PubMed

Biosensors (Basel). 2024 Feb 21;14(3):114. doi: 10.3390/bios14030114.ABSTRACTIn a chamber-based digital PCR (dPCR) chip fabricated with polydimethylsiloxane (PDMS), bubble generation in the chambers at high temperatures is a critical issue. Here, we found that the main reason for bubble formation in PDMS chips is the too-high saturated vapor pressure of water at an elevated temperature. The bubbles should be completely prevented by reducing the initial pressure of the system to under 13.6 kPa to eliminate the effects of increased-pressure water vapor. Then, a cavity was designed and fabricated above the PCR reaction layer, and Parylene C was used as a shell covering the chip. The cavity was used for the negative generator in sample loading, PDMS degassing, PCR solution degassing in the digitization process and water storage in the thermal reaction process. The analysis was confirmed and finally achieved a desirable bubble-free, fast-digitization, valve-free and no-tubing connection dPCR.PMID:38534221 | DOI:10.3390/bios14030114

mSystems. 2024 Mar 27:e0022724. doi: 10.1128/msystems.00227-24. Online ahead of print.ABSTRACTCyanobacteria fix carbon dioxide and release carbon-containing compounds into the wider ecosystem, yet they are sensitive to small metabolites that may impact their growth and physiology. Several cyanobacteria can grow mixotrophically, but we currently lack a molecular understanding of how specific nutrients may alter the compounds they release, limiting our knowledge of how environmental factors might impact primary producers and the ecosystems they support. In this study, we develop a high-throughput phytoplankton culturing platform and identify how the model cyanobacterium Synechocystis sp. PCC 6803 responds to nutrient supplementation. We assess growth responses to 32 nutrients at two concentrations, identifying 15 that are utilized mixotrophically. Seven nutrient sources significantly enhance growth, while 19 elicit negative growth responses at one or both concentrations. High-throughput exometabolomics indicates that oxidative stress limits Synechocystis' growth but may be alleviated by antioxidant metabolites. Furthermore, glucose and valine induce strong changes in metabolite exudation in a possible effort to correct pathway imbalances or maintain intracellular elemental ratios. This study sheds light on the flexibility and limits of cyanobacterial physiology and metabolism, as well as how primary production and trophic food webs may be modulated by exogenous nutrients.IMPORTANCECyanobacteria capture and release carbon compounds to fuel microbial food webs, yet we lack a comprehensive understanding of how external nutrients modify their behavior and what they produce. We developed a high throughput culturing platform to evaluate how the model cyanobacterium Synechocystis sp. PCC 6803 responds to a broad panel of externally supplied nutrients. We found that growth may be enhanced by metabolites that protect against oxidative stress, and growth and exudate profiles are altered by metabolites that interfere with central carbon metabolism and elemental ratios. This work contributes a holistic perspective of the versatile response of Synechocystis to externally supplied nutrients, which may alter carbon flux into the wider ecosystem.PMID:38534128 | DOI:10.1128/msystems.00227-24

J Am Heart Assoc. 2024 Mar 27:e031616. doi: 10.1161/JAHA.123.031616. Online ahead of print.ABSTRACTBACKGROUND: Frailty is common in heart failure (HF) and is associated with death but not routinely captured clinically. Frailty is linked with inflammation and malnutrition, which can be assessed by a novel plasma multimarker score: the metabolic vulnerability index (MVX). We sought to evaluate the associations between frailty and MVX and their prognostic impact.METHODS AND RESULTS: In an HF community cohort (2003-2012), we measured frailty as a proportion of deficits present out of 32 physical limitations and comorbidities, MVX by nuclear magnetic resonance spectroscopy, and collected extensive longitudinal clinical data. Patients were categorized by frailty score (≤0.14, >0.14 and ≤0.27, >0.27) and MVX score (≤50, >50 and ≤60, >60 and ≤70, >70). Cox models estimated associations of frailty and MVX with death, adjusted for Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score and NT-proBNP (N-terminal pro-B-type natriuretic peptide). Uno's C-statistic measured the incremental value of MVX beyond frailty and clinical factors. Weibull's accelerated failure time regression assessed whether MVX mediated the association between frailty and death. We studied 985 patients (median age, 77; 48% women). Frailty and MVX were weakly correlated (Spearman's ρ=0.21). The highest frailty group experienced an increased rate of death, independent of MVX, MAGGIC score, and NT-proBNP (hazard ratio, 3.3 [95% CI, 2.5-4.2]). Frailty improved Uno's c-statistic beyond MAGGIC score and NT-proBNP (0.69-0.73). MVX only mediated 3.3% and 4.5% of the association between high and medium frailty groups and death, respectively.CONCLUSIONS: In this HF cohort, frailty and MVX are weakly correlated. Both independently contribute to stratifying the risk of death, suggesting that they capture distinct domains of vulnerability in HF.PMID:38533960 | DOI:10.1161/JAHA.123.031616

