PubMed

Theriogenology. 2022 Nov 11;196:88-96. doi: 10.1016/j.theriogenology.2022.11.013. Online ahead of print.ABSTRACTSperm cryopreservation maintains the diversities of porcine genetic resources and improves utilization efficiency of boar semen in artificial insemination practices. Freezability of boar semen presents remarkable differences among individuals. However, metabolic markers for boar semen freezability in both sperm and seminal plasma largely remain unknown. The present study thus aims to determine differences in metabolites of sperm and seminal plasma between poor (PF) and good (GF) freezability semen from a Chinese native pig and screen potential markers for semen freezability. A total of 72,048 metabolites in sperm and 66,551 metabolites in seminal plasma were identified by liquid chromatography-mass spectrometry, respectively. The proportion of lipid molecules among all metabolites in both sperm and seminal plasma was the maximum regardless of negative or positive mode. Furthermore, we identified 21 differentially expressed metabolites (DEMs) in sperm and 185 DEMs in seminal plasma between PF and GF group. Additionally, clustering analysis showed that DEMs in sperm and seminal plasma exhibited significant changes between PF and GF group. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that DEMs in sperm were mainly enriched in metabolic pathways of amino acids and caffeine. DEMs in seminal plasma were associated with AMPK and cAMP signaling pathways. Taken together, these results demonstrate that sperm and seminal plasma of native pigs present differential metabolome between PF and GF semen.PMID:36401936 | DOI:10.1016/j.theriogenology.2022.11.013

Food Chem. 2022 Nov 7;405(Pt B):134868. doi: 10.1016/j.foodchem.2022.134868. Online ahead of print.ABSTRACTIn NMR-based untargeted analysis, Fourier transformation is applied to the time-domain data to extract observables such as frequency and intensity. Despite its wide application, this approach has several limitations that can prevent NMR from reaching its highest potential. Here, we utilized Bayesian analysis through CRAFT as an alternative method, using California-style table olives as a model system. Our hypothesis was that the time-domain analysis through CRAFT will be as successful as the traditional approach. The results showed that CRAFT generated efficient unsupervised and supervised models in a robust, and rapid/automated manner. The duration of CRAFT analysis can be further reduced by using the first 14 k complex data points of the initial part of the FID, without affecting the performance of the untargeted analysis. For unsupervised analysis, CRAFT was generally more efficient, while for supervised analysis both approaches were effective. CRAFT can be also used for identifying marker compounds driving classifications.PMID:36401894 | DOI:10.1016/j.foodchem.2022.134868

Arch Pharm Res. 2022 Nov 19. doi: 10.1007/s12272-022-01416-z. Online ahead of print.ABSTRACTVarious factors related to growing conditions can influence the nutritional quality of plants, including vegetable crops, especially the contents of health-promoting phytochemicals. In this study, the phytochemical contents of spinach (Spinacia oleracea) cultivated under greenhouse and open field conditions were comparatively analyzed using a metabolomic approach with Mass Profiler Professional (MPP) software. S. oleracea, which is one of the well-known leafy vegetables belonging to the family Chenopodiaceae, is cultivated worldwide. Although the nutritional value of spinach is high, the phytochemical contents of spinach cultivated under greenhouse and open field conditions have not been comparatively analyzed. Metabolomic analysis of the methanol (MeOH) extracts of greenhouse-cultivated spinach (GS) and open field-cultivated spinach (OFS) using ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS), followed by principal component analysis (PCA) with MPP demonstrated the differential metabolite profiles of GS and OFS. The active compounds 1-3 were isolated and identified using LC-Q-TOF-MS-guided fractionation. Among these, 5,3',4'-trihydroxy-3-methoxy-6,7-methylenedioxyflavone 4'-glucuronide (2) exhibited growth-inhibitory activities against Helicobacter pylori 51. Distribution analysis of compound 2 revealed that the anti-H. pylori compound 2 is an OFS-specific bioactive phytochemical. This indicates that the phytochemical quality of OFS is better than that of GS. These findings will aid in providing vital data for vegetable processors, dieticians, nutritionists, and consumers to select optimal green leafy vegetables.PMID:36401778 | DOI:10.1007/s12272-022-01416-z

