Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 17

Publication Record

Connections

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.
Schmidt AF, Holmes MV, Preiss D, Swerdlow DI, Denaxas S, Fatemifar G, Faraway R, Finan C, Valentine D, Fairhurst-Hunter Z, Hartwig FP, Horta BL, Hypponen E, Power C, Moldovan M, van Iperen E, Hovingh K, Demuth I, Norman K, Steinhagen-Thiessen E, Demuth J, Bertram L, Lill CM, Coassin S, Willeit J, Kiechl S, Willeit K, Mason D, Wright J, Morris R, Wanamethee G, Whincup P, Ben-Shlomo Y, McLachlan S, Price JF, Kivimaki M, Welch C, Sanchez-Galvez A, Marques-Vidal P, Nicolaides A, Panayiotou AG, Onland-Moret NC, van der Schouw YT, Matullo G, Fiorito G, Guarrera S, Sacerdote C, Wareham NJ, Langenberg C, Scott RA, Luan J, Bobak M, Malyutina S, Pająk A, Kubinova R, Tamosiunas A, Pikhart H, Grarup N, Pedersen O, Hansen T, Linneberg A, Jess T, Cooper J, Humphries SE, Brilliant M, Kitchner T, Hakonarson H, Carrell DS, McCarty CA, Lester KH, Larson EB, Crosslin DR, de Andrade M, Roden DM, Denny JC, Carty C, Hancock S, Attia J, Holliday E, Scott R, Schofield P, O'Donnell M, Yusuf S, Chong M, Pare G, van der Harst P, Said MA, Eppinga RN, Verweij N, Snieder H, Lifelines Cohort authors, Christen T, Mook-Kanamori DO, ICBP Consortium, Gustafsson S, Lind L, Ingelsson E, Pazoki R, Franco O, Hofman A, Uitterlinden A, Dehghan A, Teumer A, Baumeister S, Dörr M, Lerch MM, Völker U, Völzke H, Ward J, Pell JP, Meade T, Christophersen IE, Maitland-van der Zee AH, Baranova EV, Young R, Ford I, Campbell A, Padmanabhan S, Bots ML, Grobbee DE, Froguel P, Thuillier D, Roussel R, Bonnefond A, Cariou B, Smart M, Bao Y, Kumari M, Mahajan A, Hopewell JC, Seshadri S, METASTROKE Consortium of the ISGC, Dale C, Costa RPE, Ridker PM, Chasman DI, Reiner AP, Ritchie MD, Lange LA, Cornish AJ, Dobbins SE, Hemminki K, Kinnersley B, Sanson M, Labreche K, Simon M, Bondy M, Law P, Speedy H, Allan J, Li N, Went M, Weinhold N, Morgan G, Sonneveld P, Nilsson B, Goldschmidt H, Sud A, Engert A, Hansson M, Hemingway H, Asselbergs FW, Patel RS, Keating BJ, Sattar N, Houlston R, Casas JP, Hingorani AD
(2019) BMC Cardiovasc Disord 19: 240
MeSH Terms: Anticholesteremic Agents, Biomarkers, Brain Ischemia, Cholesterol, LDL, Down-Regulation, Dyslipidemias, Genome-Wide Association Study, Humans, Myocardial Infarction, Polymorphism, Single Nucleotide, Proprotein Convertase 9, Randomized Controlled Trials as Topic, Risk Assessment, Risk Factors, Serine Proteinase Inhibitors, Stroke, Treatment Outcome
Show Abstract · Added March 24, 2020
BACKGROUND - We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9.
METHODS - Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration.
RESULTS - The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable.
CONCLUSIONS - Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
0 Communities
1 Members
0 Resources
17 MeSH Terms
Sulfated pentagalloylglucoside is a potent, allosteric, and selective inhibitor of factor XIa.