J Am Heart Assoc. 2024 Mar 27:e033676. doi: 10.1161/JAHA.123.033676. Online ahead of print.ABSTRACTBACKGROUND: Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) is a critical glycolytic regulator responsible for upregulation of glycolysis in response to insulin and adrenergic signaling. PFKFB2, the cardiac isoform of PFK-2, is degraded in the heart in the absence of insulin signaling, contributing to diabetes-induced cardiac metabolic inflexibility. However, previous studies have not examined how the loss of PFKFB2 affects global cardiac metabolism and function.METHODS AND RESULTS: To address this, we have generated a mouse model with a cardiomyocyte-specific knockout of PFKFB2 (cKO). Using 9-month-old cKO and control mice, we characterized the impacts of PFKFB2 on cardiac metabolism, function, and electrophysiology. cKO mice have a shortened life span of 9 months. Metabolically, cKO mice are characterized by increased glycolytic enzyme abundance and pyruvate dehydrogenase activity, as well as decreased mitochondrial abundance and beta oxidation, suggesting a shift toward glucose metabolism. This was supported by a decrease in the ratio of palmitoyl carnitine to pyruvate-dependent mitochondrial respiration in cKO relative to control animals. Metabolomic, proteomic, and Western blot data support the activation of ancillary glucose metabolism, including pentose phosphate and hexosamine biosynthesis pathways. Physiologically, cKO animals exhibited impaired systolic function and left ventricular dilation, represented by reduced fractional shortening and increased left ventricular internal diameter, respectively. This was accompanied by electrophysiological alterations including increased QT interval and other metrics of delayed ventricular conduction.CONCLUSIONS: Loss of PFKFB2 results in metabolic remodeling marked by cardiac ancillary pathway activation. This could delineate an underpinning of pathologic changes to mechanical and electrical function in the heart.PMID:38533937 | DOI:10.1161/JAHA.123.033676

Food Funct. 2024 Mar 27. doi: 10.1039/d3fo05711a. Online ahead of print.ABSTRACTAlzheimer's Disease (AD) is a fatal age-related neurodegenerative condition with a multifactorial etiology contributing to 70% of dementia globally. The search for a multi-target agent to hit different targets involved in the pathogenesis of AD is crucial. In the present study, the neuroprotective effects of four Morus extracts were assessed in LPS-induced AD in mice. Among the studied species, M. macroura exhibited a profound effect on alleviating the loss of cognitive function, improved the learning ability, restored the acetylcholine esterase (AChE) levels to normal, and significantly reduced the tumor necrosis factor alpha (TNF-α) brain content in LPS-treated mice. To investigate the secondary metabolome of the studied Morus species, ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-HRMS/MS), aided with feature-based molecular networking, was employed. Among the annotated features, aryl benzofurans and prenylated flavonoids were suggested as being responsible for the observed neuroprotective effect. Furthermore, some of the detected metabolites were proposed as new natural products such as moranoline di-O-hexoside (1), isomers of trimethoxy-dihydrochalcone-O-dihexoside (59 & 76), (hydroxy-dimethoxyphenyl)butenone-O-hexoside (82), and O-methylpreglabridin-O-sulphate (105). In conclusion, our findings advocate the potential usage of M. macroura leaves for the management of AD, yet after considering further clinical trials.PMID:38533683 | DOI:10.1039/d3fo05711a

Contemp Clin Trials Commun. 2024 Feb 1;38:101264. doi: 10.1016/j.conctc.2024.101264. eCollection 2024 Apr.ABSTRACT[This corrects the article DOI: 10.1016/j.conctc.2023.101233.].PMID:38533474 | PMC:PMC10964043 | DOI:10.1016/j.conctc.2024.101264

