PubMed

Nat Metab. 2023 Apr 3. doi: 10.1038/s42255-023-00771-5. Online ahead of print.ABSTRACTCancer cells fuel their increased need for nucleotide supply by upregulating one-carbon (1C) metabolism, including the enzymes methylenetetrahydrofolate dehydrogenase-cyclohydrolase 1 and 2 (MTHFD1 and MTHFD2). TH9619 is a potent inhibitor of dehydrogenase and cyclohydrolase activities in both MTHFD1 and MTHFD2, and selectively kills cancer cells. Here, we reveal that, in cells, TH9619 targets nuclear MTHFD2 but does not inhibit mitochondrial MTHFD2. Hence, overflow of formate from mitochondria continues in the presence of TH9619. TH9619 inhibits the activity of MTHFD1 occurring downstream of mitochondrial formate release, leading to the accumulation of 10-formyl-tetrahydrofolate, which we term a 'folate trap'. This results in thymidylate depletion and death of MTHFD2-expressing cancer cells. This previously uncharacterized folate trapping mechanism is exacerbated by physiological hypoxanthine levels that block the de novo purine synthesis pathway, and additionally prevent 10-formyl-tetrahydrofolate consumption for purine synthesis. The folate trapping mechanism described here for TH9619 differs from other MTHFD1/2 inhibitors and antifolates. Thus, our findings uncover an approach to attack cancer and reveal a regulatory mechanism in 1C metabolism.PMID:37012496 | DOI:10.1038/s42255-023-00771-5

Nat Cell Biol. 2023 Apr 3. doi: 10.1038/s41556-023-01117-9. Online ahead of print.ABSTRACTMetabolism is intertwined with various cellular processes, including controlling cell fate, influencing tumorigenesis, participating in stress responses and more. Metabolism is a complex, interdependent network, and local perturbations can have indirect effects that are pervasive across the metabolic network. Current analytical and technical limitations have long created a bottleneck in metabolic data interpretation. To address these shortcomings, we developed Metaboverse, a user-friendly tool to facilitate data exploration and hypothesis generation. Here we introduce algorithms that leverage the metabolic network to extract complex reaction patterns from data. To minimize the impact of missing measurements within the network, we introduce methods that enable pattern recognition across multiple reactions. Using Metaboverse, we identify a previously undescribed metabolite signature that correlated with survival outcomes in early stage lung adenocarcinoma patients. Using a yeast model, we identify metabolic responses suggesting an adaptive role of citrate homeostasis during mitochondrial dysfunction facilitated by the citrate transporter, Ctp1. We demonstrate that Metaboverse augments the user's ability to extract meaningful patterns from multi-omics datasets to develop actionable hypotheses.PMID:37012464 | DOI:10.1038/s41556-023-01117-9

Br J Cancer. 2023 Apr 3. doi: 10.1038/s41416-023-02253-7. Online ahead of print.ABSTRACTBACKGROUND: Cisplatin (CDDP) is a mainstay treatment for advanced head and neck squamous cell carcinomas (HNSCC) despite a high frequency of innate and acquired resistance. We hypothesised that tumours acquire CDDP resistance through an enhanced reductive state dependent on metabolic rewiring.METHODS: To validate this model and understand how an adaptive metabolic programme might be imprinted, we performed an integrated analysis of CDDP-resistant HNSCC clones from multiple genomic backgrounds by whole-exome sequencing, RNA-seq, mass spectrometry, steady state and flux metabolomics.RESULTS: Inactivating KEAP1 mutations or reductions in KEAP1 RNA correlated with Nrf2 activation in CDDP-resistant cells, which functionally contributed to resistance. Proteomics identified elevation of downstream Nrf2 targets and the enrichment of enzymes involved in generation of biomass and reducing equivalents, metabolism of glucose, glutathione, NAD(P), and oxoacids. This was accompanied by biochemical and metabolic evidence of an enhanced reductive state dependent on coordinated glucose and glutamine catabolism, associated with reduced energy production and proliferation, despite normal mitochondrial structure and function.CONCLUSIONS: Our analysis identified coordinated metabolic changes associated with CDDP resistance that may provide new therapeutic avenues through targeting of these convergent pathways.PMID:37012319 | DOI:10.1038/s41416-023-02253-7

