Metabolite
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BACKGROUND: We applied a training and testing approach to develop and validate a plasma metabolite panel for the detection of early-stage pancreatic ductal adenocarcinoma (PDAC) alone and in combination with a previously validated protein panel for early-stage PDAC. METHODS: A comprehensive metabolomics platform was initially applied to plasmas collected from 20 PDAC cases and 80 controls. Candidate markers were filtered based on a second independent cohort that included nine invasive intraductal papillary mucinous neoplasm cases and 51 benign pancreatic cysts. Blinded validation of the resulting metabolite panel was performed in an independent test cohort consisting of 39 resectable PDAC cases and 82 matched healthy controls. The additive value of combining the metabolite panel with a previously validated protein panel was evaluated. RESULTS: Five metabolites (acetylspermidine, diacetylspermine, an indole-derivative, and two lysophosphatidylcholines) were selected as a panel based on filtering criteria. A combination rule was developed for distinguishing between PDAC and healthy controls using the Training Set. In the blinded validation study with early-stage PDAC samples and controls, the five metabolites yielded areas under the curve (AUCs) ranging from 0.726 to 0.842, and the combined metabolite model yielded an AUC of 0.892 (95% confidence interval [CI] = 0.828 to 0.956). Performance was further statistically significantly improved by combining the metabolite panel with a previously validated protein marker panel consisting of CA 19-9, LRG1, and TIMP1 (AUC = 0.924, 95% CI = 0.864 to 0.983, comparison DeLong test one-sided P= .02). CONCLUSIONS: A metabolite panel in combination with CA19-9, TIMP1, and LRG1 exhibited substantially improved performance in the detection of early-stage PDAC compared with a protein panel alone.
- MeSH
- duktální karcinom slinivky břišní genetika metabolismus patologie MeSH
- invazivní růst nádoru MeSH
- lidé MeSH
- metabolom * MeSH
- mucinózní adenokarcinom genetika metabolismus patologie MeSH
- nádorové biomarkery krev genetika MeSH
- nádory slinivky břišní genetika metabolismus patologie MeSH
- následné studie MeSH
- papilární karcinom genetika metabolismus patologie MeSH
- staging nádorů MeSH
- studie případů a kontrol MeSH
- transkriptom * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
The adult human brain represents only 2% of the body's total weight, however it is one of the most metabolically active organs in the mammalian body. Its high metabolic activity necessitates an efficacious waste clearance system. Besides the blood, there are two fluids closely linked to the brain and spinal cord drainage system: interstitial fluid (ISF) and cerebrospinal fluid (CSF). The aim of this review is to summarize the latest research clarifying the channels of metabolite removal by fluids from brain tissue, subarachnoid space (SAS) and brain dura (BD). Special attention is focused on lymphatic vascular structures in the brain dura, their localizations within the meninges, morphological properties and topographic anatomy. The review ends with an account of the consequences of brain lymphatic drainage failure. Knowledge of the physiological state of the clearance system is crucial in order to understand the changes related to impaired brain drainage.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive loss of cognitive functions. Today the diagnosis of AD relies on clinical evaluations and is only late in the disease. Biomarkers for early detection of the underlying neuropathological changes are still lacking and the biochemical pathways leading to the disease are still not completely understood. The aim of this study was to identify the metabolic changes resulting from the disease phenotype by a thorough and systematic metabolite profiling approach. For this purpose CSF samples from 79 AD patients and 51 healthy controls were analyzed by gas and liquid chromatography-tandem mass spectrometry (GC-MS and LC-MS/MS) in conjunction with univariate and multivariate statistical analyses. In total 343 different analytes have been identified. Significant changes in the metabolite profile of AD patients compared to healthy controls have been identified. Increased cortisol levels seemed to be related to the progression of AD and have been detected in more severe forms of AD. Increased cysteine associated with decreased uridine was the best paired combination to identify light AD (MMSE>22) with specificity and sensitivity above 75%. In this group of patients, sensitivity and specificity above 80% were obtained for several combinations of three to five metabolites, including cortisol and various amino acids, in addition to cysteine and uridine.
