PubMed

Cancers (Basel). 2023 Jul 25;15(15):3764. doi: 10.3390/cancers15153764.ABSTRACTMultiple myeloma (MM) is an incurable haematological malignancy of plasma cells in the bone marrow. In rare cases, an aggressive form of MM called extramedullary multiple myeloma (EMM) develops, where myeloma cells enter the bloodstream and colonise distal organs or soft tissues. This variant is associated with refractoriness to conventional therapies and a short overall survival. The molecular mechanisms associated with EMM are not yet fully understood. Here, we analysed the proteome of bone marrow mononuclear cells and blood plasma from eight patients (one serial sample) with EMM and eight patients without extramedullary spread. The patients with EMM had a significantly reduced overall survival with a median survival of 19 months. Label-free mass spectrometry revealed 225 proteins with a significant differential abundance between bone marrow mononuclear cells (BMNCs) isolated from patients with MM and EMM. This plasma proteomics analysis identified 22 proteins with a significant differential abundance. Three proteins, namely vascular cell adhesion molecule 1 (VCAM1), pigment epithelium derived factor (PEDF), and hepatocyte growth factor activator (HGFA), were verified as the promising markers of EMM, with the combined protein panel showing excellent accuracy in distinguishing EMM patients from MM patients. Metabolomic analysis revealed a distinct metabolite signature in EMM patient plasma compared to MM patient plasma. The results provide much needed insight into the phenotypic profile of EMM and in identifying promising plasma-derived markers of EMM that may inform novel drug development strategies.PMID:37568580 | DOI:10.3390/cancers15153764

J Clin Med. 2023 Jul 28;12(15):4978. doi: 10.3390/jcm12154978.ABSTRACTBACKGROUND: Preoperative fasting and surgery cause metabolic stress, insulin resistance with ketosis, and postoperative nausea and vomiting (PONV). Oral carbohydrate loading strategy (CHO) improves outcomes in labor and general surgery. We aimed to compare the effectiveness of CHO with standard fasting in patients undergoing elective cesarean delivery (CD) under spinal anesthesia.METHODS: A single-center, parallel, prospective randomized controlled trial (RCT) was conducted in a tertiary university obstetrics department at Pomeranian Medical University in Szczecin, Poland. Patients were randomly assigned (1:1 ratio) to the CHO group (oral carbohydrate 2 h before elective CD, n = 75) or the SF group (control-standard fasting, n = 73). The main outcome measures were incidence and severity of PONV at 6 and 24 h after CD, time to the first peristalsis, time to first bowel movement, and biochemical parameters indicating ketosis in mothers and their children.RESULTS: A total of 148 adult females with singleton pregnancies undergoing elective CD under spinal anesthesia (ASA I and II) were included in the final analysis. At 24 h after CD, 8.0% from the CHO group vs. 20.55% reported three or more episodes of vomiting or dry retching as compared to patients in the SF group (p = 0.041). Preoperative CHO supplementation decreased preoperative feelings of hunger (p < 0.001) and thirst (p < 0.001). Laboratory results in the CHO group showed higher plasma pH (p = 0.001) and glucose (p < 0.001), lower F2-isoprostane in plasma (p = 0.049) and urine (p = 0.018), lower urine F2-isoprostane/creatinine ratio (p = 0.045) than in the SF group. HOMA-IR (p < 0.001) and lactate (p < 0.001) were higher in the CHO group than in the control group.CONCLUSIONS: There was no significant difference in the incidence or severity of early PONV at 6 h. The incidence of vomiting or dry retching at 24 h after cesarean delivery was lower in the CHO group as compared to standard starvation, but the combined results of PONV frequency and severity on the Wengritzky scale did not differ between the two study groups. Preoperative CHO supplementation decreased preoperative feelings of hunger and thirst, enhancing the comfort of pregnant women.TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04069806.PMID:37568381 | DOI:10.3390/jcm12154978

