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Endogenous bradykinin and B1-B5 during angiotensin-converting enzyme inhibitor-associated angioedema.
Hubers SA, Kohm K, Wei S, Yu C, Nian H, Grabert R, Sexton DJ, Brown NJ
(2018) J Allergy Clin Immunol 142: 1636-1639.e5
MeSH Terms: Aged, Angioedema, Angiotensin-Converting Enzyme Inhibitors, Bradykinin, Enalapril, Female, Humans, Kininogen, High-Molecular-Weight, Lisinopril, Male, Middle Aged, Peptide Fragments, Quinapril
Added November 7, 2018
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1 Members
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13 MeSH Terms
Excipients for the lyoprotection of MAPKAP kinase 2 inhibitory peptide nano-polyplexes.
Mukalel AJ, Evans BC, Kilchrist KV, Dailing EA, Burdette B, Cheung-Flynn J, Brophy CM, Duvall CL
(2018) J Control Release 282: 110-119
MeSH Terms: Cell Line, Drug Stability, Enzyme Inhibitors, Excipients, Freeze Drying, Humans, Intracellular Signaling Peptides and Proteins, Nanoparticles, Peptides, Protein-Serine-Threonine Kinases, Sucrose, Trehalose, Trisaccharides
Show Abstract · Added May 22, 2018
Herein, excipients are investigated to ameliorate the deleterious effects of lyophilization on peptide-polymer nano-polyplex (NP) morphology, cellular uptake, and bioactivity. The NPs are a previously-described platform technology for intracellular peptide delivery and are formulated from a cationic therapeutic peptide and the anionic, pH-responsive, endosomolytic polymer poly(propylacrylic acid) (PPAA). These NPs are effective when formulated and immediately used for delivery into cells and tissue, but they are not amenable to reconstitution following storage as a lyophilized powder due to aggregation. To develop a lyophilized NP format that facilitates longer-term storage and ease of use, MAPKAP kinase 2 inhibitory peptide-based NPs (MK2i-NPs) were prepared in the presence of a range of concentrations of the excipients sucrose, trehalose, and lactosucrose prior to lyophilization and storage. All excipients improved particle morphology post-lyophilization and significantly improved MK2i-NP uptake in human coronary artery smooth muscle cells relative to lyophilized NPs without excipient. In particular, MK2i-NPs lyophilized with 300 mM lactosucrose as an excipient demonstrated a 5.23 fold increase in cellular uptake (p < 0.001), a 2.52 fold increase in endosomal disruption (p < 0.05), and a 2.39 fold increase in ex vivo bioactivity (p < 0.01) compared to MK2i-NPs lyophilized without excipients. In sum, these data suggest that addition of excipients, particularly lactosucrose, maintains and even improves the uptake and therapeutic efficacy of peptide-polymer NPs post-lyophilization relative to freshly-made formulations. Thus, the use of excipients as lyoprotectants is a promising approach for the long-term storage of biotherapeutic NPs and poises this NP platform for clinical translation.
Copyright © 2018 Elsevier B.V. All rights reserved.
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2 Members
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13 MeSH Terms
Angiotensin receptor blocker vs ACE inhibitor effects on HDL functionality in patients on maintenance hemodialysis.
Kaseda R, Tsuchida Y, Gamboa JL, Zhong J, Zhang L, Yang H, Dikalova A, Bian A, Davies S, Fogo AF, Linton MF, Brown NJ, Ikizler TA, Kon V
(2018) Nutr Metab Cardiovasc Dis 28: 582-591
MeSH Terms: Adult, Angiotensin II Type 1 Receptor Blockers, Angiotensin-Converting Enzyme Inhibitors, Biomarkers, Cholesterol, HDL, Double-Blind Method, Female, Humans, Inflammation Mediators, Kidney Failure, Chronic, Male, Middle Aged, Oxidative Stress, Ramipril, Renal Dialysis, Tennessee, Time Factors, Treatment Outcome, Valsartan
Show Abstract · Added August 3, 2018
BACKGROUND AND AIMS - Angiotensin receptor blockers (ARB) and angiotensin converting enzyme inhibitors (ACEI) reduce cardiovascular events in the general population. Maintenance hemodialysis (MHD) patients are at high cardiovascular risk but few studies have directly addressed the comparative efficacy of these drugs. MHD disrupts the normally atheroprotective actions of high density lipoprotein (HDL), therefore, we compared ACEI or ARB treatment on HDL functions in MHD.
