmacology ; Erythrocytes/metabolism
Chemical Substances	Hemoglobins ; hemoglobin AS (52012-19-8) ; Oxygen (S88TT14065) ; Blood Substitutes
Language	English
Publishing date	2023-03-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1526-4602
ISSN (online)	1526-4602
DOI	10.1021/acs.biomac.3c00051
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Article: Mechanical stimuli such as shear stress and piezo1 stimulation generate red blood cell extracellular vesicles.

Sangha, Gurneet S / Weber, Callie M / Sapp, Ryan M / Setua, Saini / Thangaraju, Kiruphagaran / Pettebone, Morgan / Rogers, Stephen C / Doctor, Allan / Buehler, Paul W / Clyne, Alisa M

Frontiers in physiology

2023 Volume 14, Page(s) 1246910

Abstract: Introduction: ...

Abstract	Introduction:
Language	English
Publishing date	2023-08-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2023.1246910
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Article ; Online: The alternative initiation factor eIF2A plays key role in RAN translation of myotonic dystrophy type 2 CCUG•CAGG repeats.

Tusi, Solaleh Khoramian / Nguyen, Lien / Thangaraju, Kiruphagaran / Li, Jian / Cleary, John D / Zu, Tao / Ranum, Laura P W

Human molecular genetics

2021 Volume 30, Issue 11, Page(s) 1020–1029

Abstract: Repeat-associated non-ATG (RAN) proteins have been reported in 11 microsatellite expansion disorders but the factors that allow RAN translation to occur and the effects of different repeat motifs and alternative AUG-like initiation codons are unclear. We ...

Abstract	Repeat-associated non-ATG (RAN) proteins have been reported in 11 microsatellite expansion disorders but the factors that allow RAN translation to occur and the effects of different repeat motifs and alternative AUG-like initiation codons are unclear. We studied the mechanisms of RAN translation across myotonic dystrophy type 2 (DM2) expansion transcripts with (CCUG) or without (CAGG) efficient alternative AUG-like codons. To better understand how DM2 LPAC and QAGR RAN proteins are expressed, we generated a series of CRISPR/Cas9-edited HEK293T cell lines. We show that LPAC and QAGR RAN protein levels are reduced in protein kinase R (PKR)-/- and PKR-like endoplasmic reticulum kinase (PERK)-/- cells, with more substantial reductions of CAGG-encoded QAGR in PKR-/- cells. Experiments using mutant eIF2α-S51A HEK293T cells show that p-eIF2α is required for QAGR production. In contrast, LPAC levels were only partially reduced in these cells, suggesting that both non-AUG and close-cognate initiation occur across CCUG RNAs. Overexpression of the alternative initiation factor eIF2A increases LPAC and QAGR protein levels but, notably, has a much larger effect on QAGR expressed from CAGG-expansion RNAs that lack efficient close-cognate codons. The effects of eIF2A on increasing LPAC are consistent with previous reports that eIF2A affects CUG-initiation translation. The observation that eIF2A also increases QAGR proteins is novel because CAGG expansion transcripts do not contain CUG or similarly efficient close-cognate AUG-like codons. For QAGR but not LPAC, the eIF2A-dependent increases are not seen when p-eIF2α is blocked. These data highlight the differential regulation of DM2 RAN proteins and eIF2A as a potential therapeutic target for DM2 and other RAN diseases.
MeSH term(s)	CRISPR-Cas Systems/genetics ; DNA Repeat Expansion/genetics ; Eukaryotic Initiation Factor-2/genetics ; HEK293 Cells ; Humans ; Microsatellite Repeats/genetics ; Myotonic Dystrophy/genetics ; Myotonic Dystrophy/physiopathology ; Protein Biosynthesis/genetics ; eIF-2 Kinase/genetics
Chemical Substances	Eukaryotic Initiation Factor-2 ; EIF2AK2 protein, human (EC 2.7.11.1) ; EIF2AK3 protein, human (EC 2.7.11.1) ; eIF-2 Kinase (EC 2.7.11.1)
Language	English
Publishing date	2021-04-15
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddab098
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Article ; Online: In vitro effects of emicizumab on activated clotting time in blood samples from cardiac surgical patients.

Tanaka, Kenichi A / Henderson, Reney / Thangaraju, Kiruphagaran / Morita, Yoshihisa / Mazzeffi, Michael A / Strauss, Erik / Katneni, Upendra / Buehler, Paul W

Haemophilia : the official journal of the World Federation of Hemophilia

2021 Volume 28, Issue 1, Page(s) 183–190

Abstract: Background: Heparin management in hemophilia A (HA) patients with a factor VIII (FVIII) inhibitor can be challenging due to severe activated clotting time (ACT) prolongations. It is important to better understand the impact of emicizumab, a FVIII ... ...