Cell Oncol (Dordr). 2022 Nov 19. doi: 10.1007/s13402-022-00740-2. Online ahead of print.ABSTRACTBACKGROUND: Although isocitrate dehydrogenase 2 (IDH2) mutations have been the hotspots in recent anticancer studies, the impact of wild-type IDH2 on cancer cell growth and metabolic alterations is still elusive.METHODS: IDH2 expression in CRC tissues was evaluated by immunohistochemistry, and the correlation between the expression level and the patient's survival rate was analyzed. Cell functional assays included CCK8 and colony formation for cell proliferation in vitro and ectopic xenograft as in vivo experimental model for tumor progression. A targeted metabolomic procedure was performed by liquid chromatography/tandem mass spectrometry to profile the metabolites from glycolysis and tricarboxylic acid (TCA) cycle. Mitochondrial function was assessed by measuring cellular oxygen consumption (OCR) and mitochondrial membrane potential (ΔΨ). Confocal microscope analysis and Western blotting were applied to detect the expression of GLUT1 and NF-κB signaling. O-GlcNAcylation and the interaction of IDH2 with OGT were confirmed by co-immunoprecipitation, followed by Western blotting analysis.RESULTS: IDH2 protein was highly expressed in CRC tissues, and correlated with poor survival of CRC patients. Wild-type IDH2 promoted CRC cell growth in vitro and tumor progression in xenograft mice. Overexpression of wild-type IDH2 significantly increased glycolysis and TCA cycle metabolites, the ratios of NADH/NAD+ and ATP/ADP, OCR and mitochondrial membrane potential (ΔΨ) in CRC cells. Furthermore, α-KG activated NF-κB signaling to promote glucose uptake by upregulating GLUT1. Interesting, O-GlcNAcylation enhanced the protein half-time of IDH2 by inhibiting ubiquitin-mediated proteasome degradation. The O-GlcNAc transferase (OGT)-IDH2 axis promoted CRC progression.CONCLUSION: Wild-type IDH2 reprogrammed glucose metabolism and bioenergetic production via the NF-κB signaling pathway to promote CRC development and progression. O-GlcNAcylation of IDH2 elevated the stability of IDH2 protein. And the axis of OGT-IDH2 played an essential promotive role in tumor progression, suggesting a novel potential therapeutic strategy in CRC treatment.PMID:36401762 | DOI:10.1007/s13402-022-00740-2

Environ Sci Pollut Res Int. 2022 Nov 19. doi: 10.1007/s11356-022-24258-0. Online ahead of print.ABSTRACTFulvic acid (FA) can significantly alleviate cadmium (Cd) stress, but the specific metabolic response of FA to Cd toxicity is still not clarified. In the present study, we used untargeted metabolomic [gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS)] analysis to profile cucumber metabolism in response to Cd stress after spray application of FA. Our results showed that 331 differentially enriched metabolites (DEMs) were identified in leaf materials. These DEMs were enriched in 21 shared pathways in comparative groups of "Cd treatment vs. the control treatment" and "FA + Cd treatment vs. the Cd treatment." Specifically, treatment with FA significantly enhanced the organic acid content (citric acid, isocitric acid, 2-oxoglutaric acid, fumaric acid, and malic acid), which would contribute to provide sufficient substrates for the tricarboxylic acid (TCA) cycle and amino acid biosynthesis, thereby ensuring the normal production of energy and amino acid. At the same time, FA significantly increased the amino acid content (aspartate, citrulline, histidine, leucine, and phenylalanine). The accumulation of organic acid and amino acid can act as chelating agents for heavy metal ions and as scavengers of reactive oxygen species (ROS), thereby reducing intracellular oxidative damage. Furthermore, the application of FA improves antioxidant enzymes and accelerates ROS clearance. The improved contents of organic acid and amino acid, and the increased activity of antioxidant enzymes both played a central role in the reduction of malondialdehyde (MDA, 14.08%), hydrogen peroxide (H2O2, 61.70%) contents, and superoxide anion radical (O2-, 30.41%) production rate in plants under Cd stress. Taken together, the present study demonstrates the effects of FA on the antioxidant capacity and carbohydrate and amino acid metabolism of cucumber seedlings exposed to Cd stress, which provides comprehensive insights into the regulation of plants' response to Cd toxicity with FA was applied in cucumber.PMID:36401696 | DOI:10.1007/s11356-022-24258-0