Cancer Epidemiol Biomarkers Prev. 2023 Apr 3:EPI-22-0724. doi: 10.1158/1055-9965.EPI-22-0724. Online ahead of print.ABSTRACTBACKGROUND: Human gut microbiome has complex relationships with the host, contributing to metabolism, immunity, and carcinogenesis.METHODS: Summary-level data for gut microbiota and metabolites were obtained from MiBioGen, FINRISK and human metabolome consortia. Summary-level data for CRC were derived from a genome-wide association study meta-analysis. In forward MR, we employed genetic instrumental variables (IVs) for 24 gut microbiota taxa and six bacterial metabolites to examine their causal relationship with CRC. We also utilized a lenient threshold for nine apriori gut microbiota taxa as secondary analyses. In reverse MR, we explored association between genetic liability to colorectal neoplasia and abundance of microbiota studied above using 95, 19, and 7 IVs for CRC, adenoma, and polyps, respectively.RESULTS: Forward MR didn't find evidence indicating causal relationship between any of the gut microbiota taxa or six bacterial metabolites tested and CRC risk. However, reverse MR supported genetic liability to colorectal adenomas was causally related with increased abundance of two taxa: Gammaproteobacteria (β=0.027, which represents a 0.027 increase in log-transformed relative abundance values of Gammaproteobacteria for per one-unit increase in log odds ratio of adenoma risk; P=7.06×10-8), Enterobacteriaceae (β=0.023, P=1.29×10-5).CONCLUSIONS: We find genetic liability to colorectal neoplasia may be associated with abundance of certain microbiota taxa. It is more likely that subset of CRC genetic liability variants changes gut biology by influencing both gut microbiota and CRC risk.IMPACT: This study highlights the need of future complementary studies to explore causal mechanisms linking both host genetic variation with gut microbiome and CRC susceptibility.PMID:37012201 | DOI:10.1158/1055-9965.EPI-22-0724

Physiol Genomics. 2023 Apr 3. doi: 10.1152/physiolgenomics.00180.2022. Online ahead of print.ABSTRACTSex differences in energy metabolism during acute, sub-maximal exercise are well documented. Whether these sex differences influence metabolic and physiologic responses to sustained, physically demanding activities is not well characterized. This study aimed to identify sex differences within changes in the serum metabolome in relation to changes in body composition, physical performance, and circulating markers of endocrine and metabolic status during a 17-day military training exercise. Blood was collected, and body composition and lower-body power measured before and after training on 72 cadets (18 women). Total daily energy expenditure (TDEE) was assessed using doubly labeled water in a subset. TDEE was greater in men (4,085±482kcal/d) than women (2,982±472kcal/d, p<0.001), but not after adjustment for dry lean mass (DLM). Men tended to lose more DLM than women (-0.2[-0.3,-0.1] vs. -0.0[-0.0,0.0] kg, p=0.063, Cohen's d=0.50) and have greater reductions in lower body power (-244[-314,-174] vs. -130[-209,-51] Watts, p=0.085, d=0.49). Reductions in DLM and lower body power were correlated (r=0.325, p=0.006). Women demonstrated greater fat oxidation than men (Δfat mass/DLM: -0.20[-0.24,-0.17] vs. -0.15[-0.17,-0.13] kg, p=0.012, d=0.64). Metabolites within pathways of fatty acid, endocannabinoid, lysophospholipid, phosphatidylcholine, phosphatidylethanolamine, and plasmalogen metabolism increased in women relative to men. Independent of sex, changes in metabolites related to lipid metabolism were inversely associated with changes in body mass and positively associated with changes in endocrine and metabolic status. These data suggest that during sustained military training, women preferentially mobilize fat stores compared with men, which may be beneficial for mitigating loss of lean mass and lower body power.PMID:37012051 | DOI:10.1152/physiolgenomics.00180.2022

