PubMed

Cell Chem Biol. 2023 Dec 21:S2451-9456(23)00432-4. doi: 10.1016/j.chembiol.2023.12.002. Online ahead of print.ABSTRACTMycobacterial bioenergetics is a validated target space for antitubercular drug development. Here, we identify BB2-50F, a 6-substituted 5-(N,N-hexamethylene)amiloride derivative as a potent, multi-targeting bioenergetic inhibitor of Mycobacterium tuberculosis. We show that BB2-50F rapidly sterilizes both replicating and non-replicating cultures of M. tuberculosis and synergizes with several tuberculosis drugs. Target identification experiments, supported by docking studies, showed that BB2-50F targets the membrane-embedded c-ring of the F1Fo-ATP synthase and the catalytic subunit (substrate-binding site) of succinate dehydrogenase. Biochemical assays and metabolomic profiling showed that BB2-50F inhibits succinate oxidation, decreases the activity of the tricarboxylic acid (TCA) cycle, and results in succinate secretion from M. tuberculosis. Moreover, we show that the lethality of BB2-50F under aerobic conditions involves the accumulation of reactive oxygen species. Overall, this study identifies BB2-50F as an effective inhibitor of M. tuberculosis and highlights that targeting multiple components of the mycobacterial respiratory chain can produce fast-acting antimicrobials.PMID:38151019 | DOI:10.1016/j.chembiol.2023.12.002

Biochem Biophys Res Commun. 2023 Dec 19;694:149383. doi: 10.1016/j.bbrc.2023.149383. Online ahead of print.ABSTRACTMetformin is currently a strong candidate antitumor agent for multiple cancers, and has the potential to inhibit cancer cell viability, growth, and proliferation. Metabolic reprogramming is a critical feature of cancer cells. However, the effects of metformin which targets glucose metabolism on HepG2 cancer cells remain unclear. In this study, to explore the effects of metformin on glucose metabolism in HepG2 cells, we conducted real-time metabolomic monitoring of live HepG2 cells treated with metformin using 13C in-cell NMR spectroscopy. Metabolic tracing with U-13C6-glucose revealed that metformin significantly increased the production of 13C-G3P and 13C-glycerol, which were reported to attenuate liver cancer development, but decreased the production of potential oncogenesis-supportive metabolites, including 13C-lactate, 13C-alanine, 13C-glycine, and 13C-glutamate. Moreover, the expression levels of enzymes associated with the measured metabolites were carried out. The results showed that the levels of ALT1, MCT4, GPD2 and MPC1 were greatly reduced, which were consistent with the changes of measured metabolites in 13C in-cell NMR spectroscopy. Overall, our approach directly provides fundamental insights into the effects of metformin on glucose metabolism in live HepG2 cells, and highlights the potential mechanism of metformin, including the increase in production of G3P and glycerol derived from glucose, as well as the inhibition of glucose incorporation into lactate, alanine, glutamate, and glycine.PMID:38150918 | DOI:10.1016/j.bbrc.2023.149383

Food Chem. 2023 Dec 22;440:138266. doi: 10.1016/j.foodchem.2023.138266. Online ahead of print.ABSTRACTIon exchange chromatography and SDS-PAGE followed by identification by MALDI-TOF/TOF, and two-dimensional gas chromatography with time-of-flight mass spectrometry (GC × GC-TOF-MS) were used for comprehensive proteomics and volatilomics evaluation of the effects of pre-fermentative oxygenation, skin contact and use of pectolytic enzymes in production of Malvazija istarska white wine, respectively. Many protein species and an unprecedented number of volatiles have been identified and (semi)quantified, revealing high complexity of the observed effects. Compared to a standard control wine, oxygenation treatment modulated the protein composition and resulted with a volatilome characterized by decreased levels of several important volatiles. Skin contact treatments, especially in combination with pectolytic enzymes, significantly increased the levels of a large number of proteins, but were also deprived of particular protein species found in other wines. Wines obtained by skin contact with exogenous enzymes exhibited the most complex volatile composition with increased levels of many key monoterpenoids, alcohols and esters.PMID:38150900 | DOI:10.1016/j.foodchem.2023.138266

