PubMed

Front Microbiol. 2024 Oct 9;15:1420922. doi: 10.3389/fmicb.2024.1420922. eCollection 2024.ABSTRACTWalnut (Juglans spp.), a significant deciduous tree of economic and ecological importance, faces substantial threats from walnut anthracnose, primarily caused by Colletotrichum gloeosporioides. Bacillus velezensis has shown promise in mitigating this fungal pathogen. To delve deeper into the induction mechanism of B. velezensis on walnut plant resistance, we conducted a metabolomic analysis on walnut leaves from six different treatment groups. Specifically, the groups were defined as follows: Group B.v. was inoculated with B. velezensis alone, Group CK served as the blank control, and Group C.g. was inoculated solely with C. gloeosporioides. Group B.v.-C.g. received B. velezensis followed by C. gloeosporioides inoculation. Group B.v.+C.g. underwent simultaneous inoculation with both B. velezensis and C. gloeosporioides, while Group C.g.-B.v. was treated first with C. gloeosporioides then B. velezensis. A total of 1,503 metabolites were detected, mainly including flavonoids, terpenoids, and steroids. The results revealed that B. velezensis spraying not only enhanced the inherent resistance of walnut plants but also significantly regulated walnut plants already infected with C. gloeosporioides. This was mainly achieved by inducing walnut plants to adjust their metabolic pathways such as salicylic acid, jasmonic acid, and abscisic acid, thereby strengthening their stress response. Transcriptomic and metabolomic correlation analyses showed that in the comparisons of B.v. vs. CK, C.g. vs. CK, and C.g.-B.v. vs. C.g., 59, 244, and 122 differential abundance metabolites were detected, along with 7860, 3677, and 5587 differential genes, respectively. Amino acid synthesis, starch and sucrose metabolism, photosynthesis, phenylpropane metabolism, purine metabolism, and glutathione metabolism played crucial roles in walnut's disease resistance mechanism. Further analysis revealed that B. velezensis induced walnut plants to regulate multiple genes, such as LOC109005403, LOC108985444 and LOC118344177, resulting in the production of defensive metabolites such as palmitic acid, coumarin and ferulic acid, thereby enhancing their resistance to C. gloeosporioides. In summary, B. velezensis induces systemic resistance in walnut plants by modulating the metabolic pathways of salicylic acid, jasmonic acid, and abscisic acid. It enhances this resistance by strengthening cell walls, synthesizing defensive secondary metabolites, and regulating energy metabolism and stress responses. These findings provide a solid theoretical foundation for the future field application of B. velezensis in controlling walnut anthracnose.PMID:39444687 | PMC:PMC11496756 | DOI:10.3389/fmicb.2024.1420922

Front Microbiol. 2024 Oct 9;15:1467841. doi: 10.3389/fmicb.2024.1467841. eCollection 2024.ABSTRACTBACKGROUND: The ability of yaks to adapt to the extreme environment of low temperatures and hypoxia at cold seasons on the Qinghai-Tibet Plateau (QTP) is related to the host genome; however, the convergent evolution of rumen microbiomes in host adaption is unknown.METHODS: Here, we conducted a multi-omics study on the rumen fluid of grazing yaks from warm (July) and cold (December) seasons on the QTP to evaluate the convergent evolution of rumen microbiomes in the adaptation of grazing yaks to cold-seasons environments.RESULTS: The results showed that grazing yaks at cold seasons had higher fibrolytic enzyme activities and volatile fatty acids (VFAs) concentrations, and the relative abundance of Firmicutes and the ratio Firmicutes to Bacteroidetes was significantly higher than that of yaks at warm seasons. Macrogenomic analyses showed that genes involved in forming VFAs and arginine were significantly enriched in cold-season yaks. Transcriptome analyses of the rumen epithelium showed that 72 genes associated with VFAs absorption and transport were significantly upregulated in cold-season yaks. Metabolomic analyses showed that the levels of ornithine, related to efficient nitrogen utilization, were significantly upregulated in cold-season yaks.CONCLUSION: The synergistic role of rumen microbiomes in the adaptation of grazing yaks to extreme environments at cold seasons was revealed by multi-omics study.PMID:39444681 | PMC:PMC11496799 | DOI:10.3389/fmicb.2024.1467841