Environ Res. 2023 Apr 1:115825. doi: 10.1016/j.envres.2023.115825. Online ahead of print.ABSTRACTThis study focused on assessing the microbiological and chemical contamination of air, soil and leachate in uncontrolled refuse storage areas in central Poland. The research included an analysis of the number of microorganisms (culture method), endotoxin concentration (gas chromatography-mass spectrometry), heavy metals level (atomic absorption spectrometry), elemental characteristics (elemental analyser), cytotoxicity assessment against A-549 (human lung) and Caco-2 (human colon adenocarcinoma) cell lines (PrestoBlue™ test) and toxic compound identification (ultra-high-performance liquid chromatography-quadrupole time-of-flight ultrahigh-resolution mass spectrometry). Microbial contamination differed depending on the dump and the group of tested microorganisms. The number of bacteria was: 4.3 × 102-1.8 × 103nullCFUnullm-3 (air); 1.1 × 103 CFU-1.2 × 106nullCFUnullmL-1 (leachate); 1.0 × 106nullCFUnullg-1 - 3.9 × 106nullCFUnullg-1 (soil). Respectively, the number of fungi was: 2.2 × 102-4.6 × 102nullCFUnullm-3; 1.8 × 102-3.9 × 103nullCFUnullg-1. Metal levels (Fe, Mn, Pb, Zn, Al, Hg, Cd, Cu, Cr) were higher than in the control sample; however, the average concentrations did not exceed the permissible standards. The cytotoxicity of soil and leachate samples depended on the dump, sample and cell line tested. The leachates were more cytotoxic than soil extracts. Compounds belonging to pesticides, surfactants and biocides, chemicals and/or polymer degradation products, medicinal drugs and insect repellents were found. The detection of potential pathogens in the air, soil and leachate, the presence of toxic compounds and the confirmation of the cytotoxic effect of leachate and soil on human cell lines justify the need for further research on the risks posed by illegal dumps. These studies should aim at developing a unified assessment method and a method to minimise the risk of contaminants spreading in the environment, including harmful biological agents.PMID:37011789 | DOI:10.1016/j.envres.2023.115825

Aquat Toxicol. 2023 Mar 30;258:106515. doi: 10.1016/j.aquatox.2023.106515. Online ahead of print.ABSTRACTBenzophenone-3 (BP-3) as one of frequently used organic UV filters has been considered an emerging pollutant due to its toxicities. Benzophenone-8 (BP-8) is one of the main metabolites of BP-3 in organisms. Current reports show that BP-8 may be more toxic than BP-3. However, difference of their toxicities on embryonic development has rarely been reported. In this study, zebrafish embryos were chosen as the target organism to explore the developmental toxicities of BP-3 and BP-8. Non-targeted metabolomic analysis was performed to compare their modes of action. Results showed that BP-8 exposures led to higher bioaccumulation and lower hatching rate of zebrafish larvae than BP-3. Both BP-8 and BP-3 exposures caused behavioral abnormalities of zebrafish larvae, but no significant difference was found between them. At the metabolome level, 1 μg/L BP-3 and 1 μg/L BP-8 exposures altered neuroactive ligand-receptor interaction pathway and FoxO signaling pathway, respectively, which might be involved in the abnormal behaviors in zebrafish larvae. For higher exposure groups (30 and 300 μg/L), both BP-3 and BP-8 exposures changed metabolism of cofactors and vitamins of zebrafish larvae. Exposure of BP-3 altered the metabolism by pantothenate and CoA biosynthesis pathway, while BP-8 exposure changed riboflavin metabolism and folate biosynthesis. The above results indicated different modes of action of BP-3 and BP-8 in zebrafish embryonic development. This study sheds new light to biological hazards of BP-3 due to its metabolism in aquatic organisms.PMID:37011548 | DOI:10.1016/j.aquatox.2023.106515

J Nat Prod. 2023 Apr 3. doi: 10.1021/acs.jnatprod.2c01143. Online ahead of print.ABSTRACTMyxobacteria represent an underinvestigated source of chemically diverse and biologically active secondary metabolites. Here, we report the discovery, isolation, structure elucidation, and biological evaluation of two new bacterial sterols, termed nannosterols A and B (1, 2), from the terrestrial myxobacterium Nannocystis sp. (MNa10993). Nannosterols feature a cholestanol core with numerous modifications including a secondary alcohol at position C-15, a terminal vicinal diol side chain at C-24-C-25 (1, 2), and a hydroxy group at the angular methyl group at C-18 (2), which is unprecedented for bacterial sterols. Another rare chemical feature of bacterial triterpenoids is a ketone group at position C-7, which is also displayed by 1 and 2. The combined exploration based on myxobacterial high-resolution secondary metabolome data and genomic in silico investigations exposed the nannosterols as frequently produced sterols within the myxobacterial suborder of Nannocystineae. The discovery of the nannosterols provides insights into the biosynthesis of these new myxobacterial sterols, with implications in understanding the evolution of sterol production by prokaryotes.PMID:37011180 | DOI:10.1021/acs.jnatprod.2c01143