Plant Physiol Biochem. 2023 Dec 22;206:108290. doi: 10.1016/j.plaphy.2023.108290. Online ahead of print.ABSTRACTIn the rhizosphere, the activities within all processes and functions are primarily influenced by plant roots, microorganisms present in the rhizosphere, and the interactions between roots and microorganisms. The rhizosphere, a dynamic zone surrounding the roots, provides an ideal environment for a diverse microbial community, which significantly shapes plant growth and development. Microbial activity in the rhizosphere can promote plant growth by increasing nutrient availability, influencing plant hormonal signaling, and repelling or outcompeting pathogenic microbial strains. Understanding the associations between plant roots and soil microorganisms has the potential to revolutionize crop yields, improve productivity, minimize reliance on chemical fertilizers, and promote sustainable plant growth technologies. The rhizosphere microbiome could play a vital role in the next green revolution and contribute to sustainable and eco-friendly agriculture. However, there are still knowledge gaps concerning plant root-environment interactions, particularly regarding roots and microorganisms. Advances in metabolomics have helped to understand the chemical communication between plants and soil biota, yet challenges persist. This article provides an overview of the latest advancements in comprehending the communication and interplay between plant roots and microbes, which have been shown to impact crucial factors such as plant growth, gene expression, nutrient absorption, pest and disease resistance, and the alleviation of abiotic stress. By improving these aspects, sustainable agriculture practices can be implemented to increase the overall productivity of plant ecosystems.PMID:38150841 | DOI:10.1016/j.plaphy.2023.108290

Poult Sci. 2023 Dec 13;103(2):103371. doi: 10.1016/j.psj.2023.103371. Online ahead of print.ABSTRACTPhillygenin (PHI) and Baicalin (Bai) are the major chemical ingredients extracted from Forsythia suspensa and Scutellaria baicalensis, respectively. The mixture of Forsythia suspensa and Scutellaria baicalensis according to the theories of Traditional Chinese Veterinary Medicine, compounded formulation can effectively exert heat-clearing and detoxifying effect, but the synergistic anti-IBV activity of PHI combined with Bai was unclear. Here, the protection of PHI combined with Bai on avian infectious bronchitis virus (IBV) M41 infection and the change of respiratory microbiota and metabolomics profiles in broilers that infected with IBV were investigated. According to the experimental findings, the combination of PHI and Bai effectively alleviated broilers' slowing-growth weight and respiratory symptoms. This was accompanied by a reduction in viral copies and histopathological changes, as well as an increase of antiviral protein (G3BP1) level in tracheas and anti-IBV antibody levels in serum. In addition, 16s RNA sequencing revealed that IBV infection significantly changed respiratory microbiota composition at different taxonomic levels and respiratory metabolism composition in broilers. Interestingly, PHI combined with Bai modulated the composition of respiratory microfloras, especially the abundance of Firmicutes and Lactobacillaceae were upregulated, as well as the abundance of Proteobacteria was downregulated. The metabolomics results indicated that PHI combined with Bai involved in glucose, lipids, amino acids and nucleotide metabolism during IBV infection. In summary, PHI combined with Bai exhibited a synergistic effect on preventing infectious bronchitis (IB), with the protection being closely associated with the composition of respiratory microbiota and metabolites. Therefore, adding the mixture of PHI and Bai to the chicken drinking water is recommended to prevent and control IB in clinical.PMID:38150830 | DOI:10.1016/j.psj.2023.103371

