-
Arthritis & Rheumatology (Hoboken, N.J.) Aug 2016
Topics: Acetamides; Phenylacetates
PubMed: 26990165
DOI: 10.1002/art.39687 -
The American Journal of Clinical... Apr 2024Predicting response to exclusive enteral nutrition (EEN) in active Crohn's disease (CD) could lead to therapy personalization and pretreatment optimization.
BACKGROUND
Predicting response to exclusive enteral nutrition (EEN) in active Crohn's disease (CD) could lead to therapy personalization and pretreatment optimization.
OBJECTIVES
This study aimed to explore the ability of pretreatment parameters to predict fecal calprotectin (FCal) levels at EEN completion in a prospective study in children with CD.
METHODS
In children with active CD, clinical parameters, dietary intake, cytokines, inflammation-related blood proteomics, and diet-related metabolites, metabolomics and microbiota in feces, were measured before initiation of 8 wk of EEN. Prediction of FCal levels at EEN completion was performed using machine learning. Data are presented with medians (IQR).
RESULTS
Of 37 patients recruited, 15 responded (FCal < 250 μg/g) to EEN (responders) and 22 did not (nonresponders). Clinical and immunological parameters were not associated with response to EEN. Responders had lesser (μmol/g) butyrate [responders: 13.2 (8.63-18.4) compared with nonresponders: 22.3 (12.0-32.0); P = 0.03], acetate [responders: 49.9 (46.4-68.4) compared with nonresponders: 70.4 (57.0-95.5); P = 0.027], phenylacetate [responders: 0.175 (0.013-0.611) compared with nonresponders: 0.943 (0.438-1.35); P = 0.021], and a higher microbiota richness [315 (269-347) compared with nonresponders: 243 (205-297); P = 0.015] in feces than nonresponders. Responders consumed (portions/1000 kcal/d) more confectionery products [responders: 0.55 (0.38-0.72) compared with nonresponders: 0.19 (0.01-0.38); P = 0.045]. A multicomponent model using fecal parameters, dietary data, and clinical and immunological parameters predicted response to EEN with 78% accuracy (sensitivity: 80%; specificity: 77%; positive predictive value: 71%; negative predictive value: 85%). Higher taxon abundance from Ruminococcaceae, Lachnospiraceae, and Bacteroides and phenylacetate, butyrate, and acetate were the most influential variables in predicting lack of response to EEN.
CONCLUSIONS
We identify microbial signals and diet-related metabolites in feces, which could comprise targets for pretreatment optimization and personalized nutritional therapy in pediatric CD.
Topics: Child; Humans; Crohn Disease; Enteral Nutrition; Prospective Studies; Remission Induction; Microbiota; Metabolome; Butyrates; Acetates; Phenylacetates
PubMed: 38569785
DOI: 10.1016/j.ajcnut.2023.12.027 -
The Journal of Clinical Investigation Dec 1997This study explores the role of mevalonate inhibitors in the activation of NF-kbeta and the induction of inducible nitric oxide synthase (iNOS) and cytokines (TNF-alpha,...
This study explores the role of mevalonate inhibitors in the activation of NF-kbeta and the induction of inducible nitric oxide synthase (iNOS) and cytokines (TNF-alpha, IL-1beta, and IL-6) in rat primary astrocytes, microglia, and macrophages. Lovastatin and sodium phenylacetate (NaPA) were found to inhibit LPS- and cytokine-mediated production of NO and expression of iNOS in rat primary astrocytes; this inhibition was not due to depletion of end products of mevalonate pathway (e.g., cholesterol and ubiquinone). Reversal of the inhibitory effect of lovastatin on LPS-induced iNOS expression by mevalonate and farnesyl pyrophosphate and reversal of the inhibitory effect of NaPA on LPS-induced iNOS expression by farnesyl pyrophosphate, however, suggests a role of farnesylation in the LPS-mediated induction of iNOS. The inhibition of LPS-mediated induction of iNOS by FPT inhibitor II, an inhibitor of Ras farnesyl protein transferase, suggests that farnesylation of p21(ras) or other proteins regulates the induction of iNOS. Inhibition of LPS-mediated activation of NF-kbeta by lovastatin, NaPA, and FPT inhibitor II in astrocytes indicates that the observed inhibition of iNOS expression is mediated via inhibition of NF-kbeta activation. In addition to iNOS, lovastatin and NaPA also inhibited LPS-induced expression of TNF-alpha, IL-1beta, and IL-6 in rat primary astrocytes, microglia, and macrophages. This study delineates a novel role of the mevalonate pathway in controlling the expression of iNOS and different cytokines in rat astrocytes, microglia, and macrophages that may be important in developing therapeutics against cytokine- and NO-mediated neurodegenerative diseases.
