2-[F]Fluoropropionic Acid PET Imaging of Doxorubicin-induced Cardiotoxicity.

Purpose: Treatment of pediatric cancers with doxorubicin is a common and predictable cause of cardiomyopathy. Early diagnosis of treatment-induced cardiotoxicity and intervention are major determinants for the prevention of advanced disease. The onset of cardiomyopathies is often accompanied by profound changes in lipid metabolism, including an enhanced uptake of short-chain fatty acids (SCFA).

Micronuclear collapse from oxidative damage.

Chromosome-containing micronuclei are a hallmark of aggressive cancers. Micronuclei frequently undergo irreversible collapse, exposing their enclosed chromatin to the cytosol. Micronuclear rupture catalyzes chromosomal rearrangements, epigenetic abnormalities, and inflammation, yet mechanisms safeguarding micronuclear integrity are poorly understood.

Cystine rather than cysteine is the preferred substrate for β-elimination by cystathionine γ-lyase: implications for dietary methionine restriction.

Dietary methionine restriction (MR) increases longevity by improving health. In experimental models, MR is accompanied by decreased cystathionine β-synthase activity and increased cystathionine γ-lyase activity. These enzymes are parts of the transsulfuration pathway which produces cysteine and 2-oxobutanoate.

Stabilization of guinea pig transglutaminase 2 solutions.

Mammalian transglutaminase 2 exhibits poor long-term stability in solution. Reconstituting lyophilized transglutaminase 2 in solutions containing dithiothreitol and EDTA alone and together with glycerol stabilizes the activity of this enzyme for several weeks.

Advances in PSMA theranostics.

The validation of prostate specific membrane antigen (PSMA) as a molecular target in metastatic castration-resistant prostate cancer has stimulated the development of multiple classes of theranostic ligands that specifically target PSMA. Theranostic ligands are used to image disease or selectively deliver cytotoxic radioactivity to cells expressing PSMA according to the radioisotope conjugated to the ligand. PSMA theranostics is a rapidly advancing field that is now integrating into clinical management of prostate cancer patients.

Neutrophil-Derived Myeloperoxidase and Hypochlorous Acid Critically Contribute to 20-Hydroxyeicosatetraenoic Acid Increases that Drive Postischemic Angiogenesis.

Compensatory angiogenesis is an important adaptation for recovery from critical ischemia. We recently identified 20-hydroxyeicosatetraenoic acid (20-HETE) as a novel contributor of ischemia-induced angiogenesis. However, the precise mechanisms by which ischemia promotes 20-HETE increases that drive angiogenesis are unknown.

Synthesis and Evaluation of C-Labeled Triazolones as Probes for Imaging Fatty Acid Synthase Expression by Positron Emission Tomography.

Cancer cells require lipids to fulfill energetic, proliferative, and signaling requirements. Even though these cells can take up exogenous fatty acids, the majority exhibit a dependency on de novo fatty acid synthesis. Fatty acid synthase (FASN) is the rate-limiting enzyme in this process.

A Trifunctional Theranostic Ligand Targeting Fibroblast Activation Protein-α (FAPα).

Purpose: Fibroblast activation protein-α (FAPα) is uniquely expressed in activated fibroblasts, including cancer-associated fibroblasts that populate tumor stroma and contribute to proliferation and immunosuppression. Radiolabeled FAPα inhibitors enable imaging of multiple human cancers, but time-dependent clearance from tumors currently limits their utility as FAPα-targeted radiotherapeutics. We sought to increase the area under the curve (AUC) by constructing a trifunctional ligand that binds FAPα with high affinity and also binds albumin and theranostic radiometals.

Mechanism of Fully Reversible, pH-Sensitive Inhibition of Human Glutamine Synthetase by Tyrosine Nitration.

Glutamine synthetase (GS) catalyzes an ATP-dependent condensation of glutamate and ammonia to form glutamine. This reaction-and therefore GS-are indispensable for the hepatic nitrogen metabolism. Nitration of tyrosine 336 (Y336) inhibits human GS activity.

Cystamine and cysteamine as inhibitors of transglutaminase activity .

Cystamine is commonly used as a transglutaminase inhibitor. This disulphide undergoes reduction to the aminothiol compound, cysteamine. Thus, the mechanism by which cystamine inhibits transglutaminase activity could be due to either cystamine or cysteamine, which depends on the local redox environment.

Fluorination at the 4 position alters the substrate behavior of L-glutamine and L-glutamate: Implications for positron emission tomography of neoplasias.

Two 4-fluoro-L-glutamine diastereoisomers [(2,4)-4-FGln, (2,4)-4-FGln] were previously developed for positron emission tomography. Label uptake into two tumor cell types was greater with [F](2,4)-4-FGln than with [F](2,4)-4-FGln. In the present work we investigated the enzymology of two diastereoisomers of 4-FGln, two diastereoisomers of 4-fluoroglutamate (4-FGlu) (potential metabolites of the 4-FGln diastereoisomers) and another fluoro-derivative of L-glutamine [(2,4)-4-(3-fluoropropyl)glutamine (FP-Gln)].