Al-Horani RA, Ponnusamy P, Mehta AY, Gailani D, Desai UR
(2013) J Med Chem 56: 867-78
MeSH Terms: Allosteric Regulation, Carbohydrate Sequence, Chromatography, Liquid, Enzyme Activation, Factor XIa, Glucosides, Hydrolysis, Kinetics, Magnetic Resonance Spectroscopy, Molecular Mimicry, Molecular Sequence Data, Serine Proteinase Inhibitors, Spectrometry, Mass, Electrospray Ionization, Sulfuric Acid Esters, Thrombelastography
Show Abstract · Added May 19, 2014
Inhibition of factor XIa (FXIa) is a novel paradigm for developing anticoagulants without major bleeding consequences. We present the discovery of sulfated pentagalloylglucoside (6) as a highly selective inhibitor of human FXIa. Biochemical screening of a focused library led to the identification of 6, a sulfated aromatic mimetic of heparin. Inhibitor 6 displayed a potency of 551 nM against FXIa, which was at least 200-fold more selective than other relevant enzymes. It also prevented activation of factor IX and prolonged human plasma and whole blood clotting. Inhibitor 6 reduced V(MAX) of FXIa hydrolysis of chromogenic substrate without affecting the K(M), suggesting an allosteric mechanism. Competitive studies showed that 6 bound in the heparin-binding site of FXIa. No allosteric small molecule has been discovered to date that exhibits equivalent potency against FXIa. Inhibitor 6 is expected to open up a major route to allosteric FXIa anticoagulants with clinical relevance.
0 Communities
1 Members
0 Resources
15 MeSH Terms
Regulated intramembrane cleavage of the EGF receptor.
Liao HJ, Carpenter G
(2012) Traffic 13: 1106-12
MeSH Terms: Amyloid Precursor Protein Secretases, Calpain, Cell Line, Tumor, Cell Membrane, Cell Nucleus, Epidermal Growth Factor, ErbB Receptors, Gene Expression, Glycoproteins, HEK293 Cells, Humans, Ionomycin, Proteolysis, Quinazolines, Serine Endopeptidases, Serine Proteinase Inhibitors, Tyrphostins
Show Abstract · Added August 23, 2013
Following the addition of EGF or ionomycin to A431 cells, protease activity mediates cleavage of the EGF receptor producing a 60 kDa fragment that includes the intracellular domain (ICD). This fragment is located in both membrane and nuclear fractions. On the basis of sensitivity to chemical inhibitors and overexpression of cDNAs, the rhomboid intramembrane proteases, not γ-secretase proteases, are identified as responsible for the cleavage event. Agonist-initiated cleavage occurs slowly over 3-24 h. Inhibition of calpain protease activity significantly increased the detectable level of ICD fragment.
© 2012 John Wiley & Sons A/S.
0 Communities
2 Members
0 Resources
17 MeSH Terms
Evidence indicating the existence of a novel family of serine protease inhibitors that may be involved in marine invertebrate immunity.
Xue Q, Itoh N, Schey KL, Cooper RK, La Peyre JF
(2009) Fish Shellfish Immunol 27: 250-9
MeSH Terms: Amino Acid Sequence, Animals, Base Sequence, Crassostrea, Gene Expression Profiling, Gene Expression Regulation, Invertebrates, Kinetics, Marine Biology, Molecular Sequence Data, Sequence Alignment, Serine Proteinase Inhibitors, Subtilisins
Show Abstract · Added May 27, 2014
A new serine protease inhibitor, designated cvSI-2, was purified and characterized from the plasma of the eastern oyster, Crassostrea virginica. CvSI-2 inhibited the serine protease subtilisin A in a slow-tight binding manner, with an overall dissociation constant Ki* of 0.18 nM. It also inhibited perkinsin, the major extracellular protease of the oyster protozoan parasite Perkinsus marinus. Sequencing of cvSI-2 cloned cDNA revealed an open reading frame of 258 bp encoding a polypeptide of 85 amino acids, with the 18 N-terminal amino acids forming a signal peptide. The mature cvSI-2 molecule predicted consisted of 67 amino acids with 12 cysteine residues and a calculated molecular mass of 7202.96 Da. Overall 91% of the cvSI-2 amino acid sequence predicted from cDNA was confirmed by tandem mass spectrometry sequencing of purified cvSI-2. In addition, serine 43 and a threonine substitution at this position were observed. CvSI-2 amino acid sequence showed a 38% identity and 54% similarity with that of cvSI-1, the first protease inhibitor purified and characterized from a bivalve mollusc. Like cvSI-1, cvSI-2 gene was expressed in the basophil cells of digestive tubules. BLAST search found multiple ESTs from the eastern oyster, Pacific oyster, Mediterranean mussel, and sea vase, a tunicate, which could encode proteins with sequences similar to cvSI-1 and cvSI-2. Our findings indicate that cvSI-1 and cvSI-2 are members of a novel family of serine protease inhibitors in bivalve molluscs and perhaps other marine invertebrates, which share the characteristic cysteine array C-X(4-9)-C-X(4-6)-C-X(7)-C-X(4)-C-T-C-X(6-9)-C-X(5)-C-X(3-7)-C-X(6-10)-C-X(4)-C-X-C.