Front Plant Sci. 2024 Mar 8;15:1368880. doi: 10.3389/fpls.2024.1368880. eCollection 2024.ABSTRACTINTRODUCTION: Anoectochilus roxburghii is a rare, endangered herb with diverse pharmacological properties. Understanding the main metabolite types and characteristics of wild A. roxburghii is important for efficiently utilizing resources and examining quality according to origin.METHODS: Samples were collected from the main production areas across five regions in Fujian Province, China. An untargeted metabolomics analysis was performed on the entire plants to explore their metabolic profiles. We utilized UPLC-MS/MS to specifically quantify eight targeted flavonoids in these samples. Subsequently, correlation analysis was conducted to investigate the relationships between the flavonoids content and both the biological characteristics and geographical features.RESULTS: A comprehensive analysis identified a total of 3,170 differential metabolites, with terpenoids and flavonoids being the most prevalent classes. A region-specific metabolite analysis revealed that the Yongchun (YC) region showed the highest diversity of unique metabolites, including tangeretin and oleanolic acid. Conversely, the Youxi (YX) region was found to have the smallest number of unique metabolites, with only one distinct compound identified. Further investigation through KEGG pathway enrichment analysis highlighted a significant enrichment in pathways related to flavonoid biosynthesis. Further examination of the flavonoid category showed that flavonols were the most differentially abundant. We quantified eight specific flavonoids, finding that, on average, the YX region exhibited higher levels of these compounds. Correlation analysis highlighted a significant association between flavonoids and habitat, especially temperature and humidity.DISCUSSION: Untargeted metabolomics via LC-MS was suitable for identifying region-specific metabolites and their influence via habitat heterogeneity. The results of this study serve as a new theoretical reference for unique markers exclusively present in a specific sample group.PMID:38533408 | PMC:PMC10964796 | DOI:10.3389/fpls.2024.1368880

Front Plant Sci. 2024 Mar 12;15:1357316. doi: 10.3389/fpls.2024.1357316. eCollection 2024.ABSTRACTINTRODUCTION: High-throughput phenotyping technologies together with metabolomics analysis can speed up the development of highly efficient and effective biostimulants for enhancing crop tolerance to drought stress. The aim of this study was to examine the morphophysiological and metabolic changes in tomato plants foliarly treated with two protein hydrolysates obtained by enzymatic hydrolysis of vegetal proteins from Malvaceae (PH1) or Fabaceae (PH2) in comparison with a control treatment, as well as to investigate the mechanisms involved in the enhancement of plant resistance to repeated drought stress cycles.METHODS: A phenotyping device was used for daily monitoring morphophysiological traits while untargeted metabolomics analysis was carried out in leaves of the best performing treatment based on phenotypic results.Results: PH1 treatment was the most effective in enhancing plant resistance to water stress due to the better recovery of digital biomass and 3D leaf area after each water stress event while PH2 was effective in mitigating water stress only during the recovery period after the first drought stress event. Metabolomics data indicated that PH1 modified primary metabolism by increasing the concentration of dipeptides and fatty acids in comparison with untreated control, as well as secondary metabolism by regulating several compounds like phenols. In contrast, hormones and compounds involved in detoxification or signal molecules against reactive oxygen species were downregulated in comparison with untreated control.CONCLUSION: The above findings demonstrated the advantages of a combined phenomics-metabolomics approach for elucidating the relationship between metabolic and morphophysiological changes associated with a biostimulant-mediated increase of crop resistance to repeated water stress events.PMID:38533405 | PMC:PMC10963501 | DOI:10.3389/fpls.2024.1357316