Biosens Bioelectron. 2023 Dec 22;248:115968. doi: 10.1016/j.bios.2023.115968. Online ahead of print.ABSTRACTScreening for high-risk human papillomavirus (HPV) infection is one of the most important preventative measures for cervical cancer. However, fast, convenient, and low-cost HPV detection remains challenging, especially in resource-limited settings. Here, we report a portable all-in-one device (PAD) for point-of-care testing (POCT) for HPV16 and HPV18 DNA in cervical swabs. The PAD was engineered to integrate modules for extraction-free sample lysis, loop-mediated isothermal amplification (LAMP) with lyophilized reagent beads, and real-time colorimetric signal sensing into a single miniaturized device, considerably shortening the sample-to-result time to 15 min. The precision liquid handling in the completely sealed microfluidic chip is achieved by a uniquely designed pressure-balanced automatic liquid flow mechanism, thereby eliminating the need for manual manipulation of liquids and thus the risk of biohazards. The PAD employs an improved real-time colorimetric LAMP (rcLAMP) assay with a limit of detection (LOD) of 1 copy/μL, enabled by enhanced assay chemistry to maximize the reaction kinetics. To validate this device for clinical application, we tested 206 clinical cervical swab samples and obtained a sensitivity of 92.1% and a specificity of 99.0%. This custom PAD enabled by microfluidic and electronic engineering techniques can be configured for the simultaneous detection of HPV16 and HPV18 or other pathogens in point-of-care applications.PMID:38150799 | DOI:10.1016/j.bios.2023.115968

Mar Environ Res. 2023 Dec 18;194:106303. doi: 10.1016/j.marenvres.2023.106303. Online ahead of print.ABSTRACTThe tropical ascidian Eudistoma vannamei, endemic to the northeastern coast of Brazil, is considered a prolific source of secondary metabolites and hosts Actinomycetota that produce bioactive compounds. Herein, we used an omics approach to study the ascidian as a holobiont, including the microbial diversity through 16S rRNA gene sequencing and metabolite production using mass spectrometry-based metabolomics. Gene sequencing analysis revealed all samples of E. vannamei shared about 50% of the observed ASVs, and Pseudomonadota (50.7%), Planctomycetota (9.58%), Actinomycetota (10.34%), Bacteroidota (12.05%) were the most abundant bacterial phyla. Analysis of tandem mass spectrometry (MS/MS) data allowed annotation of compounds, including phospholipids, amino acids, and pyrimidine alkaloids, such as staurosporine, a member of a well-known chemical class recognized as a microbial metabolite. Isolated bacteria, mainly belonging to Streptomyces and Micromonospora genera, were cultivated and extracted with ethyl acetate. MS/MS analysis of bacterial extracts allowed annotation of compounds not detected in the ascidian tissue, including marineosin and dihydroergotamine, yielding about 30% overlapped ions between host and isolated bacteria. This study reveals E. vannamei as a rich source of microbial and chemical diversity and, furthermore, highlights the importance of omic tools for a comprehensive investigation of holobiont systems.PMID:38150785 | DOI:10.1016/j.marenvres.2023.106303

J Hazard Mater. 2023 Dec 15;465:133267. doi: 10.1016/j.jhazmat.2023.133267. Online ahead of print.ABSTRACTLead (Pb) is present in aquatic environments with a continuous or pulse form due to the regular or irregular discharge of wastewater. These two modes of exposure result in different toxicological effects on aquatic animals. To compare the effects of Pb exposure mode on the swimming behavior of amphibian larvae, this study proposed a combination method to examine the brain-gut axis (gut bacteria, histopathology, metabolomics, and ethology) in order to evaluate the ecotoxic differences in Pelophylax nigromaculatus tadpoles (Gs 21-28) when exposed to continuous (CE100) versus pulse exposure (PE100) of environmental concentrations of Pb (100 μg/L). The results showed that: 1) CE100 significantly decreased the movement distance and swimming activity of the tadpoles compared to PE100 and the control, while there were no significant differences between the control group and PE100. 2) At the phyla level, compared to PE100, CE100 treatment significantly decreased the abundance of Actinobacteria, Firmicutes, Proteobacteria, and Bacteroidetes and increased the abundance of Fusobacteria in the gut. At the genus level, compared to PE100, CE100 significantly increased the abundance of U114 and decreased the abundance of Anaerorhabdus, Exiguobacterium and Microbacterium. 3) Compared to PE100, CE100 changed the metabolites of the brain-gut axis pathway, such as quinolinic acid, L-valine, L-dopa, L-histidine, urocanic acid, L-threonine, γ-aminobutyric acid (GABA), L-glutamate (Glu), acetylcholine (Ach), L-tyrosine (Tyr), L-tryptophan (Trp), and levodopa (DOPA). 4) CE100 and PE100 played a repressive role in the histidine metabolism and tyrosine metabolism pathways and played a promoting role in the purine metabolism and pyrimidine metabolism pathways. This study provides a method for evaluating the toxic effects of heavy metal exposure via two different exposure modes (pulse versus continuous) which tadpoles may encounter in the natural environment from a combined study examining the brain-gut axis.PMID:38150764 | DOI:10.1016/j.jhazmat.2023.133267