Front Cardiovasc Med. 2024 Oct 9;11:1430477. doi: 10.3389/fcvm.2024.1430477. eCollection 2024.ABSTRACTBACKGROUND: Prior research has established a correlation between immune cell activity and heart failure (HF), but the causal nature of this relationship remains unclear. Furthermore, the potential influence of metabolite levels on this interaction has not been comprehensively explored. To address these gaps, we employed a bidirectional Mendelian randomization (MR) approach in two stages to examine whether metabolite levels can mediate the causal relationship between immune cells and HF.METHODS: Genetic information was extracted from summary data of genome-wide association studies. By applying a two-sample, two-step MR approach, we investigated the causal relationships among immune cells, metabolite levels, and HF, with a specific focus on the mediating effects of metabolites. Sensitivity analysis techniques were implemented to ensure the robustness of our findings.RESULTS: MR analysis revealed significant causal associations between HF and eight specific immune cells and five metabolites. Mediation analysis further identified three mediated relationships. Particularly, hexadecenedioate (C16:1-DC) mediated the influence of both the CD28- CD127- CD25++ CD8br%CD8br (mediation proportion: 19.2%) and CD28+ CD45RA + CD8br%T cells (mediation proportion: 11.9%) on HF. Additionally, the relationship between IgD + CD38br AC cells and HF appeared to be mediated by the phosphate to alanine ratio (mediation proportion: 16.3%). Sensitivity analyses validated that the used instrumental variables were free from pleiotropy and heterogeneity.CONCLUSION: This study provides evidence that certain immune cell levels are associated with the risk of HF and that metabolite levels may mediate these relationships. However, to strengthen these findings, further validation using MR analyses with larger sample sizes is essential.PMID:39444553 | PMC:PMC11496177 | DOI:10.3389/fcvm.2024.1430477

Front Bioeng Biotechnol. 2024 Oct 9;12:1468974. doi: 10.3389/fbioe.2024.1468974. eCollection 2024.ABSTRACTNon-proteinogenic amino acids (npAAs) are valuable building blocks for the development of advanced pharmaceuticals and agrochemicals. The surge in interest in their synthesis is primarily due to the potential to enhance and diversify existing bioactive molecules. This can be achieved by altering these bioactive molecules to improve their effectiveness, reducing resistance compared to their natural counterparts or generating molecules with novel functions. Traditional production of npAAs in native hosts requires specialized conditions and complex cultivation media. Furthermore, these compounds are often found in organisms that challenge genetic manipulation. Thus, the recombinant production of these npAAs in a model organism like Escherichia coli paves the way for groundbreaking advancements in synthetic biology. Two synthetic operons, comprising of five heterologous proteins were genomically integrated into E. coli for the synthesis of npAAs β-methylphenylalanine (BmePhe), β-hydroxyenduracididine (BhEnd), and enduracididine (End). Proteomic and metabolomic analysis confirmed production of these compounds in E. coli for the first time. Interestingly, we discovered that the exogenous addition of pathway precursors to the E. coli system enhanced the yield of BmePhe by 2.5 times, whereas it concurrently attenuated the production of BhEnd and End, signifying a selective precursor-dependent yield enhancement. The synthetic biology landscape is broadened in this study by expanding the repertoire of amino acids beyond the conventional set of 22 standard proteinogenic amino acids. The biosynthesized npAAs, End, BhEnd, and BmePhe hold promise for engineering proteins with modified functions, integrating into novel metabolites and/or enhancing biological stability and activity. Additionally, these amino acids' biological production and subsequent purification present an alternative to traditional chemical synthesis methods, paving a direct pathway for pharmacological evaluation.PMID:39444519 | PMC:PMC11496134 | DOI:10.3389/fbioe.2024.1468974

Front Endocrinol (Lausanne). 2024 Oct 9;15:1476774. doi: 10.3389/fendo.2024.1476774. eCollection 2024.ABSTRACTBACKGROUND: Recurrent pregnancy loss (RPL) affects women's reproductive health seriously, with immune dysfunction playing a key role in its cause, yet the exact mechanisms remain elusive. We aim to investigate potential mechanisms and identify biomarkers linked to RPL.METHODS: Immune cytokine testing and metabolomic profiling were conducted on the serum of 34 RPL patients and 30 healthy individuals. The metabolic pathways of the differential metabolites were analyzed, and specific metabolites were validated through targeted profiling. Potential biomarkers were identified, and the relationships between immune cytokines and differential metabolites were explored.RESULTS: In the RPL group, serum interleukin-6 and interleukin-10 levels were significantly higher, while interleukin-2 and interferon-γ were significantly lower. A total of 296 differential metabolites were detected by untargeted metabolomic profiling between the RPL and control groups, with most linked to amino acid metabolism. Targeted metabolomic profiling of amino acid metabolism revealed upregulation of indole-3-acetic acid, tyrosine, glycine, isoleucine, tryptophan, lysine, aspartic acid, arginine, leucine, threonine, glutamic acid, cystine, and phenylpyruvic acid (PPA) in the RPL group. Moreover, PPA and 5-hydroxy-L-tryptophan showed great potential in predicting RPL in a diagnostic model. Cystine and tyrosine were associated with immune cytokines in correlation analysis.CONCLUSION: The study highlights the role of amino acid metabolism in RPL pathogenesis, suggesting that PPA and 5-HTP may be potential predictive indicators, while cystine and tyrosine may potentially regulate immune responses related to RPL. Further investigation into the molecular mechanisms underlying these findings could potentially result in the creation of novel diagnostic and therapeutic approaches for RPL.PMID:39444455 | PMC:PMC11496058 | DOI:10.3389/fendo.2024.1476774