0 Communities
1 Members
0 Resources
13 MeSH Terms
Aprotinin exacerbates left ventricular dysfunction after ischemia/reperfusion in mice lacking tumor necrosis factor receptor I.
Sabbagh MJ, Looper JM, Zavadzkas JA, Stroud RE, Ford RL, Rivers WT, Koval CN, McEvoy MD, Reeves ST, Spinale FG
(2008) J Cardiovasc Pharmacol 52: 355-62
MeSH Terms: Animals, Aprotinin, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Animal, Myocardium, Random Allocation, Receptors, Tumor Necrosis Factor, Type I, Reperfusion Injury, Serine Proteinase Inhibitors, Tumor Necrosis Factor-alpha, Ventricular Dysfunction, Left
Show Abstract · Added October 17, 2015
Aprotinin is a serine protease inhibitor with diverse biological effects; until recently, it was utilized in the context of ischemia/reperfusion (I/R). It has been hypothesized that a signaling pathway modulated by aprotinin in the context of I/R is the tumor necrosis factor-alpha receptor (TNFR) pathway. An intact mouse model of I/R (30 min ischemia and 60 min reperfusion) was used and left ventricular (LV) peak + maximal rate of left ventricular (LV) peak pressure (dP/dt) was measured in wild-type mice (WT, C57BL/6; n = 10), WT mice with aprotinin (4 mL/kg; n = 10), transgenic mice devoid of the TNFRI (TNFRI-null; n = 10), and TNFRI-null with aprotinin (n=10). Following I/R, LV peak + dP/dt decreased in both WT groups, but remained similar to baseline values in the TNFRI-null group. In contrast, aprotinin caused a marked reduction in LV peak + dP/dt in the TNFRI-null group following I/R. Soluble plasma TNF levels increased in the WT and TNFRI-null mice with I/R and was reduced with aprotinin. Soluble TNFRI and TNFRII levels, indicative of TNF activation, increased in the WT mice following I/R and remained elevated with aprotinin. Soluble TNFRII levels were increased in the TNFRI-null mice following I/R and remained elevated with aprotinin. The new and unique findings of this study were twofold. First, aprotinin failed to improve LV function after I/R despite a reduction in circulating TNF levels. Second, genetic ablation of TNFRI uncovered a negative inotropic effect of aprotinin. These findings demonstrate that complex biological pathways and interactions are affected with broad spectrum serine protease inhibition, which are relevant to myocardial function in the context of I/R.
0 Communities
1 Members
0 Resources
13 MeSH Terms
Aprotinin exerts differential and dose-dependent effects on myocardial contractility, oxidative stress, and cytokine release after ischemia-reperfusion.
McEvoy MD, Taylor AG, Zavadzkas JA, Mains IM, Ford RL, Stroud RE, Jeffords LB, Beck CU, Reeves ST, Spinale FG
(2008) Ann Thorac Surg 86: 568-75
MeSH Terms: Animals, Aprotinin, Cardiac Surgical Procedures, Disease Models, Animal, Dose-Response Relationship, Drug, Elasticity, Image Processing, Computer-Assisted, Interleukin-6, Mice, Mice, Inbred Strains, Myocardial Contraction, Myocardial Reperfusion Injury, Myocardium, Oxidative Stress, Peroxidase, Serine Proteinase Inhibitors, Tumor Necrosis Factor-alpha, Ventricular Function, Left
Show Abstract · Added October 17, 2015
BACKGROUND - Cardiac surgery can result in left ventricular ischemia and reperfusion (I/R), the release of cytokines such as tumor necrosis factor, and oxidative stress with release of myeloperoxidase. Although aprotinin has been used in cardiac surgery, the likely multiple effects of this serine protease inhibitor limit clinical utility. This study tested the hypothesis that different aprotinin doses cause divergent effects on left ventricular contractility, cytokine release, and oxidative stress in the context of I/R.