J Sep Sci. 2023 Aug 11:e2300175. doi: 10.1002/jssc.202300175. Online ahead of print.ABSTRACTPrevious clinical studies have found that the efficacy of processed Qixue Shuangbu Prescription has been significantly improved in the treatment of chronic heart failure. However, the absorbed constituents and synergistic mechanisms of processed Qixue Shuangbu Prescription to enhance the therapeutic effect of chronic heart failure remain unclear. In this study, we propose an integrated strategy combining plasma metabolomics, network pharmacology, and molecular docking to study the absorbed constituents and synergistic mechanisms of processed Qixue Shuangbu Prescription. A total of 34 prototype constituents and 24 metabolites were identified in rat plasma after administration of crude and processed Qixue Shuangbu Prescription. As a result, six potential absorbed constituents and six potential targets for the treatment of chronic heart failure were identified. In addition, the result of molecular docking indicated that the key constituents exhibited good affinity to hub targets. This study showed that the multiomics approach could effectively clarify absorbed constituents and synergistic mechanisms of traditional Chinese medicine processing from a new perspective.PMID:37568244 | DOI:10.1002/jssc.202300175

J Assist Reprod Genet. 2023 Aug 12. doi: 10.1007/s10815-023-02904-x. Online ahead of print.ABSTRACTPURPOSE: The purpose of this study was to investigate alterations in serum metabolites during endometrial transformation and possible associations with recurrent implantation failure (RIF) in hormonal replacement therapy (HRT)-frozen embryo transfer (FET) cycles.METHODS: We performed a prospective study involving 100 patients scheduled for HRT-FET cycles during January 2022 to April 2022. Blood serum samples were collected on the day of progesterone administration (dPA) and on the third day of progesterone administration (d3PA). Gas chromatography-mass spectrometry (GC-MS) analysis was performed to identify and quantify serum metabolites. A nested case-control study including 19 RIF patients and 19 matching controls was conducted to explore the predictive value of serum metabolites for RIF. Partial least squares discriminant analysis (PLS-DA) and receiver operating characteristic (ROC) curve analysis were performed to establish prediction models.MAIN RESULTS: We identified 105 serum metabolites, with 76 of them exhibiting significant alterations during the initial 3 days of endometrial transformation. Metabolites involved in amino acid metabolism and tricarboxylic acid (TCA) cycle showed lower levels during endometrial transformation. In the nested case-control study, the prediction model based on the ratio of serum metabolites between d3PA and dPA showed the highest area under the ROC curve (AUC), accuracy, and R2 and Q2 values. Eight metabolites, including indol-3-propionic acid, beta-alanine, myristoleic acid, malic acid, indole, DL-isocitric acid, proline, and itaconic acid, exhibited high predictive values for RIF.CONCLUSION: This study demonstrates alterations in serum metabolites during endometrial transformation, particularly in amino acid metabolism and TCA cycle. The identified metabolites, especially indol-3-propionic acid and malic acid, show potential as predictive markers for RIF. These findings contribute to a better understanding of the metabolic changes associated with endometrial receptivity and provide insights for the development of personalized approaches to improve implantation outcomes in FET cycles.PMID:37568040 | DOI:10.1007/s10815-023-02904-x

Sci Rep. 2023 Aug 11;13(1):13047. doi: 10.1038/s41598-023-39757-4.ABSTRACTThe saltwater hard clam Mercenaria mercenaria (M. mercenaria) as a representative of low-value shellfish, enhancing its flavor quality, is the key to enter the high-end market. Nevertheless, there has not been reported research on the flavor quality of M. mercenaria. This study compared the flavor quality of selective and non-selective saltwater hard clams of M. mercenaria by using various indicators: proximate component, free amino acids, nucleotides, and metabolomic analysis. The results indicated that selective breeding contributed to the significant improvement contents of crude protein, flavor-associated free amino acids (glutamic acid, aspartic acid, proline, etc.), and nucleotides (AMP) (P < 0.05). Then, the metabolome was utilized to assess the metabolite changes in the pre/post-selective breeding of M. mercenaria and further understand the flavor characteristics and metabolic status. In the metabolomics assay, among the 3143 quantified metabolites, a total of 102 peaks were identified as significantly different metabolites (SDMs) between the selective and non-selective varieties of M. mercenaria (VIP > 1 and P < 0.05). These results can provide new insights for future research on improving the quality of saltwater bivalves through selective breeding.PMID:37567877 | DOI:10.1038/s41598-023-39757-4