Surg Infect (Larchmt). 2023 Apr;24(3):245-249. doi: 10.1089/sur.2023.021.ABSTRACTGastroesophageal reflux disease (GERD), reflux esophagitis (RE), and peptic ulcer disease (PUD) are commonly encountered in clinical practice. More than simple anatomic abnormalities, these conditions are tethered to a variety of external influences as well as those related to genomics, transcriptomics, and metabolomics. Furthermore, each of these conditions is clearly related to abnormalities of the microbiota of the oropharynx, esophagus, and gastrointestinal tract. Certain therapeutics used to address these conditions such as antibiotic agents and proton pump inhibitors worsen microbiome dysbiosis while pursuing clinical benefit. Therapeutics that protect, shape adaptively, or restore microbiota balance are key aspects of current and future therapy to pursue. How the microbiota is involved in clinical condition genesis and progression, as well as how therapeutic support or derange the microbiota are herein explored.PMID:37010961 | DOI:10.1089/sur.2023.021

J Proteome Res. 2023 Apr 3. doi: 10.1021/acs.jproteome.2c00780. Online ahead of print.ABSTRACTIn this study, we present high-throughput (HT) venomics, a novel analytical strategy capable of performing a full proteomic analysis of a snake venom within 3 days. This methodology comprises a combination of RP-HPLC-nanofractionation analytics, mass spectrometry analysis, automated in-solution tryptic digestion, and high-throughput proteomics. In-house written scripts were developed to process all the obtained proteomics data by first compiling all Mascot search results for a single venom into a single Excel sheet. Then, a second script plots each of the identified toxins in so-called Protein Score Chromatograms (PSCs). For this, for each toxin, identified protein scores are plotted on the y-axis versus retention times of adjacent series of wells in which a toxin was fractionated on the x-axis. These PSCs allow correlation with parallel acquired intact toxin MS data. This same script integrates the PSC peaks from these chromatograms for semiquantitation purposes. This new HT venomics strategy was performed on venoms from diverse medically important biting species; Calloselasma rhodostoma, Echis ocellatus, Naja pallida, Bothrops asper, Bungarus multicinctus, Crotalus atrox, Daboia russelii, Naja naja, Naja nigricollis, Naja mossambica, and Ophiophagus hannah. Our data suggest that high-throughput venomics represents a valuable new analytical tool for increasing the throughput by which we can define venom variation and should greatly aid in the future development of new snakebite treatments by defining toxin composition.PMID:37010854 | DOI:10.1021/acs.jproteome.2c00780

J Cancer Res Clin Oncol. 2023 Apr 3. doi: 10.1007/s00432-023-04712-3. Online ahead of print.ABSTRACTPURPOSE: The evolutionary-conserved Wnt/β-CATENIN (WBC) pathway has been implicated in the pathogenesis of different solid malignant tumors. We evaluated the prognostic relevance of β-CATENIN, a pivotal mediator of WBC activation, in patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC).METHODS: We analyzed if patients with HPV-positive HNSCC from the "The Cancer Genome Atlas" (TCGA cohort, n = 41) can be stratified based on their CTNNB1 mRNA expression. Moreover, in a tissue microarray (TMA) of primary tumor sections from HPV-positive HNSCC patients treated in a tertiary academic center (in-house cohort, n = 31), we evaluated the prognostic relevance of β-CATENIN expression on protein level.RESULTS: In silico mining of CTNNB1 expression in HPV-positive HNSCC revealed that high CTNNB1 expression was linked to better overall survival (OS, p = 0.062). Moreover, high β-CATENIN expression was significantly associated with a better OS in our in-house cohort (p = 0.035).CONCLUSION: Based on these findings, we postulate that β-CATENIN expression could serve (potentially in conjunction with other WBC pathway members) as a marker for better survival outcomes in patients with HPV-positive HNSCC. However, it is evident that future studies on bigger cohorts are warranted.PMID:37010585 | DOI:10.1007/s00432-023-04712-3