Medicine (Baltimore). 2022 Nov 18;101(46):e31419. doi: 10.1097/MD.0000000000031419.ABSTRACTMicrobiota composition in breast milk affects intestinal and respiratory microbiota colonization and the mucosal immune system's development in infants. The metabolomic content of breast milk is thought to interact with the microbiota and may influence developing infant immunity. One hundred seven Gambian mothers and their healthy, vaginally delivered, exclusively breastfed infants were included in our study. We analyzed 32 breast milk samples, 51 maternal rectovaginal swabs and 30 infants' rectal swabs at birth. We also analyzed 9 breast milk samples and 18 infants' nasopharyngeal swabs 60 days post-delivery. We used 16S rRNA gene sequencing to determine the microbiota composition. Metabolomic profiling analysis was performed on colostrum and mature breast milk samples using a multiplatform approach combining 1-H Nuclear Magnetic Resonance Spectroscopy and Gas Chromatography-Mass Spectrometry. Bacterial communities were distinct in composition and diversity across different sample types. Breast milk composition changed over the first 60 days of lactation. α-1,4- and α-1,3-fucosylated human milk oligosaccharides, and other 33 key metabolites in breast milk (monosaccharides, sugar alcohols and fatty acids) increased between birth and day 60 of life. This study's results indicate that infant gut and respiratory microbiota are unique bacterial communities, distinct from maternal gut and breast milk, respectively. Breast milk microbiota composition and metabolomic profile change throughout lactation. These changes may contribute to the infant's immunological, metabolic, and neurological development and could consist the basis for future interventions to correct disrupted early life microbial colonization.PMID:36401392 | DOI:10.1097/MD.0000000000031419

J Transl Med. 2022 Nov 18;20(1):532. doi: 10.1186/s12967-022-03739-3.ABSTRACTBACKGROUND: The crosstalk of purine biosynthesis and metabolism exists to balance the cell energy production, proliferation, survival and cytoplasmic environment stability, but disorganized mechanics of with respect to developing heart failure (HF) is currently unknown.METHODS: We conducted a multi-omics wide analysis, including microarray-based transcriptomes, and full spectrum metabolomics with respect to chronic HF. Based on expression profiling by array, we applied a bioinformatics platform of quantifiable metabolic pathway changes based on gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), Shapley Additive Explanations (SHAP), and Xtreme Gradient Boosting (XGBoost) algorithms to comprehensively analyze the dynamic changes of metabolic pathways and circular network in the HF development. Additionally, left ventricular tissue from patients undergoing myocardial biopsy and transplantation were collected to perform the protein and full spectrum metabolic mass spectrometry.RESULTS: Systematic bioinformatics analysis showed the purine metabolism reprogramming was significantly detected in dilated cardiomyopathy. In addition, this result was also demonstrated in metabolomic mass spectrometry. And the differentially expressed metabolites analysis showing the guanine, urea, and xanthine were significantly detected. Hub markers, includes IMPDH1, ENTPD2, AK7, AK2, and CANT1, also significantly identified based on XGBoost, SHAP model and PPI network.CONCLUSION: The crosstalk in the reactions involved in purine metabolism may involving in DCM metabolism reprogramming, and as coregulators of development of HF, which may identify as potential therapeutic targets. And the markers of IMPDH1, ENTPD2, AK7, AK2, and CANT1, and metabolites involved in purine metabolism shown an important role.PMID:36401332 | DOI:10.1186/s12967-022-03739-3