METHODS AND RESULTS - HDL was isolated at the starting point (pre) and 3-6 months later (post) in 30 MHD randomly assigned to placebo, ramipril or valsartan. Outcomes included cholesterol efflux, inflammatory cytokine response, effects on Toll-like receptors (TLR), superoxide production, methylarginine and serum amyloid A (SAA) levels. HDL from ARB- or ACEI-treated subjects was more effective in maintaining efflux than HDL of placebo. HDL from ARB- or ACEI-treated subjects but not placebo lessened cellular superoxide production. In contrast, neither ARB nor ACEI improved HDL anti-inflammatory effect. Indeed, HDL of ACEI-treated subjects potentiated the cytokine responses in association with activation of TLR but did not alter the HDL content of methylarginines or SAA.
CONCLUSION - Both ACEI and ARB stabilized HDL cholesterol acceptor function and sustained cellular anti-oxidative effects but not anti-inflammatory effects, and ACEI-treatment instead amplified the HDL inflammatory response. The findings reveal possible utility of antagonizing angiotensin actions in MDH and suggest a possible mechanism for superiority of ARB vs ACEI in the setting of advanced kidney disease.
Copyright © 2018 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.
1 Communities
3 Members
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19 MeSH Terms
The Vasculature in Prediabetes.
Wasserman DH, Wang TJ, Brown NJ
(2018) Circ Res 122: 1135-1150
MeSH Terms: Angiotensin-Converting Enzyme Inhibitors, Animals, Blood Vessels, Cardiovascular Diseases, Combined Modality Therapy, Diabetes Mellitus, Type 2, Diet, Reducing, Disease Progression, Endothelium, Vascular, Extracellular Matrix, Fatty Acids, Nonesterified, Fibrinolysis, Glucose, Humans, Hyperglycemia, Hypoglycemic Agents, Inflammation, Insulin Resistance, Life Style, Metabolic Syndrome, Mice, MicroRNAs, Microcirculation, Muscle, Skeletal, Obesity, Prediabetic State, Risk, Weight Loss
Show Abstract · Added March 26, 2019
The frequency of prediabetes is increasing as the prevalence of obesity rises worldwide. In prediabetes, hyperglycemia, insulin resistance, and inflammation and metabolic derangements associated with concomitant obesity cause endothelial vasodilator and fibrinolytic dysfunction, leading to increased risk of cardiovascular and renal disease. Importantly, the microvasculature affects insulin sensitivity by affecting the delivery of insulin and glucose to skeletal muscle; thus, endothelial dysfunction and extracellular matrix remodeling promote the progression from prediabetes to diabetes mellitus. Weight loss is the mainstay of treatment in prediabetes, but therapies that improved endothelial function and vasodilation may not only prevent cardiovascular disease but also slow progression to diabetes mellitus.
© 2018 American Heart Association, Inc.
1 Communities
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28 MeSH Terms
Using Human 'Experiments of Nature' to Predict Drug Safety Issues: An Example with PCSK9 Inhibitors.
Jerome RN, Pulley JM, Roden DM, Shirey-Rice JK, Bastarache LA, R Bernard G, B Ekstrom L, Lancaster WJ, Denny JC
(2018) Drug Saf 41: 303-311
MeSH Terms: Cholesterol, LDL, Enzyme Inhibitors, Female, Genotype, Humans, Hypercholesterolemia, Male, Phenotype, Polymorphism, Single Nucleotide, Product Surveillance, Postmarketing, Proprotein Convertase 9, Risk Factors, Spinal Dysraphism
Show Abstract · Added March 14, 2018
INTRODUCTION - When a new drug enters the market, its full array of side effects remains to be defined. Current surveillance approaches targeting these effects remain largely reactive. There is a need for development of methods to predict specific safety events that should be sought for a given new drug during development and postmarketing activities.