Front Cell Infect Microbiol. 2024 Mar 12;14:1349397. doi: 10.3389/fcimb.2024.1349397. eCollection 2024.ABSTRACTBACKGROUND: Graves' disease (GD), characterized by immune aberration, is associated with gut dysbiosis. Despite the growing interest, substantial evidence detailing the precise impact of gut microbiota on GD's autoimmune processes remains exceedingly rare.OBJECTIVE: This study was designed to investigate the influence of gut microbiota on immune dysregulation in GD.METHODS: It encompassed 52 GD patients and 45 healthy controls (HCs), employing flow cytometry and enzyme-linked immunosorbent assay to examine lymphocyte and cytokine profiles, alongside lipopolysaccharide (LPS) levels. Gut microbiota profiles and metabolic features were assessed using 16S rRNA gene sequencing and targeted metabolomics.RESULTS: Our observations revealed a disturbed B-cell distribution and elevated LPS and pro-inflammatory cytokines in GD patients compared to HCs. Significant differences in gut microbiota composition and a marked deficit in short-chain fatty acid (SCFA)-producing bacteria, including ASV263(Bacteroides), ASV1451(Dialister), and ASV503(Coprococcus), were observed in GD patients. These specific bacteria and SCFAs showed correlations with thyroid autoantibodies, B-cell subsets, and cytokine levels. In vitro studies further showed that LPS notably caused B-cell subsets imbalance, reducing conventional memory B cells while increasing naïve B cells. Additionally, acetate combined with propionate and butyrate showcased immunoregulatory functions, diminishing cytokine production in LPS-stimulated cells.CONCLUSION: Overall, our results highlight the role of gut dysbiosis in contributing to immune dysregulation in GD by affecting lymphocyte status and cytokine production.PMID:38533382 | PMC:PMC10963416 | DOI:10.3389/fcimb.2024.1349397

Front Microbiol. 2024 Mar 12;15:1373827. doi: 10.3389/fmicb.2024.1373827. eCollection 2024.ABSTRACTINTRODUCTION: The mulberry industry has thrived in China for millennia, offering significant ecological and economic benefits. However, the prevalence of mulberry ring rot disease poses a serious threat to the quality and yield of mulberry leaves.METHODS: In this study, we employed a combination of transcriptomic and metabolomic analyses to elucidate the changes occurring at the transcriptional and metabolic levels in Morus notabilis in response to this disease infestation. Key metabolites identified were further validated through in vitro inhibition experiments.RESULTS: The findings revealed significant enrichment in Kyoto Encyclopedia of Genes and Genomes pathways, particularly those related to flavonoid biosynthesis. Notably, naringenin, kaempferol, and quercetin emerged as pivotal players in M. notabilis' defense mechanism against this disease pathogen. The upregulation of synthase genes, including chalcone synthase, flavanone-3-hydroxylase, and flavonol synthase, suggested their crucial roles as structural genes in this process. In vitro inhibition experiments demonstrated that kaempferol and quercetin exhibited broad inhibitory properties, while salicylic acid and methyl jasmonate demonstrated efficient inhibitory effects.DISCUSSION: This study underscores the significance of the flavonoid biosynthesis pathway in M. notabilis' defense response against mulberry ring rot disease, offering a theoretical foundation for disease control measures.PMID:38533335 | PMC:PMC10963518 | DOI:10.3389/fmicb.2024.1373827

Compr Rev Food Sci Food Saf. 2024 Mar;23(2):e13325. doi: 10.1111/1541-4337.13325.ABSTRACTThis manuscript presents a comprehensive review of high-resolution mass spectrometry in the field of food analysis and metabolomics. We have followed the historical evolution of metabolomics, its associated techniques and technologies, and its increasing role in food science and research. The review provides a critical comparison and synthesis of tentative identification guidelines proposed for over 15 years, offering a condensed resource for researchers in the field. We have also examined a wide range of recent metabolomics studies, showcasing various methodologies and highlighting key findings as a testimony of the versatility of the field and the possibilities it offers. In doing so, we have also carefully provided a compilation of the software tools that may be employed in this type of studies. The manuscript also explores the prospects of high-resolution mass spectrometry and metabolomics in food science. By covering the history, guidelines, applications, and tools of metabolomics, this review attempts to become a comprehensive guide for researchers in a rapidly evolving field.PMID:38532695 | DOI:10.1111/1541-4337.13325