Food Microbiol. 2023 Oct;115:104328. doi: 10.1016/j.fm.2023.104328. Epub 2023 Jul 7.ABSTRACTDrug-resistant Salmonella is widely distributed in the meat production chain, endangering food safety and public health. Acidification of meat products during processing can induce acid stress, which may alter antibiotic resistance. Our study investigated the effects of acid stress on the antibiotic resistance and metabolic profile of Salmonella Typhimurium, and explored the underlying mechanisms using metabolomic and transcriptomic analysis. We found that acid-stressed 14028s was more sensitive to small molecule hydrophobic antibiotics (SMHA) while more resistant to meropenem (MERO). Metabolomic analysis revealed that enhanced sensitivity to SMHA was correlated with increased purine metabolism and tricarboxylic acid cycle. Transcriptomic analysis revealed the downregulation of chemotaxis-related genes, which are also associated with SMHA sensitivity. We also found a significant downregulation of the ompF gene, which encodes a major outer membrane protein OmpF of Salmonella. The decreased expression of OmpF porin hindered the influx of MERO, leading to enhanced resistance of the bacteria to the drug. Our findings contribute to greatly improve the understanding of the relationship between Salmonella metabolism, gene expression, and changes in drug resistance after acid stress, while providing a structural framework for exploring the relationship between bacterial stress responses and antibiotic resistance.PMID:37567621 | DOI:10.1016/j.fm.2023.104328

Int J Biol Macromol. 2023 Aug 9:126246. doi: 10.1016/j.ijbiomac.2023.126246. Online ahead of print.ABSTRACTRoot bark (Lycii cortex) of Lycium contains high contents of characteristic bioactive compounds, including kukoamine A (KuA) and kukoamine B (KuB). RIPENING INHIBITOR (RIN) is well known as a master regulator of Solanaceaous fruit ripening. However, the role of RIN in the biosynthetic pathway of KuA in Lycium remains unclear. In this study, integrated transcriptomic, metabolomic analyses and hairy root system are used to characterize the role of RIN in KuA biosynthesis in Lycium. The ultra performance liquid chromatography electrospray ionization tandem mass spectrometry analysis revealed that KuA was significantly induced in LrRIN1 RNAi lines and not detected in overexpression lines. A total of 20,913 differentially expressed genes (DEGs) and 60 differentially accumulated metabolites (DAMs) were detected in LrRIN1 transgenic hairy roots, which were used for weighted gene co-expression network analysis. Our result reveals a high association between KuA and structural genes in the phenolamide pathway, which shows a negative correlation with LrRIN1. In addition, overexpression of the polyamine pathway gene thermospermine synthase LcTSPMS, a potential target gene of Lycium RIN, increased the contents of both KuA and KuB in L. chinense hairy root, indicating that TSPMS is responsible for KuA biosynthesis and is also the common upstream biosynthetic gene for both KuA and KuB. Our results lay a solid foundation for uncovering the biosynthetic pathway of KuA, which will facilitate the molecular breeding and genetic improvement of Lycium species.PMID:37567520 | DOI:10.1016/j.ijbiomac.2023.126246

