PubMed

Environ Sci Technol. 2023 Dec 12. doi: 10.1021/acs.est.3c07020. Online ahead of print.ABSTRACTPer- and polyfluoroalkyl substances (PFAS) represent significant stress to organisms and are known to disrupt microbial community structure and function. Nevertheless, a detailed knowledge of the soil microbial community responding to PFAS stress at the metabolism level is required. Here we integrated UPLC-HRMS-based metabolomics data with 16S rRNA and ITS amplicon data across soil samples collected adjacent to a fluoropolymer production facility to directly identify the biochemical intermediates in microbial metabolic pathways and the interactions with microbial community structure under PFAS stress. A strong correlation between metabolite and microbial diversity was observed, which demonstrated significant variations in soil metabolite profiles and microbial community structures along with the sampling locations relative to the facility. Certain key metabolites were identified in the metabolite-PFAS co-occurrence network, functioning on microbial metabolisms including lipid metabolism, amino acid metabolism, and secondary metabolite biosynthesis. These results provide novel insights into the impacts of PFAS contamination on soil metabolomes and microbiomes. We suggest that soil metabolomics is an informative and useful tool that could be applied to reinforce the chemical evidence on the disruption of microbial ecological traits.PMID:38086098 | DOI:10.1021/acs.est.3c07020

Menopause. 2023 Dec 12. doi: 10.1097/GME.0000000000002287. Online ahead of print.ABSTRACTOBJECTIVE: This study aimed to identify menopause-related gut microbial features, as well as their related metabolites and inflammatory protein markers, and link with cardiometabolic risk factors in women with and without HIV.METHODS: In the Women's Interagency HIV Study, we performed shotgun metagenomic sequencing on 696 stool samples from 446 participants (67% women with HIV), and quantified plasma metabolomics and serum proteomics in a subset (~86%). We examined the associations of menopause (postmenopausal vs premenopausal) with gut microbial features in a cross-sectional repeated-measures design and further evaluated those features in relation to metabolites, proteins, and cardiometabolic risk factors.RESULTS: Different overall gut microbial composition was observed by menopausal status in women with HIV only. We identified a range of gut microbial features that differed between postmenopausal and premenopausal women with HIV (but none in women without HIV), including abundance of 32 species and functional potentials involving 24 enzymatic reactions and lower β-glucuronidase bacterial gene ortholog. Specifically, highly abundant species Faecalibacterium prausnitzii, Bacteroides species CAG:98, and Bifidobacterium adolescentis were depleted in postmenopausal versus premenopausal women with HIV. Menopause-depleted species (mainly Clostridia) in women with HIV were positively associated with several glycerophospholipids, while negatively associated with imidazolepropionic acid and fibroblast growth factor 21. Mediation analysis suggested that menopause may decrease plasma phosphatidylcholine plasmalogen C36:1 and C36:2 levels via reducing abundance of species F. prausnitzii and Acetanaerobacterium elongatum in women with HIV. Furthermore, waist-to-hip ratio was associated with menopause-related microbes, metabolites, and fibroblast growth factor 21 in women with HIV.CONCLUSIONS: Menopause was associated with a differential gut microbiome in women with HIV, related to metabolite and protein profiles that potentially contribute to elevated cardiometabolic risk.PMID:38086007 | DOI:10.1097/GME.0000000000002287

J Proteome Res. 2023 Dec 12. doi: 10.1021/acs.jproteome.3c00512. Online ahead of print.ABSTRACTPMart is a web-based tool for reproducible quality control, exploratory data analysis, statistical analysis, and interactive visualization of 'omics data, based on the functionality of the pmartR R package. The newly improved user interface supports more 'omics data types, additional statistical capabilities, and enhanced options for creating downloadable graphics. PMart supports the analysis of label-free and isobaric-labeled (e.g., TMT, iTRAQ) proteomics, nuclear magnetic resonance (NMR) and mass-spectrometry (MS)-based metabolomics, MS-based lipidomics, and ribonucleic acid sequencing (RNA-seq) transcriptomics data. At the end of a PMart session, a report is available that summarizes the processing steps performed and includes the pmartR R package functions used to execute the data processing. In addition, built-in safeguards in the backend code prevent users from utilizing methods that are inappropriate based on omics data type. PMart is a user-friendly interface for conducting exploratory data analysis and statistical comparisons of omics data without programming.PMID:38085827 | DOI:10.1021/acs.jproteome.3c00512

