PubMed

BMC Med. 2023 Dec 18;21(1):504. doi: 10.1186/s12916-023-03227-5.ABSTRACTBACKGROUND: Solute carrier family 13 member 5 (SLC13A5) is a Na+-coupled citrate co-transporter that mediates entry of extracellular citrate into the cytosol. SLC13A5 inhibition has been proposed as a target for reducing progression of kidney disease. The aim of this study was to leverage the Mendelian randomization paradigm to gain insight into the effects of SLC13A5 inhibition in humans, towards prioritizing and informing clinical development efforts.METHODS: The primary Mendelian randomization analyses investigated the effect of SLC13A5 inhibition on measures of kidney function, including creatinine and cystatin C-based measures of estimated glomerular filtration rate (creatinine-eGFR and cystatin C-eGFR), blood urea nitrogen (BUN), urine albumin-creatinine ratio (uACR), and risk of chronic kidney disease and microalbuminuria. Secondary analyses included a paired plasma and urine metabolome-wide association study, investigation of secondary traits related to SLC13A5 biology, a phenome-wide association study (PheWAS), and a proteome-wide association study. All analyses were compared to the effect of genetically predicted plasma citrate levels using variants selected from across the genome, and statistical sensitivity analyses robust to the inclusion of pleiotropic variants were also performed. Data were obtained from large-scale genetic consortia and biobanks, with sample sizes ranging from 5023 to 1,320,016 individuals.RESULTS: We found evidence of associations between genetically proxied SLC13A5 inhibition and higher creatinine-eGFR (p = 0.002), cystatin C-eGFR (p = 0.005), and lower BUN (p = 3 × 10-4). Statistical sensitivity analyses robust to the inclusion of pleiotropic variants suggested that these effects may be a consequence of higher plasma citrate levels. There was no strong evidence of associations of genetically proxied SLC13A5 inhibition with uACR or risk of CKD or microalbuminuria. Secondary analyses identified evidence of associations with higher plasma calcium levels (p = 6 × 10-13) and lower fasting glucose (p = 0.02). PheWAS did not identify any safety concerns.CONCLUSIONS: This Mendelian randomization analysis provides human-centric insight to guide clinical development of an SLC13A5 inhibitor. We identify plasma calcium and citrate as biologically plausible biomarkers of target engagement, and plasma citrate as a potential biomarker of mechanism of action. Our human genetic evidence corroborates evidence from various animal models to support effects of SLC13A5 inhibition on improving kidney function.PMID:38110950 | DOI:10.1186/s12916-023-03227-5

Sci Rep. 2023 Dec 18;13(1):22472. doi: 10.1038/s41598-023-50156-7.ABSTRACTHepatocellular carcinoma (HCC) is a prevalent malignancy and there is a lack of effective biomarkers for HCC diagnosis. Living organisms are complex, and different omics molecules interact with each other to implement various biological functions. Genomics and metabolomics, which are the top and bottom of systems biology, play an important role in HCC clinical management. Fatty acid metabolism is associated with malignancy, prognosis, and immune phenotype in cancer, which is a potential hallmark in malignant tumors. In this study, the genes and metabolites related to fatty acid metabolism were thoroughly investigated by a dynamic network construction algorithm named EWS-DDA for the early diagnosis and prognosis of HCC. Three gene ratios and eight metabolite ratios were identified by EWS-DDA as potential biomarkers for HCC clinical management. Further analysis using biological analysis, statistical analysis and document validation in the discovery and validation sets suggested that the selected potential biomarkers had great clinical prognostic value and helped to achieve effective early diagnosis of HCC. Experimental results suggested that in-depth evaluation of fatty acid metabolism from different omics viewpoints can facilitate the further understanding of pathological alterations associated with HCC characteristics, improving the performance of early diagnosis and clinical prognosis.PMID:38110715 | DOI:10.1038/s41598-023-50156-7