Mol Plant. 2024 Oct 23:S1674-2052(24)00331-9. doi: 10.1016/j.molp.2024.10.009. Online ahead of print.ABSTRACTBioactive compounds are playing an increasingly prominent role in breeding functional and nutritive fruit crops such as citrus. However, the genomic and metabolic basis for the selection and differentiation underlying bioactive compounds variations in citrus remain poorly understood. Here, we constructed a species-level variation atlas of genomes and metabolomes using 299 citrus accessions. A total of 19,829 significant SNPs were targeted to 653 annotated metabolites, among which multiple significant signals were identified for secondary metabolites, especially flavonoids. Significantly differential accumulation of bioactive compounds in phenylpropane pathway, mainly flavonoids and coumarins, were unveiled across ancestral citrus species during differentiation, which is likely associated with the divergent haplotype distribution and/or expression profiles of relevant genes, including p-coumaroyl coenzyme A 2'-hydroxylases, flavone synthases, cytochrome P450 enzymes, prenyltransferases and UDP-glycosyltransferases. Moreover, we elucidated the citrus varieties with excellent antioxidant and anticancer capacities, clarifying the robust associations between distinct bioactivities and specific metabolites. Thus, these findings provide citrus breeding options for enrichment of beneficial flavonoids and avoidance of the potential risk of coumarins. This study will illuminate the application of genomic and metabolic engineering strategies in developing modern healthy citrus cultivars.PMID:39444162 | DOI:10.1016/j.molp.2024.10.009

Metallomics. 2024 Oct 23:mfae048. doi: 10.1093/mtomcs/mfae048. Online ahead of print.ABSTRACTStreptomyces scabiei is the causative agents of common scab on root and tuber crops. Life in the soil imposes intense competition between soil-dwelling microorganisms and we evaluated here the antimicrobial properties of S. scabiei. Under laboratory culture conditions, increasing peptone levels correlated with increased growth inhibitory properties of S. scabiei. Comparative metabolomics showed that production of S. scabiei siderophores (desferrioxamines, pyochelin, scabichelin and turgichelin) increased with the quantity of peptone thereby suggesting that they participate in growth inhibition. Mass spectrometry imaging further confirmed that the zones of secreted siderophores and growth inhibition coincided. Moreover, either the repression of siderophore production or the neutralization of their iron-chelating activity both led to increased microbial growth. Replacement of peptone by natural nitrogen sources regularly used as fertilizers such as ammonium nitrate, ammonium sulfate, sodium nitrate, and urea also triggered siderophore production in S. scabiei. The observed effect is not mediated by alkalinization of the medium as increasing the pH without providing additional nitrogen sources did not induce siderophore production. The nitrogen-induced siderophore production also inhibited the growth of important plant pathogens. Overall, our work suggests that not only the iron availability but also the nitrogen fertilizer sources could significantly impact the competition for iron between crop-colonizing microorganisms.PMID:39444076 | DOI:10.1093/mtomcs/mfae048

Anal Bioanal Chem. 2024 Oct 24. doi: 10.1007/s00216-024-05588-z. Online ahead of print.ABSTRACTUntargeted metabolomics UHPLC-HRMS workflows typically employ narrowbore 2.1-mm inner diameter (i.d.) columns. However, the wide concentration range of the metabolome and the need to often analyze small sample amounts poses challenges to these approaches. Reducing the column diameter could be a potential solution. Herein, we evaluated the performance of a microbore 1.0-mm i.d. setup compared to the 2.1-mm i.d. benchmark for untargeted metabolomics. The 1.0-mm i.d. setup was implemented on a micro-UHPLC system, while the 2.1-mm i.d. on a standard UHPLC, both coupled to quadrupole-orbitrap HRMS. On polar standard metabolites, a sensitivity gain with an average 3.8-fold increase over the 2.1-mm i.d., along with lower LOD (LODavg 1.48 ng/mL vs. 6.18 ng/mL) and LOQ (LOQavg 4.94 ng/mL vs. 20.60 ng/mL), was observed. The microbore method detected and quantified all metabolites at LLOQ with respect to 2.1, also demonstrating good repeatability with lower CV% for retention times (0.29% vs. 0.63%) and peak areas (4.65% vs. 7.27%). The analysis of various samples, in both RP and HILIC modes, including different plasma volumes, dried blood spots (DBS), and colorectal cancer (CRC) patient-derived organoids (PDOs), in full scan-data dependent mode (FS-DDA) reported a significant increase in MS1 and MS2 features, as well as MS/MS spectral matches by 38.95%, 39.26%, and 18.23%, respectively. These findings demonstrate that 1.0-mm i.d. columns in UHPLC-HRMS could be a potential strategy to enhance coverage for low-amount samples while maintaining the same analytical throughput and robustness of 2.1-mm i.d. formats, with reduced solvent consumption.PMID:39443364 | DOI:10.1007/s00216-024-05588-z