Planta. 2023 Dec 12;259(1):18. doi: 10.1007/s00425-023-04296-9.ABSTRACTLead disrupts plant metabolic homeostasis and key structural elements. Utilizing modern biotechnology tools, it's feasible to develop Pb-tolerant varieties by discovering biological players regulating plant metabolic pathways under stress. Lead (Pb) has been used for a variety of purposes since antiquity despite its toxic nature. After arsenic, lead is the most hazardous heavy metal without any known beneficial role in the biological system. It is a crucial inorganic pollutant that affects plant biochemical and morpho-physiological attributes. Lead toxicity harms plants throughout their life cycle and the extent of damage depends on the concentration and duration of exposure. Higher levels of lead exposure disrupt numerous key metabolic activities of plants including oxygen-evolving complex, organelles integrity, photosystem II connectivity, and electron transport chain. This review summarizes the detrimental effects of lead toxicity on seed germination, crop growth, and yield, oxidative and ultra-structural alterations, as well as nutrient absorption, transport, and assimilation. Further, it discusses the Pb-induced toxic modulation of stomatal conductance, photosynthesis, respiration, metabolic-enzymatic activity, osmolytes accumulation, and antioxidant activity. It is a comprehensive review that reports on omics-based studies along with morpho-physiological and biochemical modifications caused by lead stress. With advances in DNA sequencing technologies, genomics and transcriptomics are gradually becoming popular for studying Pb stress effects in plants. Proteomics and metabolomics are still underrated and there is a scarcity of published data, and this review highlights both their technical and research gaps. Besides, there is also a discussion on how the integration of omics with bioinformatics and the use of the latest biotechnological tools can aid in developing Pb-tolerant crops. The review concludes with core challenges and research directions that need to be addressed soon.PMID:38085368 | DOI:10.1007/s00425-023-04296-9

Microb Biotechnol. 2023 Dec 12. doi: 10.1111/1751-7915.14379. Online ahead of print.ABSTRACTTetracycline is a commonly used human and veterinary antibiotic that is mostly discharged into environment and thereby tetracycline-resistant bacteria are widely isolated. To combat these resistant bacteria, further understanding for tetracycline resistance mechanisms is needed. Here, GC-MS based untargeted metabolomics with biochemistry and molecular biology techniques was used to explore tetracycline resistance mechanisms of Edwardsiella tarda. Tetracycline-resistant E. tarda (LTB4-RTET ) exhibited a globally repressed metabolism against elevated proton motive force (PMF) as the most characteristic feature. The elevated PMF contributed to the resistance, which was supported by the three results: (i) viability was decreased with increasing PMF inhibitor carbonylcyanide-3-chlorophenylhydrazone; (ii) survival is related to PMF regulated by pH; (iii) LTB4-RTET were sensitive to gentamicin, an antibiotic that is dependent upon PMF to kill bacteria. Meanwhile, gentamicin-resistant E. tarda with low PMF are sensitive to tetracycline is also demonstrated. These results together indicate that the combination of tetracycline with gentamycin will effectively kill both gentamycin and tetracycline resistant bacteria. Therefore, the present study reveals a PMF-enhanced tetracycline resistance mechanism in LTB4-RTET and provides an effective approach to combat resistant bacteria.PMID:38085112 | DOI:10.1111/1751-7915.14379

ACS Synth Biol. 2023 Dec 12. doi: 10.1021/acssynbio.3c00363. Online ahead of print.ABSTRACTThe variability in phenotypic outcomes among biological replicates in engineered microbial factories presents a captivating mystery. Establishing the association between phenotypic variability and genetic drivers is important to solve this intricate puzzle. We applied a previously developed auxin-inducible depletion of hexokinase 2 as a metabolic engineering strategy for improved nerolidol production in Saccharomyces cerevisiae, and biological replicates exhibit a dichotomy in nerolidol production of either 3.5 or 2.5 g L-1 nerolidol. Harnessing Oxford Nanopore's long-read genomic sequencing, we reveal a potential genetic cause─the chromosome integration of a 2μ sequence-based yeast episomal plasmid, encoding the expression cassettes for nerolidol synthetic enzymes. This finding was reinforced through chromosome integration revalidation, engineering nerolidol and valencene production strains, and generating a diverse pool of yeast clones, each uniquely fingerprinted by gene copy numbers, plasmid integrations, other genomic rearrangements, protein expression levels, growth rate, and target product productivities. Τhe best clone in two strains produced 3.5 g L-1 nerolidol and ∼0.96 g L-1 valencene. Comparable genotypic and phenotypic variations were also generated through the integration of a yeast integrative plasmid lacking 2μ sequences. Our work shows that multiple factors, including plasmid integration status, subchromosomal location, gene copy number, sesquiterpene synthase expression level, and genome rearrangement, together play a complicated determinant role on the productivities of sesquiterpene product. Integration of yeast episomal/integrative plasmids may be used as a versatile method for increasing the diversity and optimizing the efficiency of yeast cell factories, thereby uncovering metabolic control mechanisms.PMID:38084917 | DOI:10.1021/acssynbio.3c00363