Abstract	Background: Heparin management in hemophilia A (HA) patients with a factor VIII (FVIII) inhibitor can be challenging due to severe activated clotting time (ACT) prolongations. It is important to better understand the impact of emicizumab, a FVIII mimetic on ACT, and tissue factor (TF)-based coagulation assays. Methods: Whole blood from 18 patients undergoing cardiopulmonary bypass (CPB) were mixed in vitro with pooled normal plasma, FVIII-deficient or FVIII-inhibitor plasma to affect functional FVIII levels. ACTs and heparin concentration by protamine titration were measured in whole blood mixture with/without emicizumab (50-100 μg/ml). Thrombin generation and plasmin generation were measured in the patient's plasma mixed with normal plasma or FVIII-inhibitor plasma to assess the impact of emicizumab under low TF activation. Results: FVIII inhibitors prolonged ACTs by 2.2-fold compared to those in normal plasma mixture at baseline. During CPB, ACTs in normal plasma mixture, and FVIII-deficient mixture were in 400s, but ACTs reached 900s in FVIII-inhibitor mixture. Emicizumab shortened ACTs by up to 100s in normal plasma mixture, and FVIII-deficient mixtures. ACTs remained over 600s in FVIII-inhibitor mixture, despite adding emicizumab at 100 μg/ml. Heparin concentration measured by TF-based protamine titration was unaffected. Emicizumab enhanced thrombin peak in the presence of FVIII inhibitors, whereas plasmin generation was mainly affected by thrombin generation, and systemic use of ɛ-aminocaproic acid. Conclusions: FVIII inhibitors extensively prolong ACTs in heparinized whole blood, and clinical levels of emicizumab partially reverse ACT values. Protamine titration should be considered for optimal heparin monitoring in emicizumab-treated patients with FVIII inhibitors.
MeSH term(s)	Antibodies, Bispecific ; Antibodies, Monoclonal, Humanized ; Blood Coagulation Tests ; Factor VIII ; Hemophilia A/drug therapy ; Humans
Chemical Substances	Antibodies, Bispecific ; Antibodies, Monoclonal, Humanized ; emicizumab (7NL2E3F6K3) ; Factor VIII (9001-27-8)
Language	English
Publishing date	2021-11-04
Publishing country	England
Document type	Journal Article
ZDB-ID	1229713-6
ISSN	1365-2516 ; 1351-8216 ; 1355-0691
ISSN (online)	1365-2516
ISSN	1351-8216 ; 1355-0691
DOI	10.1111/hae.14452
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Article ; Online: Extracellular Vesicle Size Reveals Cargo Specific to Coagulation and Inflammation in Pediatric and Adult Sickle Cell Disease.

Thangaraju, Kiruphagaran / Setua, Saini / Lisk, Christina / Swindle, Delaney / Stephenson, Daniel / Dzieciatkowska, Monika / Lamb, Derek R / Moitra, Parikshit / Pak, David / Hassell, Kathryn / George, Gemlyn / Nuss, Rachelle / Davizon-Castillo, Pavel / Stenmark, Kurt R / D'Alessandro, Angelo / Irwin, David C / Buehler, Paul W

Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis

2023 Volume 29, Page(s) 10760296231186144

Abstract: Aberrant coagulation in sickle cell disease (SCD) is linked to extracellular vesicle (EV) exposure. However, there is no consensus on the contributions of small EVs (SEVs) and large EVs (LEVs) toward underlying coagulopathy or on their molecular cargo. ... ...

Abstract	Aberrant coagulation in sickle cell disease (SCD) is linked to extracellular vesicle (EV) exposure. However, there is no consensus on the contributions of small EVs (SEVs) and large EVs (LEVs) toward underlying coagulopathy or on their molecular cargo. The present observational study compared the thrombin potential of SEVs and LEVs isolated from the plasma of stable pediatric and adult SCD patients. Further, EV lipid and protein contents were analyzed to define markers consistent with activation of thrombin and markers of underlying coagulopathy. Results suggested that LEVs-but not SEVs-from pediatrics and adults similarly enhanced phosphatidylserine (PS)-dependent thrombin generation, and cell membrane procoagulant PS (18:0;20:4 and 18:0;18:1) were the most abundant lipids found in LEVs. Further, LEVs showed activated coagulation in protein pathway analyses, while SEVs demonstrated high levels of cholesterol esters and a protein pathway analysis that identified complement factors and inflammation. We suggest that thrombin potential of EVs from both stable pediatric and adult SCD patients is similarly dependent on size and show lipid and protein contents that identify underlying markers of coagulation and inflammation.
MeSH term(s)	Humans ; Adult ; Child ; Thrombin/metabolism ; Anemia, Sickle Cell ; Extracellular Vesicles/metabolism ; Proteins/metabolism ; Inflammation/metabolism ; Lipids
Chemical Substances	Thrombin (EC 3.4.21.5) ; Proteins ; Lipids
Language	English
Publishing date	2023-08-12
Publishing country	United States
Document type	Observational Study ; Journal Article
ZDB-ID	1237357-6
ISSN	1938-2723 ; 1076-0296
ISSN (online)	1938-2723
ISSN	1076-0296
DOI	10.1177/10760296231186144
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Article ; Online: Coagulation potential and the integrated omics of extracellular vesicles from COVID-19 positive patient plasma.