OBJECTIVE - We present here a safety signal identification approach applied to a new set of drug entities, inhibitors of the serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9).
METHODS - Using phenome-wide association study (PheWAS) methods, we analyzed available genotype and clinical data from 29,722 patients, leveraging the known effects of changes in PCSK9 to identify novel phenotypes in which this protein and its inhibitors may have impact.
RESULTS - PheWAS revealed a significantly reduced risk of hypercholesterolemia (odds ratio [OR] 0.68, p = 7.6 × 10) in association with a known loss-of-function variant in PCSK9, R46L. Similarly, laboratory data indicated significantly reduced beta mean low-density lipoprotein cholesterol (- 14.47 mg/dL, p = 2.58 × 10) in individuals carrying the R46L variant. The R46L variant was also associated with an increased risk of spina bifida (OR 5.90, p = 2.7 × 10), suggesting that further investigation of potential connections between inhibition of PCSK9 and neural tube defects may be warranted.
CONCLUSION - This novel methodology provides an opportunity to put in place new mechanisms to assess the safety and long-term tolerability of PCSK9 inhibitors specifically, and other new agents in general, as they move into human testing and expanded clinical use.
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13 MeSH Terms
Acute kidney injury is a risk factor for subsequent proteinuria.
Parr SK, Matheny ME, Abdel-Kader K, Greevy RA, Bian A, Fly J, Chen G, Speroff T, Hung AM, Ikizler TA, Siew ED
(2018) Kidney Int 93: 460-469
MeSH Terms: Acute Kidney Injury, Aged, Angiotensin II Type 1 Receptor Blockers, Angiotensin-Converting Enzyme Inhibitors, Antihypertensive Agents, Blood Pressure, Comorbidity, Databases, Factual, Diabetes Mellitus, Diabetic Nephropathies, Disease Progression, Female, Glomerular Filtration Rate, Hospitalization, Hospitals, Veterans, Humans, Hypertension, Kidney, Male, Middle Aged, Prevalence, Prognosis, Proteinuria, Renal Insufficiency, Chronic, Retrospective Studies, Risk Factors, Severity of Illness Index, Time Factors, United States
Show Abstract · Added November 29, 2018
Acute kidney injury (AKI) is associated with subsequent chronic kidney disease (CKD), but the mechanism is unclear. To clarify this, we examined the association of AKI and new-onset or worsening proteinuria during the 12 months following hospitalization in a national retrospective cohort of United States Veterans hospitalized between 2004-2012. Patients with and without AKI were matched using baseline demographics, comorbidities, proteinuria, estimated glomerular filtration rate, blood pressure, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (ACEI/ARB) use, and inpatient exposures linked to AKI. The distribution of proteinuria over one year post-discharge in the matched cohort was compared using inverse probability sampling weights. Subgroup analyses were based on diabetes, pre-admission ACEI/ARB use, and AKI severity. Among the 90,614 matched AKI and non-AKI pairs, the median estimated glomerular filtration rate was 62 mL/min/1.73m. The prevalence of diabetes and hypertension were 48% and 78%, respectively. The odds of having one plus or greater dipstick proteinuria was significantly higher during each month of follow-up in patients with AKI than in patients without AKI (odds ratio range 1.20-1.39). Odds were higher in patients with Stage II or III AKI (odds ratios 1.32-1.81) than in Stage I AKI (odds ratios 1.18-1.32), using non-AKI as the reference group. Results were consistent regardless of diabetes status or baseline ACEI/ARB use. Thus, AKI is a risk factor for incident or worsening proteinuria, suggesting a possible mechanism linking AKI and future CKD. The type of proteinuria, physiology, and clinical significance warrant further study as a potentially modifiable risk factor in the pathway from AKI to CKD.
Published by Elsevier Inc.
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29 MeSH Terms
Hypoxia-inducible factor prolyl-4-hydroxylation in FOXD1 lineage cells is essential for normal kidney development.