J Biol Chem. 2023 Aug 9:105147. doi: 10.1016/j.jbc.2023.105147. Online ahead of print.ABSTRACTThe vertebrate host's immune system and resident commensal bacteria deploy a range of highly reactive small molecules that provide a barrier against infections by microbial pathogens. Gut pathogens, such as Vibrio cholerae, sense and respond to these stressors by modulating the expression of exotoxins that are crucial for colonization. Here, we employ mass-spectrometry-based profiling, metabolomics, expression assays and biophysical approaches to show that transcriptional activation of the hemolysin gene hlyA in V. cholerae is regulated by intracellular forms of sulfur with sulfur-sulfur bonds termed reactive sulfur species (RSS). We first present a comprehensive sequence similarity network analysis of the arsenic repressor (ArsR) superfamily of transcriptional regulators where RSS and H2O2 sensors segregate into distinct clusters. We show that HlyU, transcriptional activator of hlyA in V. cholerae, belongs to the RSS-sensing cluster and readily reacts with organic persulfides, showing no reactivity and or DNA-dissociation following treatment with GSSG or H2O2. Surprisingly, in V. cholerae cell cultures, both sulfide and peroxide treatment downregulate HlyU-dependent transcriptional activation of hlyA. However, RSS metabolite profiling shows that both sulfide and peroxide treatment raise the endogenous inorganic sulfide and disulfide levels to a similar extent, accounting for this crosstalk, and confirming that V. cholerae attenuates HlyU-mediated activation of hlyA in a specific response to intracellular RSS. These findings provide new evidence that gut pathogens may harness RSS-sensing as an evolutionary adaptation that allows them to overcome the gut inflammatory response by modulating the expression of exotoxins.PMID:37567478 | DOI:10.1016/j.jbc.2023.105147

Immunobiology. 2023 Jul 27;228(5):152722. doi: 10.1016/j.imbio.2023.152722. Online ahead of print.ABSTRACTThe pathogenesis of primary Sjogren's syndrome (pSS) has not been fully elucidated. We explored differentially expressed proteins and metabolic pathways in pSS using proteomics and metabolomics. 456 named proteins in total were identified, among which 50 were significantly changed in the pSS. Altered proteins were significantly associated with signaling pathways such as antigen processing and presentation, human immunodeficiency virus 1 infection, and FC gamma R-mediated phagocytosis. Meanwhile, 12 proteins, such as SH3BGRL3, TPM4, and CA1, can be used as potential clinical molecular markers. Moreover, 128 metabolites were significantly expressed in the pSS group. A total of 96 pathways were significantly enriched including central carbon metabolism in cancer, taurine and hypotaurine metabolism, and ABC transporters. Notably, both proteomics and metabolomics enriched glycolysis/gluconeogenesis metabolism, pentose phosphate pathway, and glutathione metabolism pathways. In this study, the progression mechanism of pSS was analyzed and novel biomarkers were identified by proteomics and metabolomics.PMID:37567091 | DOI:10.1016/j.imbio.2023.152722

Food Chem. 2023 Jul 29;431:137035. doi: 10.1016/j.foodchem.2023.137035. Online ahead of print.ABSTRACTPostmortem aging is a value-added process for meat. The objective of this study was to evaluate the dynamic changes and metabolic pathways of metabolites in Mongolian sheep during early postmortem chilled aging. Widely targeted metabolomic was used to analyze the metabolites of mutton within five days of chilled aging. A total of 1093 metabolites were identified in Mongolian sheep, covering 16 subclasses. Multivariate statistical analysis showed that 467 metabolites had significant changes during aging, including amino acid and its metabolites, fatty acyl, and glycerophospholipid. In particular, 60 metabolites decreased, while other 407 metabolites increased with aging time. The Kyoto encyclopedia of genes and genomes pathway analysis revealed that protein digestion and absorption, amino acyl-trNA biosynthesis, unsaturated fatty acid biosynthesis, nucleotide metabolism and carbon metabolism were the main enrichment pathways in aging. These findings provide a more comprehensive insight into metabolic profiling and metabolic pathways during chilled aging in mutton.PMID:37567080 | DOI:10.1016/j.foodchem.2023.137035