J Hazard Mater. 2023 Dec 13;465:133245. doi: 10.1016/j.jhazmat.2023.133245. Online ahead of print.ABSTRACTMercury is a hazardous pollutant of global concern. While advances have been made in identifying the detrimental effects caused by Hg species in phytoplankton, knowledge gaps remain regarding the metabolomic perturbations induced by inorganic mercury (Hg(II)) and monomethylmercury (MeHg) in these organisms. Diatoms represent a major phytoplankton group essential in various global biogeochemical cycles. The current study combined targeted metabolomics, bioaccumulation, and physiological response assays to investigate metabolic perturbations in diatom Cyclotella meneghiniana exposed for 2 h to nanomolar concentrations of Hg(II) and MeHg. Our findings highlight that such exposures induce reprogramming of the metabolism of amino acids, nucleotides, fatty acids, carboxylic acids and antioxidants. These alterations were primarily mercury-species dependent. MeHg exposure induced more pronounced reprogramming of the metabolism of diatoms than Hg(II), which led to less pronounced effects on ROS generation, membrane permeability and chlorophyll concentrations. Hg(II) treatments presented distinct physiological responses, with more robust metabolic perturbations at higher exposures. The present study provides first-time insights into the main metabolic alterations in diatom C. meneghiniana during short-term exposure to Hg species, deepening our understanding of the molecular basis of these perturbations.PMID:38150761 | DOI:10.1016/j.jhazmat.2023.133245

J Agric Food Chem. 2023 Dec 27. doi: 10.1021/acs.jafc.3c06015. Online ahead of print.ABSTRACTAtopic dermatitis (AD) is a complex inflammatory skin disease induced by multiple factors. AD can also cause intestinal inflammation and disorders of the gut microbiota. Ginseng is a kind of edible and medicinal plant; its main active components are ginsenosides. Ginsenosides have a variety of anti-inflammatory effects and regulate the gut microbiota; however, their role in AD and the underlying mechanisms are unclear. In this study, we found that intragastric administration of ginsenoside F2 improved AD-like skin symptoms and reduced inflammatory cell infiltration, serum immunoglobulin E levels, and mRNA expression of inflammatory cytokines in AD mice. 16s rRNA sequencing analysis showed that ginsenoside F2 altered the intestinal microbiota structure and enriched the short-chain fatty acid-producing microbiota in AD mice. Metabolomic analysis revealed that ginsenoside F2 significantly increased the propionic acid (Pa) content of feces and serum in AD mice, which was positively correlated with significant enrichment of Parabacteroides goldsteinii and Lactobacillus plantarum in the intestines. Pa inhibits inflammatory responses in the gut and skin of AD mice through the G-protein-coupled receptor43/NF-κB pathway, thereby improving skin AD symptoms. These results revealed, for the first time, the mechanism by which ginsenoside F2 improves AD through the Pa (a metabolite of intestinal microbiota)-gut-skin axis.PMID:38150707 | DOI:10.1021/acs.jafc.3c06015