Setua, Saini / Thangaraju, Kiruphagaran / Dzieciatkowska, Monika / Wilkerson, Rebecca B / Nemkov, Travis / Lamb, Derek R / Tagaya, Yutaka / Boyer, Tori / Rowden, Tobi / Doctor, Allan / D'Alessandro, Angelo / Buehler, Paul W

Scientific reports

2022 Volume 12, Issue 1, Page(s) 22191

Abstract: Extracellular vesicles (EVs) participate in cell-to-cell communication and contribute toward homeostasis under physiological conditions. But EVs can also contribute toward a wide array of pathophysiology like cancer, sepsis, sickle cell disease, and ... ...

Abstract	Extracellular vesicles (EVs) participate in cell-to-cell communication and contribute toward homeostasis under physiological conditions. But EVs can also contribute toward a wide array of pathophysiology like cancer, sepsis, sickle cell disease, and thrombotic disorders. COVID-19 infected patients are at an increased risk of aberrant coagulation, consistent with elevated circulating levels of ultra-high molecular weight VWF multimers, D-dimer and procoagulant EVs. The role of EVs in COVID-19 related hemostasis may depend on cells of origin, vesicular cargo and size, however this is not well defined. We hypothesized that the procoagulant potential of EV isolates from COVID-19 (+) patient plasmas could be defined by thrombin generation assays. Here we isolated small EVs (SEVs) and large EVs (LEVs) from hospitalized COVID-19 (+) patient (n = 21) and healthy donor (n = 20) plasmas. EVs were characterized by flow cytometry, Transmission electron microscopy, nanoparticle tracking analysis, plasma thrombin generation and a multi-omics approach to define coagulation potential. These data were consistent with differences in EV metabolite, lipid, and protein content when compared to healthy donor plasma isolated SEVs and LEVs. Taken together, the effect of EVs on plasma procoagulant potential as defined by thrombin generation and supported by multi-omics is enhanced in COVID-19. Further, we observe that this effect is driven both by EV size and phosphatidyl serine.
MeSH term(s)	Humans ; Thrombin/metabolism ; COVID-19/complications ; Extracellular Vesicles/metabolism ; Blood Coagulation ; Thrombosis/metabolism
Chemical Substances	Thrombin (EC 3.4.21.5)
Language	English
Publishing date	2022-12-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-26473-8
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Article ; Online: Genomic variants reveal differential evolutionary constraints on human transglutaminases and point towards unrecognized significance of transglutaminase 2.

Thangaraju, Kiruphagaran / Király, Róbert / Demény, Máté A / András Mótyán, János / Fuxreiter, Mónika / Fésüs, László

PloS one

2017 Volume 12, Issue 3, Page(s) e0172189

Abstract: Transglutaminases (TGMs) catalyze Ca2+-dependent transamidation of proteins with specified roles in blood clotting (F13a) and in cornification (TGM1, TGM3). The ubiquitous TGM2 has well described enzymatic and non-enzymatic functions but in-spite of ... ...