J Transl Med. 2022 Nov 18;20(1):530. doi: 10.1186/s12967-022-03758-0.ABSTRACTBACKGROUND: Liver cancer is the fifth leading cause of cancer death worldwide, but early diagnosis and treatment of liver cancer remains a clinical challenge. How to screen and diagnose liver cancer early and prolong the survival rate is still the focus of researchers.METHODS: Cell experiments were used to detect the effect of WZ35 on the colony formation ability and proliferation activity of hepatoma cells, nude mouse experiment to observe the in vivo anticancer activity and toxic side effects of WZ35; metabolomics analysis, glucose metabolism experiment and Seahorse analysis of liver cancer cells treated with WZ35; cell experiments combined with bioinformatics analysis to explore the mechanism of WZ35-mediated metabolic reprogramming to exert anticancer activity; tissue microarray and case analysis to evaluate the clinical significance of biomarkers for early diagnosis, treatment and prognosis evaluation of liver cancer.RESULTS: WZ35 inhibited the proliferation activity of various cell lines of liver cancer, and showed good therapeutic effect in nude mice model of hepatocellular carcinoma without obvious toxic and side effects; WZ35 inhibited the absorption of glucose in hepatoma cells, and the drug effect glycolysis, phosphorylation and purine metabolism are relatively seriously damaged; WZ35 mainly inhibits YAP from entering the nucleus as a transcription factor activator by activating oxidative stress in liver cancer cells, reducing the transcription of GLUT1, and finally reducing its GLUT1. Tissue microarray and case analysis showed that GLUT1 and YAP were highly expressed and correlated in liver cancer patients, and were associated with poor patient prognosis. The GLUT1-YAP risk model had a high score in predicting prognosis.CONCLUSION: The study confirms that WZ35 is a small molecule glycolysis inhibitor, and through its properties, it mediates metabolic reprogramming dominated by impaired glycolysis, oxidative phosphorylation and purine metabolism to inhibit the proliferation activity of liver cancer cells. Our findings present novel insights into the pathology of liver cancer and potential targets for new therapeutic strategies. GLUT1-YAP has important reference significance for predicting the stages of disease progression in liver cancer patients and have the potential to serve as novel biomarkers for the diagnosis and treatment of liver cancer.PMID:36401321 | DOI:10.1186/s12967-022-03758-0

Sci Rep. 2022 Nov 18;12(1):19824. doi: 10.1038/s41598-022-23300-y.ABSTRACTSportomics is a subject-centered holistic method similar to metabolomics focusing on sports as the metabolic challenge. Dried blood spot is emerging as a technique due to its simplicity and reproducibility. In addition, mass spectrometry and integrative computational biology enhance our ability to understand exercise-induced modifications. We studied inflammatory blood proteins (Alpha-1-acid glycoprotein-A1AG1; Albumin; Cystatin C; C-reactive protein-CRP; Hemoglobin-HBA; Haptoglobin-HPT; Insulin-like growth factor 1; Lipopolysaccharide binding protein-LBP; Mannose-binding lectin-MBL2; Myeloperoxidase-PERM and Serum amyloid A1-SAA1), in 687 samples from 97 World-class and Olympic athletes across 16 sports in nine states. Data were analyzed with Spearman's rank-order correlation. Major correlations with CRP, LBP; MBL2; A1AG1, and SAA1 were found. The pairs CRP-SAA1 and CRP-LBP appeared with a robust positive correlation. Other pairs, LBP-SAA1; A1AG1-CRP; A1AG1-SAA1; A1AG1-MBL, and A1AG1-LBP, showed a broader correlation across the sports. The protein-protein interaction map revealed 1500 interactions with 44 core proteins, 30 of them linked to immune system processing. We propose that the inflammation follow-up in exercise can provide knowledge for internal cargo management in training, competition, recovery, doping control, and a deeper understanding of health and disease.PMID:36400821 | DOI:10.1038/s41598-022-23300-y