Topics: Alkyl and Aryl Transferases; Animals; Anticholesteremic Agents; Astrocytes; Cells, Cultured; Cytokines; Enzyme Induction; Enzyme Inhibitors; Humans; Interleukin-1; Interleukin-6; Lipopolysaccharides; Lovastatin; Macrophages; Mevalonic Acid; Microglia; Mitogens; NF-kappa B; Nitric Acid; Nitric Oxide Synthase; Phenylacetates; Polyisoprenyl Phosphates; Rats; Sesquiterpenes; Tumor Necrosis Factor-alpha
PubMed: 9389730
DOI: 10.1172/JCI119812 -
Microbiology (Reading, England) Dec 2014Ferroglobus placidus was discovered to oxidize completely the aromatic amino acids tyrosine, phenylalanine and tryptophan when Fe(III) oxide was provided as an electron...
Ferroglobus placidus was discovered to oxidize completely the aromatic amino acids tyrosine, phenylalanine and tryptophan when Fe(III) oxide was provided as an electron acceptor. This property had not been reported previously for a hyperthermophilic archaeon. It appeared that F. placidus follows a pathway for phenylalanine and tryptophan degradation similar to that of mesophilic nitrate-reducing bacteria, Thauera aromatica and Aromatoleum aromaticum EbN1. Phenylacetate, 4-hydroxyphenylacetate and indole-3-acetate were formed during anaerobic degradation of phenylalanine, tyrosine and tryptophan, respectively. Candidate genes for enzymes involved in the anaerobic oxidation of phenylalanine to phenylacetate (phenylalanine transaminase, phenylpyruvate decarboxylase and phenylacetaldehyde : ferredoxin oxidoreductase) were identified in the F. placidus genome. In addition, transcription of candidate genes for the anaerobic phenylacetate degradation, benzoyl-CoA degradation and glutaryl-CoA degradation pathways was significantly upregulated in microarray and quantitative real-time-PCR studies comparing phenylacetate-grown cells with acetate-grown cells. These results suggested that the general strategies for anaerobic degradation of aromatic amino acids are highly conserved amongst bacteria and archaea living in both mesophilic and hyperthermophilic environments. They also provided insights into the diverse metabolism of Archaeoglobaceae species living in hyperthermophilic environments.
Topics: Amino Acids, Aromatic; Anaerobiosis; Archaeoglobales; Biotransformation; Gene Expression Profiling; Indoleacetic Acids; Metabolic Networks and Pathways; Microarray Analysis; Molecular Sequence Data; Oxidation-Reduction; Phenylacetates; Real-Time Polymerase Chain Reaction; Sequence Analysis, DNA
PubMed: 25269449
DOI: 10.1099/mic.0.083261-0 -
Plant Physiology Jun 2019Polar auxin transport plays a pivotal role in plant growth and development. PIN-FORMED (PIN) auxin efflux carriers regulate directional auxin movement by establishing...