Biol Sex Differ. 2024 Mar 26;15(1):26. doi: 10.1186/s13293-024-00602-6.ABSTRACTBACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key player of lipid metabolism with higher plasma levels in women throughout their life. Statin treatment affects PCSK9 levels also showing evidence of sex-differential effects. It remains unclear whether these differences can be explained by genetics.METHODS: We performed genome-wide association meta-analyses (GWAS) of PCSK9 levels stratified for sex and statin treatment in six independent studies of Europeans (8936 women/11,080 men respectively 14,825 statin-free/5191 statin-treated individuals). Loci associated in one of the strata were tested for statin- and sex-interactions considering all independent signals per locus. Independent variants at the PCSK9 gene locus were then used in a stratified Mendelian Randomization analysis (cis-MR) of PCSK9 effects on low-density lipoprotein cholesterol (LDL-C) levels to detect differences of causal effects between the subgroups.RESULTS: We identified 11 loci associated with PCSK9 in at least one stratified subgroup (p < 1.0 × 10-6), including the PCSK9 gene locus and five other lipid loci: APOB, TM6SF2, FADS1/FADS2, JMJD1C, and HP/HPR. The interaction analysis revealed eight loci with sex- and/or statin-interactions. At the PCSK9 gene locus, there were four independent signals, one with a significant sex-interaction showing stronger effects in men (rs693668). Regarding statin treatment, there were two significant interactions in PCSK9 missense mutations: rs11591147 had stronger effects in statin-free individuals, and rs11583680 had stronger effects in statin-treated individuals. Besides replicating known loci, we detected two novel genome-wide significant associations: one for statin-treated individuals at 6q11.1 (within KHDRBS2) and one for males at 12q24.22 (near KSR2/NOS1), both with significant interactions. In the MR of PCSK9 on LDL-C, we observed significant causal estimates within all subgroups, but significantly stronger causal effects in statin-free subjects compared to statin-treated individuals.CONCLUSIONS: We performed the first double-stratified GWAS of PCSK9 levels and identified multiple biologically plausible loci with genetic interaction effects. Our results indicate that the observed sexual dimorphism of PCSK9 and its statin-related interactions have a genetic basis. Significant differences in the causal relationship between PCSK9 and LDL-C suggest sex-specific dosages of PCSK9 inhibitors.PMID:38532495 | DOI:10.1186/s13293-024-00602-6

Cancer Metab. 2024 Mar 26;12(1):10. doi: 10.1186/s40170-024-00335-5.ABSTRACTBACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has been associated with the host dysmetabolism of branched-chain amino acids (BCAAs), however, the implications for the role of BCAA metabolism in PDAC development or progression are not clear. The mitochondrial catabolism of valine, leucine, and isoleucine is a multistep process leading to the production of short-chain R-CoA species. They can be subsequently exported from mitochondria as short-chain carnitines (SC-CARs), utilized in anabolic pathways, or released from the cells.METHODS: We examined the specificities of BCAA catabolism and cellular adaptation strategies to BCAA starvation in PDAC cells in vitro. We used metabolomics and lipidomics to quantify major metabolic changes in response to BCAA withdrawal. Using confocal microscopy and flow cytometry we quantified the fluorescence of BODIPY probe and the level of lipid droplets (LDs). We used BODIPY-conjugated palmitate to evaluate transport of fatty acids (FAs) into mitochondria. Also, we have developed a protocol for quantification of SC-CARs, BCAA-derived metabolites.RESULTS: Using metabolic profiling, we found that BCAA starvation leads to massive triglyceride (TG) synthesis and LD accumulation. This was associated with the suppression of activated FA transport into the mitochondrial matrix. The suppression of FA import into mitochondria was rescued with the inhibitor of the acetyl-CoA carboxylase (ACC) and the activator of AMP kinase (AMPK), which both regulate carnitine palmitoyltransferase 1A (CPT1) activation status.CONCLUSIONS: Our data suggest that BCAA catabolism is required for the import of long chain carnitines (LC-CARs) into mitochondria, whereas the disruption of this link results in the redirection of activated FAs into TG synthesis and its deposition into LDs. We propose that this mechanism protects cells against mitochondrial overload with LC-CARs and it might be part of the universal reaction to amino acid perturbations during cancer growth, regulating FA handling and storage.PMID:38532464 | DOI:10.1186/s40170-024-00335-5