Sci Rep. 2023 Dec 19;13(1):22560. doi: 10.1038/s41598-023-49981-7.ABSTRACTThis study explores the sphingolipid class of oligohexosylceramides (OHCs), a rarely studied group, in barley (Hordeum vulgare L.) through a new lipidomics approach. Profiling identified 45 OHCs in barley (Hordeum vulgare L.), elucidating their fatty acid (FA), long-chain base (LCB) and sugar residue compositions; and was accomplished by monophasic extraction followed by reverse-phased high performance liquid chromatography electrospray ionisation quadrupole-time-of-flight tandem mass spectrometry (HPLC-ESI-QqTOF-MS/MS) employing parallel reaction monitoring (PRM). Results revealed unknown ceramide species and highlighted distinctive FA and LCB compositions when compared to other sphingolipid classes. Structurally, the OHCs featured predominantly trihydroxy LCBs associated with hydroxylated FAs and oligohexosyl residues consisting of two-five glucose units in a linear 1 → 4 linkage. A survey found OHCs in tissues of major cereal crops while noting their absence in conventional dicot model plants. This study found salinity stress had only minor effects on the OHC profile in barley roots, leaving questions about their precise functions in plant biology unanswered.PMID:38110595 | DOI:10.1038/s41598-023-49981-7

Drug Des Devel Ther. 2023 Dec 11;17:3709-3722. doi: 10.2147/DDDT.S412743. eCollection 2023.ABSTRACTPURPOSE: Stroke is a leading cause of disability and death globally. However, there are few clinical drugs for stroke therapy. Novel and effective neuroprotectants are called on the way.METHODS: In this study, 93 steroids from a constructed steroidal library were randomly numbered and blindly evaluated in an L-glutamate-induced HT-22 oxidative stress model. The neuroprotective effects of 5 candidates were further investigated in potassium deprivation-induced apoptosis of cerebellar granule neurons (CGNs), D-glutamate-induced excitotoxicity of CGNs, and cortical neuron (CN) models.RESULTS: Interestingly, unblinding revealed that cholest-4-ene-3,6-dione (78), a cholesterol derivative, was first found to have comprehensive neuroprotective effects in all cell models. 78 administration also decreased the infarction volume and improved motor function in middle cerebral artery occlusion (MCAO) model rats. Additionally, 78 treatment decreased intercellular reactive oxygen species (ROS) and NO production in the HT-22 cell model. Finally, lipidomics and molecular docking results showed that 78 may exert its neuroprotective effects by increasing platelet-activating factor (PAF) analog 1-(9Z-pentadecenoyl)-glycero-3-phosphocholine production.CONCLUSION: This study indicates that 78, a novel neuroprotectant, is a promising therapeutic candidate with comprehensive neuroprotective effects for the treatment of ischemic stroke by decreasing ROS/reactive nitrogen species (RNS) levels and increasing 1-(9Z-pentadecenoyl)-glycero-3-phospho-choline production.PMID:38107659 | PMC:PMC10722991 | DOI:10.2147/DDDT.S412743

Sci Rep. 2023 Dec 15;13(1):22496. doi: 10.1038/s41598-023-49601-4.ABSTRACTIn COVID-19 clinical symptoms can persist even after negativization also in individuals who have had mild or moderate disease. We here investigated the biomarkers that define the post-COVID-19 clinical state analyzing the exhaled breath condensate (EBC) of 38 post COVID-19 patients and 38 sex and age-matched healthy controls via nuclear magnetic resonance (NMR)-based metabolomics. Predicted gene-modulated microRNAs (miRNAs) related to COVID-19 were quantified from EBC of 10 patients and 10 controls. Finally, clinical parameters from all post-COVID-19 patients were correlated with metabolomic data. Post-COVID-19 patients and controls showed different metabolic phenotype ("metabotype"). From the metabolites, by using enrichment analysis we identified miRNAs that resulted up-regulated (hsa-miR146a-5p) and down-regulated (hsa-miR-126-3p and hsa-miR-223-3p) in post-COVID-19. Taken together, our multiomics data indicate that post-COVID-19 patients before rehabilitation are characterized by persistent inflammation, dysregulation of liver, endovascular thrombotic and pulmonary processes, and physical impairment, which should be the primary clinical targets to contrast the post-acute sequelae of COVID-19.PMID:38110483 | DOI:10.1038/s41598-023-49601-4

