PubMed

Sci Adv. 2023 Oct 6;9(40):eadf0837. doi: 10.1126/sciadv.adf0837. Epub 2023 Oct 6.ABSTRACTIntratumor heterogeneity (ITH) profoundly affects therapeutic responses and clinical outcomes. However, the widespread methods for assessing ITH based on genomic sequencing or pathological slides, which rely on limited tissue samples, may lead to inaccuracies due to potential sampling biases. Using a newly established multicenter breast cancer radio-multiomic dataset (n = 1474) encompassing radiomic features extracted from dynamic contrast-enhanced magnetic resonance images, we formulated a noninvasive radiomics methodology to effectively investigate ITH. Imaging ITH (IITH) was associated with genomic and pathological ITH, predicting poor prognosis independently in breast cancer. Through multiomic analysis, we identified activated oncogenic pathways and metabolic dysregulation in high-IITH tumors. Integrated metabolomic and transcriptomic analyses highlighted ferroptosis as a vulnerability and potential therapeutic target of high-IITH tumors. Collectively, this work emphasizes the superiority of radiomics in capturing ITH. Furthermore, we provide insights into the biological basis of IITH and propose therapeutic targets for breast cancers with elevated IITH.PMID:37801493 | DOI:10.1126/sciadv.adf0837

Andrology. 2023 Oct 6. doi: 10.1111/andr.13541. Online ahead of print.ABSTRACTBACKGROUND: The unique epigenetic architecture that sperm cells acquire during spermiogenesis by retaining <15% of either canonical or variant histone proteins in their genome is essential for normal embryogenesis. Whilst heterogeneous levels of retained histones are found in morphologically normal spermatozoa, their effect on reproductive outcomes is not fully understood.METHODS: Processed spermatozoa (n = 62) were tested for DNA integrity by sperm chromatin dispersion assay, and retained histones were extracted and subjected to dot-blot analysis. The impact of retained histone modifications in normozoospermic patients on sperm functional characteristics, embryo quality, metabolic signature in embryo spent culture medium and pregnancy outcome was studied.RESULTS: Dot-blot analysis showed heterogeneous levels of retained histones in the genome of normozoospermic ejaculates. Post-wash sperm yield was affected by an increase in H3K27Me3 and H4K20Me3 levels in the sperm chromatin (p < 0.05). Also, spermatozoa with higher histone H3 retention had increased DNA damage (p < 0.05). Spermatozoa from these cohorts, when injected into donor oocytes, correlated to a significant decrease in the fertilisation rate with an increase in sperm histone H3 (p < 0.05) and H3K27Me3 (p < 0.01). An increase in histone H3 negatively affected embryo quality (p < 0.01) and clinical pregnancy outcome post-embryo transfer (p < 0.05). On the other hand, spent culture medium metabolites assessed by high-resolution (800 MHz) nuclear magnetic resonance showed an increased intensity of the amino acid methionine in the non-pregnant group than in the pregnant group (p < 0.05) and a negative correlation with sperm histone H3 in the pregnant group (p < 0.05).DISCUSSION AND CONCLUSION: Histone retention in spermatozoa can be one of the factors behind the development of idiopathic male infertility. Such spermatozoa may influence embryonic behaviour and thereby affect the success rate of assisted reproductive technology procedures. These results, although descriptive in nature, warrant further research to address the underlying mechanisms behind these clinically important observations.PMID:37801310 | DOI:10.1111/andr.13541

Environ Sci Pollut Res Int. 2023 Oct 6. doi: 10.1007/s11356-023-29980-x. Online ahead of print.ABSTRACTImidacloprid (IMI) and cadmium (Cd) are pollutants of concern in the environment. Although investigations about their combined toxicity to organisms such as earthworms, aquatic worms, Daphnia magna, and zebrafish have been carried out, their combined toxicity to mammals remains unknow. In this study, twenty-four 8-week-old mice were arbitrarily separated into 4 groups: CK (control group), IMI (15 mg/kg bw/day, 1/10 LD50), Cd (15 mg/kg bw/day, 1/10 LD50), and IMI + Cd (15 mg/kg bw/day IMI + 15 mg/kg bw/d Cd) and the combined toxic effects of IMI and Cd were examined with biochemical (oxidative stress testing) and omics approaches (metabolomics and lipidomics). The results revealed changes in each treatment group in terms of oxidative stress, abnormalities in lipid metabolism, and disturbances in amino acid metabolism. Co-administration had antagonistic effects on MDA accumulation and lipid metabolism disorders while acting synergistically on changes in SOD and GSH-Px activities. It is worth noting that after analysis, the changes caused by mixed administration in vivo were closer to those caused by IMI administration alone. This study provides new insights into the combined toxicity of neonicotinoids and heavy metals, which is helpful for relevant environmental governance and further investigations about their impacts on human health and the environment.PMID:37801250 | DOI:10.1007/s11356-023-29980-x