Evolution. 2023 Dec 27:qpad233. doi: 10.1093/evolut/qpad233. Online ahead of print.ABSTRACTUnderstanding species boundaries maintenance in the face of hybridization/introgression, is an intriguing yet complex topic in evolutionary biology. The underlying mechanisms, however, remain elusive. To address this, we propose to investigate the role of climatic shifts in shaping genetic structure and influencing species boundaries. We combine multi-locus genetic data and species distribution modeling to explore how past and current climatic shifts affect the genetic structure and demographic history of two Taiwan endemic gingers, Zingiber pleiostachyum and Z. shuanglongense. We identified a well-delimited genetic structure with evidence of admixture, indicating incomplete reproductive isolation between the two gingers. This is likely due to secondary contact and range overlap during the Last Glacial Maximum, leading to sporadic instances of hybridization. Niche overlap tests based on climate and soil data indicate that these two gingers occupy similar but non-identical ecological niches. Furthermore, we found that the considerable differences in their current geographic distribution and altitude preferences might have resulted from different seed dispersal capabilities and competitive exclusion due to their similar niche preferences. Our results reveal a model where altitudinal differentiation and dispersal strategy synergistically reinforce the species divergence, thereby illuminating the importance of these factors in shaping and maintaining the island's biodiversity.PMID:38150395 | DOI:10.1093/evolut/qpad233

Aging (Albany NY). 2023 Dec 26;15. doi: 10.18632/aging.205106. Online ahead of print.ABSTRACTGlycans are an essential structural component of immunoglobulin G (IgG) that modulate its structure and function. However, regulatory mechanisms behind this complex posttranslational modification are not well known. Previous genome-wide association studies (GWAS) identified 29 genomic regions involved in regulation of IgG glycosylation, but only a few were functionally validated. One of the key functional features of IgG glycosylation is the addition of galactose (galactosylation), a trait which was shown to be associated with ageing. We performed GWAS of IgG galactosylation (N=13,705) and identified 16 significantly associated loci, indicating that IgG galactosylation is regulated by a complex network of genes that extends beyond the galactosyltransferase enzyme that adds galactose to IgG glycans. Gene prioritization identified 37 candidate genes. Using a recently developed CRISPR/dCas9 system we manipulated gene expression of candidate genes in the in vitro IgG expression system. Upregulation of three genes, EEF1A1, MANBA and TNFRSF13B, changed the IgG glycome composition, which confirmed that these three genes are involved in IgG galactosylation in this in vitro expression system.PMID:38149987 | DOI:10.18632/aging.205106

Environ Sci Technol. 2023 Dec 27. doi: 10.1021/acs.est.3c07588. Online ahead of print.ABSTRACTDioxin(-like) exposures are linked to adverse health effects, including cancer. However, metabolic alterations induced by these chemicals remain largely unknown. Beyond known dioxin(-like) compounds, we leveraged a chemical-wide approach to assess chlorinated co-exposures and parent compound products [termed dioxin(-like)-related compounds] among 137 occupational workers. Endogenous metabolites were profiled by untargeted metabolomics, namely, reversed-phase chromatography with negative electrospray ionization (C18-negative) and hydrophilic interaction liquid chromatography with positive electrospray ionization (HILIC-positive). We performed a metabolome-wide association study to select dioxin(-like) associated metabolic features using a 20% false discovery rate threshold. Metabolic features were then characterized by pathway enrichment analyses. There are no significant features associated with polychlorinated dibenzo-p-dioxins (PCDDs), a subgroup of known dioxin(-like) compounds. However, 3,110 C18-negative and 2,894 HILIC-positive features were associated with at least one of the PCDD-related compounds. Abundant metabolic changes were also observed for polychlorinated dibenzofuran-related and polychlorinated biphenyl-related compounds. These metabolic features were primarily enriched in pathways of amino acids, lipid and fatty acids, carbohydrates, cofactors, and nucleotides. Our study highlights the potential of chemical-wide analysis for comprehensive exposure assessment beyond targeted chemicals. Coupled with advanced endogenous metabolomics, this approach allows for an in-depth exploration of metabolic alterations induced by environmental chemicals.PMID:38149779 | DOI:10.1021/acs.est.3c07588