Prostate. 2024 Oct 23. doi: 10.1002/pros.24815. Online ahead of print.ABSTRACTBACKGROUNDS: SWI/SNF complexes represent a family of multi-subunit chromatin remodelers that are affected by alterations in >20% of human tumors. While mutations of SWI/SNF genes are relatively uncommon in prostate cancer (PCa), the literature suggests that deregulation of various subunits plays a role in prostate tumorigenesis. To assess SWI/SNF functions in a clinical context, we studied the mutually exclusive, paralogue accessory subunits SMARCD1, SMARCD2, and SMARCD3 that are included in every known complex and are sought to confer specificity.METHODS: Performing immunohistochemistry (IHC), the protein levels of the SMARCD family members were measured using a tissue microarray (TMA) comprising malignant samples and matching healthy tissue of non-metastatic PCa patients (n = 168). Moreover, IHC was performed in castration-resistant tumors (n = 9) and lymph node metastases (n = 22). To assess their potential role as molecular biomarkers, SMARCD1 and SMARCD3 protein levels were correlated with clinical parameters such as T stage, Gleason score, biochemical recurrence, and progression-free survival.RESULTS: SMARCD1 protein levels in non-metastatic primary tumors, lymph node metastases, and castration-resistant samples were significantly higher than in benign tissues. Likewise, SMARCD3 protein expression was elevated in tumor tissue and especially lymph node metastases compared to benign samples. While SMARCD1 levels in primary tumors did not exhibit significant associations with any of the tested clinical parameters, SMARCD3 exhibited an inverse correlation with pre-operative PSA levels. Moreover, low SMARCD3 expression was associated with progression to metastasis.CONCLUSIONS: In congruence with previous literature, our results implicate that both SMARCD1 and SMARCD3 may exhibit relevant functions in the context of prostate tumorigenesis. Moreover, our approach suggests a potential role of SMARCD3 as a novel prognostic marker in clinically non-metastatic PCa.PMID:39442954 | DOI:10.1002/pros.24815

J Adv Res. 2024 Oct 21:S2090-1232(24)00472-7. doi: 10.1016/j.jare.2024.10.017. Online ahead of print.ABSTRACTINTRODUCTION: Gut microbial homeostasis is closely associated with myocardial infarction (MI). However, little is known about how gut microbiota influences miRNAs-regulated MI.OBJECTIVES: This study aims to elucidate the connections between miR-30a-5p, MI, gut microbiota, and gut microbial metabolite-related pathways, to explore potential strategy for preventing and treating MI.METHODS: We evaluated the effects of knocking out (KO) or overexpressing (OE) miR-30a-5p on MI by assessing cardiac structure and function, myocardial enzyme levels, and apoptosis. Then, we applied 16S rDNA sequencing and metabolomics to explore how intestinal microecology and its microorganisms affect miR-30a-5p-regulated MI.RESULTS: The results showed that KO exacerbated MI, whereas OE improved MI damage, compared to the wild-type (WT) mice. KO exacerbated intestinal barrier structure deterioration and further downregulated the expression of Cloudin-1, Occludin, and ZO-1 in MI mice. 16S rDNA sequencing-analyzed gut microbiome of KO and WT mice found that KO mainly reduced g_Lactobacillus. Transplanting fecal microorganisms from KO mice aggravated MI damage in WT mice. However, administering probiotics (mainly containing lactobacilli) helped neutralize these damages. Intriguingly, fecal microbiota transplantation from OE mice reduced MI damage. Analysis of intestinal microbial metabolites in KO and WT mice found that KO may mainly affect ABC transporters. ABCC1 was identified as the target of KO-aggravated MI. Furthermore, fecal transplantation microorganisms of MI patients aggravated MI injury in mice and miR-30a-5p and ABCC1 were involved in the process.CONCLUSIONS: Our findings demonstrate that miR-30a-5p regulates MI by affecting intestinal microbiota homeostasis and targeting ABCC1. This highlights the critical importance of maintaining a healthy gut microbiota homeostasis in MI management.PMID:39442873 | DOI:10.1016/j.jare.2024.10.017