J Mol Neurosci. 2023 Oct 6. doi: 10.1007/s12031-023-02162-7. Online ahead of print.ABSTRACTMild traumatic brain injury (mTBI) and repetitive mTBI (RmTBI) are silent epidemics, and so far, there is no objective diagnosis. The severity of the injury is solely based on the Glasgow Coma Score (GCS) scale. Most patients suffer from one or more behavioral abnormalities, such as headache, amnesia, cognitive decline, disturbed sleep pattern, anxiety, depression, and vision abnormalities. Additionally, most neuroimaging modalities are insensitive to capture structural and functional alterations in the brain, leading to inefficient patient management. Metabolomics is one of the established omics technologies to identify metabolic alterations, mostly in biofluids. NMR-based metabolomics provides quantitative metabolic information with non-destructive and minimal sample preparation. We employed whole-blood NMR analysis to identify metabolic markers using a high-field NMR spectrometer (800 MHz). Our approach involves chemical-free sample pretreatment and minimal sample preparation to obtain a robust whole-blood metabolic profile from a rat model of concussion. A single head injury was given to the mTBI group, and three head injuries to the RmTBI group. We found significant alterations in blood metabolites in both mTBI and RmTBI groups compared with the control, such as alanine, branched amino acid (BAA), adenosine diphosphate/adenosine try phosphate (ADP/ATP), creatine, glucose, pyruvate, and glycerphosphocholine (GPC). Choline was significantly altered only in the mTBI group and formate in the RmTBI group compared with the control. These metabolites corroborate previous findings in clinical and preclinical cohorts. Comprehensive whole-blood metabolomics can provide a robust metabolic marker for more accurate diagnosis and treatment intervention for a disease population.PMID:37801210 | DOI:10.1007/s12031-023-02162-7

Microbiol Spectr. 2023 Oct 6:e0397622. doi: 10.1128/spectrum.03976-22. Online ahead of print.ABSTRACTCharacterizing the mode of action of anti-malarial compounds that emerge from high-throughput phenotypic screens is central to understanding how parasite resistance to these drugs can emerge. Here, we have employed untargeted metabolomics to inform on the mechanism of action of anti-malarial leads with different speed of kill profiles being developed by the Novartis Institute of Tropical Diseases (NITD). Time-resolved global changes in malaria parasite metabolite profiles upon drug treatment were quantified using liquid chromatography-based mass spectrometry and compared to untreated controls. Using this approach, we confirmed previously reported metabolomics profiles of the fast-killing (2.5 h) drug dihydroartemisinin (DHA) and the slower killing atovaquone. A slow-acting anti-malarial lead from NITD of imidazolopiperazine (IZP) class, GNF179, elicited little or no discernable metabolic change in malaria parasites in the same 2.5-h window of drug exposure. In contrast, fast-killing drugs, DHA and the spiroindolone (NITD246), elicited similar metabolomic profiles both in terms of kinetics and content. DHA and NITD246 induced peptide losses consistent with disruption of hemoglobin catabolism and also interfered with the pyrimidine biosynthesis pathway. Two members of the recently described class of anti-malarial agents of the 5-aryl-2-amino-imidazothiadiazole class also exhibited a fast-acting profile that featured peptide losses indicative of disrupted hemoglobin catabolism. Our screen demonstrates that structurally unrelated, fast-acting anti-malarial compounds generate similar biochemical signatures in Plasmodium pointing to a common mechanism associated with rapid parasite death. These profiles may be used to identify and possibly predict the mode of action of other fast-acting drug candidates. IMPORTANCE In malaria drug discovery, understanding the mode of action of lead compounds is important as it helps in predicting the potential emergence of drug resistance in the field when these drugs are eventually deployed. In this study, we have employed metabolomics technologies to characterize the potential targets of anti-malarial drug candidates in the developmental pipeline at NITD. We show that NITD fast-acting leads belonging to spiroindolone and imidazothiadiazole class induce a common biochemical theme in drug-exposed malaria parasites which is similar to another fast-acting, clinically available drug, DHA. These biochemical features which are absent in a slower acting NITD lead (GNF17) point to hemoglobin digestion and inhibition of the pyrimidine pathway as potential action points for these drugs. These biochemical themes can be used to identify and inform on the mode of action of fast drug candidates of similar profiles in future drug discovery programs.PMID:37800971 | DOI:10.1128/spectrum.03976-22