METHODS - Left ventricular I/R (30 minutes I, 60 minutes R) was induced in mice, and left ventricular contractility (maximal end-systolic elastance) determined. Mice were randomly allocated to 2 x 10(4) kallikrein inhibitory units (KIU)/kg aprotinin (n = 11), 4 x 10(4) KIU/kg aprotinin (n = 10), and vehicle (saline, n = 10). Based upon a fluorogenic assay, aprotinin doses of 2 and 4 x 10(4) KIU/kg resulted in plasma concentrations similar to those of the half and full Hammersmith doses, respectively.
RESULTS - After I/R, maximal end-systolic elastance fell by more than 40% from baseline (p < 0.05), and this effect was attenuated by 2 x 10(4) KIU/kg but not 4 x 10(4) KIU/kg aprotinin. Tumor necrosis factor increased by more than 60% from control (p < 0.05) with I/R, but was reduced with 4 x 10(4) KIU/kg aprotinin. Myeloperoxidase increased with I/R, and was reduced to the greatest degree by 2 x 10(4) KIU/kg aprotinin.
CONCLUSIONS - Aprotinin influences left ventricular contractility, cytokine release, and oxidative stress, which are dose dependent. These results provide mechanistic evidence that multiple pathways are differentially affected by aprotinin in a context relevant to cardiac surgery.
0 Communities
1 Members
0 Resources
18 MeSH Terms
A novel slow-tight binding serine protease inhibitor from eastern oyster (Crassostrea virginica) plasma inhibits perkinsin, the major extracellular protease of the oyster protozoan parasite Perkinsus marinus.
Xue QG, Waldrop GL, Schey KL, Itoh N, Ogawa M, Cooper RK, Losso JN, La Peyre JF
(2006) Comp Biochem Physiol B Biochem Mol Biol 145: 16-26
MeSH Terms: Amino Acid Sequence, Animals, Base Sequence, Crassostrea, DNA, Complementary, Eukaryota, Kinetics, Molecular Sequence Data, Serine Endopeptidases, Serine Proteinase Inhibitors, Subtilisin
Show Abstract · Added May 27, 2014
A serine protease inhibitor was purified from plasma of the eastern oyster, Crassostrea virginica. The inhibitor is a 7609.6 Da protein consisting of 71 amino acids with 12 cysteine residues that are postulated to form 6 intra-chain disulfide bridges. Sequencing of the cloned cDNA identified an open reading frame encoding a polypeptide of 90 amino acids, with the 19 N-terminal amino acids forming a signal peptide. No sequence similarity with known proteins was found in sequence databases. The protein inhibited the serine proteases subtilisin A, trypsin and perkinsin, the major extracellular protease of the oyster protozoan parasite, Perkinsus marinus, in a slow binding manner. The mechanism of inhibition involves a rapid binding of inhibitor to the enzyme to form a weak enzyme-inhibitor complex followed by a slow isomerization to form a very tight binding enzyme-inhibitor complex. The overall dissociation constants K(i) with subtilisin A, perkinsin and trypsin were 0.29 nM, 13.7 nM and 17.7 nM, respectively. No inhibition of representatives of the other protease classes was detected. This is the first protein inhibitor of proteases identified from a bivalve mollusk and it represents a new protease inhibitor family. Its tight binding to subtilisin and perkinsin suggests it plays a role in the oyster host defense against P. marinus.
0 Communities
1 Members
0 Resources
11 MeSH Terms
The membrane-anchored serine protease, TMPRSS2, activates PAR-2 in prostate cancer cells.
