PubMed

Microb Cell. 2023 Nov 23;10(12):292-295. doi: 10.15698/mic2023.12.810. eCollection 2023 Dec 4.ABSTRACTExtracellular DNA (exDNA) can be actively released by living cells and different putative functions have been attributed to it. Further, homologous exDNA has been reported to exert species-specific inhibitory effects on several organisms. Here, we demonstrate by different experimental evidence, including 1H-NMR metabolomic fingerprint, that the growth rate decline in Saccharomyces cerevisiae fed-batch cultures is determined by the accumulation of exDNA in the medium. Sequencing of such secreted exDNA represents a portion of the entire genome, showing a great similarity with extrachromosomal circular DNA (eccDNA) already reported inside yeast cells. The recovered DNA molecules were mostly single strands and specifically associated to the yeast metabolism displayed during cell growth. Flow cytometric analysis showed that the observed growth inhibition by exDNA corresponded to an arrest in the S phase of the cell cycle. These unprecedented findings open a new scenario on the functional role of exDNA produced by living cells.PMID:38053574 | PMC:PMC10695634 | DOI:10.15698/mic2023.12.810

Environ Sci Technol. 2023 Dec 5;57(48):19169-19179. doi: 10.1021/acs.est.3c00812. Epub 2023 Nov 22.ABSTRACTBivalves serve as an ideal ecological indicator; hence, their use by the NOAA Mussel Watch Program to monitor environmental health. This study aimed to expand the baseline knowledge of using metabolic end points in environmental monitoring by investigating the dreissenid mussel metabolome in the field. Dreissenids were caged at four locations along the Maumee River for 30 days. The mussel metabolome was measured using nuclear magnetic resonance spectroscopy, and mussel tissue chemical contaminants were analyzed using gas or liquid chromatography coupled with mass spectrometry. All Maumee River sites had a distinct mussel metabolome compared to the reference site and revealed changes in the energy metabolism and amino acids. Data also highlighted the importance of considering seasonality or handling effects on the metabolome at the time of sampling. The furthest upstream site presented a specific mussel tissue chemical signature of pesticides (atrazine and metolachlor), while a downstream site, located at Toledo's wastewater treatment plant, was characterized by polycyclic aromatic hydrocarbons and other organic contaminants. Further research into the dreissenid mussel's natural metabolic cycle and metabolic response to specific anthropogenic stressors is necessary before successful implementation of metabolomics in a biomonitoring program.PMID:38053340 | DOI:10.1021/acs.est.3c00812

Cancer Metab. 2023 Dec 5;11(1):23. doi: 10.1186/s40170-023-00324-0.ABSTRACTBACKGROUND: Bladder cancer (BLCA) research in Koreans is still lacking, especially in focusing on the prediction of BLCA. The current study aimed to discover metabolic signatures related to BLCA onset and confirm its potential as a biomarker.METHODS: We designed two nested case-control studies using Korean Cancer Prevention Study (KCPS)-II. Only males aged 35-69 were randomly selected and divided into two sets by recruitment organizations [set 1, BLCA (n = 35) vs. control (n = 35); set 2, BLCA (n = 31) vs. control (n = 31)]. Baseline serum samples were analyzed by non-targeted metabolomics profiling, and OPLS-DA and network analysis were performed. Calculated genetic risk score (GRS) for BLCA from all KCPS participants was utilized for interpreting metabolomics data.RESULTS: Critical metabolic signatures shown in the BLCA group were dysregulation of lysine metabolism and tryptophan-indole metabolism. Furthermore, the prediction model consisting of metabolites (lysine, tryptophan, indole, indoleacrylic acid, and indoleacetaldehyde) reflecting these metabolic signatures showed mighty BLCA predictive power (AUC: 0.959 [0.929-0.989]). The results of metabolic differences between GRS-high and GRS-low groups in BLCA indicated that the pathogenesis of BLCA is associated with a genetic predisposition. Besides, the predictive ability for BLCA on the model using GRS and five significant metabolites was powerful (AUC: 0.990 [0.980-1.000]).CONCLUSION: Metabolic signatures shown in the present research may be closely associated with BLCA pathogenesis. Metabolites involved in these could be predictive biomarkers for BLCA. It could be utilized for early diagnosis, prognostic diagnosis, and therapeutic targets for BLCA.PMID:38053135 | DOI:10.1186/s40170-023-00324-0