J Agric Food Chem. 2023 Oct 6. doi: 10.1021/acs.jafc.3c05051. Online ahead of print.ABSTRACTThis study was aimed to investigate the therapeutic effect and mechanism of AKHO on 5-fluorouracil (5-FU)-induced intestinal mucositis in mice. Mouse body weight, diarrhea score, and H&E staining were applied to judge the therapeutic effect of AKHO. 16S rDNA and nontargeted metabolomics have been used to study the mechanism. WB, ELISA, and immunohistochemistry were adopted to validate possible mechanisms. The results demonstrated that AKHO significantly reduced diarrhea scores and intestinal damage induced by 5-FU in mice. AKHO lowered the serum levels of LD and DAO, and upregulated the expressions of ZO-1 and occludin in the ileum. Also, AKHO upregulated the abundance of Lactobacillus in the gut and suppressed KEGG pathways such as cortisol synthesis and secretion and arachidonic acid metabolism. Further validation studies indicated that AKHO downregulated the expressions of prostaglandin E2 (PGE2), microsomal prostaglandin E synthase-1 (mPGES-1), and PGE2 receptor EP4, as well as upregulated the expression of glucocorticoid (GC) receptor (GR), leading to improved intestinal epithelial barrier function. Taken together, AKHO elicited protective effects against 5-FU-induced mucositis by regulating the expressions of tight junction proteins via modulation of GC/GR and mPGES-1/PGE2/EP4 pathway, providing novel insights into the utilization and development of this pharmaceutical/food resource.PMID:37800952 | DOI:10.1021/acs.jafc.3c05051

Anal Chem. 2023 Oct 6. doi: 10.1021/acs.analchem.2c05734. Online ahead of print.ABSTRACTThe metabolic cross-talk between tumor and immune cells plays key roles in immune cell function and immune checkpoint blockade therapy. However, the characterization of tumor immunometabolism and its spatiotemporal alterations during immune response in a complex tumor microenvironment is challenging. Here, a 3D tumor-immune cell coculture spheroid model was developed to mimic tumor-immune interactions, combined with mass spectrometry imaging-based spatially resolved metabolomics to visualize tumor immunometabolic alterations during immune response. The inhibition of T cells was simulated by coculturing breast tumor spheroids with Jurkat T cells, and the reactivation of T cells can be monitored through diminishing cancer PD-L1 expressions by berberine. This system enables simultaneously screening and imaging discriminatory metabolites that are altered during T cell-mediated antitumor immune response and characterizing the distributions of berberine and its metabolites in tumor spheroids. We discovered that the transport and catabolism of glutamine were significantly reprogrammed during the antitumor immune response at both metabolite and enzyme levels, corresponding to its indispensable roles in energy metabolism and building new biomass. The combination of spatially resolved metabolomics with the 3D tumor-immune cell coculture spheroid visually reveals metabolic interactions between tumor and immune cells and possibly helps decipher the role of immunometabolic alterations in tumor immunotherapy.PMID:37800909 | DOI:10.1021/acs.analchem.2c05734