BMC Plant Biol. 2024 Mar 26;24(1):219. doi: 10.1186/s12870-024-04902-2.ABSTRACTBACKGROUND: Drought is considered the main environmental factor restricting apple production and thus the development of the apple industry. Rootstocks play an important role in enhancing the drought tolerance of apple plants. Studies of the physiology have demonstrated that 'ZC9-3' is a strong drought-resistant rootstock, whereas 'Jizhen-2' is a weak drought-resistant rootstock. However, the metabolites in these two apple rootstock varieties that respond to drought stress have not yet been characterized, and the molecular mechanisms underlying their responses to drought stress remain unclear.RESULTS: In this study, the physiological and molecular mechanisms underlying differences in the drought resistance of 'Jizhen-2' (drought-sensitive) and 'ZC9-3' (drought-resistant) apple rootstocks were explored. Under drought stress, the relative water content of the leaves was maintained at higher levels in 'ZC9-3' than in 'Jizhen-2', and the photosynthetic, antioxidant, and osmoregulatory capacities of 'ZC9-3' were stronger than those of 'Jizhen-2'. Metabolome analysis revealed a total of 95 and 156 differentially accumulated metabolites in 'Jizhen-2' and 'ZC9-3' under drought stress, respectively. The up-regulated metabolites in the two cultivars were mainly amino acids and derivatives. Transcriptome analysis revealed that there were more differentially expressed genes and transcription factors in 'ZC9-3' than in 'Jizhen-2' throughout the drought treatment. Metabolomic and transcriptomic analysis revealed that amino acid biosynthesis pathways play key roles in mediating drought resistance in apple rootstocks. A total of 13 metabolites, including L-α-aminoadipate, L-homoserine, L-threonine, L-isoleucine, L-valine, L-leucine, (2S)-2-isopropylmalate, anthranilate, L-tryptophan, L-phenylalanine, L-tyrosine, L-glutamate, and L-proline, play an important role in the difference in drought resistance between 'ZC9-3' and 'Jizhen-2'. In addition, 13 genes encoding O-acetylserine-(thiol)-lyase, S-adenosylmethionine synthetase, ketol-acid isomeroreductase, dihydroxyacid dehydratase, isopropylmalate isomerase, branched-chain aminotransferase, pyruvate kinase, 3-dehydroquinate dehydratase/shikimate 5-dehydrogenase, N-acetylglutamate-5-P-reductase, and pyrroline-5-carboxylate synthetase positively regulate the response of 'ZC9-3' to drought stress.CONCLUSIONS: This study enhances our understanding of the response of apple rootstocks to drought stress at the physiological, metabolic, and transcriptional levels and provides key insights that will aid the cultivation of drought-resistant apple rootstock cultivars. Especially, it identifies key metabolites and genes underlying the drought resistance of apple rootstocks.PMID:38532379 | DOI:10.1186/s12870-024-04902-2

Comp Med. 2024 Feb 1;74(1):3-11. doi: 10.30802/AALAS-CM-23-000044.ABSTRACTL-368,899 is a selective small-molecule oxytocin receptor (OXTR) antagonist originally developed in the 1990s to prevent preterm labor. Although its utility for that purpose was limited, L-368,899 is now one of the most commonly used drugs in animal research for the selective blockade of neural OXTR after peripheral delivery. A growing number of rodent and primate studies have used L-368,899 to evaluate whether certain behaviors are oxytocin dependent. These studies have improved our understanding of oxytocin's function in the brains of rodents and monkeys, but very little work has been done in other mammals, and only a single paper in macaques has provided any evidence that L-368,899 can be detected in the CNS after peripheral delivery. The current study sought to extend those findings in a novel species: coyotes ( Canis latrans ). Coyotes are ubiquitous North American canids that form long-term monogamous pair-bonds. Although monogamy is rare in rodents and primates, all wild canid species studied to date exhibit social monogamy. Coyotes are therefore an excellent model organism for the study of oxytocin and social bonds. Our goal was to determine whether L-368,899 is a viable candidate for future use in behavioral studies in coyotes. We used captive coyotes at the USDA National Wildlife Research Center's Predator Research Facility to evaluate the pharmacokinetics of L-368,899 in blood and CSF during a 90-min time course after intramuscular injection. We then characterized the binding affinity and selectivity of L-368,899 to coyote OXTR and the structurally similar vasopressin 1a receptor. We found that L-368,899 peaked in CSF at 15 to 30 min after intramuscular injection and slowly accumulated in blood. L-368,899 was 40 times more selective for OXTR than vasopressin 1a receptors and bound to the coyote OXTR with an affinity of 12 nM. These features of L-368,899 support its utility in future studies to probe the oxytocin system of coyotes.PMID:38532262 | DOI:10.30802/AALAS-CM-23-000044