J Heart Lung Transplant. 2022 Oct 1:S1053-2498(22)02162-3. doi: 10.1016/j.healun.2022.09.017. Online ahead of print.ABSTRACTBACKGROUND: Continuous-flow left ventricular assist devices commonly lead to aortic regurgitation, which results in decreased pump efficiency and worsening heart failure. We hypothesized that non-physiological wall shear stress and oscillatory shear index alter the abundance of structural proteins in aortic valves of left ventricular assist device (LVAD) patients.METHODS: Doppler images of aortic valves of patients undergoing heart transplants were obtained. Eight patients had been supported with LVADs, whereas 10 were not. Aortic valve tissue was collected and protein levels were analyzed using mass spectrometry. Echocardiographic images were analyzed and wall shear stress and oscillatory shear index were calculated. The relationship between normalized levels of individual proteins and in vivo echocardiographic measurements was evaluated.RESULTS: Of the 57 proteins of interest, there was a strong negative correlation between levels of 15 proteins and the wall shear stress (R < -0.500, p ≤ 0.05), and a moderate negative correlation between 16 proteins and wall shear stress (R -0.500 to -0.300, p ≤ 0.05). Gene ontology analysis demonstrated clusters of proteins involved in cellular structure. Proteins negatively correlated with WSS included those with cytoskeletal, actin/myosin, cell-cell junction and extracellular functions. C: In aortic valve tissue, 31 proteins were identified involved in cellular structure and extracellular junctions with a negative correlation between their levels and wall shear stress. These findings suggest an association between the forces acting on the aortic valve (AV) and leaflet protein abundance, and may form a mechanical basis for the increased risk of aortic leaflet degeneration in LVAD patients.PMID:36400676 | DOI:10.1016/j.healun.2022.09.017

Trends Parasitol. 2022 Nov 15:S1471-4922(22)00259-8. doi: 10.1016/j.pt.2022.10.006. Online ahead of print.ABSTRACTTick-borne diseases (TBDs) are a growing global health concern. Despite extensive studies, ill-defined tick-associated pathologies remain with unknown aetiologies. Human immunological responses after tick bite, and inter-individual variations of immune-response phenotypes, are not well characterised. Current reductive experimental methodologies limit our understanding of more complex tick-associated illness, which results from the interactions between the host, tick, and microbes. An unbiased, systems-level integration of clinical metadata and biological host data - obtained via transcriptomics, proteomics, and metabolomics - offers to drive the data-informed generation of testable hypotheses in TBDs. Advanced computational tools have rendered meaningful analysis of such large data sets feasible. This review highlights the advantages of integrative system biology approaches as essential for understanding the complex pathobiology of TBDs.PMID:36400674 | DOI:10.1016/j.pt.2022.10.006

Sci Total Environ. 2022 Nov 15:160222. doi: 10.1016/j.scitotenv.2022.160222. Online ahead of print.ABSTRACTGeosmin has been commonly detected both in various aquatic environments and biota, but its exact toxicological mechanisms to organisms need further experimentation. In the present study, zebrafish embryos were exposed to geosmin at nominal concentrations of 50, 500 and 5000 ng/L for 120 h post-fertilization (hpf), followed by locomotor activity and biochemical parameter examination, and multi-omics investigation of the transcriptome and metabolome. The results showed that geosmin exposure significantly reduced the mitochondrial electron transport chain (ETC) complexes I-V, ATP content and mitochondrial respiration and suppressed the locomotor behavior of zebrafish larvae. Transcriptomics analysis revealed that the transcripts of genes involved in oxidative phosphorylation, glycolysis, and lipid metabolism were significantly affected, indicating that geosmin disrupts energy metabolism. Furthermore, metabolomics results showed that 3 classes of lipids, namely glycerophospholipids (GPs), sphingolipids (SLs) and fatty acyls (FAs) were significantly decreased after geosmin exposure. This study provides novel insight into the underlying mechanisms of geosmin-induced energy metabolism and highlights the need for concern about geosmin exposure.PMID:36400299 | DOI:10.1016/j.scitotenv.2022.160222