Mol Med Rep. 2023 Nov;28(5):224. doi: 10.3892/mmr.2023.13111. Epub 2023 Oct 6.ABSTRACTGastrodia elata Blume has been widely used to treat various central and peripheral nerve diseases, and Para‑hydroxybenzaldehyde (PHBA) is one of the indicated components suggested to provide a neuroprotective effect. In our previous, it was shown that PHBA protected mitochondria against cerebral ischemia‑reperfusion (I/R) injury in rats. In the present study, how PHBA regulated the metabolic mechanism in blood following cerebral I/R was assessed to identify an effective therapeutic target for the prevention and treatment of ischemic stroke (IS). First, a rat model of cerebral ischemia‑reperfusion injury was established via middle cerebral artery occlusion/reperfusion (MCAO/R). The therapeutic effect of PHBA on brain I/R was evaluated by assessing the neurological function score, triphenyl tetrazolium chloride, hematoxylin and eosin, and Nissl staining. Next, a non‑targeted metabolomic based on high‑performance liquid chromatography quadrupole time‑of‑flight mass spectrometry was established to identify differential metabolites. Finally, a targeted metabolic spectrum was analyzed and the potential therapeutic targets were verified by Western blotting. The results showed that the neurological function score, cerebral infarction area, hippocampal morphology, and the number of neurons in the PHBA group were significantly improved compared with the model group. Metabonomic analysis showed that 13 different metabolites were identified between the model and PHBA group, which may be involved in the 'tricarboxylic acid cycle', 'glutathione metabolism', and 'mutual transformation of pentose and glucuronates', amongst others. Among these, the levels of the most significant differential metabolite, dGMP, decreased significantly following PHBA treatment. Western blotting was used to verify the expression of membrane‑associated guanosine kinase PSD‑95 and the subunit of glutamate AMPA receptor GluA1, which significantly increased after PHBA treatment. In addition, it was also found that PHBA increased the expression of the light chain‑3 protein and autophagy effector protein 1, whilst the expression of sequestosome‑1 decreased, indicating that PHBA promoted autophagy. Similarly, in TUNEL staining and detection of apoptosis‑related proteins, it was found that MCAO/R upregulated the expression of Bax and cleaved‑caspase‑3 whilst downregulating the expression of Bcl‑2 and increasing the apoptosis of hippocampal neurons; PHBA reversed this situation. These results suggest that cerebral I/R causes postsynaptic dysfunction by disrupting the interaction between PSD‑95 and AMPARs, and the inhibition of the autophagy system eventually leads to the apoptosis of hippocampal neurons.PMID:37800608 | DOI:10.3892/mmr.2023.13111

Arthritis Rheumatol. 2023 Oct 6. doi: 10.1002/art.42724. Online ahead of print.ABSTRACTOBJECTIVE: Investigate the hypothesis that interferon (IFN) stimulated gene (ISG) expression in systemic lupus erythematosus (SLE) monocytes is linked to changes in metabolic reprogramming and epigenetic regulation of ISG expression.METHODS: Monocytes from healthy volunteers and SLE patients at baseline or following IFNα treatment were analyzed by extracellular flux analysis, proteomics, metabolomics, chromatin immunoprecipitation and gene expression. The histone demethylases KDM6A/B were inhibited using GSK-J4. GSK-J4 was tested in pristane and resiquimod (R848) models of IFN-driven SLE.RESULTS: SLE monocytes had enhanced rates of glycolysis and oxidative phosphorylation compared to healthy control (HC) monocytes, as well as increased levels of isocitrate dehydrogenase (IDH2) and its product, α-ketoglutarate (α-KG). As α-KG is a required cofactor for histone demethylases KDM6A and KDM6B, we hypothesized that IFNα may be driving 'trained immune' responses through altering histone methylation. IFNα priming (day 1) resulted in a sustained increase in the expression of ISGs in primed cells (day 5) and enhanced expression on restimulation with IFNα. Importantly decreased H3K27 trimethylation was observed at the promoters of ISGs following IFNα priming. Finally, GSK-J4 (KDM6A/B inhibitor) resulted in decreased ISG expression in SLE patient monocytes, as well as reduced autoantibody production, ISG expression and kidney pathology in R848-treated Balb/c mice.CONCLUSION: Our study suggests chronic IFNα exposure alters epigenetic regulation of ISG expression in SLE monocytes via changes in immunometabolism, a mechanism reflecting trained immunity to type I IFN. Importantly, it opens the possibility that targeting histone modifying enzymes such as KDM6A/B may reduce IFN responses in SLE.PMID:37800478 | DOI:10.1002/art.42724

Front Immunol. 2023 Sep 20;14:1250762. doi: 10.3389/fimmu.2023.1250762. eCollection 2023.ABSTRACTAdenine nucleotides (AN) are ubiquitous metabolites that regulate cellular energy metabolism and modulate cell communication and inflammation. To understand how disturbances in AN balance arise and affect cellular function, robust quantification techniques for these metabolites are crucial. However, due to their hydrophilicity, simultaneous quantification of AN across various biological samples has been challenging. Here we present a hydrophilic interaction high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) based method for the quantification of 26 adenosine nucleotides and precursors as well as metabolic products of nicotinamide adenine dinucleotide (NAD) in plasma, liver, and adipose tissue samples as well as cell culture supernatants and cells. Method validation was performed with regard to linearity, accuracy, precision, matrix effects, and carryover. Finally, analysis of cell culture supernatants derived from intestinal organoids and RAW 264.7 cells illustrates that the here described method is a reliable and easy-to-use tool to quantify AN and opens up new avenues to understand the role of AN generation and breakdown for cellular functions.PMID:37799723 | PMC:PMC10548204 | DOI:10.3389/fimmu.2023.1250762