Wilson S, Greer B, Hooper J, Zijlstra A, Walker B, Quigley J, Hawthorne S
(2005) Biochem J 388: 967-72
MeSH Terms: Boron Compounds, Calcium, Catalysis, Cell Line, Tumor, Humans, Male, Prostatic Neoplasms, RNA, Messenger, Receptor, PAR-2, Recombinant Proteins, Serine Endopeptidases, Serine Proteinase Inhibitors, Signal Transduction, Substrate Specificity, Suramin
Show Abstract · Added December 30, 2013
TMPRSS2 is a type II transmembrane-bound serine protease that has gained interest owing to its highly localized expression in the prostate and its overexpression in neoplastic prostate epithelium. Once activated, the serine protease domain of TMPRSS2 is released from the cell surface into the extracellular space. PAR (protease-activated receptor)-2 belongs to a family of G-protein-coupled receptors (PAR-1-4) that are activated by specific serine proteases, which are expressed in many normal and malignant cell types. Previous in vitro studies on prostate cancer cells suggest a role for PAR-2 in prostate cancer metastasis. A polyclonal anti-human TMPRSS2 antibody was generated against the TMPRSS2 serine protease domain. The antibody showed specific reactivity with recombinant expressed TMPRSS2, and so was used to extract and purify the cleaved active TMPRSS2 protease from prostate cancer cells. Reverse transcriptase PCR and Western blot analysis were used to show the expression of both TMPRSS2 and PAR-2 in the androgen-dependent LNCaP prostate cancer cell line. Treatment of LNCaP cells with the cellular immunopurified TMPRSS2 protease induced a transient increase in intracellular calcium, which is indicative of G-protein-coupled-receptor activation. This calcium mobilization was inhibited by cellular pre-treatment with a specific PAR-2 antagonist, but not with a PAR-1 antagonist; inhibition of the protease activity also failed to mobilize calcium, suggesting that TMPRSS2 is capable of cleaving and thereby activating the PAR-2 receptor. The calcium mobilization was also inhibited by cellular pre-treatment with suramin or 2-APB (2-aminoethoxydiphenyl borate), indicating that a G-protein pathway is involved and that subsequent calcium release is mainly from intracellular stores. The present study describes how TMPRSS2 may contribute to prostate tumour metastasis via the activation of PAR-2.
0 Communities
1 Members
0 Resources
15 MeSH Terms
The potential role of aprotinin in the perioperative management of malignant tumors.
Vaporciyan AA, Putnam JB, Smythe WR
(2004) J Am Coll Surg 198: 266-78
MeSH Terms: Animals, Aprotinin, Blood Loss, Surgical, Disease Progression, Female, Hemostasis, Humans, Kallikreins, Kidney, Meningeal Neoplasms, Meningioma, Mesothelioma, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasms, Neovascularization, Pathologic, Ovarian Neoplasms, Pneumonectomy, Sarcoma, Serine Proteinase Inhibitors, Urinary Bladder Neoplasms, Urokinase-Type Plasminogen Activator
Added March 27, 2014
0 Communities
1 Members
0 Resources
22 MeSH Terms
Inhibition of retinal neovascularization by intravitreal injection of human rPAI-1 in a rat model of retinopathy of prematurity.
Penn JS, Rajaratnam VS
(2003) Invest Ophthalmol Vis Sci 44: 5423-9
MeSH Terms: Animals, Animals, Newborn, Disease Models, Animal, Dose-Response Relationship, Drug, Female, Gelatinases, Humans, Infant, Newborn, Injections, Plasminogen Activator Inhibitor 1, Pregnancy, Rats, Rats, Sprague-Dawley, Recombinant Proteins, Retinal Neovascularization, Retinopathy of Prematurity, Serine Proteinase Inhibitors, Urokinase-Type Plasminogen Activator, Vitreous Body
Show Abstract · Added October 9, 2013
PURPOSE - Restructuring of extracellular matrix at actively extending blood vessel tips involves secretion of plasminogen activator (PA). Findings in earlier studies conducted in the authors' laboratory have suggested that angiostatic steroids suppress the PA activity essential for the invasive aspect of angiogenesis by increasing synthesis of plasminogen activator inhibitor (PAI)-1. This experiment was designed to test the effect of administration of exogenous PAI-1 on retinal neovascularization (NV) in an animal model of retinopathy of prematurity (ROP).
METHODS - At birth, Sprague-Dawley rats were placed into incubators and exposed to an atmosphere alternating between 50% and 10% O(2) every 24 hours. After 14 days, the animals were removed to room air, at which time each received a single intravitreal injection of 5 microL of buffer vehicle or one of five doses of PAI-1, ranging from 3.0 microg/mL to 2.0 mg/mL. Animals were killed 6 days later, and retinal NV was assessed using adenosine diphosphatase (ADPase) histochemical staining.
RESULTS - Retinal neovascularization decreased with increasing PAI-1 dosage. The most effective dose tested (2.0 mg/mL) caused a 52% reduction in retinal NV relative to vehicle (P < 0.005). Normal vasculogenesis, as determined by measuring retinal vascular area, was unaffected.
CONCLUSIONS - PAI-1 inhibits pathologic angiogenesis without adversely affecting normal vasculogenesis, an attractive feature for ROP therapies. Moreover, PAI's relationship to matrix metalloproteinases, which are also implicated in angiogenesis, suggests that the proteolytic aspect of the process may provide additional downstream therapeutic targets.
1 Communities
1 Members
0 Resources
19 MeSH Terms