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Phenylketonuria
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
In the presence of a defect in phenylalanine hydroxylase, the first compound that accumulates is phenylalanine itself. In classic PKU, the plasma concentration of phenylalanine is virtually always above 1200 μmol/L. It is transaminated (see Figure 15.1) to form phenylpyruvic acid, the phenylketone for which the disease was named. There is a roughly linear relationship between the concentrations of phenylalanine in the blood and the urinary excretion of phenylpyruvic acid [44]. This is the compound that is responsible for the positive ferric chloride (FeCl3) test. A deep green color is seen on the addition of 10 percent (FeCl3) to the urine of patients with untreated PKU (see Figure 15.2). Phenylpyruvic acid is subsequently converted to phenyllactic acid, phenylacetic acid, and phenylacetylglutamine. Phenylpyruvate is also hydroxylated in the ortho position, ultimately yielding orthohydroxyphenylacetic acid. These are not abnormal metabolites, but normal ones that occur in abnormal amounts in PKU. It is current theory that it is this abnormal chemical milieu in which the patient with PKU lives that produces the severely impaired mental development and other manifestations of the disease.
Urine metabolomics and proteomics in prenatal health
Published in Moshe Hod, Vincenzo Berghella, Mary E. D'Alton, Gian Carlo Di Renzo, Eduard Gratacós, Vassilios Fanos, New Technologies and Perinatal Medicine, 2019
Daniela Duarte, Maria do Céu Almeida, Pedro Domingues, Ana M. Gil
To our knowledge, all PTB metabolomic studies have searched for urinary predictive biomarkers (Table 20.2), mostly considering small cohorts. Amino acid and choline metabolism disturbances have been suggested, with basis on increased levels of 2-HIBA, 3-methylhistidine, and choline and decreased 4-HPA levels (the latter observed in common with other prenatal conditions), as viewed by NMR (21,25). However, an MS study of a similar cohort did not find any significant metabolite changes (23). A more recent report addressed maternal urine of a larger pre-PTB cohort, split into pre-medically induced (pre-iPTB) and pre-spontaneous (pre-sPTB), during the first trimester (34). Increased levels of lysine, a steroid conjugate, 2-Py, and decreases in TMAO, glycine, and formate were suggested to help predict sPTB. In relation to iPTB, decreased levels of phenylacetylglutamine and increased levels of N-acetyl glycoproteins were found in first trimester maternal urine. The latter was suggested to be linked to inflammation preceding iPTB.
The Role of the Gut Microbiome in Cardiovascular Disease
Published in Stephen T. Sinatra, Mark C. Houston, Nutritional and Integrative Strategies in Cardiovascular Medicine, 2022
These interactions provide novel therapeutic pathways for BP regulation. The regulation of BP via SCFA receptors has provided new insights into the interactions between the gut microbiota and BP control systems. Other hypertension intervention methods via the gut microbiome worth considering include24: Angiotensin-converting enzyme inhibitory (ACEI) peptides made by the microbiome via fermentation lower BP.Lactobacilli are natural ACEI and produce biologically active peptides that inhibit ACE.Phenylacetylglutamine (PAG), a gut metabolite, is negatively associated with pulse-wave velocity (PWV) and systolic blood pressure (SBP).Probiotics with over 1011 CFU of multiple strains administered over 8 weeks decreased SBP and diastolic blood pressure (DBP).Gut-derived hormones such as gastrin, glucagon-like peptide-1 (GLP-1), and others regulate gut sodium reabsorption and renal sodium homeostasis and BP.Blockade of the gut Na+/H+ exchanger-3 (NHE3) will lower BP.Probiotics have been shown to lower BP.