N Biotechnol. 2024 Oct 21:S1871-6784(24)00552-1. doi: 10.1016/j.nbt.2024.10.002. Online ahead of print.ABSTRACTPlants face multiple challenges from environmental pollutants and higher emissions of atmospheric CO2. Therefore, a hydroponic-based experiment was used to explore the combined effects of elevated [CO2] (700 ppm) and exogenous cyanide (CN-) (3.0mg CN/L) on rice seedlings under nitrogen deficiency, utilizing metabonomics and transcriptomic analysis. Elevated [CO2] significantly improved the growth of CN--treated rice seedlings compared to those with ambient [CO2] (350 ppm), and it also significantly affected CN- assimilation. Transcriptome analysis revealed distinct impacts on differentially expressed genes (DEGs) across treatments and tissues. KEGG analysis showed variability in DEGs enriched in amino acid (AA) and energy metabolism pathways due to elevated [CO2] and CN-. Metabonomics indicated that higher input of [CO2] and exogenous CN- more severely impacted energy metabolism elements than the individual species of AAs. Positive synergistic effects of elevated [CO2] and CN- were observed for glutamine and asparagine in shoots, and methionine in roots, wherein negative effects were noted for phenylalanine in shoots, and phenylalanine, valine, and alanine in roots. Meanwhile, positive effects on fumarate in shoots and α-ketoglutarate and succinate in roots were also found. Overall, elevated [CO2] enhances growth in CN--treated rice seedlings under nitrogen deficiency by altering AA and energy metabolism. This is the first attempt to provide new evidence of [CO2]-based gaseous fertilization as an energy-saving strategy for rice plants fed with biodegradable N-containing pollutants as a supporting N source under N deficient conditions.PMID:39442870 | DOI:10.1016/j.nbt.2024.10.002

Biomed J. 2024 Oct 21:100802. doi: 10.1016/j.bj.2024.100802. Online ahead of print.ABSTRACTHyperpolarized (HP) magnetic resonance imaging (MRI) is a groundbreaking imaging platform advancing from research to clinical practice, offering new possibilities for real-time, non-invasive metabolic imaging. This review explores the latest advancements, challenges, and future directions of HP MRI, emphasizing its transformative impact on both translational research and clinical applications. By employing techniques such as dissolution Dynamic Nuclear Polarization (dDNP), Parahydrogen-Induced Polarization (PHIP), Signal Amplification by Reversible Exchange (SABRE), and Spin-Exchange Optical Pumping (SEOP), HP MRI achieves enhanced nuclear spin polarization, enabling in vivo visualization of metabolic pathways with exceptional sensitivity. Current challenges, such as limited imaging windows, complex pre-scan protocols, and data processing difficulties, are addressed through innovative solutions like advanced pulse sequences, bolus tracking, and kinetic modeling. We highlight the evolution of HP MRI technology, focusing on its potential to revolutionize disease diagnosis and monitoring by revealing metabolic processes beyond the reach of conventional MRI and positron emission tomography (PET). Key advancements include the development of novel tracers like [2-13C]pyruvate and [1-13C]-alpha-ketoglutarate and improved data analysis techniques, broadening the scope of clinical metabolic imaging. Future prospects emphasize integrating artificial intelligence, standardizing imaging protocols, and developing new hyperpolarized agents to enhance reproducibility and expand clinical capabilities particularly in oncology, cardiology, and neurology. Ultimately, we envisioned HP MRI as a standardized modality for dynamic metabolic imaging in clinical practice.PMID:39442802 | DOI:10.1016/j.bj.2024.100802