Pharm Biol. 2024 Dec;62(1):1-12. doi: 10.1080/13880209.2023.2289577. Epub 2023 Dec 12.ABSTRACTCONTEXT: Shenxiang Suhe pill (SXSH), a traditional Chinese medicine, is clinically effective against coronary heart disease, but the mechanism of cardiac-protective function is unclear.OBJECTIVE: We investigated the cardiac-protective mechanism of SXSH via modulating gut microbiota and metabolite profiles.MATERIALS AND METHODS: Sprague-Dawley (SD) male rats were randomly divided into 6 groups (n = 8): Sham, Model, SXSH (Low, 0.063 g/kg; Medium, 0.126 g/kg; High, 0.252 g/kg), and Ato (atorvastatin, 20 mg/kg). Besides the Sham group, rats were modelled with acute myocardial infarction (AMI) by ligating the anterior descending branch of the left coronary artery (LAD). After 3, 7, 14 days' administration, ultrasound, H&E staining, serum enzymic assay, 16S rRNA sequencing were conducted to investigate the SXSH efficacy. Afterwards, five groups of rats: Sham, Model, Model-ABX (AMI with antibiotics-feeding), SXSH (0.126 g/kg), SXSH-ABX were administrated for 14 days to evaluate the gut microbiota-dependent SXSH efficacy, and serum untargeted metabolomics test was performed.RESULTS: 0.126 g/kg of SXSH intervention for 14 days increased ejection fraction (EF, 78.22%), fractional shortening (FS, 109.07%), and aortic valve flow velocities (AV, 21.62%), reduced lesion area, and decreased serum LDH (8.49%) and CK-MB (10.79%). Meanwhile, SXSH upregulated the abundance of Muribaculaceae (199.71%), Allobaculum (1744.09%), and downregulated Lactobacillus (65.51%). The cardiac-protective effect of SXSH was disrupted by antibiotics administration. SXSH altered serum metabolites levels, such as downregulation of 2-n-tetrahydrothiophenecarboxylic acid (THTC, 1.73%), and lysophosphatidylcholine (lysoPC, 4.61%).DISCUSSION AND CONCLUSION: The cardiac-protective effect and suggested mechanism of SXSH could provide a theoretical basis for expanding its application in clinic.PMID:38084911 | DOI:10.1080/13880209.2023.2289577

J Inherit Metab Dis. 2023 Dec 12. doi: 10.1002/jimd.12696. Online ahead of print.ABSTRACTIn this study, we investigated the metabolic signatures of different mitochondrial defects (two different complex I and complex V, and the one MDH2 defect) in human skin fibroblasts (HSF). We hypothesized that using a selective culture medium would cause defect specific adaptation of the metabolome and further our understanding of the biochemical implications for the studied defects. All cells were cultivated under galactose stress condition and compared to glucose-based cell culture condition. We investigated the bioenergetic profile using Seahorse XFe96 cell analyzer and assessed the extracellular metabolic footprints and the intracellular metabolic fingerprints using NMR. The galactose-based culture condition forced a bioenergetic switch from a glycolytic to an oxidative state in all cell lines which improved overall separation of controls from the different defect groups. The extracellular metabolome was discriminative for separating controls from defects but not the specific defects, whereas the intracellular metabolome suggests CI and CV changes and revealed clear MDH2 defect-specific changes in metabolites associated with the TCA cycle, malate aspartate shuttle, and the choline metabolism, which are pronounced under galactose condition.PMID:38084664 | DOI:10.1002/jimd.12696