Nat Commun. 2023 Dec 5;14(1):8039. doi: 10.1038/s41467-023-43606-3.ABSTRACTMonoacylglycerol lipase (MAGL) regulates endocannabinoid 2-arachidonoylglycerol (2-AG) and eicosanoid signalling. MAGL inhibition provides therapeutic opportunities but clinical potential is limited by central nervous system (CNS)-mediated side effects. Here, we report the discovery of LEI-515, a peripherally restricted, reversible MAGL inhibitor, using high throughput screening and a medicinal chemistry programme. LEI-515 increased 2-AG levels in peripheral organs, but not mouse brain. LEI-515 attenuated liver necrosis, oxidative stress and inflammation in a CCl4-induced acute liver injury model. LEI-515 suppressed chemotherapy-induced neuropathic nociception in mice without inducing cardinal signs of CB1 activation. Antinociceptive efficacy of LEI-515 was blocked by CB2, but not CB1, antagonists. The CB1 antagonist rimonabant precipitated signs of physical dependence in mice treated chronically with a global MAGL inhibitor (JZL184), and an orthosteric cannabinoid agonist (WIN55,212-2), but not with LEI-515. Our data support targeting peripheral MAGL as a promising therapeutic strategy for developing safe and effective anti-inflammatory and analgesic agents.PMID:38052772 | DOI:10.1038/s41467-023-43606-3

Food Chem Toxicol. 2023 Dec 3:114305. doi: 10.1016/j.fct.2023.114305. Online ahead of print.ABSTRACTTriclosan (TCS) is an antimicrobial compound incorporated into more than 2000 consumer products. This compound is frequently detected in the human body and causes ubiquitous contamination in the environment, thereby raising concerns about its impact on human health and environmental pollution. Here, we demonstrated that 20 weeks' exposure of TCS drove the development of glucose intolerance by inducing compositional and functional alterations in intestinal microbiota in rats. Fecal-transplantation experiments corroborated the involvement of gut microbiota in TCS-induced glucose-tolerance impairment. 16S rRNA gene-sequencing analysis of cecal contents showed that TCS disrupted the gut microbiota composition in rats and increased the ratio of Firmicutes to Bacteroidetes. Cecal metabolomic analyses detected that TCS altered host metabolic pathways that are linked to host glucose and amino acid metabolism, particularly branched-chain amino acid (BCAA) biosynthesis. BCAA measurement confirmed the increase in serum BCAAs in rats exposed to TCS. Western blot and immunostaining results further confirmed that elevated BCAAs stimulated mTOR, a nutrient-sensing complex, and following IRS-1 serine phosphorylation, resulted in insulin resistance and glucose intolerance. These results suggested that TCS may induce glucose metabolism imbalance by regulating BCAA concentration by remodeling the gut microbiota.PMID:38052405 | DOI:10.1016/j.fct.2023.114305

Transl Res. 2023 Dec 3:S1931-5244(23)00202-5. doi: 10.1016/j.trsl.2023.12.001. Online ahead of print.ABSTRACTTransplant centers are currently facing a lack of tools to ensure adequate evaluation of the quality of the available organs, as well as a significant shortage of kidney donors. Therefore, efforts are being made to facilitate the effective use of available organs and expand the donor pool, particularly with expanded criteria donors. Fulfilling a need, we aim to present an innovative analytical method based on solid-phase microextraction (SPME) - chemical biopsy. In order to track changes affecting the organ throughout the entire transplant procedure, porcine kidneys were subjected to multiple samplings at various time points. The application of small-diameter SPME probes assured the minimal invasiveness of the procedure. Porcine model kidney autotransplantation was executed for the purpose of simulating two types of donor scenarios: donors with a beating heart (HBD) and donors after cardiac death (DCD). All renal grafts were exposed to continuous normothermic ex vivo perfusion. Following metabolomic and lipidomic profiling using high-performance liquid chromatography coupled to a mass spectrometer, we observed differences in the profiles of HBD and DCD kidneys. The alterations were predominantly related to energy and glucose metabolism, and differences in the levels of essential amino acids, purine nucleosides, lysophosphocholines, phosphoethanolamines, and triacylglycerols were noticed. Our results indicate the potential of implementing chemical biopsy in the evaluation of graft quality and monitoring of renal function during perfusion.PMID:38052298 | DOI:10.1016/j.trsl.2023.12.001