J Exp Bot. 2023 Apr 3:erad125. doi: 10.1093/jxb/erad125. Online ahead of print.ABSTRACTPlant amino acid transporters (AATs) regulate not only long-distance transport and reallocation of nitrogen (N) from source to sink organs, but also amount of amino acids in leaves hijacked by invaded pathogens. However, the function of AATs in plant defense responses to pathogen infection remains unknown. In this study, we found that rice amino acid transporter gene OsLHT1 was expressed in leaves and up-regulated by maturing, N starvation and inoculation of blast fungus Magnaporthe oryzae. Knockout of OsLHT1 resulted in development stage- and N supply-dependent premature senescence of leaves at vegetative growth stage. In comparison to wild type, Oslht1 mutant lines showed sustained rusty red spots on fully mature leaf blades irrespective of N supply levels. Notably, no relationship between the severity of leaf rusty red spots and concentration of total N or amino acids was found in Oslht1 mutants at different developmental stages. Disruption of OsLHT1 altered transport and metabolism of amino acids and biosynthesis of flavones and flavonoids, enhanced expression of jasmonic acid- and salicylic acid-related defense genes and production of jasmonic acid and salicylic acid, accumulation of reactive oxygen species. OsLHT1 inactivation dramatically prevented the leaf invasion of M. oryzae, the hemi-biotrophic ascomycete fungus. Overall, these results establish a module connecting the activity of amino acid transporter with leaf metabolism and defense to rice blast fungus.PMID:37010326 | DOI:10.1093/jxb/erad125

Plant Physiol. 2023 Apr 3:kiad207. doi: 10.1093/plphys/kiad207. Online ahead of print.ABSTRACTThe primary cell wall is a fundamental plant constituent that is flexible but sufficiently rigid to support the plant cell shape. Although many studies have demonstrated that reactive oxygen species (ROS) serve as important signaling messengers to modify the cell wall structure and affect cellular growth, the regulatory mechanism underlying the spatial-temporal regulation of ROS activity for cell wall maintenance remains largely unclear. Here, we demonstrate a role of the Arabidopsis (Arabidopsis thaliana) multi-copper oxidase-like protein skewed 5 (SKU5) and its homolog SKU5-similar 1 (SKS1) in root cell wall formation through modulating ROS homeostasis. Loss of SKU5 and SKS1 function resulted in aberrant division planes, protruding cell walls, ectopic deposition of iron, and NADPH oxidase-dependent ROS overproduction in the root epidermis-cortex and cortex-endodermis junctions. A decrease of ROS level or inhibition of NADPH oxidase activity rescued the cell wall defects of sku5 sks1 double mutants. SKU5 and SKS1 proteins were activated by iron treatment, and iron over-accumulated in the walls between root epidermis and cortex cell layers of sku5 sks1. The glycosylphosphatidylinositol-anchored motif was crucial for membrane association and functionality of SKU5 and SKS1. Overall, our results identified SKU5 and SKS1 as regulators of ROS at the cell surface for regulation of cell wall structure and root cell growth.PMID:37010107 | DOI:10.1093/plphys/kiad207

J Clin Invest. 2023 Apr 3;133(7):e161913. doi: 10.1172/JCI161913.ABSTRACTAfter androgen deprivation, prostate cancer frequently becomes castration resistant (CRPC), with intratumoral androgen production from extragonadal precursors that activate the androgen receptor pathway. 3β-Hydroxysteroid dehydrogenase-1 (3βHSD1) is the rate-limiting enzyme for extragonadal androgen synthesis, which together lead to CRPC. Here, we show that cancer-associated fibroblasts (CAFs) increased epithelial 3βHSD1 expression, induced androgen synthesis, activated the androgen receptor, and induced CRPC. Unbiased metabolomics revealed that CAF-secreted glucosamine specifically induced 3βHSD1. CAFs induced higher GlcNAcylation in cancer cells and elevated expression of the transcription factor Elk1, which induced higher 3βHSD1 expression and activity. Elk1 genetic ablation in cancer epithelial cells suppressed CAF-induced androgen biosynthesis in vivo. In patient samples, multiplex fluorescent imaging showed that tumor cells expressed more 3βHSD1 and Elk1 in CAF-enriched areas compared with CAF-deficient areas. Our findings suggest that CAF-secreted glucosamine increases GlcNAcylation in prostate cancer cells, promoting Elk1-induced HSD3B1 transcription, which upregulates de novo intratumoral androgen synthesis to overcome castration.PMID:37009898 | DOI:10.1172/JCI161913