Environ Sci Pollut Res Int. 2024 Mar 27. doi: 10.1007/s11356-024-32967-x. Online ahead of print.ABSTRACTImazethapyr is a widely used imidazolinone herbicide worldwide, and its potential adverse effects on non-target plants have raised concerns. Understanding the mechanisms of imazethapyr phytotoxicity is crucial for its agro-ecological risk assessment. Here, the comprehensive molecular responses and metabolic alterations of Arabidopsis in response to imazethapyr were investigated. Our results showed that root exposure to imazethapyr inhibited shoot growth, reduced chlorophyll contents, induced photoinhibition and decreased photosynthetic activity. By non-target metabolomic analysis, we identified 75 metabolites that were significantly changed after imazethapyr exposure, and they are mainly enriched in carbohydrate, lipid and amino acid metabolism. Transcriptomic analysis confirmed that imazethapyr significantly downregulated the genes involved in photosynthetic electron transport and the carbon cycle. In detail, 48 genes in the photosynthetic lightreaction and 11 genes in Calvin cycle were downregulated. Additionally, the downregulation of genes related to electron transport in mitochondria provides strong evidence for imazethapyr inhibiting photosynthetic carbon fixation and cellular energy metabolism as one of mechanisms of toxicity. These results revealed the molecular and metabolic basis of imazethapyr toxicity on non-target plants, contributing to environmental risk assessment and mitigate negative impact of imazethapyr residues in agricultural soils.PMID:38532215 | DOI:10.1007/s11356-024-32967-x

Transl Psychiatry. 2024 Mar 26;14(1):163. doi: 10.1038/s41398-024-02886-z.ABSTRACTMajor depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are classified as major mental disorders and together account for the second-highest global disease burden, and half of these patients experience symptom onset in adolescence. Several studies have reported both similar and unique features regarding the risk factors and clinical symptoms of these three disorders. However, it is still unclear whether these disorders have similar or unique metabolic characteristics in adolescents. We conducted a metabolomics analysis of plasma samples from adolescent healthy controls (HCs) and patients with MDD, BD, and SCZ. We identified differentially expressed metabolites between patients and HCs. Based on the differentially expressed metabolites, correlation analysis, metabolic pathway analysis, and potential diagnostic biomarker identification were conducted for disorders and HCs. Our results showed significant changes in plasma metabolism between patients with these mental disorders and HCs; the most distinct changes were observed in SCZ patients. Moreover, the metabolic differences in BD patients shared features with those in both MDD and SCZ, although the BD metabolic profile was closer to that of MDD than to SCZ. Additionally, we identified the metabolites responsible for the similar and unique metabolic characteristics in multiple metabolic pathways. The similar significant differences among the three disorders were found in fatty acid, steroid-hormone, purine, nicotinate, glutamate, tryptophan, arginine, and proline metabolism. Interestingly, we found unique characteristics of significantly altered glycolysis, glycerophospholipid, and sphingolipid metabolism in SCZ; lysine, cysteine, and methionine metabolism in MDD and BD; and phenylalanine, tyrosine, and aspartate metabolism in SCZ and BD. Finally, we identified five panels of potential diagnostic biomarkers for MDD-HC, BD-HC, SCZ-HC, MDD-SCZ, and BD-SCZ comparisons. Our findings suggest that metabolic characteristics in plasma vary across psychiatric disorders and that critical metabolites provide new clues regarding molecular mechanisms in these three psychiatric disorders.PMID:38531835 | DOI:10.1038/s41398-024-02886-z