Genomics. 2023 Dec 3:110751. doi: 10.1016/j.ygeno.2023.110751. Online ahead of print.ABSTRACTAgeing is an evolutionarily conserved and irreversible biological process in different species. Numerous studies have reported that taking medicine is an effective approach to slow ageing. Lemon extract (LE) is a natural extract of lemon fruit that contains a variety of bioactive phytochemicals. Various forms of LE have been shown to play a role in anti-ageing and improving ageing-related diseases. However, studies on the molecular mechanism of LE in Drosophila ageing have not been reported. In this study, we found that 0.05 g/L LE could significantly extend Drosophila lifespan and greatly improve antioxidative and anti-heat stress abilities. Furthermore, transcriptome and metabolome analyses of 10 d flies between the LE-fed and control groups suggested that the differentially expressed gene ppo1 (Prophenoloxidase 1) and metabolite L-DOPA (Levodopa) were co-enriched in the tyrosine metabolism pathway. Overall, our results indicate that affecting metabolism was the main reason for LE extending Drosophila lifespan.PMID:38052259 | DOI:10.1016/j.ygeno.2023.110751

Nature. 2023 Dec 5. doi: 10.1038/s41586-023-06906-8. Online ahead of print.ABSTRACTDetermining structure and phenotypic context of molecules detected in untargeted metabolomics experiments remains challenging. Here, we present reverse metabolomics as a discovery strategy, where MS/MS spectra are acquired from newly synthesized compounds and searched for in public metabolomics data to uncover phenotypic associations. To demonstrate the concept, we broadly synthesized and explored multiple classes of metabolites in humans - N-acyl amides, fatty acid esters of hydroxy fatty acids, bile acid esters and conjugated bile acids. Using repository scale analysis,15,16 we discovered that some conjugated bile acids were associated with inflammatory bowel disease (IBD). Using four distinct human IBD cohorts for validation, we found that Glu, Ile/Leu, Phe, Thr, Trp and Tyr conjugated cholic acids were elevated in Crohn's disease. Several of these compounds and related structures were shown to affect pathways associated with inflammatory bowel disease, such as interferon-gamma production in CD4+ T cells40 and PXR agonism.41 Bacteria belonging to the Bifidobacterium, Clostridium, and Enterococcus genera were able to produce these bile amidates when cultured. Because searching repositories with MS/MS spectra has only recently become possible, reverse metabolomics approach can now be employed as a general strategy to discover other molecules from human and animal ecosystems.PMID:38052229 | DOI:10.1038/s41586-023-06906-8

Cell Host Microbe. 2023 Nov 21:S1931-3128(23)00454-7. doi: 10.1016/j.chom.2023.11.004. Online ahead of print.ABSTRACTGut microbiota has been linked to infant neurodevelopment. Here, an association between infant composite cognition and gut microbiota composition is established as soon as 6 months. Higher diversity and evenness characterize microbial communities of infants with composite cognition above (Inf-aboveCC) versus below (Inf-belowCC) median values. Metaproteomic and metabolomic analyses establish an association between microbial histidine ammonia lyase and infant histidine metabolome with cognition. Fecal transplantation from Inf-aboveCC versus Inf-belowCC donors into germ-free mice shows that memory, assessed by a novel object recognition test, is a transmissible trait. Furthermore, Inf-aboveCC mice are enriched in species belonging to Phocaeicola, as well as Bacteroides and Bifidobacterium, previously linked to cognition. Finally, Inf-aboveCC mice show lower fecal histidine and urocanate:histidine and urocanate:glutamate ratios in the perirhinal cortex compared to Inf-belowCC mice. Overall, these findings reveal a causative role of gut microbiota on infant cognition, pointing at the modulation of histidine metabolite levels as a potential underlying mechanism.PMID:38052208 | DOI:10.1016/j.chom.2023.11.004