J Transl Med. 2023 Apr 3;21(1):241. doi: 10.1186/s12967-023-04070-1.ABSTRACTBACKGROUND: Remote ischemic preconditioning (RIPC) refers to a brief episode of exposure to potential adverse stimulation and prevents injury during subsequent exposure. RIPC has been shown to increase tolerance to ischemic injury and improve cerebral perfusion status. Exosomes have a variety of activities, such as remodeling the extracellular matrix and transmitting signals to other cells. This study aimed to investigate the potential molecular mechanism of RIPC-mediated neuroprotection.METHODS: Sixty adult male military personnel participants were divided into the control group (n = 30) and the RIPC group (n = 30). We analyzed the differential metabolites and proteins in the serum exosomes of RIPC participants and control subjects.RESULTS: Eighty-seven differentially expressed serum exosomal metabolites were found between the RIPC and control groups, which were enriched in pathways related to tyrosine metabolism, sphingolipid metabolism, serotonergic synapses, and multiple neurodegeneration diseases. In addition, there were 75 differentially expressed exosomal proteins between RIPC participants and controls, which involved the regulation of insulin-like growth factor (IGF) transport, neutrophil degranulation, vesicle-mediated transport, etc. Furthermore, we found differentially expressed theobromine, cyclo gly-pro, hemopexin (HPX), and apolipoprotein A1 (ApoA1), which are associated with neuroprotective benefits in ischemia/reperfusion injury. In addition, five potential metabolite biomarkers, including ethyl salicylate, ethionamide, piperic acid, 2, 6-di-tert-butyl-4-hydroxymethylphenol and zerumbone, that separated RIPC from control individuals were identified.CONCLUSION: Our data suggest that serum exosomal metabolites are promising biomarkers for RIPC, and our results provide a rich dataset and framework for future analyses of cerebral ischemia‒reperfusion injury under ischemia/reperfusion conditions.PMID:37009888 | DOI:10.1186/s12967-023-04070-1

Gut Microbes. 2023 Jan-Dec;15(1):2195792. doi: 10.1080/19490976.2023.2195792.ABSTRACTReliable biomarkers for common disorders of gut-brain interaction characterized by abdominal pain, including irritable bowel syndrome (IBS), are critically needed to enhance care and develop individualized therapies. The dynamic and heterogeneous nature of the pathophysiological mechanisms that underlie visceral hypersensitivity have challenged successful biomarker development. Consequently, effective therapies for pain in IBS are lacking. However, recent advances in modern omics technologies offer new opportunities to acquire deep biological insights into mechanisms of pain and nociception. Newer methods for large-scale data integration of complementary omics approaches have further expanded our ability to build a holistic understanding of complex biological networks and their co-contributions to abdominal pain. Here, we review the mechanisms of visceral hypersensitivity, focusing on IBS. We discuss candidate biomarkers for pain in IBS identified through single omics studies and summarize emerging multi-omics approaches for developing novel biomarkers that may transform clinical care for patients with IBS and abdominal pain.PMID:37009874 | DOI:10.1080/19490976.2023.2195792

Exp Mol Med. 2023 Apr 3. doi: 10.1038/s12276-023-00967-5. Online ahead of print.ABSTRACTMyocardial regeneration capacity declines during the first week after birth, and this decline is linked to adaptation to oxidative metabolism. Utilizing this regenerative window, we characterized the metabolic changes in myocardial injury in 1-day-old regeneration-competent and 7-day-old regeneration-compromised mice. The mice were either sham-operated or received left anterior descending coronary artery ligation to induce myocardial infarction (MI) and acute ischemic heart failure. Myocardial samples were collected 21 days after operations for metabolomic, transcriptomic and proteomic analyses. Phenotypic characterizations were carried out using echocardiography, histology and mitochondrial structural and functional assessments. In both groups, MI induced an early decline in cardiac function that persisted in the regeneration-compromised mice over time. By integrating the findings from metabolomic, transcriptomic and proteomic examinations, we linked regeneration failure to the accumulation of long-chain acylcarnitines and insufficient metabolic capacity for fatty acid beta-oxidation. Decreased expression of the redox-sensitive mitochondrial Slc25a20 carnitine-acylcarnitine translocase together with a decreased reduced:oxidized glutathione ratio in the myocardium in the regeneration-compromised mice pointed to a defect in the redox-sensitive acylcarnitine transport to the mitochondrial matrix. Rather than a forced shift from the preferred adult myocardial oxidative fuel source, our results suggest the facilitation of mitochondrial fatty acid transport and improvement of the beta-oxidation pathway as a means to overcome the metabolic barrier for repair and regeneration in adult mammals after MI and heart failure.PMID:37009793 | DOI:10.1038/s12276-023-00967-5