- MeSH
- Alzheimerova nemoc diagnóza metabolismus MeSH
- cystein MeSH
- hydrokortison MeSH
- lidé MeSH
- metabolom MeSH
- plynová chromatografie s hmotnostně spektrometrickou detekcí MeSH
- progrese nemoci MeSH
- senzitivita a specificita MeSH
- studie případů a kontrol MeSH
- uridin MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
SCOPE: Intake of flavonoids from the diet can be substantial, and epidemiological studies suggest that these compounds can decrease the incidence of cardiovascular diseases by involvement with increased platelet aggregation. Although parent flavonoids possess antiplatelet effects, the clinical importance is disputable due to their very low bioavailability. Most of them are metabolized by human colon bacteria to smaller phenolic compounds, which reach higher plasma concentrations than the parent flavonoids. In this study, a series of 29 known flavonoid metabolites is tested for antiplatelet potential. METHODS AND RESULTS: Four compounds appear to have a biologically relevant antiplatelet effect using whole human blood. 4-Methylcatechol (4-MC) is clearly the most efficient being about 10× times more active than clinically used acetylsalicylic acid. This ex vivo effect is also confirmed using a potentially novel in-vivo-like ex ovo hen's egg model of thrombosis, where 4-MC significantly increases the survival of the eggs. The mechanism of action is studied and it seems that it is mainly based on the influence on intracellular calcium signaling. CONCLUSION: This study shows that some flavonoid metabolites formed by human microflora have a strong antiplatelet effect. This information can help to explain the antiplatelet potential of orally given flavonoids.
- MeSH
- agregace trombocytů účinky léků MeSH
- inhibitory agregace trombocytů farmakologie MeSH
- inhibitory cyklooxygenasy farmakologie MeSH
- inhibitory enzymů farmakologie MeSH
- katecholy farmakologie MeSH
- kuřecí embryo MeSH
- kyselina arachidonová farmakologie MeSH
- lidé MeSH
- preklinické hodnocení léčiv metody MeSH
- pyrogalol farmakologie MeSH
- serotonin metabolismus MeSH
- thromboxan-A-synthasa antagonisté a inhibitory MeSH
- trombóza farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- kuřecí embryo MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Novel antimicrobial agents are urgently needed to combat antimicrobial resistance from multidrug-resistant organisms. Actinobacteria are key sources of bioactive metabolites with diverse biological activities. Despite their contributions to drug discovery, the process from strain identification to drug manufacturing faces many challenges, especially the rediscovery of known compounds. Recent technological and scientific advancements have accelerated drug development. Efforts to isolate and screen rare actinobacterial species could yield novel bioactive compounds. This review summarizes techniques for selectively isolating rare actinobacteria, improving bioactive metabolite production, and discovering potential strains. Notably, new genomic strategies and new discoveries regarding spectroscopic signature-based bioactive natural products containing specific structural motifs are also discussed. Furthermore, this review updates the compounds derived from rare actinobacteria and their biological applications.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Regular intake of polyphenol-rich food has been associated with a wide variety of beneficial health effects, including the prevention of cardiovascular diseases. However, the parent flavonoids have mostly low bioavailability and, hence, their metabolites have been hypothesized to be bioactive. One of these metabolites, 3-hydroxyphenylacetic acid (3-HPAA), formed by the gut microbiota, was previously reported to exert vasorelaxant effects ex vivo. The aim of this study was to shed more light on this effect in vivo, and to elucidate the mechanism of action. 3-HPAA gave rise to a dose-dependent decrease in arterial blood pressure when administered i.v. both as a bolus and infusion to spontaneously hypertensive rats. In contrast, no significant changes in heart rate were observed. In ex vivo experiments, where porcine hearts from a slaughterhouse were used to decrease the need for laboratory animals, 3-HPAA relaxed precontracted porcine coronary artery segments via a mechanism partially dependent on endothelium integrity. This relaxation was significantly impaired after endothelial nitric oxide synthase inhibition. In contrast, the blockade of SKCa or IKCa channels, or muscarinic receptors, did not affect 3-HPAA relaxation. Similarly, no effects of 3-HPAA on cyclooxygenase nor L-type calcium channels were observed. Thus, 3-HPAA decreases blood pressure in vivo via vessel relaxation, and this mechanism might be based on the release of nitric oxide by the endothelial layer.
Significant attrition limits drug discovery. The available chemical entities present with drug-like features contribute to this limitation. Using specific examples of promiscuous receptor-ligand interactions, a case is made for expanding the chemical space for drug-like molecules. These ligand-receptor interactions are poor candidates for the drug discovery process. However, provided herein are specific examples of ligand-receptor or transcription-factor interactions, namely, the pregnane X receptor (PXR) and the aryl hydrocarbon receptor (AhR), and itsinteractions with microbial metabolites. Discrete examples of microbial metabolite mimicry are shown to yield more potent and non-toxic therapeutic leads for pathophysiological conditions regulated by PXR and AhR. These examples underscore the opinion that microbial metabolite mimicry of promiscuous ligand-receptor interactions is warranted, and will likely expand the existing chemical space of drugs.
- MeSH
- léčivé přípravky * MeSH
- lidé MeSH
- objevování léků MeSH
- pregnanový X receptor * MeSH
- receptory aromatických uhlovodíků * MeSH
- steroidní receptory * MeSH
- střeva MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Research Support, N.I.H., Extramural MeSH