Plant Physiol Biochem. 2022 Nov 11;194:111-121. doi: 10.1016/j.plaphy.2022.11.008. Online ahead of print.ABSTRACTCrataegus is an economically important plant due to its medicinal and health-promoting properties. Flavonoids are the main functional components of Crataegus fruit. Fruits of naturally pollinated Crataegus maximowiczii possess an extraordinary black skin and are rich in anthocyanins and other flavonoids. However, the composition of anthocyanins and the overall molecular mechanism of anthocyanin biosynthesis in C. maximowiczii fruits have not been fully elucidated. In this study, the metabolome and transcriptome of C. maximowiczii fruits with black and red skin were analyzed. The results revealed that the differential metabolites and genes were enriched in the anthocyanin biosynthesis pathways in C. maximowiczii fruits. In total, 52 differentially accumulated flavonoid metabolites, 12 differentially accumulated anthocyanins and 22 differentially expressed genes were identified. After weighted gene coexpression network analysis, two modules were found to be highly interrelated with the accumulation of anthocyanin components. The coexpression networks of these two modules were used to identify key candidate transcription factors associated with anthocyanin biosynthesis, such as MYB5, MYB113, bHLH60, ERF105, bZIP44, NAC082, and WRKY11. The results revealed that cyanidin-based anthocyanins were the main pigments responsible for the black coloration of C. maximowiczii fruits. Based on these differentially accumulated anthocyanins and key genes, genetic and metabolic regulatory networks of anthocyanin biosynthesis were also proposed. Overall, this study elucidates the molecular basis of the formation of black color in C. maximowiczii fruits, and provides an intensive study on anthocyanin biosynthesis in C. maximowiczii for comprehensive utilization.PMID:36399912 | DOI:10.1016/j.plaphy.2022.11.008

Biochem Biophys Res Commun. 2022 Nov 9;637:127-135. doi: 10.1016/j.bbrc.2022.11.010. Online ahead of print.ABSTRACTFatigue, a most commonly sub-health condition, may cause people more susceptible to many diseases. Cordycepin, a principal active ingredient from Cordyceps militaris, exerts various pharmacological activities including anti-diabetes, anti-inflammatory, immunomodulatory and antioxidant effects. However, the anti-fatigue effect of cordycepin and specific mechanism remained unclear. This study aimed to investigate the beneficial effect of cordycepin on physical fatigue and elucidate the potential mechanism. 20 mg/kg, 40 mg/kg of cordycepin and 500 mg/kg taurine were respectively treated to mice for 28 days before weight-loaded swimming test. The results revealed that cordycepin significantly prolonged the weight-loaded swimming time of mice. Meanwhile, cordycepin decreased the levels of lactic acid, blood uric nitrogen, and malondialdehyde, and increased the contents of superoxide dismutase, glutathione, nicotinamide adenine dinucleotide phosphate, hepatic glycogen, muscle glycogen and ATP. The metabolomic study by GC-MS showed that eight biomarkers were found in livers, including L-lactic acid, L-asparagine, 3-phosphoglyceric acid, inosine, D-galactose, L-tyrosine, glyceric acid and L-threonine. There were seven biomarkers in gastrocnemius, including D-ribose-5-phosphate, acetic acid, propionic acid, butyric acid, palmitic acid, oxaloacetic acid and citric acid. The results of metabolomics indicated that cordycepin might relieve fatigue by regulating energy metabolism and pentose phosphate pathway. Furthermore, we found cordycepin significantly enhanced the protein levels of TIGAR, SIRT1, PGC-1α, NRF1 and TFAM in gastrocnemius of weight-loaded swimming mice. Taken together, the present study demonstrated that cordycepin possessed an anti-fatigue effect via activating TIGAR/SIRT1/PGC-1α signaling pathway. Our study indicated that cordycepin may be a potentially efficient candidate for fatigue.PMID:36399798 | DOI:10.1016/j.bbrc.2022.11.010