Heliyon. 2023 Apr;9(4):e15010. doi: 10.1016/j.heliyon.2023.e15010. Epub 2023 Mar 28.ABSTRACTVarious metabolomics studies have reported increased phenylalanine serum concentrations in SARS-CoV-2 positive cases and have correlated increased phenylalanine with COVID-19 severity. In this study, we report similar results based upon metabolomics analysis of serum collected from a South African cohort of adults with confirmed COVID-19. The novelty of this study is the inclusion of HIV positive cases in the African context. We found that pre-existing HIV co-infection exacerbates the disruption of phenylalanine metabolism in COVID-19. What is lacking in literature is biological context and deeper understanding of perturbed phenylalanine metabolism in COVID-19. We delve deep into the metabolism of phenylalanine in COVID-19 and posit new insights for COVID-19 cases co-infected with HIV; namely, HIV-COVID-19 co-infected individuals do not have sufficient bioavailability of tetrahydrobiopterin (BH4). Hence, we identify BH4 as a potential supplement to alleviate/lessen COVID-19 symptoms.PMID:37009248 | PMC:PMC10043972 | DOI:10.1016/j.heliyon.2023.e15010

iScience. 2023 Mar 9;26(4):106359. doi: 10.1016/j.isci.2023.106359. eCollection 2023 Apr 21.ABSTRACTAs modern biological sciences evolve from investigation of individual molecules and pathways to growing emphasis on global and systems-based processes, increasing efforts have focused on combining the study of genomics with that of the other omics technologies, including epigenomics, transcriptomics, quantitative proteomics, global analyses of post-translational modifications (PTMs) and metabolomics, to characterize specific biological or pathological processes. In addition, emerging genome-wide functional screening technologies further help researchers identify key regulators of immune functions. Derived from these multi-omics technologies, single cell sequencing analysis on multiple layers offers an overview of intra-tissue or intra-organ immune cell heterogeneity. In this review, we summarize advances in multi-omics tools to explore immune cell functions and applications of these multi-omics approaches in the analysis of clinical immune disorders, aiming to provide an outlook on the potential opportunities and challenges that these technologies pose in future investigation in the field of immunology.PMID:37009227 | PMC:PMC10060681 | DOI:10.1016/j.isci.2023.106359

Yale J Biol Med. 2023 Mar 31;96(1):23-42. doi: 10.59249/KFYZ8002. eCollection 2023 Mar.ABSTRACTObjective: We aim to comprehensively describe the transcriptional activity and signaling of pulmonary parenchymal and immune cells before and after cardiopulmonary bypass (CPB) by using a multi-omic approach coupled with functional cellular assays. We hypothesize that key signaling pathways from specific cells within the lung alter pulmonary endothelial cell function resulting in worsening or improving disease. Methods: We collected serial tracheobronchial lavage samples from intubated patients less than 2-years-old undergoing surgery with CPB. Samples were immediately processed for single cell RNA sequencing (10x Genomics). Cell clustering, cell-type annotation, and visualization were performed, and differentially expressed genes (DEG) between serial samples were identified. Metabolomic and proteomic analyses were performed on the supernatant using mass spectrometry and a multiplex assay (SomaScan) respectively. Functional assays were done using electric cell-substrate impedance sensing to measure resistance across human pulmonary microvascular endothelial cells (HPMECs). Results: Analysis of eight patients showed a heterogeneous mixture of pulmonary parenchymal and immune cells. Cell clustering demonstrated time-dependent changes in the transcriptomic signature indicating altered cellular phenotypes after CPB. DEG analysis was represented by genes involved in host defense, innate immunity, and the mitochondrial respiratory transport chain. Ingenuity pathway analysis showed upregulation of the integrated stress response across all cell types after CPB. Metabolomic analysis demonstrated upregulation of ascorbate and aldarate metabolism. Unbiased proteomic analysis revealed upregulation of proteins involved in cytokine and chemokine pathways. Post-CPB patient supernatant improved HMPEC barrier function, suggesting a protective cellular response to CPB. Conclusion: Children who undergo CPB for cardiac surgery have distinct cell populations, transcriptional activity, and metabolism that change over time. The response to ischemia-reperfusion injury in the lower airway of children appears to be protective, with the need to identify potential targets through future investigations.PMID:37009190 | PMC:PMC10052603 | DOI:10.59249/KFYZ8002