J Nutr. 2023 Dec 16:S0022-3166(23)72814-9. doi: 10.1016/j.tjnut.2023.12.025. Online ahead of print.ABSTRACTBACKGROUND: Low potassium intake is associated with a higher risk of type 2 diabetes and hypertension. Both conditions occur more frequently in Black populations, who also consume less potassium-rich foods.OBJECTIVE: Using metabolomics to identify dysregulated metabolic pathways associated with low potassium excretion may procure more accurate entry points for nutritional prevention and intervention for type 2 diabetes and hypertension.METHOD: 440 White and 350 Black adults from the African-PREDICT study (aged 20-30 years) were included. Twenty-four-hour blood pressure (BP) was measured. Potassium, sodium, and fasting glucose levels were analyzed in 24-hour urine and plasma samples. Liquid chromatography-tandem mass spectrometry-based metabolomics included the analyses of amino acids and acylcarnitines in spot urine samples.RESULTS: Black participants had lower urinary potassium levels than Whites (36.6 vs. 51.1 mmol/day) (p<0.001). In White but not Black adults, urinary potassium correlated positively with 2-aminoadipic acid (2-AAA) (r=0.176), C3-[propionyl]carnitine (r=0.137), C4-[butyryl]carnitine (r=0.169) and C5-[isovaleryl]carnitine (r=0.167) in unadjusted, and 2-AAA (r=0.158) and C4-carnitine (r=0.160) in adjusted analyses (all p<0.05 and q<0.05). Elevated C0-, C3-, and C5-carnitine in turn were positively associated with SBP (Black and White groups), DBP (Black group) and glucose (White group) (all ρ<0.05).CONCLUSION: Racial differences are an important consideration when investigating nutrient-metabolite relationships and the role thereof in cardiovascular disease. Only in White adults did urinary potassium associate with 2-AAA and short-chain acylcarnitines. These metabolites were positively related to BP and fasting plasma glucose levels. In White adults, the metabolomic profiles related to potassium excretion may contribute to BP regulation and glucose homeostasis.CLINICAL TRIAL REGISTRY NUMBER: ClinicalTrials.gov (NCT03292094).PMID:38110181 | DOI:10.1016/j.tjnut.2023.12.025

J Ethnopharmacol. 2023 Dec 16:117570. doi: 10.1016/j.jep.2023.117570. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Cistanche deserticola (C. deserticola) is an edible and traditional medicine widely used in China, which has been confirmed to be effective in the treatment of postmenopausal osteoporosis (PMOP). Despite its proven efficacy, the exact role of C. deserticola in bone metabolism and its underlying mechanism has remained unclear.AIM OF THE STUDY: In this research, we employed an in vivo model utilizing ovariectomized (OVX) rats to characterize the anti-osteoporotic activity and metabolic mechanism of the ethanol extract of C. deserticola (CHE).MATERIALS AND METHODS: Fifty female Sprague-Dawley (SD) rats were randomly divided into five groups including sham operation group, model group, 0.1 g/kg estradiol valerate (EV) group as the positive control, low (0.6 g/kg) and high (1.2 g/kg) dosage CHE groups. Biochemical parameter analyses and histopathological experiments were conducted to assess the pharmacodynamic effects. Metabolomic analysis was conducted on serum samples to examine the metabolic profiles, identify potential biomarkers, and elucidate the metabolic pathways associated with CHE in OVX rats.RESULTS: CHE treatment demonstrated significant anti-osteoporosis activity by regulating serum biochemical markers of bone turnover, improving cancellous bone structure, and reversing the decrease in bone mineral density. Furthermore, the clinical equivalent dose group (CHL) achieved superior overall outcomes. The main interventions of CHE on OVX rats involved the modulation of several key pathways, including steroid hormone biosynthesis, arachidonic acid metabolism, tyrosine and tryptophan metabolism, biotin metabolism, regulation of TRP channels by inflammatory mediators, primary bile acid biosynthesis, regulation of lipolysis in adipocytes, and bile secretion. 23 potential efficacy-related biomarkers within the metabolic network were identified. Among them, long-chain unsaturated fatty acids (eg. DHA and docosapentaenoic acid), steroid hormones, amino acids and carbohydrates were strongly correlated with bone resorption and formation markers. Additionally, it was observed four pathways (nucleotide, carbon, amino acid, and lipid metabolism) were implicated in the effects of CHE.CONCLUSION: This study demonstrates that CHE improves bone loss in PMOP mainly through regulating lipid metabolism pathways, which provides an evidence base for CHE treatment of PMOP.PMID:38110131 | DOI:10.1016/j.jep.2023.117570