ACS Appl Mater Interfaces. 2023 Dec 5. doi: 10.1021/acsami.3c17097. Online ahead of print.ABSTRACTMicroglial cells play a critical role in glioblastoma multiforme (GBM) progression, which is considered a highly malignant brain cancer. The activation of microglia can either promote or inhibit GBM growth depending on the stage of the tumor development and on the microenvironment conditions. The current treatments for GBM have limited efficacy; therefore, there is an urgent need to develop novel and efficient strategies for drug delivery and targeting: in this context, a promising strategy consists of using nanoplatforms. This study investigates the microglial response and the therapeutic efficacy of dual-cell membrane-coated and doxorubicin-loaded hexagonal boron nitride nanoflakes tested on human microglia and GBM cells. Obtained results show promising therapeutic effects on glioma cells and an M2 microglia polarization, which refers to a specific phenotype or activation state that is associated with anti-inflammatory and tissue repair functions, highlighted through proteomic analysis.PMID:38051559 | DOI:10.1021/acsami.3c17097

Vet Res Commun. 2023 Dec 5. doi: 10.1007/s11259-023-10271-2. Online ahead of print.ABSTRACTBovine laminitis disorder results in animal welfare and economic concerns in dairy and beef farms worldwide. However, the affected metabolic pathways, pathophysiologic characteristics, and inflammatory mechanisms remain unclear, hampering the development of new diagnostics. Using cerumen (earwax) as a source of volatile metabolites (cerumenomic) that carry valuable biological information has interesting implications for veterinary medicine. Nonetheless, up to now, no applications of veterinary cerumenomic assays have been made to identify bovine laminitis. This work aims to develop a veterinary cerumenomic assay for bovine laminitis identification that is non-invasive, robust, accurate, and sensitive to detecting the metabolic disturbances in bovine volatile metabolome. Twenty earwax samples (10 from healthy/control calves and 10 from laminitis calves) were collected from Nellore cattle, followed by Headspace/Gas Chromatography-Mass Spectrometry (HS/GC-MS) analysis and biomarker selection in two multivariate approaches: semiquantitative (intensity data) and semiqualitative (binary data). Following the analysis, cerumen volatile metabolites were indicated as candidate biomarkers for identifying bovine laminitis by monitoring their intensity or occurrence. In the semiquantitative strategy, the p-cresol presented the highest diagnostic figures of merit (area under the curve: 0.845, sensitivity: 0.700, and specificity: 0.900). Regarding the binary approach, a panel combining eight variables/volatiles, with formamide being the most prominent one, showed an area under the curve, sensitivity, and specificity of 0.97, 0.81, and 0.90, respectively. In summary, this work describes the first veterinary cerumenomic assay for bovine laminitis that indicates new metabolites altered during the inflammatory condition, paving the way for developing laminitis early diagnosis by monitoring the cerumen metabolites.PMID:38051450 | DOI:10.1007/s11259-023-10271-2

Funct Plant Biol. 2023 Dec;50(12):1130. doi: 10.1071/FP23023_CO.ABSTRACTSoil salinisation is a growing threat to global agriculture, reducing crop yields. Brassicaceae crops are vital vegetables and cash crops. Salt stress significantly affects the growth and development of Brassicaceae crops. A better understanding of the molecular and physiological mechanisms of salt tolerance is of theoretical and practical importance to improve Brassicaceae crop's salt tolerance and crop quality. Combined with previous research results, we discuss recent advances in research on salt stress response and salt tolerance in Brassicaceae crops. We summarised recent research progress on the physiological and molecular mechanisms of ionic homeostasis, antioxidant regulation, hormonal regulation and accumulation of osmotic-adjustment substances. We also discussed the molecular mechanism of Brassicaceae crop salt tolerant varieties from the perspective of differentially expressed genes, differentially expressed proteins and metabolites through transcriptome, proteome and metabonomic analysis methods. This paper summarises the molecular mechanisms in the perspective of differentially expressed genes, differentially expressed proteins, and metabolites through transcriptomic, proteome and metabolomics analysis. The review provides abundant data for accelerating the breeding of salt-tolerant Brassicaceae and laid a foundation for understanding the mechanism of salt tolerance of Brassicaceae crops and breeding salt-tolerance varieties.PMID:38051337 | DOI:10.1071/FP23023_CO