Cureus. 2023 Nov 8;15(11):e48534. doi: 10.7759/cureus.48534. eCollection 2023 Nov.ABSTRACTOvarian masses, ranging from benign cysts to malignant tumors, present complex diagnostic challenges in women's healthcare. Early detection of ovarian masses is paramount for improving patient outcomes, as delayed diagnoses often lead to advanced-stage disease with limited treatment options. This comprehensive review explores screening methods' current state, limitations, and emerging technologies to facilitate earlier detection. The limitations of existing screening methods, such as low sensitivity and specificity, underscore the need for improved early detection strategies. Imaging-based techniques, including transvaginal ultrasound, magnetic resonance imaging, and computed tomography, are vital in evaluating ovarian masses. However, the emergence of artificial intelligence (AI) and machine learning (ML) applications enhances the accuracy of image interpretation. Blood-based biomarkers, such as CA-125, have been the focus of research for ovarian mass detection. While CA-125 remains widely used, its limitations have prompted investigations into alternative serum biomarkers, including HE4 and miRNA, along with liquid biopsy and circulating tumor DNA. Ultrasound-based scoring systems, such as the risk of malignancy index (RMI), Ovarian-Adnexal Reporting and Data System (O-RADS), and guidelines from the International Ovarian Tumor Analysis (IOTA) group, provide structured approaches for classifying ovarian masses. These systems aid healthcare providers in clinical decision-making. Emerging technologies, such as liquid biopsy, AI, and proteomic/metabolomic approaches, offer promising avenues for enhancing early detection and risk assessment. Liquid biopsy provides noninvasive, real-time monitoring of ovarian masses, while AI and ML applications improve the accuracy of image interpretation. Proteomic and metabolomic studies reveal novel biomarkers and molecular insights. High-risk populations, often associated with genetic mutations such as BRCA1 and BRCA2, require specialized screening strategies. Current guidelines recommend screening modalities, risk-reduction strategies, and shared decision-making. Ongoing research focuses on refining risk assessment and personalized screening for high-risk individuals. This review underscores the importance of early detection in managing ovarian masses, emphasizing the need for improved screening methods, tailored approaches for high-risk populations, and ongoing research to further enhance diagnostic accuracy and patient outcomes.PMID:38084173 | PMC:PMC10710762 | DOI:10.7759/cureus.48534

Adv Sci (Weinh). 2023 Dec 11:e2307648. doi: 10.1002/advs.202307648. Online ahead of print.ABSTRACTT-2 toxin causes renal dysfunction with proteinuria and glomerular podocyte damage. This work explores the role of metabolic disorder/reprogramming-mediated epigenetic modification in the progression of T-2 toxin-stimulated podocyte injury. A metabolomics experiment is performed to assess metabolic responses to T-2 toxin infection in human podocytes. Roles of protein O-linked-N-acetylglucosaminylation (O-GlcNAcylation) in regulating T-2 toxin-stimulated podocyte injury in mouse and podocyte models are assessed. O-GlcNAc target proteins are recognized by mass spectrometry and co-immunoprecipitation experiments. Moreover, histone acetylation and autophagy levels are measured. T-2 toxin infection upregulates glucose transporter type 1 (GLUT1) expression and enhances hexosamine biosynthetic pathway in glomerular podocytes, resulting in a significant increase in β-arrestin-1 O-GlcNAcylation. Decreasing β-arrestin-1 or O-GlcNAc transferase (OGT) effectively prevents T-2 toxin-induced renal dysfunction and podocyte injury. Mechanistically, O-GlcNAcylation of β-arrestin-1 stabilizes β-arrestin-1 to activate the mammalian target of rapamycin (mTOR) pathway as well as to inhibit autophagy during podocyte injury by promoting H4K16 acetylation. To sum up, OGT-mediated β-arrestin-1 O-GlcNAcylation is a vital regulator in the development of T-2 toxin-stimulated podocyte injury via activating the mTOR pathway to suppress autophagy. Targeting β-arrestin-1 or OGT can be a potential therapy for T-2 toxin infection-associated glomerular injury, especially podocyte injury.PMID:38083975 | DOI:10.1002/advs.202307648