Kobayashi H, Liu J, Urrutia AA, Burmakin M, Ishii K, Rajan M, Davidoff O, Saifudeen Z, Haase VH
(2017) Kidney Int 92: 1370-1383
MeSH Terms: Anemia, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Hypoxia, Clinical Trials, Phase III as Topic, Disease Models, Animal, Enzyme Inhibitors, Forkhead Transcription Factors, Humans, Hydroxylation, Hypoxia-Inducible Factor-Proline Dioxygenases, Kidney, Kidney Diseases, Mice, Molecular Targeted Therapy, Mutation, Organ Size, Procollagen-Proline Dioxygenase, Renal Insufficiency, Stromal Cells
Show Abstract · Added November 21, 2017
Hypoxia in the embryo is a frequent cause of intra-uterine growth retardation, low birth weight, and multiple organ defects. In the kidney, this can lead to low nephron endowment, predisposing to chronic kidney disease and arterial hypertension. A key component in cellular adaptation to hypoxia is the hypoxia-inducible factor pathway, which is regulated by prolyl-4-hydroxylase domain (PHD) dioxygenases PHD1, PHD2, and PHD3. In the adult kidney, PHD oxygen sensors are differentially expressed in a cell type-dependent manner and control the production of erythropoietin in interstitial cells. However, the role of interstitial cell PHDs in renal development has not been examined. Here we used a genetic approach in mice to interrogate PHD function in FOXD1-expressing stroma during nephrogenesis. We demonstrate that PHD2 and PHD3 are essential for normal kidney development as the combined inactivation of stromal PHD2 and PHD3 resulted in renal failure that was associated with reduced kidney size, decreased numbers of glomeruli, and abnormal postnatal nephron formation. In contrast, nephrogenesis was normal in animals with individual PHD inactivation. We furthermore demonstrate that the defect in nephron formation in PHD2/PHD3 double mutants required intact hypoxia-inducible factor-2 signaling and was dependent on the extent of stromal hypoxia-inducible factor activation. Thus, hypoxia-inducible factor prolyl-4-hydroxylation in renal interstitial cells is critical for normal nephron formation.
Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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20 MeSH Terms
Defective Sphingosine-1-phosphate metabolism is a druggable target in Huntington's disease.
Di Pardo A, Amico E, Basit A, Armirotti A, Joshi P, Neely MD, Vuono R, Castaldo S, Digilio AF, Scalabrì F, Pepe G, Elifani F, Madonna M, Jeong SK, Park BM, D'Esposito M, Bowman AB, Barker RA, Maglione V
(2017) Sci Rep 7: 5280
MeSH Terms: Aged, Aldehyde-Lyases, Animals, Disease Models, Animal, Enzyme Inhibitors, Gene Expression Regulation, Humans, Huntington Disease, Lysophospholipids, Male, Mice, Molecular Targeted Therapy, Phosphotransferases (Alcohol Group Acceptor), Receptors, Lysosphingolipid, Sphingosine
Show Abstract · Added April 11, 2018
Huntington's disease is characterized by a complex and heterogeneous pathogenic profile. Studies have shown that disturbance in lipid homeostasis may represent a critical determinant in the progression of several neurodegenerative disorders. The recognition of perturbed lipid metabolism is only recently becoming evident in HD. In order to provide more insight into the nature of such a perturbation and into the effect its modulation may have in HD pathology, we investigated the metabolism of Sphingosine-1-phosphate (S1P), one of the most important bioactive lipids, in both animal models and patient samples. Here, we demonstrated that S1P metabolism is significantly disrupted in HD even at early stage of the disease and importantly, we revealed that such a dysfunction represents a common denominator among multiple disease models ranging from cells to humans through mouse models. Interestingly, the in vitro anti-apoptotic and the pro-survival actions seen after modulation of S1P-metabolizing enzymes allows this axis to emerge as a new druggable target and unfolds its promising therapeutic potential for the development of more effective and targeted interventions against this incurable condition.
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1 Members
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15 MeSH Terms
Kinetic processivity of the two-step oxidations of progesterone and pregnenolone to androgens by human cytochrome P450 17A1.