Sci Total Environ. 2023 Dec 16:169382. doi: 10.1016/j.scitotenv.2023.169382. Online ahead of print.ABSTRACTHeat stress (HS) is a major environmental threat that affects duck production in subtropical and tropical regions, especially in summer. This study aimed to evaluate the physiological and metabolic responses of Pekin ducks to chronic HS conditions via liquid chromatography-mass spectrometry (LC-MS) using a paired-fed (PF) experimental design. On the basis of equivalent feed intake (HS vs. PF), HS significantly reduced growth performance and the percentage of leg and breast muscles, however, markedly increased the percentage of abdominal fat and breast skin fat. Serum metabolomics results revealed that heat-stressed ducks showed enhanced glycolysis and pentose phosphate pathways, as demonstrated by higher glucose 6-phosphate and 6-phogluconic acid levels in the PF vs. HS comparison. HS decreased hepatic mRNA levels of mitochondrial fatty acid β-oxidation-related genes (MCAD and SCAD) compared to the PF group, resulting in acetylcarnitine accumulation in serum. Moreover, HS elevated the concentrations of serum amino acids and mRNA levels of ubiquitination-related genes (MuRF1 and MAFbx) in the skeletal muscle and amino acid transporter-related genes (SLC1A1 and SLC7A1) and gluconeogenesis-related genes (PCK1 and PCase) in the liver compared to the PF group. When compared to the normal control group (NC), HS further decreased growth performance, but it elevated the abdominal fat rate. However, increased mRNA levels of ubiquitination-related genes and serum amino acid accumulation were not observed in the HS group compared to the NC group, implying that reduced feed intake masked the effect of HS on skeletal muscle breakdown and is a form of protection for the organism. These results suggest that chronic HS induces protein degradation in the skeletal muscle to provide amino acids for hepatic gluconeogenesis to provide sufficient energy, as Pekin ducks under HS conditions failed to efficiently oxidise fatty acids and ketones in the mitochondria, leading to poor growth performance and slaughter characteristics.PMID:38110095 | DOI:10.1016/j.scitotenv.2023.169382

Anal Chem. 2023 Dec 18. doi: 10.1021/acs.analchem.3c03215. Online ahead of print.ABSTRACTThe direct and unambiguous detection and identification of individual metabolite molecules present in complex biological mixtures constitute a major challenge in (bio)analytical research. In this context, nuclear magnetic resonance (NMR) spectroscopy has proven to be particularly powerful owing to its ability to provide both qualitative and quantitative atomic-level information on multiple analytes simultaneously in a noninvasive manner. Nevertheless, NMR suffers from a low inherent sensitivity and, moreover, lacks selectivity regarding the number of individual analytes to be studied in a mixture of a myriad of structurally and chemically very different molecules, e.g., metabolites in a biofluid. Here, we describe a method that circumvents these shortcomings via performing selective, photochemically induced dynamic nuclear polarization (photo-CIDNP) enhanced NMR spectroscopy on unmodified complex biological mixtures, i.e., human urine and serum, which yields a single, background-free one-dimensional NMR spectrum. In doing this, we demonstrate that photo-CIDNP experiments on unmodified complex mixtures of biological origin are feasible, can be performed straightforwardly in the native aqueous medium at physiological metabolite concentrations, and act as a spectral filter, facilitating the analysis of NMR spectra of complex biofluids. Due to its noninvasive nature, the method is fully compatible with state-of-the-art metabolomic protocols providing direct spectroscopic information on a small, carefully selected subset of clinically relevant metabolites. We anticipate that this approach, which, in addition, can be combined with existing high-throughput/high-sensitivity NMR methodology, holds great promise for further in-depth studies and development for use in metabolomics and many other areas of analytical research.PMID:38109875 | DOI:10.1021/acs.analchem.3c03215