Acta Obstet Gynecol Scand. 2023 Dec 11. doi: 10.1111/aogs.14750. Online ahead of print.ABSTRACTINTRODUCTION: Increased BMI has been identified as a risk factor for most pregnancy complications, but the underlying metabolic factors mediating the detrimental effects of BMI are largely unknown. We aimed to compare metabolic profiles in overweight/obese women (body mass index [BMI] ≥ 25 kg/m2 ) and normal weight/underweight women (BMI < 25 kg/m2 ) across gestation. We also explored how gestational weight gain (GWG) affected maternal metabolic profiles.MATERIAL AND METHODS: Exploratory nested case-control study based on a prospective longitudinal cohort of women who were healthy prior to pregnancy and gave birth at Oslo University Hospital from 2002 to 2008. The sample consisted of 48 women who were overweight/obese and 59 normal-weight/underweight women. Plasma samples from four time points in pregnancy (weeks 14-16, 22-24, 30-32 and 36-38) were analyzed by nuclear magnetic resonance spectroscopy and 91 metabolites were measured. Linear regression models were fitted for each of the metabolites at each time point.RESULTS: Overweight or obese women had higher levels of lipids in very-low-density lipoprotein (VLDL), total triglycerides, triglycerides in VLDL, total fatty acids, monounsaturated fatty acids, saturated fatty acids, leucine, valine, and total branched-chain amino acids in pregnancy weeks 14-16 compared to underweight and normal-weight women. Docosahexaenoic acid and degree of unsaturation were significantly lower in overweight/obese women in pregnancy weeks 36-38. In addition, overweight or obese women had higher particle concentration of XXL-VLDL and glycoprotein acetyls (GlycA) at weeks 14-16 and 30-32. GWG did not seem to affect the metabolic profile, regardless of BMI group when BMI was treated as a dichotomous variable, ≥25 kg/m2 (yes/no).CONCLUSIONS: Overweight or obese women had smaller pregnancy-related metabolic alterations than normal-weight/underweight women. There was a trend toward higher triglyceride and VLDL particle concentration in overweight/obese women. As this was a hypothesis-generating study, the similarities with late-onset pre-eclampsia warrant further investigation. The unfavorable development of fatty acid composition in overweight/obese women, with possible implication for the offspring, should also be studied further in the future.PMID:38083835 | DOI:10.1111/aogs.14750

Annu Int Conf IEEE Eng Med Biol Soc. 2023 Jul;2023:1-4. doi: 10.1109/EMBC40787.2023.10341007.ABSTRACTMetabolite annotation is a major bottleneck in untargeted metabolomics studies by liquid chromatography coupled with mass spectrometry (LC-MS). This is in part due to the limited publicly available spectral libraries, which consist of tandem mass spectrometry (MS/MS) data acquired from just a fraction of known compounds. Machine learning and deep learning methods provide the opportunity to predict molecular fingerprints based on MS/MS data. The predicted molecular fingerprints can then be used to help rank candidate metabolite IDs obtained based on predicted formula or measured precursor m/z of the unknown metabolite. This approach is particularly useful to help annotate metabolites whose corresponding MS/MS spectra cannot be matched with those in spectral libraries. We previously reported application of a convolutional neural network (CNN) for molecular fingerprint prediction using MS/MS spectra obtained from the MoNA repository and NIST 20. In this paper, we investigate high-dimensional representation of the spectral data and molecular fingerprints to improve accuracy in molecular fingerprint prediction.PMID:38082953 | DOI:10.1109/EMBC40787.2023.10341007

Mil Med Res. 2023 Dec 12;10(1):64. doi: 10.1186/s40779-023-00500-9.ABSTRACTBACKGROUND: Cell metabolism plays a pivotal role in tumor progression, and targeting cancer metabolism might effectively kill cancer cells. We aimed to investigate the role of hexokinases in prostate cancer (PCa) and identify a crucial target for PCa treatment.METHODS: The Cancer Genome Atlas (TCGA) database, online tools and clinical samples were used to assess the expression and prognostic role of ADP-dependent glucokinase (ADPGK) in PCa. The effect of ADPGK expression on PCa cell malignant phenotypes was validated in vitro and in vivo. Quantitative proteomics, metabolomics, and extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) tests were performed to evaluate the impact of ADPGK on PCa metabolism. The underlying mechanisms were explored through ADPGK overexpression and knockdown, co-immunoprecipitation (Co-IP), ECAR analysis and cell counting kit-8 (CCK-8) assays.RESULTS: ADPGK was the only glucokinase that was both upregulated and predicted worse overall survival (OS) in prostate adenocarcinoma (PRAD). Clinical sample analysis demonstrated that ADPGK was markedly upregulated in PCa tissues vs. non-PCa tissues. High ADPGK expression indicates worse survival outcomes, and ADPGK serves as an independent factor of biochemical recurrence. In vitro and in vivo experiments showed that ADPGK overexpression promoted PCa cell proliferation and migration, and ADPGK inhibition suppressed malignant phenotypes. Metabolomics, proteomics, and ECAR and OCR tests revealed that ADPGK significantly accelerated glycolysis in PCa. Mechanistically, ADPGK binds aldolase C (ALDOC) to promote glycolysis via AMP-activated protein kinase (AMPK) phosphorylation. ALDOC was positively correlated with ADPGK, and high ALDOC expression was associated with worse survival outcomes in PCa.CONCLUSIONS: In summary, ADPGK is a driving factor in PCa progression, and its high expression contributes to a poor prognosis in PCa patients. ADPGK accelerates PCa glycolysis and progression by activating ALDOC-AMPK signaling, suggesting that ADPGK might be an effective target and marker for PCa treatment and prognosis evaluation.PMID:38082365 | DOI:10.1186/s40779-023-00500-9