Gonzalez E, Guengerich FP
(2017) J Biol Chem 292: 13168-13185
MeSH Terms: 17-alpha-Hydroxypregnenolone, Androstenedione, Animals, Binding Sites, Biocatalysis, Cytochrome P-450 Enzyme Inhibitors, Cytochromes b5, Dehydroepiandrosterone, Humans, Imidazoles, Kinetics, Ligands, Models, Molecular, NADPH-Ferrihemoprotein Reductase, Naphthalenes, Oxidation-Reduction, Pregnenolone, Progesterone, Protein Conformation, Rats, Recombinant Proteins, Stereoisomerism, Steroid 17-alpha-Hydroxylase
Show Abstract · Added March 14, 2018
Cytochrome P450 (P450, CYP) 17A1 plays a critical role in steroid metabolism, catalyzing both the 17α-hydroxylation of pregnenolone and progesterone and the subsequent 17α,20-lyase reactions to form dehydroepiandrosterone (DHEA) and androstenedione (Andro), respectively, critical for generating glucocorticoids and androgens. Human P450 17A1 reaction rates examined are enhanced by the accessory protein cytochrome (), but the exact role of in P450 17A1-catalyzed reactions is unclear as are several details of these reactions. Here, we examined in detail the processivity of the 17α-hydroxylation and lyase steps. did not enhance reaction rates by decreasing the rates of any of the steroids. Steroid binding to P450 17A1 was more complex than a simple two-state system. Pre-steady-state experiments indicated lag phases for Andro production from progesterone and for DHEA from pregnenolone, indicating a distributive character of the enzyme. However, we observed processivity in pregnenolone/DHEA pulse-chase experiments. ()-Orteronel was three times more inhibitory toward the conversion of 17α-hydroxypregnenolone to DHEA than toward the 17α-hydroxylation of pregnenolone. IC values for ()-orteronel were identical for blocking DHEA formation from pregnenolone and for 17α-hydroxylation, suggestive of processivity. Global kinetic modeling helped assign sets of rate constants for individual or groups of reactions, indicating that human P450 17A1 is an inherently distributive enzyme but that some processivity is present, some of the 17α-OH pregnenolone formed from pregnenolone did not dissociate from P450 17A1 before conversion to DHEA. Our results also suggest multiple conformations of P450 17A1, as previously proposed on the basis of NMR spectroscopy and X-ray crystallography.
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
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23 MeSH Terms
Design, Synthesis, and Biological Activity of Substrate Competitive SMYD2 Inhibitors.
Cowen SD, Russell D, Dakin LA, Chen H, Larsen NA, Godin R, Throner S, Zheng X, Molina A, Wu J, Cheung T, Howard T, Garcia-Arenas R, Keen N, Pendleton CS, Pietenpol JA, Ferguson AD
(2016) J Med Chem 59: 11079-11097
MeSH Terms: Cell Line, Tumor, Cell Proliferation, Dose-Response Relationship, Drug, Drug Design, Enzyme Inhibitors, HCT116 Cells, Histone-Lysine N-Methyltransferase, Humans, Molecular Structure, Structure-Activity Relationship
Show Abstract · Added April 9, 2017
Protein lysine methyltransferases (KMTs) have emerged as important regulators of epigenetic signaling. These enzymes catalyze the transfer of donor methyl groups from the cofactor S-adenosylmethionine to specific acceptor lysine residues on histones, leading to changes in chromatin structure and transcriptional regulation. These enzymes also methylate an array of nonhistone proteins, suggesting additional mechanisms by which they influence cellular physiology. SMYD2 is reported to be an oncogenic methyltransferase that represses the functional activity of the tumor suppressor proteins p53 and RB. HTS screening led to identification of five distinct substrate-competitive chemical series. Determination of liganded crystal structures of SMYD2 contributed significantly to "hit-to-lead" design efforts, culminating in the creation of potent and selective inhibitors that were used to understand the functional consequences of SMYD2 inhibition. Taken together, these results have broad implications for inhibitor design against KMTs and clearly demonstrate the potential for developing novel therapies against these enzymes.
1 Communities
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10 MeSH Terms