Annu Rev Biophys. 2023 Dec 18. doi: 10.1146/annurev-biophys-030722-021957. Online ahead of print.ABSTRACTOver the past decades, our understanding of microbial metabolism has increased dramatically. Metabolomics, a family of techniques that are used to measure the quantities of small molecules in biological samples, has been central to these efforts. Advances in analytical chemistry have made it possible to measure the relative and absolute concentrations of more and more compounds with increasing levels of certainty. In this review, we highlight how metabolomics has contributed to understanding microbial metabolism and in what ways it can still be deployed to expand our systematic understanding of metabolism. To that end, we explain how metabolomics was used to (a) characterize network topologies of metabolism and its regulation networks, (b) elucidate the control of metabolic function, and (c) understand the molecular basis of higher-order phenomena. We also discuss areas of inquiry where technological advances should continue to increase the impact of metabolomics, as well as areas where our understanding is bottlenecked by other factors such as the availability of statistical and modeling frameworks that can extract biological meaning from metabolomics data. Expected final online publication date for the Annual Review of Biophysics, Volume 53 is May 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.PMID:38109374 | DOI:10.1146/annurev-biophys-030722-021957

J Proteome Res. 2023 Dec 18. doi: 10.1021/acs.jproteome.3c00665. Online ahead of print.ABSTRACTProton magnetic resonance spectroscopy (1H-MRS) of surgically collected tumor specimens may contribute to investigating cancer metabolism and the significance of the "total choline" (tCho) peak (3.2 ppm) as malignancy and therapy response biomarker. To ensure preservation of intrinsic metabolomic information, standardized handling procedures are needed. The effects of time to freeze (cold ischemia) were evaluated in (a) surgical epithelial ovarian cancer (EOC) specimens using high-resolution (HR) 1H-MRS (9.4 T) of aqueous extracts and (b) preclinical EOC samples (xenografts in SCID mice) investigated by in vivo MRI-guided 1H-MRS (4.7 T) and by HR-1H-MRS (9.4 T) of tumor extracts or intact fragments (using magic-angle-spinning (MAS) technology). No significant changes were found in the levels of 27 of 29 MRS-detected metabolites (including the tCho profile) in clinical specimens up to 2 h cold ischemia, besides an increase in lysine and a decrease in glutathione. EOC xenografts showed a 2-fold increase in free choline within 2 h cold ischemia, without further significant changes for any MRS-detected metabolite (including phosphocholine and tCho) up to 6 h. At shorter times (≤1 h), HR-MAS analyses showed unaltered tCho components, along with significant changes in lactate, glutamate, and glutamine. Our results support the view that a time to freeze of 1 h represents a safe threshold to ensure the maintenance of a reliable tCho profile in EOC specimens.PMID:38109371 | DOI:10.1021/acs.jproteome.3c00665

Emerg Top Life Sci. 2023 Dec 18;7(4):455-464. doi: 10.1042/ETLS20230082.ABSTRACTMetabolic networks are well placed to orchestrate the coordination of multiple cellular processes associated with embryonic development such as cell growth, proliferation, differentiation and cell movement. Here, we discuss the advantages that gastruloids, aggregates of mammalian embryonic stem cells that self-assemble a rudimentary body plan, have for uncovering the instructive role of metabolic pathways play in directing developmental processes. We emphasise the importance of using such reductionist systems to link specific pathways to defined events of early mammalian development and their utility for obtaining enough material for metabolomic studies. Finally, we review the ways in which the basic gastruloid protocol can be adapted to obtain specific models of embryonic cell types, tissues and regions. Together, we propose that gastruloids are an ideal system to rapidly uncover new mechanistic links between developmental signalling pathways and metabolic networks, which can then inform precise in vivo studies to confirm their function in the embryo.PMID:38108463 | DOI:10.1042/ETLS20230082

Microbiol Spectr. 2023 Dec 12;11(6):e0310423. doi: 10.1128/spectrum.03104-23. Epub 2023 Nov 21.ABSTRACTAs the population ages and medical technology advances, anesthesia procedures for elderly patients are becoming more common, leading to an increased prevalence of postoperative cognitive dysfunction. However, the etiology and correlation between the gut microbiota and cognitive dysfunction are poorly understood, and research in this area is limited. In this study, mice with postoperative cognitive dysfunction were found to have reduced levels of fatty acid production and anti-inflammatory flora in the gut, and Bacteroides was associated with increased depression, leading to cognitive dysfunction and depression. Furthermore, more specific microbial species were identified in the disease model, suggesting that modulation of host metabolism through gut microbes may be a potential avenue for preventing postoperative cognitive dysfunction.PMID:38108273 | DOI:10.1128/spectrum.03104-23