Front Microbiol. 2023 Sep 20;14:1195709. doi: 10.3389/fmicb.2023.1195709. eCollection 2023.ABSTRACTFlammulina filiformis, a typical agaric fungus, is a widely cultivated and consumed edible mushroom. Elongation of its stipe (as the main edible part) is closely related to its yield and commercial traits; however, the endogenous hormones during stipe elongation and their regulatory mechanisms are not well understood. Gibberellin (GA) plays an important role in the regulation of plant growth, but little has been reported in macro fungi. In this study, we first treated F. filiformis stipes in the young stage with PBZ (an inhibitor of GA) and found that PBZ significantly inhibited elongation of the stipe. Then, we performed GA-targeted metabolome and transcriptome analyses of the stipe at both the young and elongation stages. A total of 13 types of GAs were detected in F. filiformis; the contents of ten of them, namely, GA3, GA4, GA8, GA14, GA19, GA20, GA24, GA34, GA44, and GA53, were significantly decreased, and the contents of three (GA5, GA9, and GA29) were significantly increased during stipe elongation. Transcriptome analysis showed that the genes in the terpenoid backbone biosynthesis pathway showed varying expression patterns: HMGS, HMGR, GPS, and FPPS were significantly upregulated, while CPS/KS had no significant difference in transcript level during stipe elongation. In total, 37 P450 genes were annotated to be involved in GA biosynthesis; eight of them were upregulated, twelve were downregulated, and the rest were not differentially expressed. In addition, four types of differentially expressed genes involved in stipe elongation were identified, including six signal transduction genes, five cell cycle-controlling genes, twelve cell wall-related enzymes and six transcription factors. The results identified the types and content of GAs and the expression patterns of their synthesis pathways during elongation in F. filiformis and revealed the molecular mechanisms by which GAs may affect the synthesis of cell wall components and the cell cycle of the stipe through the downstream action of cell wall-related enzymes, transcription factors, signal transduction and cell cycle control, thus regulating stipe elongation. This study is helpful for understanding the roles of GAs in stipe development in mushrooms and lays the foundation for the rational regulation of stipe length in agaric mushrooms during production.PMID:37799602 | PMC:PMC10548271 | DOI:10.3389/fmicb.2023.1195709

Front Plant Sci. 2023 Sep 19;14:1255682. doi: 10.3389/fpls.2023.1255682. eCollection 2023.ABSTRACTThe lack of irrigation water in agricultural soils poses a significant constraint on global crop production. In-depth investigation into microRNAs (miRNAs) has been widely used to achieve a comprehensive understanding of plant defense mechanisms. However, there is limited knowledge on the association of miRNAs with drought tolerance in cigar tobacco. In this study, a hydroponic experiment was carried out to identify changes in plant physiological characteristics, miRNA expression and metabolite profile under drought stress, and examine the mitigating effects of selenium (Se) application. The shoot dry weight of drought-stressed plants was approximately half (50.3%) of that in non-stressed (control) conditions. However, plants supplied with Se attained 38.8% greater shoot dry weight as compared to plants with no Se supply under drought stress. Thirteen miRNAs were identified to be associated with drought tolerance. These included 7 known (such as nta-miR156b and nta-miR166a) and 6 novel miRNAs (such as novel-nta-miR156-5p and novel-nta-miR209-5p) with the target genes of squamosa promoter-binding-like protein 4 (SPL4), serine/threonine protein phosphatase 2A (PPP2A), cation/calcium exchanger 4-like (CCX4), extensin-1-like (EXT1) and reduced wall acetylation 2 (RWA2). Further investigation revealed that the expression levels of Ext1 and RWA2 were significantly decreased under drought stress but increased with Se addition. Moreover, key metabolites such as catechin and N-acetylneuraminic acid were identified, which may play a role in the regulation of drought tolerance. The integrated analysis of miRNA sequencing and metabolome highlighted the significance of the novel-nta-miR97-5p- LRR-RLK- catechin pathway in regulating drought tolerance. Our findings provide valuable insights into the molecular mechanisms underlying drought tolerance and Se-induced stress alleviation in cigar tobacco.PMID:37799555 | PMC:PMC10548829 | DOI:10.3389/fpls.2023.1255682