New insight into gut microbiota-derived metabolites to enhance liver regeneration via network pharmacology study
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2023
Ki-Kwang Oh, Ickwon Choi, Haripriya Gupta, Ganesan Raja, Satya Priya Sharma, Sung-Min Won, Jin-Ju Jeong, Su-Been Lee, Min-Gi Cha, Goo-Hyun Kwon, Min-Kyo Jeong, Byeong-Hyun Min, Ji-Ye Hyun, Jung-A Eom, Hee-Jin Park, Sang-Jun Yoon, Mi-Ran Choi, Dong Joon Kim, Ki-Tae Suk
The MSTM network represented the relationships between microbiota, signalling pathways, targets and metabolites, consisting of 144 nodes (25 microbiota, 36 signalling pathways, 11 targets and 72 metabolites) and 499 edges (Figure 3(C)). The purple circles represent the GM, the red circles indicate the signalling pathways, the orange circles represent the targets, and the pink circles describe the metabolites. The size of each circle indicates the number of relationships between the two. The analysis was performed using R Package. We found that Escherichia coli is the uppermost microbiota with 271 degrees of value, and the AGE-RAGE signalling pathway in diabetic complications, Toll-like receptor signalling pathway, TNF signalling pathway, HIF-1 signalling pathway, and PI3K-Akt signalling pathway were identified as significant mechanisms involved in LR. We also observed that the most significant targets are MAPK1 (32) and AKT1 (31), which exhibit higher degrees of value than other targets. In parallel, phenylacetylglutamine is the most notable metabolite due to the highest degree of value for LR. The suggested 4 elements represent underlying hallmarks of LR, indicating that these factors might orchestrate favourable effects on LR.
Analysis of the urinary metabolic profiles in irradiated rats treated with Activated Protein C (APC), a potential mitigator of radiation toxicity
Published in International Journal of Radiation Biology, 2023
Shivani Bansal, Sunil Bansal, Brian L. Fish, Yaoxiang Li, Xiao Xu, Jose A. Fernandez, John H. Griffin, Heather A. Himburg, Marjan Boerma, Meetha Medhora, Amrita K. Cheema
The prominent upregulation of shikimic acid pathway indicate IR-induced intestinal injury resulting in disturbances across related physiological events (Sun et al. 2020). Following metabolism by the disrupted gut microbiota, higher urinary levels of phenylacetylglutamine are suggestive of kidney dysfunction (Barrios et al. 2015). Perturbations in the oxalate and glyoxylate metabolism could also cause hyperoxaluria, a condition with elevated urinary levels of oxalate causing the buildup of calcium oxalate in the urine, and thus the eventual formation of kidney stones, a key cause of nephrolithiasis (Holmgren et al. 1978; Bhasin et al. 2015). Kidney malfunction due to late radiation effects is known characteristic of WAG/RijCmcr rat model post 90 days of IR exposure (Moulder and Fish 1997; Moulder 2014; Fish et al. 2016).
Hyperammonemia in the setting of Roux-en-Y gastric bypass presenting with osmotic demyelination syndrome
Published in Journal of Community Hospital Internal Medicine Perspectives, 2021
Carly Rosenberg, Michael Rhodes
In regard to the treatment of hyperammonemia, lactulose, rifaximin and hemodialysis are common modalities used to lower ammonia levels, as were used in our patient. However, alternate forms of treatment are available. A recent study by Alimirah et al. [12] demonstrated the use of novel therapies for hyperammonemia in the setting of hepatic encephalopathy. These included L-ornithine phenylacetate and glycerol phenylbutyrate, both of which are ammonia-scavenging agents used to improve cognition by decreasing ammonia levels. L-ornithine acts as a substrate for glutamine synthetase, while phenylacetate acts to excrete ornithine-related glutamine as phenylacetylglutamine in the kidneys [13]. Glycerol phenylbutyrate is converted into phenylacetate that conjugates with glutamine to form phenylacetylglutamine, which provides as an alternative form of nitrogen waste excretion [5]. For patients specifically with urea cycle disorders, nitrogen scavengers such as sodium benzoate and arginine are administered for excretion of ammonia [11].