Expert Rev Proteomics. 2023 Dec 18. doi: 10.1080/14789450.2023.2295866. Online ahead of print.ABSTRACTINTRODUCTION: Diabetes Mellitus (DM) is a chronic heterogeneous metabolic disorder characterized by hyperglycemia due to the destruction of insulin-producing pancreatic β cells and/or insulin resistance. It is now considered a global epidemic disease associated with serious threats to a patient's life. Understanding the metabolic pathways involved in disease pathogenesis and progression is important and would improve prevention and management strategies. Metabolomics is an emerging field of research that offers valuable insights into the metabolic perturbation associated with metabolic diseases, including DM.AREA COVERED: Herein, we discussed the metabolomics in type 1 and 2 DM research, including its contribution to understanding disease pathogenesis and identifying potential novel biomarkers clinically useful for disease screening, monitoring, and prognosis. In addition, we highlighted the metabolic changes associated with treatment effects, including insulin and different anti-diabetic medications.EXPERT OPINION: By analyzing the metabolome, the metabolic disturbances involved in T1DM and T2DM can be explored, enhancing our understanding of the disease progression and potentially leading to novel clinical diagnostic and effective new therapeutic approaches. In addition, identifying specific metabolites would be potential clinical biomarkers for predicting the disease and thus preventing and managing hyperglycemia and its complications.PMID:38108261 | DOI:10.1080/14789450.2023.2295866

J Med Virol. 2023 Dec;95(12):e29325. doi: 10.1002/jmv.29325.ABSTRACTHepatitis B virus (HBV) hijacks autophagy for its replication. Nucleos(t)ide analogs (NUCs) treatment suppressed HBV replication and reduced hepatocellular carcinoma (HCC) incidence. However, the use of NUCs in chronic hepatitis B (CHB) patients with normal or minimally elevated serum alanine aminotransferase (ALT) levels is still debated. Animal models are crucial for studying the unanswered issue and evaluating new therapies. MicroRNA-122 (miR-122), which regulates fatty acid and cholesterol metabolism, is downregulated during hepatitis and HCC progression. The reciprocal inhibition of miR-122 with HBV highlights its role in HCC development as a tumor suppressor. By crossbreeding HBV-transgenic mice with miR-122 knockout mice, we generated a hybrid mouse model with a high incidence of HCC up to 89% and normal ALT levels before HCC. The model exhibited early-onset hepatic steatosis, progressive liver fibrosis, and impaired late-phase autophagy. Metabolomics and microarray analysis identified metabolic signatures, including dysregulation of lipid metabolism, inflammation, genomic instability, the Warburg effect, reduced TCA cycle flux, energy deficiency, and impaired free radical scavenging. Antiviral treatment reduced HCC incidence in hybrid mice by approximately 30-35% compared to untreated mice. This effect was linked to the activation of ER stress-responsive transcription factor ATF4, clearance of autophagosome cargo p62, and suppression of the CHOP-mediated apoptosis pathway. In summary, this study suggests that despite minimal ALT elevation, HBV replication can lead to liver injury. Endoplasmic reticulum stress, reduced miR-122 levels, mitochondrial and metabolic dysfunctions, blocking protective autophagy resulting in p62 accumulation, apoptosis, fibrosis, and HCC. Antiviral may improve the above-mentioned pathogenesis through HBV suppression.PMID:38108211 | DOI:10.1002/jmv.29325

Front Microbiol. 2023 Dec 1;14:1305772. doi: 10.3389/fmicb.2023.1305772. eCollection 2023.ABSTRACTThis study delves into the impact of yeast culture (YC) on rumen epithelial development, microbiota, and metabolome, with the aim of investigating YC's mechanism in regulating rumen fermentation. Thirty male lambs of Hu sheep with similar age and body weight were selected and randomly divided into three groups with 10 lambs in each group. Lambs were fed a total mixed ration [TMR; rough: concentrate (R:C) ratio ≈ 30:70] to meet their nutritional needs. The experiment adopted completely randomized design (CRD). The control group (CON) was fed the basal diet with high concentrate, to which 20 g/d of YC was added in the low dose YC group (LYC) and 40 g/d of YC in the high dose YC group (HYC). The pretrial period was 14 days, and the experimental trial period was 60 days. At the end of a 60-day trial, ruminal epithelial tissues were collected for histomorphological analysis, and rumen microorganisms were analyzed by 16S rDNA sequencing and rumen metabolites by untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics techniques. The results showed that YC improved rumen papilla development and increased rumen papilla length (p < 0.05), while decreased cuticle thickness (p < 0.05). The 16S rDNA sequencing results showed that YC reduced the relative abundance of Prevotella_1 (p < 0.05), while significantly increased the relative abundance of Ruminococcaceae_UCG-005, uncultured_bacterium_f_Lachnospiraceae, and Ruminococcus_1 genus (p < 0.05). Metabolomics analysis showed that YC changed the abundance of metabolites related to amino acid metabolism, lipid metabolism and vitamin metabolism pathways in the rumen. In summary, YC might maintain rumen health under high-concentrate diet conditions by changing rumen microbiota structure and fermentation patterns, thereby affecting rumen metabolic profiles and repairing rumen epithelial injury.PMID:38107864 | PMC:PMC10722269 | DOI:10.3389/fmicb.2023.1305772