Polar auxin transport plays a pivotal role in plant growth and development. PIN-FORMED (PIN) auxin efflux carriers regulate directional auxin movement by establishing local auxin maxima, minima, and gradients that drive multiple developmental processes and responses to environmental signals. Auxin has been proposed to modulate its own transport by regulating subcellular PIN trafficking via processes such as clathrin-mediated PIN endocytosis and constitutive recycling. Here, we further investigated the mechanisms by which auxin affects PIN trafficking by screening auxin analogs and identified pinstatic acid (PISA) as a positive modulator of polar auxin transport in Arabidopsis (). PISA had an auxin-like effect on hypocotyl elongation and adventitious root formation via positive regulation of auxin transport. PISA did not activate SCF signaling and yet induced PIN accumulation at the cell surface by inhibiting PIN internalization from the plasma membrane. This work demonstrates PISA to be a promising chemical tool to dissect the regulatory mechanisms behind subcellular PIN trafficking and auxin transport.
Topics: Arabidopsis; Arabidopsis Proteins; Biological Transport; Cell Membrane; Endocytosis; Gravitropism; Hypocotyl; Indoleacetic Acids; Phenotype; Phenylacetates; Plant Roots; Plant Shoots; Signal Transduction
PubMed: 30936248
DOI: 10.1104/pp.19.00201 -
BMC Veterinary Research Aug 2018Robenacoxib is a non-steroidal anti-inflammatory drug available for canine and feline use for the control of pain and inflammation marketed as Onsior™. The aim of this... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Robenacoxib is a non-steroidal anti-inflammatory drug available for canine and feline use for the control of pain and inflammation marketed as Onsior™. The aim of this target animal safety study was to evaluate the 6-month safety profile of oral robenacoxib administration. It was a randomized, negative-controlled, parallel group study. Thirty-two healthy, young, experimentally naïve, purebred Beagle dogs were administered 0 (sham control, Group 1), 2, 6, and 10 mg/kg robenacoxib (corresponding to the upper end of the dosage range [1X, Group 2] and multiples thereof [3X and 5X, Group 3 and 4]), orally once daily for 6 months. Assessment of safety included general health and clinical observations, physical, neurological, ophthalmological and electrocardiographic examinations, gross and histopathological examinations and clinical pathology evaluations. Blood samples were collected for toxicokinetic assessment of robenacoxib.
RESULTS
No serious adverse events were reported. When compared with control, no treatment effect was observed for body weight, feed or water consumption, clinical pathology, urinalysis and fecal examination parameters. There were no treatment-related changes in stifle joint tissues and microscopic/histopathology examinations of all tissues/organs were normal. Salivation and soft feces were noted in all groups but observed more frequently in the treated groups as compared with control. On Day 178, increased buccal mucosal bleeding times were observed in two treated animals (Group 3 and 4) and one dog in Group 4 displayed a retinal change. Decreased hopping and conscious proprioception was noted in four treated dogs. One dog in Group 2 had ventricular premature complexes. Post-mortem changes included mild, red foci on the cecum in one dog (Group 3) and minimal duodenal discoloration in one dog (Group 4), with no corresponding histological findings in either dog. Ovarian weights were decreased in females from Group 3 and 4 with no gross or histological changes in the ovaries. Blood concentrations of robenacoxib confirmed systemic exposure of treated dogs. Exposure increased with increasing doses and there were no accumulation of robenacoxib in blood.
CONCLUSIONS
Robenacoxib was well tolerated at doses from 2 to 10 mg/kg/day and this 6-month study supports the safe use of Onsior™ (robenacoxib) tablets in dogs for the intended dosing regimen.
Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Diphenylamine; Dogs; Dose-Response Relationship, Drug; Female; Male; Organ Size; Ovary; Phenylacetates; Tablets
PubMed: 30119677
DOI: 10.1186/s12917-018-1566-1 -
Hepatology (Baltimore, Md.) Jul 2009Hyperammonemia is a feature of acute liver failure (ALF), which is associated with increased intracranial pressure (ICP) and brain herniation. We hypothesized that a...