J Physiol. 2023 Dec 27. doi: 10.1113/JP285736. Online ahead of print.NO ABSTRACTPMID:38149728 | DOI:10.1113/JP285736

Chin J Physiol. 2023 Nov-Dec;66(6):558-566. doi: 10.4103/cjop.CJOP-D-23-00126.ABSTRACTRegular moderate physical exercise is beneficial for the cardiovascular system. Our prior study has demonstrated a long-term moderate exercise (4-week of 60-min 74.0% V̇O2max treadmill running) is optimal in protecting from exhaustive exercise-induced cardiac ischemic injury. This study is aimed to investigate the effect of long-term moderate exercise on myocardial metabolome in rats. Thirteen male Sprague-Dawley rats were randomly assigned into the control group (C) and the long-term moderate exercise group (E). The targeted metabolomics of the myocardium was analyzed by ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) system. Results showed that the metabolites categories of bile acids (BAs), fatty acids (FAs), and phenylpropanoic acids were significantly decreased. The biosynthesis of unsaturated FAs pathway was significantly downregulated. The altered metabolites in the E Group included decreased FAs (pentadecanoic acid, 10Z-heptadecenoic acid, dihomo-gamma-linolenic acid, docosahexaenoic acid, docosapentaenoic acid, and 10Z-nonadecenoic acid), decreased BAs (chenodeoxycholic acid and beta-muricholic acid), decreased organic acids (glycolic acid and 2-hydroxyglutaric acid), decreased carbohydrate (N-acetylneuraminic acid, Neu5Ac), decreased amino acids (α-aminobutyric acid and norvaline), decreased phenylpropanoic acids (hydroxyphenyllactic acid), and benzoic acids (4-hydroxybenzoic acid and phthalic acid). The results indicated that long-term moderate exercise has promoted lipids utilization in myocardium while exerted little influence on carbohydrate metabolism and diminished many detrimental metabolites. Notably, decrease of myocardial carbohydrate Neu5Ac after long-term moderate exercise might predict a prospective metabolomics biomarker for cardioprotection. This research has displayed the effect of long-term moderate exercise on myocardial metabolomic profiling in rats and indicated some promising metabolites which can be applied for exercise benefits in future.PMID:38149568 | DOI:10.4103/cjop.CJOP-D-23-00126

Front Microbiol. 2023 Dec 12;14:1287802. doi: 10.3389/fmicb.2023.1287802. eCollection 2023.ABSTRACTDue to its traditional fermentation, there are obvious limits on the quality improvements in black tea. However, microbial fermentation can provide an abundance of metabolites and improve the flavor of tea. The "golden flower" fungi are widely used in the microbial fermentation of tea and has unique uses in healthcare. To further explore the improvements in black tea quality achieved via microbial fermentation, we used widely targeted metabolomics and metagenomics analyses to investigate the changes in and effects of metabolites and other microorganisms during the interaction between the "golden flower" fungi and black tea. Five key flavor metabolites were detected, the levels of catechin, epigallocatechin gallate, (-)-epicatechin gallate were decreased by different degrees after the inoculation of the "golden flower" fungus, whereas the levels of caffeine and (+)-gallocatechin increased. Botryosphaeriaceae, Botryosphaeriales, Dothideomycetes, Aspergillaceae, Trichocomaceae, and Lecanoromycetes play a positive role in the black tea fermentation process after inoculation with the "golden flower" fungi. D-Ribose can prevent hypoxia-induced apoptosis in cardiac cells, and it shows a strong correlation with Botryosphaeriaceae and Botryosphaeriales. The interaction between microorganisms and metabolites is manifested in tryptophan metabolism, starch and sucrose metabolism, and amino sugar and nucleotide sugar metabolism. In conclusion, the changes in metabolites observed during the fermentation of black tea by "golden flower" fungi are beneficial to human health. This conclusion extends the knowledge of the interaction between the "golden flower" fungi and black tea, and it provides important information for improving the quality of black tea.PMID:38149271 | PMC:PMC10750952 | DOI:10.3389/fmicb.2023.1287802