Sci Adv. 2022 Nov 16;8(46):eabo6764. doi: 10.1126/sciadv.abo6764. Epub 2022 Nov 18.ABSTRACTAlzheimer's disease (AD) is a heterogeneous disorder with abnormalities in multiple biological domains. In an advanced machine learning analysis of postmortem brain and in vivo blood multi-omics molecular data (N = 1863), we integrated epigenomic, transcriptomic, proteomic, and metabolomic profiles into a multilevel biological AD taxonomy. We obtained a personalized multilevel molecular index of AD dementia progression that predicts severity of neuropathologies, and identified three robust molecular-based subtypes that explain much of the pathologic and clinical heterogeneity of AD. These subtypes present distinct patterns of alteration in DNA methylation, RNA, proteins, and metabolites, identifiable in the brain and subsequently in blood. In addition, the genetic variations that predispose to the various AD subtypes in brain predict distinct spatial patterns of alteration in cell types, suggesting a unique influence of each putative AD variant on neuropathological mechanisms. These observations support that an individually tailored multi-omics molecular taxonomy of AD may represent distinct targets for preventive or treatment interventions.PMID:36399579 | DOI:10.1126/sciadv.abo6764

Blood Adv. 2022 Nov 18:bloodadvances.2022007456. doi: 10.1182/bloodadvances.2022007456. Online ahead of print.ABSTRACTAnti-CD19 chimeric antigen receptor (CAR) T-cell therapy is a highly effective treatment option for patients with relapsed/refractory large B cell lymphoma (r/r LBCL). However, widespread use is deterred by development of clinically significant acute inflammatory toxicities, including cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS), that induce significant morbidity and require close monitoring. Identification of host biochemical signatures that predict the severity and time-to-onset of CRS and ICANS may assist patient stratification to enable timely mitigation strategies. Here, we report pre-treatment host metabolites that are associated with CRS and ICANS induced by Axicabtagene Ciloleucel or Tisagenlecleucel therapy. Both untargeted metabolomics analysis and validation using targeted assays revealed significant association between the abundance of specific pre-treatment biochemical entities and an increased risk and/or onset of clinically significant CRS (q<.1) and ICANS (q<.25). Higher pre-treatment levels of plasma glucose, and lower levels of cholesterol and glutamate were associated with faster onset of CRS. On the other hand, low baseline levels of amino acids proline and glycine and secondary bile acid isoursodeoxycholate were significantly correlated with clinically significant CRS. Lower concentration of the amino acid hydroxyproline was associated with higher grade and faster onset of ICANS, whereas low glutamine was negatively correlated with faster development of ICANS. Overall, our data indicate that the pre-treatment host metabolome has biomarker potential in determining the risk of clinically significant CRS and ICANS, and may be useful in risk stratification of patients prior to anti-CD19 CAR T-cell therapy.PMID:36399526 | DOI:10.1182/bloodadvances.2022007456

Am J Physiol Heart Circ Physiol. 2022 Nov 18. doi: 10.1152/ajpheart.00514.2022. Online ahead of print.ABSTRACTPerturbed vitamin A metabolism is associated with type 2 diabetes and mitochondrial dysfunction that are pathophysiologically linked to the development of diabetic cardiomyopathy (DCM). However, the mechanism, by which vitamin A might regulate mitochondrial energetics in DCM has previously not been explored. To test the hypothesis that vitamin A-deficiency accelerates the onset of cardiomyopathy in diet-induced obesity (DIO), we subjected mice with Lecithin retinol acyltransferase (Lrat) germline deletion, which exhibit impaired vitamin A stores, to vitamin A-deficient high fat diet (HFD) feeding. Wildtype mice fed with a vitamin A-sufficient HFD served as controls. Cardiac structure, contractile function, and mitochondrial respiratory capacity were preserved despite vitamin A-deficiency following 20 weeks of HFD feeding. Gene profiling by RNA sequencing revealed that vitamin A is required for the expression of genes involved in cardiac fatty acid oxidation, glycolysis, tricarboxylic acid cycle, and mitochondrial oxidative phosphorylation in DIO as expression of these genes was relatively preserved under vitamin A-sufficient HFD conditions. Together, these data identify a transcriptional program, by which vitamin A preserves cardiac energetic gene expression in DIO that might attenuate subsequent onset of mitochondrial and contractile dysfunction.PMID:36399384 | DOI:10.1152/ajpheart.00514.2022