Saudi J Biol Sci. 2024 Jan;31(1):103871. doi: 10.1016/j.sjbs.2023.103871. Epub 2023 Nov 9.ABSTRACTEpithelial cancer cells rely on the extracellular matrix (ECM) attachment in order to spread to other organs. Detachment from the ECM is necessary for these cells to seed in other locations. When the attachment to the ECM is lost, cellular metabolism undergoes a significant shift from oxidative metabolism to glycolysis. Additionally, the cancer cells become more dependent on glutaminolysis to avoid a specific type of cell death known as anoikis, which is associated with ECM detachment. In our recent study, we observed increased expression of H3K27me3 demethylases, specifically KDM6A/B, in cancer cells that were resistant to anoikis. Since KDM6A/B is known to regulate cellular metabolism, we investigated the effects of suppressing KDM6A/B with GSK-J4 on the metabolic processes in these anoikis-resistant cancer cells. Our results from untargeted metabolomics revealed a profound impact of KDM6A/B inhibition on various metabolic pathways, including glycolysis, methyl histidine, spermine, and glutamate metabolism. Inhibition of KDM6A/B led to elevated reactive oxygen species (ROS) levels and depolarization of mitochondria, while reducing the levels of glutathione, an important antioxidant, by diminishing the intermediates of the glutamate pathway. Glutamate is crucial for maintaining a pool of reduced glutathione. Furthermore, we discovered that KDM6A/B regulates the key glycolytic genes expression like hexokinase, lactate dehydrogenase, and GLUT-1, which are essential for sustaining glycolysis in anoikis-resistant cancer cells. Overall, our findings demonstrated the critical role of KDM6A/B in maintaining glycolysis, glutamate metabolism, and glutathione levels. Inhibition of KDM6A/B disrupts these metabolic processes, leading to increased ROS levels and triggering cell death in anoikis-resistant cancer cells.PMID:38107766 | PMC:PMC10724685 | DOI:10.1016/j.sjbs.2023.103871

F1000Res. 2022 Oct 20;10:1021. doi: 10.12688/f1000research.73758.3. eCollection 2021.ABSTRACTBackground: Pinang yaki has bioactive compounds that have potential as a new herbal supplement. A better understanding of the bioactive compounds of pinang yaki using untargeted metabolomic profiling studies will provide clearer insight into the health benefits of pinang yaki and in particular its potential for the therapy and prevention of Covid-19. Methods: Fresh samples of pinang yaki ( Areca vestiaria) are obtained from forests in North Sulawesi Province, Indonesia. Samples were used for untargeted metabolomics analysis by UPLC-MS. Results: Based on an untargeted metabolomic profiling study of pinang yaki, 2504 compounds in ESI- and 2645 compounds in ESI+ were successfully obtained. After the analysis, 356 compounds in ESI- and 543 compounds in ESI+ were identified successfully. Major compounds Alpha-Chlorohydrin (PubChem ID: 7290) and Tagatose (PubChem ID: 439312) were found in ESI+ and ESI-. Discussion: The Top 10 metabolites from pinang yaki extract (ESI+) juga have been indicated in preventing SARS Cov2 infection and have exhibited good neuroprotective immunity. Benzothiazole (PubChem ID: 7222), L-isoleucine (PubChem ID: 6306), D-glucono-delta-lactone (PubChem ID: 736), Diethylpyrocarbonate (PubChem ID: 3051), Bis(2-Ethylhexyl) amine (PubChem ID: 7791), Cinnamic acid (PubChem ID: 444539), and Trigonelline (PubChem ID: 5570) also had potential effects as an antiviral, anti-inflammatory, and anti-Covid19. Conclusion: Untargeted metabolomic profiling showed many bioactive compounds contained in pinang yaki ( Areca vestiaria) extract. The top 10 compounds have been identified and explored for their potential benefits as anti-Covid19 supplement products. This is a preliminary study which still needs further research such as preclinical and clinical trials.PMID:38107666 | PMC:PMC10724647 | DOI:10.12688/f1000research.73758.3