Free Radic Biol Med. 2024 Mar 24:S0891-5849(24)00141-2. doi: 10.1016/j.freeradbiomed.2024.03.016. Online ahead of print.ABSTRACTAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which the death of motor neurons leads to loss of muscle function. Additionally, cognitive and circadian disruptions are common in ALS patients, contributing to disease progression and burden. Most ALS cases are sporadic, and environmental exposures contribute to their aetiology. However, animal models of these sporadic ALS cases are scarce. The small vertebrate zebrafish is a leading organism to model neurodegenerative diseases; previous studies have proposed bisphenol A (BPA) or β-methylamino-l-alanine (BMAA) exposure to model sporadic ALS in zebrafish, damaging motor neurons and altering motor responses. Here we characterise the face and predictive validity of sporadic ALS models, showing their potential for the mechanistic study of ALS drugs. We phenotypically characterise the BPA and BMAA-induced models, going beyond motor activity and motor axon morphology, to include circadian, redox, proteostasis, and metabolomic phenotypes, and assessing their predictive validity for ALS modelling. BPA or BMAA exposure induced concentration-dependent activity impairments. Also, exposure to BPA but not BMAA induced motor axonopathy and circadian alterations in zebrafish larvae. Our further study of the BPA model revealed loss of habituation to repetitive startles, increased oxidative damage, endoplasmic reticulum (ER) stress, and metabolome abnormalities. The BPA-induced model shows predictive validity, since the approved ALS drug edaravone counteracted BPA-induced motor phenotypes, ER stress, and metabolic disruptions. Overall, BPA exposure is a promising model of ALS-related redox and ER imbalances, contributing to fulfil an unmet need for validated sporadic ALS models.PMID:38531462 | DOI:10.1016/j.freeradbiomed.2024.03.016

Food Chem. 2024 Mar 18;448:139052. doi: 10.1016/j.foodchem.2024.139052. Online ahead of print.ABSTRACTThe study investigated the effect of different sodium chloride (NaCl) concentrations (10%, 15%, and 20%) on the ripening fermentation of Pixian-Douban, a traditional fermented condiment. The results showed that NaCl affected the dynamics of physicochemical parameters, volatile components, fatty acids, amino metabolites, organic acids, and microbial composition, and their dynamic modes were different. After 253 days fermentation, the 10% NaCl Pixian-Douban had significantly (p < 0.05) higher levels of total organic acids (20,308.25 mg/kg), amino metabolites (28,144.96 mg/kg), and volatiles (3.36 mg/kg) compared to 15% and 20% NaCl Pixian-Douban. Notably, the possible health risk associated with high concentration of biogenic amines in 10% NaCl Pixian-Douban is of concern. Moreover, correlation analyses indicated that the effect of NaCl on the quality of Pixian-Douban may be mainly related to bacteria. This study deepens the knowledge about the role of NaCl in ripening fermentation of Pixian-Douban and contributes to develop low-NaCl Pixian-Douban product.PMID:38531296 | DOI:10.1016/j.foodchem.2024.139052

J Agric Food Chem. 2024 Mar 26. doi: 10.1021/acs.jafc.3c07853. Online ahead of print.ABSTRACTFlammulina velutipes has two independent and functional mating type factors, HD and PR. The HD locus contains two separate subloci: HD-a and HD-b. In this study, we investigated the roles of Hd1 genes of the HD-a and HD-b subloci in the process of mating, clamp cell formation, and regulation of FvClp1 (F. velutipes clampless1 gene) gene expression in F. velutipes. To this end, we introduced Hd1 genes from mating compatible strains into F. velutipes monokaryon L11. Overexpression of Hd1 gene FvHd-a1-1 of the HD-a sublocus resulted in the formation of pseudoclamps in L11 monokaryons. L11 mutants overexpressing the Hd1 gene FvHd-b1-2 of the HD-b sublocus also similarly developed pseudoclamps in the L11 monokaryons. Moreover, these mutant L11 monokaryons produced complete clamps when crossed with monokaryotic strains that differed at the PR loci, i.e., when selective activation of the PR pathway was obtained through crossing. Thus, Hd1 genes of the two different HD subloci in F. velutipes can activate the HD mating type pathway and induce clamp cell formation. In addition, activation of the HD pathway resulted in upregulation of the FvClp1 gene. Finally, to complete clamp cell formation, activation of the PR pathway appears to be essential. Overall, these findings were beneficial for deepening our understanding of sexual reproduction and fruiting body development of edible fungi.PMID:38530934 | DOI:10.1021/acs.jafc.3c07853