J Cell Biol. 2023 Jan 2;222(1):e202007026. doi: 10.1083/jcb.202007026. Epub 2022 Nov 18.ABSTRACTMacropinocytosis is a nonspecific endocytic process that may enhance cancer cell survival under nutrient-poor conditions. Ataxia-Telangiectasia mutated (ATM) is a tumor suppressor that has been previously shown to play a role in cellular metabolic reprogramming. We report that the suppression of ATM increases macropinocytosis to promote cancer cell survival in nutrient-poor conditions. Combined inhibition of ATM and macropinocytosis suppressed proliferation and induced cell death both in vitro and in vivo. Supplementation of ATM-inhibited cells with amino acids, branched-chain amino acids (BCAAs) in particular, abrogated macropinocytosis. Analysis of ATM-inhibited cells in vitro demonstrated increased BCAA uptake, and metabolomics of ascites and interstitial fluid from tumors indicated decreased BCAAs in the microenvironment of ATM-inhibited tumors. These data reveal a novel basis of ATM-mediated tumor suppression whereby loss of ATM stimulates protumorigenic uptake of nutrients in part via macropinocytosis to promote cancer cell survival and reveal a potential metabolic vulnerability of ATM-inhibited cells.PMID:36399181 | DOI:10.1083/jcb.202007026

Gut Microbes. 2022 Jan-Dec;14(1):2147055. doi: 10.1080/19490976.2022.2147055.ABSTRACTMounting evidence points towards a pivotal role of gut microbiota in multiple sclerosis (MS) pathophysiology. Yet, whether disease-modifying treatments alter microbiota composition and whether microbiota shape treatment response and side-effects remain unclear. In this prospective observational pilot study, we assessed the effect of dimethyl fumarate (DMF) on gut microbiota and on host/microbial metabolomics in a cohort of 20 MS patients. Combining state-of-the-art microbial sequencing, metabolome mass spectrometry, and computational analysis, we identified longitudinal changes in gut microbiota composition under DMF-treatment and an increase in citric acid cycle metabolites. Notably, DMF-induced lymphopenia, a clinically relevant safety concern, was correlated with distinct baseline microbiome signatures in MS patients. We identified gastrointestinal microbiota as a key therapeutic target for metabolic properties of DMF. By characterizing gut microbial composition as a candidate risk factor for DMF-induced lymphopenia, we provide novel insights into the role of microbiota in mediating clinical side-effects.PMID:36398902 | DOI:10.1080/19490976.2022.2147055

Biosci Rep. 2022 Nov 18:BSR20221430. doi: 10.1042/BSR20221430. Online ahead of print.ABSTRACTA cross-sectional study was performed using metabolomics in overweight patients with type 2 diabetes (T2D) at different stages of the disease. To investigate the correlation between islet β cell dysfunction and metabolite changes in overweight patients with T2D, we aimed to identify potential metabolite for assessing islet β cell function. Sixty overweight adults (24 ≤ Body Mass Index (BMI) < 28 kg/m2) with T2D who were admitted to our hospital were selected. The participants were equally divided into three groups according to the disease duration: H1 (duration ≤ 5 years), H2 (5 years < duration ≤ 10 years), and H3 (duration > 10 years). Questionnaires, physical examinations, laboratory tests, and imaging studies were administered to all participants. The modified homeostasis model of assessment (HOMA) index was calculated using fasting C-peptide levels, and metabolite assays were performed using mass spectrometry. The results showed that HOMA-β and visceral fat area (VFA) were negatively correlated with diabetes duration. The VFA was positively correlated with the arginine, cysteine, methionine, proline, and succinyl/methylmalonylcarnitine levels. The HOMA-β was negatively correlated with the serine and tetradecanoyldiacylcarnitine levels and positively correlated with the aspartic acid, cysteine, homocysteine, piperamide, proline, and valine levels. The HOMA-IR was negatively correlated with the hydroxypalmitoylcarnitine levels and positively correlated with the myristoylcarnitine levels. Thus, in overweight patients with T2D at different stages of the disease, serine, aspartic acid, cysteine, homocysteine, piperamide, proline, valine, and tetradecanoyldiacylcarnitine may be associated with HOMA-β and represent potential novel biomarkers for evaluating islet β cell function.PMID:36398677 | DOI:10.1042/BSR20221430