PeerJ. 2023 Dec 12;11:e16549. doi: 10.7717/peerj.16549. eCollection 2023.ABSTRACTBACKGROUND: Fusarium wilt, caused by Fusarium oxysporum f. sp. cubense race 4 (Foc4), is the most lethal disease of bananas in Asia.METHODS: To better understand the defense response of banana to Fusarium wilt, the transcriptome and metabolome profiles of the roots from resistant and susceptible bananas inoculated with Foc4 were compared.RESULTS: After Foc4 inoculation, there were 172 and 1,856 differentially expressed genes (DEGs) in the Foc4-susceptible variety (G1) and Foc4-resistant variety (G9), respectively. In addition, a total of 800 DEGs were identified between G1 and G9, which were mainly involved in the oxidation-reduction process, cell wall organization, phenylpropanoid biosynthesis, and lipid and nitrogen metabolism, especially the DEGs of Macma4_08_g22610, Macma4_11_g19760, and Macma4_03_g06480, encoding non-classical arabinogalactan protein; GDSL-like lipase; and peroxidase. In our study, G9 showed a stronger and earlier response to Foc4 than G1. As the results of metabolomics, lipids, phenylpropanoids and polyketides, organic acids, and derivatives played an important function in response to Fusarium wilt. More importantly, Macma4_11_g19760 might be one of the key genes that gave G9 more resistance to Foc4 by a lowered expression and negative regulation of lipid metabolism. This study illustrated the difference between the transcriptomic and metabolomic profiles of resistant and susceptible bananas. These results improved the current understanding of host-pathogen interactions and will contribute to the breeding of resistant banana plants.PMID:38107578 | PMC:PMC10722978 | DOI:10.7717/peerj.16549

Conserv Physiol. 2023 Dec 15;11(1):coad099. doi: 10.1093/conphys/coad099. eCollection 2023.ABSTRACTArctic char (Salvelinus alpinus) is facing the decline of its southernmost populations due to several factors including rising temperatures and eutrophication. These conditions are also conducive to episodes of cyclic hypoxia, another possible threat to this species. In fact, lack of oxygen and reoxygenation can both have serious consequences on fish as a result of altered ATP balance and an elevated risk of oxidative burst. Thus, fish must adjust their phenotype to survive and equilibrate their energetic budget. However, their energy allocation strategy could imply a reduction in growth which could be deleterious for their fitness. Although the impact of cyclic hypoxia is a major issue for ecosystems and fisheries worldwide, our knowledge on how salmonid deal with high oxygen fluctuations remains limited. Our objective was to characterize the effects of cyclic hypoxia on growth and metabolism in Arctic char. We monitored growth parameters (specific growth rate, condition factor), hepatosomatic and visceral indexes, relative heart mass and hematocrit of Arctic char exposed to 30 days of cyclic hypoxia. We also measured the hepatic protein synthesis rate, hepatic triglycerides as well as muscle glucose, glycogen and lactate and quantified hepatic metabolites during this treatment. The first days of cyclic hypoxia slightly reduce growth performance with a downward trend in specific growth rate in mass and condition factor variation compared to the control group. This acute exposure also induced a profound metabolome reorganization in the liver with an alteration of amino acid, carbohydrate and lipid metabolisms. However, fish rebalanced their metabolic activities and successfully maintained their growth and energetic reserves after 1 month of cyclic hypoxia. These results demonstrate the impressive ability of Arctic char to cope with its changing environment but also highlight a certain vulnerability of this species during the first days of a cyclic hypoxia event.PMID:38107465 | PMC:PMC10724465 | DOI:10.1093/conphys/coad099