Antimicrob Agents Chemother. 2023 Dec 5:e0085023. doi: 10.1128/aac.00850-23. Online ahead of print.ABSTRACTBacteria possess the ability to enter a growth-arrested state known as persistence in order to survive antibiotic exposure. Clinically, persisters are regarded as the main causative agents for chronic and recurrent infectious diseases. To combat this antibiotic-tolerant population, a better understanding of the molecular physiology of persisters is required. In this study, we collected samples at different stages of the biphasic kill curve to reveal the dynamics of the cellular molecular changes that occur in the process of persister formation. After exposure to antibiotics with different modes of action, namely, vancomycin and enrofloxacin, similar persister levels were obtained. Both shared and distinct stress responses were enriched for the respective persister populations. However, the dynamics of the presence of proteins linked to the persister phenotype throughout the biphasic kill curve and the molecular profiles in a stable persistent population did show large differences, depending on the antibiotic used. This suggests that persisters at the molecular level are highly stress specific, emphasizing the importance of characterizing persisters generated under different stress conditions. Additionally, although generated persisters exhibited cross-tolerance toward tested antibiotics, combined therapies were demonstrated to be a promising approach to reduce persister levels. In conclusion, this investigation sheds light on the stress-specific nature of persisters, highlighting the necessity of tailored treatment approaches and the potential of combined therapy.PMID:38051079 | DOI:10.1128/aac.00850-23

Microbiol Spectr. 2023 Dec 5:e0363522. doi: 10.1128/spectrum.03635-22. Online ahead of print.ABSTRACTInfluenza virus infection affects both lung and intestinal bacterial community composition. Most of the published analyses focus on the characterization of the microbiota composition changes. Here we assess functional alterations of gut microbiota such as nutrient and antibiotic resistance changes during an acute respiratory tract infection. Upon influenza A virus (IAV) infection, cecal microbiota drops accompanied by a decrease in the ability to metabolize some common nutrients under aerobic conditions. At the same time, the cecal community presents an increase in resistance against clinically relevant antibiotics, particularly cephalosporins. Functional characterization of complex communities presents an additional and necessary element of analysis that nowadays is mainly limited to taxonomic description. The consequences of these functional alterations could affect treatment strategies, especially in multimicrobial infections.PMID:38051056 | DOI:10.1128/spectrum.03635-22

Microbiol Spectr. 2023 Dec 5:e0351123. doi: 10.1128/spectrum.03511-23. Online ahead of print.ABSTRACTMicrobes produce a large array of extracellular molecules, which serve as signals and cues to promote polymicrobial interactions and alter the function of microbial communities. This has been particularly well studied in the human oral microbiome, where key metabolites have been shown to impact both health and disease. Here, we used an untargeted mass spectrometry approach to comprehensively assess the extracellular metabolome of the pathogen Aggregatibacter actinomycetemcomitans and the commensal Streptococcus gordonii during mono- and co-culture. We generated and made publicly available a metabolomic data set that includes hundreds of potential metabolites and leveraged this data set to identify an operon important for glutathione secretion in A. actinomycetemcomitans.PMID:38051055 | DOI:10.1128/spectrum.03511-23