The Enzymology of 2-Hydroxyglutarate, 2-Hydroxyglutaramate and 2-Hydroxysuccinamate and Their Relationship to Oncometabolites.

Many enzymes make "mistakes". Consequently, repair enzymes have evolved to correct these mistakes. For example, lactate dehydrogenase (LDH) and mitochondrial malate dehydrogenase (mMDH) slowly catalyze the reduction of 2-oxoglutarate (2-OG) to the oncometabolite l-2-hydroxyglutarate (l-2-HG).

Linking Inflammation and Parkinson Disease: Hypochlorous Acid Generates Parkinsonian Poisons.

Inflammation is a common feature of Parkinson Disease and other neurodegenerative disorders. Hypochlorous acid (HOCl) is a reactive oxygen species formed by neutrophils and other myeloperoxidase-containing cells during inflammation. HOCl chlorinates the amine and catechol moieties of dopamine to produce chlorinated derivatives collectively termed chlorodopamine.

Central Role of Glutamate Metabolism in the Maintenance of Nitrogen Homeostasis in Normal and Hyperammonemic Brain.

Glutamate is present in the brain at an average concentration-typically 10-12 mM-far in excess of those of other amino acids. In glutamate-containing vesicles in the brain, the concentration of glutamate may even exceed 100 mM. Yet because glutamate is a major excitatory neurotransmitter, the concentration of this amino acid in the cerebral extracellular fluid must be kept low-typically µM.

Serotonin as a putative scavenger of hypohalous acid in the brain.

Neurodegenerative disorders represent the culmination of numerous insults including oxidative stress. The long etiology of most of these disorders suggests that lessening the effects of one or more of the insults could significantly delay disease onset. Antioxidants have been tested as possible therapeutics for neurodegenerative disorders, but with little success.

Critical Evaluation of the Changes in Glutamine Synthetase Activity in Models of Cerebral Stroke.

The following article addresses some seemingly paradoxical observations concerning cerebral glutamine synthetase in ischemia-reperfusion injury. In the brain, this enzyme is predominantly found in astrocytes and catalyzes part of the glutamine-glutamate cycle. Glutamine synthetase is also thought to be especially sensitive to inactivation by the oxygen- and nitrogen-centered radicals generated during strokes.

Optimized ferrozine-based assay for dissolved iron.

The following report describes a simple and optimized assay for the detection of iron in solution based on the binding of this metal by ferrozine. This assay accurately measures between 1 and 200 μM sample iron concentrations within 2½ hours.

Inhibition of human glutamine synthetase by L-methionine-S,R-sulfoximine-relevance to the treatment of neurological diseases.

At high concentrations, the glutamine synthetase inhibitor L-methionine-S,R-sulfoximine (MSO) is a convulsant, especially in dogs. Nevertheless, sub-convulsive doses of MSO are neuroprotective in rodent models of hyperammonemia, acute liver disease, and amyotrophic lateral sclerosis and suggest MSO may be clinically useful. Previous work has also shown that much lower doses of MSO are required to produce convulsions in dogs than in primates.

Preparation of 2-nitro-5-thiobenzoate for the routine determination of reagent hypochlorous acid concentrations.

Solutions of hypochlorous acid (HOCl) decay over time. This decay indicates the necessity for methods and reagents for the routine measurement of this oxidant. 2-Nitro-5-thiobenzoate is commonly used to measure HOCl concentrations.

γ-Glutamylamines and neurodegenerative diseases.

Transglutaminases catalyze the formation of γ-glutamylamines utilizing glutamyl residues and amine-bearing compounds such as lysyl residues and polyamines. These γ-glutamylamines can be released from proteins by proteases in an intact form. The free γ-glutamylamines can be catabolized to 5-oxo-L-proline and the free amine by γ-glutamylamine cyclotransferase.

Donepezil dosing strategies: pharmacokinetic considerations.

Donepezil (Aricept) is a cholinesterase inhibitor approved for the treatment of Alzheimer's disease. Immediate release formulations of 5- and 10-mg tablets were approved by the Food and Drug Administration in the United States in 1996. In July 2010, the Food and Drug Administration approved a 23-mg sustained release (SR) formulation.

Cholinesterase inhibitors: applying pharmacokinetics to clinical decision making.

Background: Cholinesterase inhibitors are indicated for the treatment of Alzheimer-type dementia. There are few direct comparative studies of adverse effects or studies to suggest clinical superiority of one inhibitor over the others.

Objective: The objective of this study was to relate pharmacokinetic differences among the agents to potential clinical considerations.

Transglutaminase activation in neurodegenerative diseases.

The following review examines the role of calcium in promoting the in vitro and in vivo activation of transglutaminases in neurodegenerative disorders. Diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease exhibit increased transglutaminase activity and rises in intracellular calcium concentrations, which may be related. The aberrant activation of transglutaminase by calcium is thought to give rise to a variety of pathological moieties in these diseases, and the inhibition has been shown to have therapeutic benefit in animal and cellular models of neurodegeneration.