JHEP Rep. 2023 Oct 13;6(1):100930. doi: 10.1016/j.jhepr.2023.100930. eCollection 2024 Jan.ABSTRACTBACKGROUND & AIMS: The constitutive androstane receptor (CAR) is a nuclear receptor that binds diverse xenobiotics and whose activation leads to the modulation of the expression of target genes involved in xenobiotic detoxification and energy metabolism. Although CAR hepatic activity is considered to be higher in women than in men, its sex-dependent response to an acute pharmacological activation has seldom been investigated.METHODS: The hepatic transcriptome, plasma markers, and hepatic metabolome, were analysed in Car+/+ and Car-/- male and female mice treated either with the CAR-specific agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or with vehicle.RESULTS: Although 90% of TCPOBOP-sensitive genes were modulated in a sex-independent manner, the remaining 10% showed almost exclusive female liver specificity. These female-specific CAR-sensitive genes were mainly involved in xenobiotic metabolism, inflammation, and extracellular matrix organisation. CAR activation also induced higher hepatic oxidative stress and hepatocyte cytolysis in females than in males. Hepatic expression of flavin monooxygenase 3 (Fmo3) was almost abolished and was associated with a decrease in hepatic trimethylamine-N-oxide (TMAO) concentration in TCPOBOP-treated females. In line with a potential role in the control of TMAO homeostasis, CAR activation decreased platelet hyper-responsiveness in female mice supplemented with dietary choline.CONCLUSIONS: More than 10% of CAR-sensitive genes are sex-specific and influence hepatic and systemic responses such as platelet aggregation. CAR activation may be an important mechanism of sexually-dimorphic drug-induced liver injury.IMPACT AND IMPLICATIONS: CAR is activated by many drugs and pollutants. Its pharmacological activation had a stronger impact on hepatic gene expression and metabolism in females than in males, and had a specific impact on liver toxicity and trimethylamine metabolism. Sexual dimorphism should be considered when testing and/or prescribing xenobiotics known to activate CAR.PMID:38149074 | PMC:PMC10749885 | DOI:10.1016/j.jhepr.2023.100930

Am J Clin Exp Urol. 2023 Dec 15;11(6):594-612. eCollection 2023.ABSTRACTProstate cancer (PCa) is the second most common cancer and constitutes about 14.7% of total cancer cases. PCa is highly prevalent and more aggressive in African-American (AA) men than in European-American (EA) men. PCa tends to be highly heterogeneous, and its complex biology is not fully understood. We use metabolomics to better understand the mechanisms behind PCa progression and disparities in its clinical outcome. Adenosine deaminase (ADA) is a key enzyme in the purine metabolic pathway; it was found to be upregulated in PCa and is associated with higher-grade PCa and poor disease-free survival. The inosine-to-adenosine ratio, which is a surrogate for ADA activity was high in PCa patient urine and higher in AA PCa compared to EA PCa. To understand the significance of high ADA in PCa, we established ADA overexpression models and performed various in vitro and in vivo studies. Our studies have revealed that an acute increase in ADA expression during later stages of tumor development enhances in vivo growth in multiple pre-clinical models. Further analysis revealed that mTOR signaling activation could be associated with this tumor growth. Chronic ADA overexpression shows alterations in the cells' adhesion machinery and a decrease in cells' ability to adhere to the extracellular matrix in vitro. Losing cell-matrix interaction is critical for metastatic dissemination which suggests that ADA could potentially be involved in promoting metastasis. This is supported by the association of higher ADA expression with higher-grade tumors and poor patient survival. Overall, our findings suggest that increased ADA expression may promote PCa progression, specifically tumor growth and metastatic dissemination.PMID:38148936 | PMC:PMC10749386