Environ Res. 2024 Oct 22:120211. doi: 10.1016/j.envres.2024.120211. Online ahead of print.ABSTRACTThe combined pollution of polycyclic aromatic hydrocarbons (PAHs) and heavy metals (HMs) has attracted wide attention due to their high toxicity, mutagenicity, carcinogenicity and teratogenicity. A thorough understanding of the progress of the relevant studies about their co-toxicity and co-contamination remediation is of great importance to prevent environmental risk and develop new efficient remediation methods. This paper summarized the factors resulting in different co-toxic effects, the interaction mechanism influencing co-toxicity and the development of remediation technologies for the co-contamination. Also, the inadequacies of the previous studies related to the co-toxic effect and the remediation methods were pointed out, while the corresponding solutions were proposed. The specific type and concentration of PAHs and HMs, the specific type of their action object and environmental factors could affect their co-toxicity by influencing each other's transmembrane process, detoxification process and increasing reactive oxygen species (ROS) and some other mechanisms that need to be further studied. The specific action mechanisms of the concentration, environmental factors and the specific type of PAHs and HMs, their effect on each other's transmembrane processes, investigations at the cellular and molecular levels, non-targeted metabolomics analysis, as well as long-term ecological effects were proposed to be further explored in order to obtain more information about the co-toxicity. The combination of two or more methods, especially combining bioremediation with other methods, is a potential development field for the remediation of co-contamination. It can make full use of the advantages of each remediation method, to achieve an increase of remediation efficiency and a decrease of both remediation cost and ecological risk. This review intends to further improve the understanding on co-toxicity and provide references for the development and innovation of remediation technologies for the co-contamination of PAHs and HMs.PMID:39442665 | DOI:10.1016/j.envres.2024.120211

Toxicon. 2024 Oct 21:108137. doi: 10.1016/j.toxicon.2024.108137. Online ahead of print.ABSTRACTSome of the most commonly identified freshwater toxins are anatoxin-a (ATX-a), cylindrospermopsin (CYN), and microcystin-LR (MC-LR). The aim of this paper was to compare different methods of extracting and concentrating these cyanotoxins and check the impact of selected physical factors on the accumulation of biomass of Dolichospermum flos-aquae, Microcystis aeruginosa, and Raphidiopsis raciborskii. The effect of different cyanobacteria cultivation conditions on the amount of cyanotoxins synthesized showed no significant changes over time in the average concentration of all tested toxins in the medium compared to the control. Mixing cultures increases the intracellular content of ATX-a. Aerating also positively affects the concentration of MC-LR intracellularly. In order to optimize the solid phase extraction (SPE) process of toxins, the C18 phase or activated carbon was used. In general, higher toxin recoveries were achieved when using the C18 phase. The best result was achieved for ATX-a, 94% recovery with elution using methanol with 0.1% trifluoroacetic acid (TFA). For MC-LR, the best recovery was 59%, and for CYN 22%. The study evaluated the various methods to release cyanotoxins from cyanobacteria showed that: the highest ATX-a concentration (0.60 μg/mg d.w) was obtained using MilliQ water and microwave treatment for 10 to 15 seconds. For MC-LR, the highest extracted amount (6.73 μg/mg d.w) resulted from methanol treatment and boiling at 100°C for 15 minutes. CYN extraction was the most effective by using MilliQ water and alternative freezing/thawing (1.54 μg/mg d.w). In conclusion, changing the optimal parameters of cyanobacterial cultivation, only slightly affects the increase in biomass accumulation and synthesis of cyanobacterial toxins. In the case of ATX, the key is the use of the TFA additive in the SPE process. No single method has been identified as the ideal approach for isolating various intracellular cyanotoxins.PMID:39442567 | DOI:10.1016/j.toxicon.2024.108137

Cell Metab. 2024 Oct 18:S1550-4131(24)00395-4. doi: 10.1016/j.cmet.2024.09.013. Online ahead of print.ABSTRACTObesity is a major risk factor for poor breast cancer outcomes, but the impact of obesity-induced tumor microenvironment (TME) metabolites on breast cancer growth and metastasis remains unclear. Here, we performed TME metabolomic analysis in high-fat diet (HFD) mouse models and found that glutathione (GSH) levels were elevated in the TME of obesity-accelerated breast cancer. The deletion of glutamate-cysteine ligase catalytic subunit (GCLC), the rate-limiting enzyme in GSH biosynthesis, in adipocytes but not tumor cells reduced obesity-related tumor progression. Mechanistically, we identified that GSH entered tumor cells and directly bound to lysosomal integral membrane protein-2 (scavenger receptor class B, member 2 [SCARB2]), interfering with the interaction between its N and C termini. This, in turn, recruited mTORC1 to lysosomes through ARF1, leading to the activation of mTOR signaling. Overall, we demonstrated that GSH links obesity and breast cancer progression by acting as an activator of mTOR signaling. Targeting the GSH/SCARB2/mTOR axis could benefit breast cancer patients with obesity.PMID:39442522 | DOI:10.1016/j.cmet.2024.09.013