Front Oncol. 2023 Sep 18;13:1289397. doi: 10.3389/fonc.2023.1289397. eCollection 2023.NO ABSTRACTPMID:37799477 | PMC:PMC10548817 | DOI:10.3389/fonc.2023.1289397

Acta Pharm Sin B. 2023 Oct;13(10):4273-4290. doi: 10.1016/j.apsb.2023.07.011. Epub 2023 Jul 15.ABSTRACTDuring the development of therapeutic microRNAs (miRNAs or miRs), it is essential to define their pharmacological actions. Rather, miRNA research and therapy mainly use miRNA mimics synthesized in vitro. After experimental screening of unique recombinant miRNAs produced in vivo, three lead antiproliferative miRNAs against human NSCLC cells, miR-22-3p, miR-9-5p, and miR-218-5p, were revealed to target folate metabolism by bioinformatic analyses. Recombinant miR-22-3p, miR-9-5p, and miR-218-5p were shown to regulate key folate metabolic enzymes to inhibit folate metabolism and subsequently alter amino acid metabolome in NSCLC A549 and H1975 cells. Isotope tracing studies further confirmed the disruption of one-carbon transfer from serine to folate metabolites by all three miRNAs, inhibition of glucose uptake by miR-22-3p, and reduction of serine biosynthesis from glucose by miR-9-5p and -218-5p in NSCLC cells. With greater activities to interrupt NSCLC cell respiration, glycolysis, and colony formation than miR-9-5p and -218-5p, recombinant miR-22-3p was effective to reduce tumor growth in two NSCLC patient-derived xenograft mouse models without causing any toxicity. These results establish a common antifolate mechanism and differential actions on glucose uptake and metabolism for three lead anticancer miRNAs as well as antitumor efficacy for miR-22-3p nanomedicine, which shall provide insight into developing antimetabolite RNA therapies.PMID:37799388 | PMC:PMC10547963 | DOI:10.1016/j.apsb.2023.07.011

Parasit Vectors. 2023 Oct 5;16(1):346. doi: 10.1186/s13071-023-05970-3.ABSTRACTBACKGROUND: Schistosoma infection is a significant public health issue, affecting over 200 million individuals and threatening 700 million people worldwide. The species prevalent in China is Schistosoma japonicum. Recent studies showed that both gut microbiota and metabolome are closely related to schistosomiasis caused by S. japonicum, but clinical study is limited and the underlying mechanism is largely unclear. This study aimed to explore alterations as well as function of gut microbiota and metabolite profile in the patients with S. japonicum infection.METHODS: This study included 20 patients diagnosed with chronic schistosomiasis caused by S. japonicum, eight patients with advanced schistosomiasis caused by S. japonicum and 13 healthy volunteers. The fresh feces of these participators, clinical examination results and basic information were collected. 16S ribosomal RNA gene sequencing was used to investigate gut microbiota, while ultraperformance liquid chromatography-mass spectrometry (UHPLC-MS) was applied to explore the metabolome of patients in different stages of schistosomiasis.RESULTS: The study found that gut microbiota and metabolites were altered in patients with different stages of S. japonicum infection. Compared with healthy control group, the gut microbial diversity in patients with chronic S. japonicum infection was decreased significantly. However, the diversity of gut microbiota in patients with chronic schistosomiasis was similar to that in patients with advanced schistosomiasis. Compared with uninfected people, patients with schistosomiasis showed decreased Firmicutes and increased Proteobacteria. As disease progressed, Firmicutes was further reduced in patients with advanced S. japonicum infection, while Proteobacteria was further increased. In addition, the most altered metabolites in patients with S. japonicum infection were lipids and lipid-like molecules as well as organo-heterocyclic compounds, correlated with the clinical manifestations and disease progress of schistosomiasis caused by S. japonicum.CONCLUSIONS: This study suggested that the gut microbiota and metabolome altered in patients in different stages of schistosomiasis, which was correlated with progression of schistosomiasis caused by S. japonicum. This inter-omics analysis may shed light on a better understanding of the mechanisms of the progression of S. japonicum infection and contribute to identifying new potential targets for the diagnosis and prognosis of S. japonicum infection. However, a large sample size of validation in clinic is needed, and further study is required to investigate the underlying mechanism.PMID:37798771 | DOI:10.1186/s13071-023-05970-3