Am J Clin Exp Urol. 2023 Dec 15;11(6):481-499. eCollection 2023.ABSTRACTBACKGROUND: Cancer detection presents challenges regarding invasiveness, cost, and reliability. As a result, exploring alternative diagnostic methods holds significant clinical importance. Urinary metabolomic profiling has emerged as a promising avenue; however, its application for cancer diagnosis may be influenced by sample preparation or storage conditions.OBJECTIVE: This study aimed to assess the impact of sample storage and processing conditions on urinary volatile organic compounds (VOCs) profiles and establish a robust standard operating procedure (SOP) for such diagnostic applications.METHODS: Five key variables were investigated: storage temperatures, durations, freeze-thaw cycles, sample collection conditions, and sample amounts. The analysis of VOCs involved stir bar sorptive extraction coupled with thermal desorption-gas chromatography/mass spectrometry (SBSE-TD-GC-MS), with compound identification facilitated by the National Institute of Standards and Technology Library (NIST). Extensive statistical analysis, including combined scatterplot and response surface (CSRS) plots, partial least squares-discriminant analysis (PLS-DA), and probability density function plots (PDFs), were employed to study the effects of the factors.RESULTS: Our findings revealed that urine storage duration, sample amount, temperature, and fasting/non-fasting sample collection did not significantly impact urinary metabolite profiles. This suggests flexibility in urine sample collection conditions, enabling individuals to contribute samples under varying circumstances. However, the influence of freeze-thaw cycles was evident, as VOC profiles exhibited distinct clustering patterns based on the number of cycles. This emphasizes the effect of freeze-thaw cycles on the integrity of urinary profiles.CONCLUSIONS: The developed SOP integrating SBSE-TD-GC-MS and statistical analyses can serve as a valuable tool for analyzing urinary organic compounds with minimal preparation and sensitive detection. The findings also support that urinary VOCs for cancer screening and diagnosis could be a feasible alternative offering a robust, non-invasive, and sensitive approach for cancer screening.PMID:38148934 | PMC:PMC10749378

Front Plant Sci. 2023 Dec 7;14:1252455. doi: 10.3389/fpls.2023.1252455. eCollection 2023.ABSTRACTINTRODUCTION: The primary metabolism of plants, which is mediated by nitrogen, is closely related to the defense response to insect herbivores.METHODS: An experimental system was established to examine how nitrogen mediated tomato resistance to an insect herbivore, the oriental fruit fly (Bactrocera dorsalis). All tomatoes were randomly assigned to the suitable nitrogen (control, CK) treatment, nitrogen excess (NE) treatment and nitrogen deficiency (ND) treatment.RESULTS: We found that nitrogen excess significantly increased the aboveground biomass of tomato and increased the pupal biomass of B. dorsalis. Metabolome analysis showed that nitrogen excess promoted the biosynthesis of amino acids in healthy fruits, including γ-aminobutyric acid (GABA), arginine and asparagine. GABA was not a differential metabolite induced by injury by B. dorsalis under nitrogen excess, but it was significantly induced in infested fruits at appropriate nitrogen levels. GABA supplementation not only increased the aboveground biomass of plants but also improved the defensive response of tomato.DISCUSSION: The biosynthesis of GABA in tomato is a resistance response to feeding by B. dorsalis in appropriate nitrogen, whereas nitrogen excess facilitates the pupal weight of B. dorsalis by inhibiting synthesis of the GABA pathway. This study concluded that excess nitrogen inhibits tomato defenses in plant-insect interactions by inhibiting GABA synthesis, answering some unresolved questions about the nitrogen-dependent GABA resistance pathway to herbivores.PMID:38148864 | PMC:PMC10751092 | DOI:10.3389/fpls.2023.1252455