Am J Hum Genet. 2024 Oct 21:S0002-9297(24)00368-9. doi: 10.1016/j.ajhg.2024.09.008. Online ahead of print.ABSTRACTBalancing the tradeoff between quantity and quality of phenotypic data is critical in omics studies. Measurements below the limit of quantification (BLQ) are often tagged in quality control fields, but these flags are currently underutilized in human genetics studies. Extreme phenotype sampling is advantageous for mapping rare variant effects. We hypothesize that genetic drivers, along with environmental and technical factors, contribute to the presence of BLQ flags. Here, we introduce "hypometric genetics" (hMG) analysis and uncover a genetic basis for BLQ flags, indicating an additional source of genetic signal for genetic discovery, especially from phenotypic extremes. Applying our hMG approach to n = 227,469 UK Biobank individuals with metabolomic profiles, we reveal more than 5% heritability for BLQ flags and report biologically relevant associations, for example, at APOC3, APOA5, and PDE3B loci. For common variants, polygenic scores trained only for BLQ flags predict the corresponding quantitative traits with 91% accuracy, validating the genetic basis. For rare coding variant associations, we find an asymmetric 65.4% higher enrichment of metabolite-lowering associations for BLQ flags, highlighting the impact of putative loss-of-function variants with large effects on phenotypic extremes. Joint analysis of binarized BLQ flags and the corresponding quantitative metabolite measurements improves power in Bayesian rare variant aggregation tests, resulting in an average of 181% more prioritized genes. Our approach is broadly applicable to omics profiling. Overall, our results underscore the benefit of integrating quality control flags and quantitative measurements and highlight the advantage of joint analysis of population-based samples and phenotypic extremes in human genetics studies.PMID:39442521 | DOI:10.1016/j.ajhg.2024.09.008

J Pharm Biomed Anal. 2024 Oct 17;253:116521. doi: 10.1016/j.jpba.2024.116521. Online ahead of print.ABSTRACTMetastasis is the leading cause of mortality in cervical cancer (CC), with a particular prevalence of lymph node and lung metastases. Patients with CC who have developed distant metastases typically face a poor prognosis, and there is a scarcity of non-invasive strategies for predicting CC metastasis. In this study, we utilized label-free proteomics and untargeted metabolomics to analyze plasma samples from 25 non-metastatic, 14 with lung metastasis, and 15 with lymph node metastasis CC patients. Pathway enrichment analysis revealed a shared inflammatory process between the two metastatic groups, while the central carbon metabolism in cancer showed distinct features in the lung metastasis cohort. Additionally, cholesterol metabolism, hypoxia-inducible factor 1, and ferroptosis signaling pathways were specifically altered in the lymph node metastasis group. Utilizing the receiver operating characteristic curve analysis and Random Forest algorithm, we identified two distinct biomarker panels for the prediction of lung metastasis and lymph node metastasis, respectively. The lung metastasis panel includes properdin, neural cell adhesion molecule 1, and keratin 6 A, whereas the lymph node metastasis panel consists of quiescin sulfhydryl oxidase 1, paraoxonase 1, and keratin 6 A. Each panel exhibited significant diagnostic potential, with high area under the curve (AUC) values for lung metastasis (training set: 0.989, testing set: 0.789) and lymph node metastasis (training set: 0.973, testing set: 0.900). This study conducted an integrated proteomic and metabolomic analysis to clarify the factors contributing to lung and lymph node metastases in CC and has successfully established two biomarker panels for their prediction.PMID:39442446 | DOI:10.1016/j.jpba.2024.116521

Animal. 2024 Sep 24;18(11):101343. doi: 10.1016/j.animal.2024.101343. Online ahead of print.ABSTRACTLaying ducks in cage environments face various stressors, including the fear of novelty, which negatively affects their behaviour and performance. The reasons behind the variation in behaviour under identical stress conditions are not well understood. This study investigated how different behaviours affect production performance, immune response, antioxidant capabilities, adrenal gene expression, and serum metabolite profiles in caged laying ducks subjected to the same stressor. Overall, 42-week-old laying ducks (N = 300) were selected, fed for 60 days, and simultaneously underwent behavioural tests. Based on their behavioural responses, 24 ducks were chosen and categorised into two groups: high-active avoidance (HAA) and low-active avoidance (LAA). The study utilised phenotypic, genetic, and metabolomic analyses, coupled with bioinformatics, to identify crucial biological processes, genes, and metabolites. The results indicated that ΔW (BW gain) and average daily egg weight (ADEW) were significantly lower in the HAA group compared to the LAA group (P < 0.05). By contrast, the feed-to-egg ratio was higher in the HAA group than in the LAA group (P < 0.05). Levels of serum immunoglobulin A, total antioxidant capacity, and the activities of enzymes like superoxide dismutase and catalase (CAT) were significantly lower in the HAA than in the LAA group (P < 0.05), whereas serum ACTH levels were significantly higher in HAA than in the LAA group (P < 0.05). The adrenal transcriptome analysis revealed 148 differentially expressed genes in the HAA group, with 97 up-regulated and 51 down-regulated. Moreover, enrichment analysis highlighted significant differences in two metabolic pathways: neuroactive ligand-receptor interaction and oxidative phosphorylation (P < 0.05). Serum metabolomics identified 11 differentially accumulated metabolites between the groups, with variations in up and down-regulation. Integrative analysis of phenotype, transcriptome, and metabolome data showed a strong correlation between the exosome component 3 (EXOSC3) gene, phenotypic traits, and differential metabolites. Thus, we deduced that the differences in average daily egg weight among ducks could be linked to variations in gabapentin and EXOSC3 gene expressions, affecting serum CAT levels.PMID:39442284 | DOI:10.1016/j.animal.2024.101343