Genome Med. 2023 Dec 11;15(1):109. doi: 10.1186/s13073-023-01257-5.ABSTRACTBACKGROUND: Damage in the ischemic core and penumbra after stroke affects patient prognosis. Microglia immediately respond to ischemic insult and initiate immune inflammation, playing an important role in the cellular injury after stroke. However, the microglial heterogeneity and the mechanisms involved remain unclear.METHODS: We first performed single-cell RNA-sequencing (scRNA-seq) and spatial transcriptomics (ST) on middle cerebral artery occlusion (MCAO) mice from three time points to determine stroke-associated microglial subclusters and their spatial distributions. Furthermore, the expression of microglial subcluster-specific marker genes and the localization of different microglial subclusters were verified on MCAO mice through RNAscope and immunofluorescence. Gene set variation analysis (GSVA) was performed to reveal functional characteristics of microglia sub-clusters. Additionally, ingenuity pathway analysis (IPA) was used to explore upstream regulators of microglial subclusters, which was confirmed by immunofluorescence, RT-qPCR, shRNA-mediated knockdown, and targeted metabolomics. Finally, the infarct size, neurological deficits, and neuronal apoptosis were evaluated in MCAO mice after manipulation of specific microglial subcluster.RESULTS: We discovered stroke-associated microglial subclusters in the brains of MCAO mice. We also identified novel marker genes of these microglial subclusters and defined these cells as ischemic core-associated (ICAM) and ischemic penumbra-associated (IPAM) microglia, according to their spatial distribution. ICAM, induced by damage-associated molecular patterns, are probably fueled by glycolysis, and exhibit increased pro-inflammatory cytokines and chemokines production. BACH1 is a key transcription factor driving ICAM generation. In contrast, glucocorticoids, which are enriched in the penumbra, likely trigger IPAM formation, which are presumably powered by the citrate cycle and oxidative phosphorylation and are characterized by moderate pro-inflammatory responses, inflammation-alleviating metabolic features, and myelinotrophic properties.CONCLUSIONS: ICAM could induce excessive neuroinflammation, aggravating brain injury, whereas IPAM probably exhibit neuroprotective features, which could be essential for the homeostasis and survival of cells in the penumbra. Our findings provide a biological basis for targeting specific microglial subclusters as a potential therapeutic strategy for ischemic stroke.PMID:38082331 | DOI:10.1186/s13073-023-01257-5

Cancer Sci. 2023 Dec 11. doi: 10.1111/cas.16035. Online ahead of print.ABSTRACTInhibition of cholesterol de novo synthesis (DNS) by statins has controversial effects on the treatment of hepatocellular carcinoma (HCC). High fatty acid conditions have been reported to limit the effect of statins on metabolism diseases. Whether high fatty acid conditions interfere with the effect of statins on HCC remains unclear. Here, we reported that inhibiting cholesterol DNS with atorvastatin promoted the oncogenic capabilities of diethylnitrosamine (DEN) in mice fed high fatty acid diets (HFD). The combined analysis of metabolomics and transcriptomics revealed that arachidonic acid (AA) metabolism was the most significant changed pathway between mice with and without atorvastatin treatment. In vitro, in the presence of AA precursor linoleic acid (LA), atorvastatin promoted the proliferation and migration ability of HCC cell lines. However, in the absence of LA, these phenomena disappeared. TCGA and tissue microarray examination revealed that prostaglandin e synthase 2 (PTGES2), a key enzyme in AA metabolism, was associated with the poor outcome of HCC patients. Overexpression of PTGES2 promoted the proliferation and migration of HCC cell lines, and knockdown of PTGES2 inhibited the proliferation and migration of cells. Additionally, atorvastatin upregulated PTGES2 expression by enhancing Sterol-regulatory element binding protein 2 (SREBP2)-mediated transcription. Knockdown of PTGES2 reversed the proliferation and migration ability enhanced by atorvastatin. Overall, our study reveals that a high fatty acid background is one of the possible conditions limiting the application of statins in HCC, under which statins promote the progression of HCC by enhancing SREBP2-mediated PTGES2 transcription.PMID:38081591 | DOI:10.1111/cas.16035