J Integr Plant Biol. 2023 Dec 5. doi: 10.1111/jipb.13592. Online ahead of print.ABSTRACTDendrocalamus brandisii (Munro) Kurz is a sympodial bamboo species with inimitable taste and flavorful shoots. Its rapid growth and use as high-quality materials make this bamboo species highly valued for both food processing and wood applications. However, genome information for D. brandisii is lacking, primarily due to its polyploidy and large genome size. Here, we assembled a high-quality genome for hexaploid D. brandisii, which comprises 70 chromosomes with a total size of 2,756 Mb, using long-read HiFi sequencing. Furthermore, we accurately separated the genome into its three constituent subgenomes. We used Oxford Nanopore Technologies (ONT) long reads to construct a transcriptomic dataset covering 15 tissues for gene annotation to complement our genome assembly, revealing differential gene expression and post-transcriptional regulation. By integrating metabolome analysis, we unveiled that well-balanced lignin formation, as well as abundant flavonoid and fructose contents, contribute to the superior quality of D. brandisii shoots. Integrating genomic, transcriptomic, and metabolomic datasets provided a solid foundation for enhancing bamboo shoot quality and developing efficient gene-editing techniques. This study should facilitate research on D. brandisii and enhance its use as food source and wood material by providing crucial genomic resources. This article is protected by copyright. All rights reserved.PMID:38051011 | DOI:10.1111/jipb.13592

Clin Neuropathol. 2023 Dec 5. doi: 10.5414/NP301590. Online ahead of print.ABSTRACTThe Brain Tumor Epidemiology Consortium (BTEC) is an international organization with membership of individuals from the scientific community with interests related to brain tumor epidemiology including surveillance, classification, methodology, etiology, and factors associated with morbidity and mortality. The 2023 annual BTEC meeting entitled "Impact of Environment on Pediatric and Adult Brain Tumors" was held in Lexington, KY, USA on May 22 - 24, 2023. The meeting gathered scientists from the United States, Canada, Australia, and Europe and included four keynote sessions covering genomic, epigenomic, and metabolomic considerations in brain tumor epidemiology, cancer clusters, environmental risk factors, and new approaches to cancer investigation. The meeting also included three abstract sessions and a brainstorming session. A summary of the meeting content is included in this report.PMID:38050756 | DOI:10.5414/NP301590

Plant Biotechnol J. 2023 Dec 4. doi: 10.1111/pbi.14203. Online ahead of print.ABSTRACTThe nutritional value of wheat grains, particularly their protein and metabolite composition, is a result of the grain-filling process, especially in the endosperm. Here, we employ laser microdissection (LMD) combined with shotgun proteomics and metabolomics to generate a cell type-specific proteome and metabolome inventory of developing wheat endosperm at the early (15 DAA) and late (26 DAA) grain-filling stages. We identified 1803 proteins and 41 metabolites from four different cell types (aleurone (AL), sub-aleurone (SA), starchy endosperm (SE) and endosperm transfer cells (ETCs). Differentially expressed proteins were detected, 67 in the AL, 31 in the SA, 27 in the SE and 50 in the ETCs between these two-time points. Cell-type accumulation of specific SUT and GLUT transporters, sucrose converting and starch biosynthesis enzymes correlate well with the respective sugar metabolites, suggesting sugar upload and starch accumulation via nucellar projection and ETC at 15 DAA in contrast to the later stage at 26 DAA. Changes in various protein levels between AL, SA and ETC support this metabolic switch from 15 to 26 DAA. The distinct spatial and temporal abundances of proteins and metabolites revealed a contrasting activity of nitrogen assimilation pathways, e.g. for GOGAT, GDH and glutamic acid, in the different cell types from 15 to 26 DAA, which can be correlated with specific protein accumulation in the endosperm. The integration of cell-type specific proteome and metabolome data revealed a complex metabolic interplay of the different cell types and a functional switch during grain development and grain-filling processes.PMID:38050335 | DOI:10.1111/pbi.14203