Nat Metab. 2023 Oct 5. doi: 10.1038/s42255-023-00890-z. Online ahead of print.ABSTRACTNeuronal activity creates an intense energy demand that must be met by rapid metabolic responses. To investigate metabolic adaptations in the neuron-enriched dentate granule cell (DGC) layer within its native tissue environment, we employed murine acute hippocampal brain slices, coupled with fast metabolite preservation and followed by mass spectrometry (MS) imaging, to generate spatially resolved metabolomics and isotope-tracing data. Here we show that membrane depolarization induces broad metabolic changes, including increased glycolytic activity in DGCs. Increased glucose metabolism in response to stimulation is accompanied by mobilization of endogenous inosine into pentose phosphates via the action of purine nucleotide phosphorylase (PNP). The PNP reaction is an integral part of the neuronal response to stimulation, because inhibition of PNP leaves DGCs energetically impaired during recovery from strong activation. Performing MS imaging on brain slices bridges the gap between live-cell physiology and the deep chemical analysis enabled by MS.PMID:37798473 | DOI:10.1038/s42255-023-00890-z

Sci Rep. 2023 Oct 5;13(1):16811. doi: 10.1038/s41598-023-43664-z.ABSTRACTFor end-stage kidney disease (ESKD) patients, hemodialysis requires durable vascular access which is often surgically created using an arteriovenous fistula (AVF). However, some ESKD patients that undergo AVF placement develop access-related hand dysfunction (ARHD) through unknown mechanisms. In this study, we sought to determine if changes in the serum metabolome could distinguish ESKD patients that develop ARHD from those that have normal hand function following AVF creation. Forty-five ESKD patients that underwent first-time AVF creation were included in this study. Blood samples were obtained pre-operatively and 6-weeks post-operatively and metabolites were extracted and analyzed using nuclear magnetic resonance spectroscopy. Patients underwent thorough examination of hand function at both timepoints using the following assessments: grip strength manometry, dexterity, sensation, motor and sensory nerve conduction testing, hemodynamics, and the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire. Nineteen of the forty-five patients displayed overt weakness using grip strength manometry (P < 0.0001). Unfortunately, the serum metabolome was indistinguishable between patients with and without weakness following AVF surgery. However, a significant correlation was found between the change in tryptophan levels and the change in grip strength suggesting a possible role of tryptophan-derived uremic metabolites in post-AVF hand-associated weakness. Compared to grip strength, changes in dexterity and sensation were smaller than those observed in grip strength, however, post-operative decreases in phenylalanine, glycine, and alanine were unique to patients that developed signs of motor or sensory disability following AVF creation.PMID:37798334 | DOI:10.1038/s41598-023-43664-z

J Ethnopharmacol. 2023 Oct 3:117274. doi: 10.1016/j.jep.2023.117274. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Inonotus hispidus is the traditional Chinese medicine Sanghuang. Since ancient times, Sanghuang has been documented to be used in the treatment of female breast diseases. However, the pharmacological mechanism of Sanghuang in the treatment of mammary gland hyperplasia (HMG) remains unclear.AIM OF THE STUDY: The ethyl acetate extract of the aging fruiting body of I. hispidus (IEAE) was used to study the pharmacological mechanism of IEAE in the treatment of HMG using non-targeted metabolomics.MATERIALS AND METHODS: The HMG rat model was established, and serum metabolomics was used to study the potential therapeutic mechanism of IEAE for HMG.RESULTS: IEAE has obvious therapeutic effect on HMG model rats, and no obvious adverse reactions were observed. Non-targeted metabolomics showed that after IEAE intervention, the upstream metabolite D-erythrose 4-phosphate was significantly downregulated, aromatic amino acids such as tryptophan, tyrosine, and phenylalanine were downregulated, and the downstream metabolites N-acetyl-L-glutamate and L-proline were significantly upregulated. After an intervention with yakuchinone A, non-targeted metabolomics analyses demonstrated that yakuchinone A restored tetrahydrocorticosterone, cortisol, and etiocholanolone to normal levels, estriol was significantly upregulated, and steroid hormone biosynthesis was significantly activated.CONCLUSION: IEAE was shown to have a good therapeutic effect on HMG in a rat model without adverse reactions. The mechanism of action was mainly based on the biosynthesis of amino acids. Small molecule metabolites such as D-erythrose 4-phosphate, N-acetyl-L-glutamate, and L-proline may be potential targets for IEAE in the treatment of HMG. Yakuchinone A is one of the main active components of IEAE, and plays a role by promoting the steroid hormone biosynthesis pathway. Estriol may be a potential target for the treatment of HMG with yakuchinone A, providing a new concept for clinical treatment of HMG.PMID:37797875 | DOI:10.1016/j.jep.2023.117274