UNLABELLED
Hyperammonemia is a feature of acute liver failure (ALF), which is associated with increased intracranial pressure (ICP) and brain herniation. We hypothesized that a combination of L-ornithine and phenylacetate (OP) would synergistically reduce toxic levels of ammonia by (1) L-ornithine increasing glutamine production (ammonia removal) through muscle glutamine synthetase and (2) phenylacetate conjugating with the ornithine-derived glutamine to form phenylacetylglutamine, which is excreted into the urine. The aims of this study were to determine the effect of OP on arterial and extracellular brain ammonia concentrations as well as ICP in pigs with ALF (induced by liver devascularization). ALF pigs were treated with OP (L-ornithine 0.07 g/kg/hour intravenously; phenylbutyrate, prodrug for phenylacetate; 0.05 g/kg/hour intraduodenally) for 8 hours following ALF induction. ICP was monitored throughout, and arterial and extracellular brain ammonia were measured along with phenylacetylglutamine in the urine. Compared with ALF + saline pigs, treatment with OP significantly attenuated concentrations of arterial ammonia (589.6 +/- 56.7 versus 365.2 +/- 60.4 mumol/L [mean +/- SEM], P= 0.002) and extracellular brain ammonia (P= 0.01). The ALF-induced increase in ICP was prevented in ALF + OP-treated pigs (18.3 +/- 1.3 mmHg in ALF + saline versus 10.3 +/- 1.1 mmHg in ALF + OP-treated pigs;P= 0.001). The value of ICP significantly correlated with the concentration of extracellular brain ammonia (r(2) = 0.36,P< 0.001). Urine phenylacetylglutamine levels increased to 4.9 +/- 0.6 micromol/L in ALF + OP-treated pigs versus 0.5 +/- 0.04 micromol/L in ALF + saline-treated pigs (P< 0.001).
CONCLUSION
L-Ornithine and phenylacetate act synergistically to successfully attenuate increases in arterial ammonia, which is accompanied by a significant decrease in extracellular brain ammonia and prevention of intracranial hypertension in pigs with ALF.
Topics: Ammonia; Animals; Arteries; Brain; Drug Combinations; Extracellular Space; Intracranial Hypertension; Liver Failure, Acute; Ornithine; Phenylacetates; Swine
PubMed: 19554542
DOI: 10.1002/hep.22917 -
British Journal of Clinical Pharmacology 19801. The haemodynamic mechanism of action of guanfacine 4 mg intravenously was investigated in resting conditions and during exercise for up to 20 h after administration... (Clinical Trial)
Clinical Trial
1. The haemodynamic mechanism of action of guanfacine 4 mg intravenously was investigated in resting conditions and during exercise for up to 20 h after administration of the drug. Cardiac output and pulmonary arterial pressure were determined by the Swan-Ganz thermodilution method. Blood pressure was measured directly. 2. During and immediately after intravenous administration of guanfacine, blood pressure peripheral resistance and pulmonary arterial pressure increased (in keeping with an alpha-sympathomimetic effect of the compound), whereas heart rate and cardiac output decreased. 3. Subsequently blood pressure fell as a result of a decrease in cardiac output. From the third hour peripheral resistance decreased, whereas cardiac output increased again, sometimes exceeding the control value. 4. During exercise blood pressure was reduced from the third hour after administration, as in resting conditions, as a result of the reduction in peripheral resistance. 5. In resting conditions guanfacine reduced heart rate at the beginning and during the whole course after administration of the drug. 6. Side-effects noted included fatigue, drowsiness and bradycardia.
Topics: Antihypertensive Agents; Blood Pressure; Cardiac Output; Clinical Trials as Topic; Guanfacine; Guanidines; Hemodynamics; Humans; Hypertension; Phenylacetates; Physical Exertion; Stroke Volume; Time Factors; Vascular Resistance
PubMed: 6994766
DOI: 10.1111/j.1365-2125.1980.tb04919.x -
Molecular Genetics and Metabolism Jan 2021Neonatal onset Urea cycle disorders (UCDs) can be life threatening with severe hyperammonemia and poor neurological outcomes. Glycerol phenylbutyrate (GPB) is safe and...
BACKGROUND/AIMS
Neonatal onset Urea cycle disorders (UCDs) can be life threatening with severe hyperammonemia and poor neurological outcomes. Glycerol phenylbutyrate (GPB) is safe and effective in reducing ammonia levels in patients with UCD above 2 months of age. This study assesses safety, ammonia control and pharmacokinetics (PK) of GPB in UCD patients below 2 months of age.