J Nucl Med. 2023 Nov 30:jnumed.123.266158. doi: 10.2967/jnumed.123.266158. Online ahead of print.ABSTRACTFunctional imaging with prostate-specific membrane antigen (PSMA) ligands has emerged as the standard imaging method for prostate cancer (PCA). In parallel, the analysis of blood-derived, cell-free DNA (cfDNA) has been shown to be a promising quantitative biomarker of PCA aggressiveness and patient outcome. This study aimed to evaluate the relationship and prognostic value of cfDNA concentrations and the PSMA-positive tumor volume (PSMA-TV) in men with PCA undergoing [68Ga]Ga-PSMA-11 PET/CT imaging. Methods: We recruited 148 men with histologically proven PCA (mean age, 70.7 ± 7.7 y) who underwent [68Ga]Ga-PSMA-11 PET/CT (184.9 ± 18.9 MBq) and blood sampling between March 2019 and August 2021. Among these, 74 (50.0%) had hormone-sensitive PCA and 74 (50.0%) had castration-resistant PCA (CRPC). All patients provided written informed consent before blood sample collection and imaging. The cfDNA was extracted and quantified, and PSMA-expressing tumor lesions were delineated to extract the PSMA-TVs. The Spearman coefficient assessed correlations between PSMA-TV and cfDNA concentrations and cfDNA's relation with clinical parameters. The Kruskal-Wallis test examined the mean cfDNA concentration differences based on PSMA-TV quartiles for significantly correlated patient groups. Log-rank and multivariate Cox regression analyses evaluated the prognostic significance of high and low cfDNA and PSMA-TV levels for overall survival. Results: Weak positive correlations were found between cfDNA concentration and PSMA-TV in the overall group (r = 0.16, P = 0.049) and the CRPC group (r = 0.31, P = 0.007) but not in hormone-sensitive PCA patients (r = -0.024, P = 0.837). In the CRPC cohort, cfDNA concentrations significantly differed between PSMA-TV quartiles 4 and 1 (P = 0.002) and between quartiles 4 and 2 (P = 0.016). Survival outcomes were associated with PSMA-TV (P < 0.0001, P = 0.004) but not cfDNA (P = 0.174, P = 0.12), as per the log-rank and Cox regression analysis. Conclusion: These findings suggest that cfDNA might serve as a biomarker of advanced, aggressive CRPC but does not reliably reflect total tumor burden or prognosis. In comparison, [68Ga]Ga-PSMA-11 PET/CT provides a highly granular and prognostic assessment of tumor burden across the spectrum of PCA disease progression.PMID:38050125 | DOI:10.2967/jnumed.123.266158

Drug Metab Dispos. 2023 Dec 1:DMD-AR-2023-001470. doi: 10.1124/dmd.123.001470. Online ahead of print.ABSTRACTTubular secretion is a primary mechanism along with glomerular filtration for renal elimination of drugs and toxicants into urine. Organic cation transporters (OCTs) and multidrug and toxic extrusion (MATE) transporters facilitate the active secretion of cationic substrates including drugs such as metformin and endogenous cations. We hypothesized that administration of cimetidine, an Oct/Mate inhibitor, will result in increased plasma levels and decreased renal clearance of metformin and endogenous Oct/Mate substrates in rats. A paired rat pharmacokinetic study was carried out, where metformin (5 mg/kg, intravenous) was administered as an exogenous substrate of Oct/Mate transporters to six Sprague-Dawley rats with and without cimetidine (100 mg/kg, intraperitoneal). When co-administered with cimetidine, metformin area under the curve increased significantly by 3.2-fold, and its renal clearance reduced significantly by 73%. Untargeted metabolomics was performed to investigate the effect of cimetidine on endogenous metabolome in the blood and urine samples. Over 8,000 features (metabolites) were detected in the blood, which were shortlisted using optimized criteria, i.e., a significant increase (p-value <0.05) in metabolite peak intensity in the cimetidine-treated group, reproducible retention time, and quality of chromatogram peak. The metabolite hits were classified into three groups that can potentially distinguish inhibition of i) extra-renal uptake transport or catabolism, ii) renal Octs, and iii) renal efflux transporters or metabolite formation. The metabolomics approach identified novel putative endogenous substrates of cationic transporters that could be tested as potential biomarkers to predict Oct/Mate transporter mediated drug-drug interactions in the preclinical stages. Significance Statement Endogenous substrates of renal transporters in animal models could be used as potential biomarkers to predict renal drug-drug interactions in early drug development. Here we demonstrated that cimetidine, an inhibitor of organic cation transporters (Oct/Mate), could alter the pharmacokinetics of an exogenous substrate (i.e., metformin) and endogenous cationic substrates in rats. Several putative endogenous metabolites of Oct/Mate transporters were identified using metabolomics approach, which could be tested as potential transporter biomarkers to predict renal drug-drug interaction of Oct/Mate substrates.PMID:38049999 | DOI:10.1124/dmd.123.001470