J Nutr. 2023 Dec 9:S0022-3166(23)72794-6. doi: 10.1016/j.tjnut.2023.12.007. Online ahead of print.ABSTRACTBACKGROUND: Oxylipins are products derived from polyunsaturated fatty acids (PUFAs) that play a role in cardiovascular disease and aging. Fish oil-derived n-3 PUFAs promote the formation of anti-inflammatory and vasodilatory oxylipins; however, there are little data on oxylipins derived from α-linolenic acid (C18:3n-3), the primary plant-derived n-3 PUFA. Walnuts are a source of C18:3n-3.OBJECTIVE: To investigate the effect on serum oxylipins of a diet enriched with walnuts at 15% energy (30-60 g/d; 2.6-5.2 g C18:3n-3/d) for 2 y compared to a control diet (abstention from walnuts) in healthy older men and women (63-79 years).METHODS: The red blood cell proportion of ALA was determined by gas-chromatography as a measure of compliance. Ultra-performance liquid chromatography - tandem mass spectrometry was used to measure serum concentrations of 53 oxylipins in participants randomly assigned to the walnut diet (n = 64) or the control diet (n = 51). Two-year concentration changes (final minus baseline) were log-transformed (base log-10) and standardized (mean-centered and divided by the standard deviation of each variable). Volcano plots were then generated (fold change ≥1.5; false discovery rate ≤0.1). For each oxylipin delta surviving multiple testing, we further assessed between-intervention group differences by ANCOVA adjusting for age, sex, BMI, and the baseline concentration of the oxylipin.RESULTS: The 2-year change in red blood cell C18:3n-3 in the walnut group was significantly higher than that in the control group (P<0.001). Compared to the control diet, the walnut diet resulted in statistically significantly greater increases in three C18:3n-3-derived oxylipins (9-HOTrE, 13-HOTrE, and 12,13-EpODE) and in the C20:5n-3 derived 14,15-diHETE, and greater reductions of the C20:4n-6-derived 5-HETE, 19-HETE, and 5,6-diHETrE.CONCLUSIONS: Long-term walnut consumption changes the serum oxylipin profile in healthy older persons. Our results add novel mechanistic evidence on the cardioprotective effects of walnuts.TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01634841.PMID:38081585 | DOI:10.1016/j.tjnut.2023.12.007

Biochem Pharmacol. 2023 Dec 9:115981. doi: 10.1016/j.bcp.2023.115981. Online ahead of print.ABSTRACTVenetoclax (VEN), in combination with low dose cytarabine (AraC) or a hypomethylating agent, is FDA approved to treat acute myeloid leukemia (AML) in patients who are over the age of 75 or cannot tolerate standard chemotherapy. Despite high response rates to these therapies, most patients succumb to the disease due to relapse and/or drug resistance, providing an unmet clinical need for novel therapies to improve AML patient survival. ME-344 is a potent isoflavone with demonstrated inhibitory activity toward oxidative phosphorylation (OXPHOS) and clinical activity in solid tumors. Given that OXPHOS inhibition enhances VEN antileukemic activity against AML, we hypothesized that ME-344 could enhance the anti-AML activity of VEN. Here we report that ME-344 enhanced VEN to target AML cell lines and primary patient samples while sparing normal hematopoietic cells. Cooperative suppression of OXPHOS was detected in a subset of AML cell lines and primary patient samples. Metabolomics analysis revealed a significant reduction of purine biosynthesis metabolites by ME-344. Further, lometrexol, a purine biosynthesis inhibitor, synergistically enhanced VEN-induced apoptosis in AML cell lines. Interestingly, AML cells with acquired AraC resistance showed significantly increased purine biosynthesis metabolites and sensitivities to ME-344. Furthermore, synergy between ME-344 and VEN was preserved in these AraC-resistant AML cells. In vivo studies revealed significantly prolonged survival upon combination therapy of ME-344 and VEN in NSGS mice bearing parental or AraC-resistant MV4-11 leukemia compared to the vehicle control. This study demonstrates that ME-344 enhances VEN antileukemic activity against preclinical models of AML by suppressing OXPHOS and/or purine biosynthesis.PMID:38081370 | DOI:10.1016/j.bcp.2023.115981