Phytomedicine. 2024 Oct 9;135:156128. doi: 10.1016/j.phymed.2024.156128. Online ahead of print.ABSTRACTBACKGROUND: Cisplatin-induced acute kidney injury (AKI) is a complex and serious clinical issue, representing a major cause of hospital-acquired AKI. Alkaloids are the main active constituents of Aconitum carmichaelii Debx, which exhibit protective effects in several kidney disease models and against other acute organ injuries. However, its activity and mechanism of action in AKI treatment remain unclear.PURPOSE: This study aimed to elucidate the effect of Aconitum carmichaelii Debx (ACA) in a model of cisplain-induced AKI and comprehensively investigate its underlying mechanisms.METHODS: The major alkaloids in ACA were analyzed using high-performance liquid chromatography. Blood urea nitrogen (BUN) and serum creatine levels were measured using automated biochemical instruments. 16S rRNA sequencing, short-chain fatty acid (SCFA) analysis, fecal microbiota transplantation (FMT), non-targeted metabolomics, and transcriptomics were performed to systematically identify prospective biomarkers after ACA treatment. Anti-inflammatory and anti-oxidative stress activities were monitored using ELISA and western blotting.RESULTS: Four main compounds (fuziline, neoline, talatisamine, and songorine) were identified in ACA. ACA significantly alleviated cisplatin-induced AKI by reducing (BUN) and serum creatine levels and improving histopathological scores. Moreover, ACA balanced cisplatin-mediated confoundments in microbial composition and function, including decreasing the levels of Escherichia-Shigella, Clostridium, and Ruminococcus, as well as increasing Ligilactobacillus, Anaerotruncus, Bacteroides and Desulfovibrio levels, accompanied by uremic toxin reduction, and augmenting serum SCFAs. The FMT experiments further confirmed that ACA exerts anti-AKI effects by affecting gut microbiota. A multi-omics study has shown that ACA regulates glutathione and tryptophan metabolism and mediates pathways that trigger inflammatory responses. Finally, ACA reduced serum levels of inflammatory factors (IL-1β, IL-6, and TNF-α), restored enzymes of the antioxidative system (SOD and CAT) and GSH values, and decreased monoester diterpene alkaloid levels in the kidney by inhibiting the expression of NF-κB pathway-related proteins and increasing Nrf2/HO-1 pathway-related protein expression.CONCLUSION: ACA protects against cisplatin-induced AKI through its anti-inflammatory and antioxidant functions, which may be associated with the restoration of gut microbiota metabolism. ACA is a potential drug for AKI and other forms of organ damage related to the disruption of the gut microbiota.PMID:39442279 | DOI:10.1016/j.phymed.2024.156128

Food Chem. 2024 Oct 19;464(Pt 2):141728. doi: 10.1016/j.foodchem.2024.141728. Online ahead of print.ABSTRACTTo illustrate the mechnism of the better flavor and color in combined fermented sausages than single fermentation with L. sakei, the growth behavior, pH, and metabolomics of L. sakei in single fermentation and in combination with S. carnosus at 0, 3, 6, 12, 24, and 48 h were studied, and the sensory evaluation of fermented beef sausage was conducted. Through KEGG topology analysis found that L. sakei is related to caffeine metabolism and citrate cycle, L. sakei and S. carnosus are related to metabolism of purine metabolism, caffeine metabolism, and alanine, aspartate and glutamate metabolism. Compared with L. sakei fermentation alone, the compound fermentation with S. carnosus increased the content of asparagine. The content of the bitter substance tyrosine decreased during the compound fermentation. As starter cultures for the L. sakei applied to provide a basis for the fermented beef sausage.PMID:39442216 | DOI:10.1016/j.foodchem.2024.141728