Exp Eye Res. 2023 Oct 3:109672. doi: 10.1016/j.exer.2023.109672. Online ahead of print.ABSTRACTLewisite (LEW) is an arsenical vesicant that can be a potentially dangerous chemical warfare agent (CWA). Eyes are particularly susceptible to vesicant induced injuries and ocular LEW exposure can act swiftly, causing burning of eyes, edema, inflammation, cell death and even blindness. In our previous studies, we developed a LEW exposure-induced corneal injury model in rabbit and showed increased inflammation, neovascularization, cell death, and structural damage to rabbit corneas upon LEW exposure. In the present study, we further assessed the metabolomic changes to delineate the possible mechanisms underlying the LEW-induced corneal injuries. This information is vital and could help the development of effective targeted therapies against ocular LEW injuries. Thus, the metabolomic changes associated with LEW exposures in rabbit corneas were assessed as a function of time, to delineate pathways from molecular perturbations at the genomic and proteomic levels. New Zealand white rabbit corneas (n = 3-6) were exposed to LEW vapor (0.2 mg/L; flow rate: 300 ml/min) for 2.5 min (short exposure; low dose) or 7.5 min (long-exposure; high dose) and then collected at 1, 3, 7, or 14 days post LEW exposure. Samples were prepared using the automated MicroLab STAR® system, and proteins precipitated to recover the chemically diverse metabolites. Metabolomic analysis was carried out by reverse phase UPLC-MS/MS and gas chromatography (GC)-MS. The data obtained were analyzed using Metabolon's software. The results showed that LEW exposures at high doses were more toxic, particularly at the day 7 post exposure time point. LEW exposure was shown to dysregulate metabolites associated with all the integral functions of the cornea and cause increased inflammation and immune response, as well as generate oxidative stress. Additionally, all important metabolic functions of the cells were also affected: lipid and nucleotide metabolism, and energetics. The high dose LEW exposures were more toxic, particularly at day 7 post LEW exposure (>10-fold increased levels of histamine, quinolinate, N-acetyl-β-alanine, GMP, and UPM). LEW exposure dysregulated integral functions of the cornea, caused inflammation and heightened immune response, and generated oxidative stress. Lipid and nucleotide metabolism, and energetics were also affected. The novel information about altered metabolic profile of rabbit cornea following LEW exposure could assist in delineating complex molecular events; thus, aid in identifying therapeutic targets to effectively ameliorate ocular trauma.PMID:37797797 | DOI:10.1016/j.exer.2023.109672

Fitoterapia. 2023 Oct 3:105695. doi: 10.1016/j.fitote.2023.105695. Online ahead of print.ABSTRACTFor centuries, food, herbal medicines, and natural products have been valuable resources for discovering novel antiviral drugs, uncovering new structure-activity relationships, and developing effective strategies to prevent/treat viral infections. One such resource is Phellinus linteus, a mushroom used in folk medicine in Taiwan, Japan, Korea, and China. In this rich historical context, the key metabolites of Phellinus linteus mycelia ethanolic extract (GKPL) impacting the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at multiple stages have yet to be explored. Thus, this study systematically identifies and assesses the inhibitory effect of GKPL on the SARS-CoV-2 virus. Initially, the concentrations and contact times of GKPL against SARS-CoV-2 pseudovirus were assessed in HepG2 cells. Subsequently, utilizing the Ultra Performance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry method, potential biomarkers in the fungal extract were discerned. Metabolomic analysis identified 18 compounds in GKPL, with hispidin and hypholomine B present in the highest amounts. These compounds were isolated using chromatographic techniques and further identified through 1D NMR spectroscopic and mass spectrometry analysis. Hispidin and hypholomine B were found to inhibit the infection of SARS-CoV-2 pseudovirus by reducing angiotensin-converting enzyme 2 gene expression in HepG2, thereby decreasing viral entry. Moreover, hispidin and hypholomine B effectively block the spike receptor-binding domain, while hypholomine B, for the first time, showed significant inhibition of 3CL protease. This suggests that GKPL, enriched with hispidin and hypholomine B, has the potential to be used as an active ingredient against SARS-CoV-2.PMID:37797793 | DOI:10.1016/j.fitote.2023.105695