Environ Res. 2023 Dec 9:117895. doi: 10.1016/j.envres.2023.117895. Online ahead of print.ABSTRACTThis study elucidated the effect patterns of aeration and bioaugmentation on indigenous microbial communities, metabolites, and metabolic pathways in the remediation of black and odorous water. This is crucial for the precise formulation and targeted development of effective microbial consortia, as well as for tracking and forecasting the bioremediation of black and odorous water. The results confirmed that combining bioaugmentation with aeration markedly enhanced the degradation of COD, NH4+-N, and TN and the conversion of Fe and Mn. Aeration significantly increased the relative abundance of Flavobacterium and Diaphorobacter, and the positive interbacterial interaction in the effective microbial consortia EM31 gave the constituent strain Klebsiella and Bacillus a dominant niche in the bioaugmentation. Furthermore, bioaugmentation improved the capacity of the indigenous microbial consortia to utilize basic carbon source, particularly the utilization of L-glycerol, I-erythritol, glucose-1-phosphate, and the catabolism of cysteine and methionine. Moreover, during the remediation of black and odorous water by aeration and bioaugmentation, Glucosinolate biosynthesis (map00966), Steroid hormone biosynthesis (map00140), Folate biosynthesis (map00790), One carbon pool by folate (map00670), and Tyrosine metabolism (map00350) were identified as key functional metabolic pathways in microbial communities.PMID:38081350 | DOI:10.1016/j.envres.2023.117895

Metabolomics. 2023 Dec 11;20(1):5. doi: 10.1007/s11306-023-02068-w.ABSTRACTINTRODUCTION: Feed additives represents a valid tool in animal nutrition to improve animal performance and livestock productivity under a sustainable perspective; however, there is a paucity of information about their comprehensive metabolomic and bioactive profiles.OBJECTIVE: In this study, we tested the ability of an untargeted metabolomics approach to discriminate nine commercial feed additives and unique blends of botanical extracts used in both ruminant and non-ruminant nutrition, according to their phytochemical profiles and different in vitro bioactive properties.METHODS: An ultra-high-performance liquid chromatography coupled with Orbitrap mass spectrometry and multivariate statistics were combined to search for potential markers, in order to better discriminate the different commercial samples.RESULTS: Several phytochemicals were identified, namely alkaloids, phenolics, organosulfurs, and terpenoids. The polyherbal formulation Zigbir was the best source of phytochemicals, accounting for a cumulative total content of phytochemicals equal to 3.03 mg Eq./g, being particularly abundant in terpenoids, stilbenes, phenolic acids, and small-molecular-weight phenolics. Multivariate statistics allowed to group the different products in 2 bioactive subclusters. The diterpenoid andrographolide recorded the highest abundance in Zigbir and Sangrovit. The most predictive biomarkers were: piperine, isoquercitrin, 6-methylthiohexyldesulfoglucosinolate, 6-methylumbelliferone, benzoic acid, (+)-(1R,2R)-1,2-diphenylethane-1,2-diol, and piperitenone. Flavonoids were highly correlated with both in vitro antioxidant and enzyme inhibition assays.CONCLUSIONS: Our findings provide new insights into the comprehensive phytochemical composition of commercial feed additives and blend of botanical extracts used for both ruminant and non-ruminant nutrition. A great importance of polyphenols in relation to the biological activities was detected.PMID:38082140 | DOI:10.1007/s11306-023-02068-w

Nat Commun. 2023 Dec 11;14(1):8188. doi: 10.1038/s41467-023-43909-5.ABSTRACTRetention time (RT) alignment is a crucial step in liquid chromatography-mass spectrometry (LC-MS)-based proteomic and metabolomic experiments, especially for large cohort studies. The most popular alignment tools are based on warping function method and direct matching method. However, existing tools can hardly handle monotonic and non-monotonic RT shifts simultaneously. Here, we develop a deep learning-based RT alignment tool, DeepRTAlign, for large cohort LC-MS data analysis. DeepRTAlign has been demonstrated to have improved performances by benchmarking it against current state-of-the-art approaches on multiple real-world and simulated proteomic and metabolomic datasets. The results also show that DeepRTAlign can improve identification sensitivity without compromising quantitative accuracy. Furthermore, using the MS features aligned by DeepRTAlign, we trained and validated a robust classifier to predict the early recurrence of hepatocellular carcinoma. DeepRTAlign provides an advanced solution to RT alignment in large cohort LC-MS studies, which is currently a major bottleneck in proteomics and metabolomics research.PMID:38081814 | DOI:10.1038/s41467-023-43909-5