Abstract	Transglutaminases (TGMs) catalyze Ca2+-dependent transamidation of proteins with specified roles in blood clotting (F13a) and in cornification (TGM1, TGM3). The ubiquitous TGM2 has well described enzymatic and non-enzymatic functions but in-spite of numerous studies its physiological function in humans has not been defined. We compared data on non-synonymous single nucleotide variations (nsSNVs) and loss-of-function variants on TGM1-7 and F13a from the Exome aggregation consortium dataset, and used computational and biochemical analysis to reveal the roles of damaging nsSNVs of TGM2. TGM2 and F13a display rarer damaging nsSNV sites than other TGMs and sequence of TGM2, F13a and TGM1 are evolutionary constrained. TGM2 nsSNVs are predicted to destabilize protein structure, influence Ca2+ and GTP regulation, and non-enzymatic interactions, but none coincide with conserved functional sites. We have experimentally characterized six TGM2 allelic variants detected so far in homozygous form, out of which only one, p.Arg222Gln, has decreased activities. Published exome sequencing data from various populations have not uncovered individuals with homozygous loss-of-function variants for TGM2, TGM3 and TGM7. Thus it can be concluded that human transglutaminases differ in harboring damaging variants and TGM2 is under purifying selection suggesting that it may have so far not revealed physiological functions.
MeSH term(s)	Alleles ; Amino Acid Substitution ; Calcium/chemistry ; Calcium/metabolism ; Databases, Protein ; Enzyme Stability/genetics ; Evolution, Molecular ; Factor XIIIa/chemistry ; Factor XIIIa/genetics ; Factor XIIIa/metabolism ; GTP-Binding Proteins/chemistry ; GTP-Binding Proteins/genetics ; GTP-Binding Proteins/metabolism ; Humans ; Mutation, Missense ; Protein Glutamine gamma Glutamyltransferase 2 ; Transglutaminases/chemistry ; Transglutaminases/genetics ; Transglutaminases/metabolism
Chemical Substances	TGM2 protein, human ; Factor XIIIa (EC 2.3.2.13) ; Protein Glutamine gamma Glutamyltransferase 2 (EC 2.3.2.13) ; TGM3 protein, human (EC 2.3.2.13) ; Transglutaminases (EC 2.3.2.13) ; GTP-Binding Proteins (EC 3.6.1.-) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2017-03-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0172189
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Article ; Online: A Pharmacokinetic and Plasmin-Generation Pharmacodynamic Assessment of a Tranexamic Acid Regimen Designed for Cardiac Surgery With Cardiopulmonary Bypass.

Strauss, Erik R / Li, Shuhui / Henderson, Reney / Carpenter, Ross / Guo, Dong / Thangaraju, Kiruphagaran / Katneni, Upendra / Buehler, Paul W / Gobburu, Jogarao V S / Tanaka, Kenichi A

Journal of cardiothoracic and vascular anesthesia

2021 Volume 36, Issue 8 Pt A, Page(s) 2473–2482

Abstract: Objectives: To examine the pharmacokinetics (PK) and pharmacodynamics of a tranexamic (TXA) regimen designed for cardiac surgery with cardiopulmonary bypass (CPB).: Design: A pilot study quantifying TXA concentrations, fibrinolysis markers, and a ... ...

Abstract	Objectives: To examine the pharmacokinetics (PK) and pharmacodynamics of a tranexamic (TXA) regimen designed for cardiac surgery with cardiopulmonary bypass (CPB). Design: A pilot study quantifying TXA concentrations, fibrinolysis markers, and a plasmin- generation (PG) assay. For comparison, PG assay was performed on pooled normal plasma (PNP) with varying TXA concentrations. Setting: A single-center, tertiary, academic medical center. Participants: Twenty patients undergoing cardiac surgery with CPB for valve surgery and/or coronary artery bypass grafting. Intervention: TXA 100 mg/h infusion for 5 hours starting before incision; 1 g TXA in CPB prime and 1 g TXA at CPB end prior to heparin reversal. Measurements and main results: The PK fit a 2-compartment disposition model. TXA concentrations were above 15 mg/L in all patients during CPB through 2 hours post-TXA infusion. During and after CPB, the TXA regimen decreased the median peak PG by 60% (95% confidence interval [CI], 56%-62%). Lowest median peak PG occurred 15 minutes postprotamine. Peak median D-dimer level of 1.24 (0.95-1.71; 95% CI) mg/L occurred at 15 minutes postprotamine and baseline-adjusted ΔD dimer correlated with increased CPB time (p = 0.004) and lower TXA level (p = 0.001). The median 24-hour chest tube output was 447 (330-664; 95% CI) mL. PG assay on PNP revealed a plateau inhibition at 5 mM TXA (786 mg/L). Conclusions: This regimen, with total perioperative dose of 2.5 grams, provided TXA concentrations above 15 mg/L for all patients from CPB initiation through 2 hours post-TXA. PG was significantly inhibited (p < 0.0001) during and after CPB, with maximum inhibition measured at 15 minutes after protamine administration.
MeSH term(s)	Antifibrinolytic Agents ; Cardiac Surgical Procedures ; Cardiopulmonary Bypass/adverse effects ; Fibrinolysin ; Humans ; Pilot Projects ; Tranexamic Acid
Chemical Substances	Antifibrinolytic Agents ; Tranexamic Acid (6T84R30KC1) ; Fibrinolysin (EC 3.4.21.7)
Language	English
Publishing date	2021-12-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1067317-9
ISSN	1532-8422 ; 1053-0770
ISSN (online)	1532-8422
ISSN	1053-0770
DOI	10.1053/j.jvca.2021.12.029
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