METHODS
This was an open-label study in UCD patients aged 0 - 2 months, consisting of an initiation/transition period (1 - 4 days) to GPB, followed by a safety extension period (6 months to 2 years). Patients presenting with a hyperammonemic crisis (HAC) did not initiate GPB until blood ammonia levels decreased to below 100 µmol/L while receiving sodium phenylacetate/sodium benzoate and/or hemodialysis. Ammonia levels, PK analytes and safety were evaluated during transition and monthly during the safety extension for 6 months and every 3 months thereafter.
RESULTS
All 16 patients with UCD (median age 0.48 months, range 0.1 to 2.0 months) successfully transitioned to GPB within 3 days. Average plasma ammonia level excluding HAC was 94.3 µmol/L at baseline and 50.4 µmol/L at the end of the transition period (p = 0.21). No patient had a HAC during the transition period. During the safety extension, the majority of patients had controlled ammonia levels, with mean plasma ammonia levels lower during GPB treatment than baseline. Mean glutamine levels remained within normal limits throughout the study. PK analyses indicate that UCD patients <2 months are able to hydrolyze GPB with subsequent absorption of phenylbutyric acid (PBA), metabolism to phenylacetic acid (PAA) and conjugation with glutamine. Plasma concentrations of PBA, PAA, and phenylacetylglutamine (PAGN) were stable during the safety extension phase and mean plasma phenylacetic acid: phenylacetylglutamine ratio remained below 2.5 suggesting no accumulation of GPB. All patients reported at least 1 treatment emergent adverse event with gastroesophageal reflux disease, vomiting, hyperammonemia, diaper dermatitis (37.5% each), diarrhea, upper respiratory tract infection and rash (31.3% each) being the most frequently reported.
CONCLUSIONS
This study supports safety and efficacy of GPB in UCD patients aged 0 -2 months who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. GPB undergoes intestinal hydrolysis with no accumulation in this population.
Topics: Age of Onset; Ammonia; Child, Preschool; Female; Glycerol; Humans; Hyperammonemia; Infant; Infant, Newborn; Male; Pediatrics; Phenylacetates; Phenylbutyrates; Renal Dialysis; Urea Cycle Disorders, Inborn
PubMed: 33388234
DOI: 10.1016/j.ymgme.2020.12.002 -
Chembiochem : a European Journal of... Mar 2020We recently reported the discovery of phenylacetate decarboxylase (PhdB), representing one of only ten glycyl-radical-enzyme reaction types known, and a promising...
We recently reported the discovery of phenylacetate decarboxylase (PhdB), representing one of only ten glycyl-radical-enzyme reaction types known, and a promising biotechnological tool for first-time biochemical synthesis of toluene from renewable resources. Here, we used experimental and computational data to evaluate the plausibility of three candidate PhdB mechanisms, involving either attack at the phenylacetate methylene carbon or carboxyl group [via H-atom abstraction from COOH or single-electron oxidation of COO (Kolbe-type decarboxylation)]. In vitro experimental data included assays with F-labeled phenylacetate, kinetic studies, and tests with site-directed PhdB mutants; computational data involved estimation of reaction energetics using density functional theory (DFT). The DFT results indicated that all three mechanisms are thermodynamically challenging (beyond the range of many known enzymes in terms of endergonicity or activation energy barrier), reflecting the formidable demands on PhdB for catalysis of this reaction. Evidence that PhdB was able to bind α,α-difluorophenylacetate but was unable to catalyze its decarboxylation supported the enzyme's abstraction of a methylene H atom. Diminished activity of H327A and Y691F mutants was consistent with proposed proton donor roles for His327 and Tyr691. Collectively, these and other data most strongly support PhdB attack at the methylene carbon.
Topics: Bacteria; Bacterial Proteins; Carboxy-Lyases; Kinetics; Phenylacetates; Thermodynamics; Toluene
PubMed: 31512343
DOI: 10.1002/cbic.201900560