Nutrition. 2023 Jul 13;116:112160. doi: 10.1016/j.nut.2023.112160. Online ahead of print.ABSTRACTOBJECTIVES: High-resolution metabolomics enables global assessment of metabolites and molecular pathways underlying physiologic processes, including substrate utilization during the fasted state. The clinical index for substrate utilization, respiratory exchange ratio (RER), is measured via indirect calorimetry. The aim of this pilot study was to use metabolomics to identify metabolic pathways and plasma metabolites associated with substrate utilization in healthy, fasted adults.METHODS: This cross-sectional study included 33 adults (mean age 27.7 ± 4.9 y, mean body mass index 24.8 ± 4 kg/m2). Participants underwent indirect calorimetry to determine resting RER after an overnight fast. Untargeted metabolomics was performed on fasted plasma samples using dual-column liquid chromatography and ultra-high-resolution mass spectrometry. Linear regression and pathway enrichment analyses identified pathways and metabolites associated with substrate utilization measured with indirect calorimetry.RESULTS: RER was significantly associated with 1389 metabolites enriched within 13 metabolic pathways (P < 0.05). Lipid-related findings included general pathways, such as fatty acid activation, and specific pathways, such as C21-steroid hormone biosynthesis and metabolism, butyrate metabolism, and carnitine shuttle. Amino acid pathways included those central to metabolism, such as glucogenic amino acids, and pathways needed to maintain reduction-oxidation reactions, such as methionine and cysteine metabolism. Galactose and pyrimidine metabolism were also associated with RER (all P < 0.05).CONCLUSIONS: The fasting plasma metabolome reflects the diverse macronutrient pathways involved in carbohydrate, amino acid, and lipid metabolism during the fasted state in healthy adults. Future studies should consider the utility of metabolomics to profile individual nutrient requirements and compare findings reported here to clinical populations.PMID:37566924 | DOI:10.1016/j.nut.2023.112160

Sci Immunol. 2023 Aug 18;8(86):eadg3517. doi: 10.1126/sciimmunol.adg3517. Epub 2023 Aug 11.ABSTRACTThe skin needs to balance tolerance of colonizing microflora with rapid detection of potential pathogens. Flexible response mechanisms would seem most suitable to accommodate the dynamic challenges of effective antimicrobial defense and restoration of tissue homeostasis. Here, we dissected macrophage-intrinsic mechanisms and microenvironmental cues that tune macrophage signaling in localized skin infection with the colonizing and opportunistic pathogen Staphylococcus aureus. Early in skin infection, the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) produced by γδ T cells and hypoxic conditions within the dermal microenvironment diverted macrophages away from a homeostatic M-CSF- and hypoxia-inducible factor 1α (HIF-1α)-dependent program. This allowed macrophages to be metabolically rewired for maximal inflammatory activity, which requires expression of Irg1 and generation of itaconate, but not HIF-1α. This multifactorial macrophage rewiring program was required for both the timely clearance of bacteria and for the provision of local immune memory. These findings indicate that immunometabolic conditioning allows dermal macrophages to cycle between antimicrobial activity and protection against secondary infections.PMID:37566679 | DOI:10.1126/sciimmunol.adg3517

Sci Adv. 2023 Aug 11;9(32):eadh0485. doi: 10.1126/sciadv.adh0485. Epub 2023 Aug 11.ABSTRACTMetabolomics, the study of metabolites (small molecules of <1500 daltons), has been posited as a potential tool to explore the past in a comparable manner to other omics, e.g., genomics or proteomics. Archaeologists have used metabolomic approaches for a decade or so, mainly applied to organic residues adhering to archaeological materials. Because of advances in sensitivity, resolution, and the increased availability of different analytical platforms, combined with the low mass/volume required for analysis, metabolomics is now becoming a more feasible choice in the archaeological sector. Additional approaches, as presented by our group, show the versatility of metabolomics as a source of knowledge about the human past when using human osteoarchaeological remains. There is tremendous potential for metabolomics within archaeology, but further efforts are required to position it as a routine technique.PMID:37566664 | DOI:10.1126/sciadv.adh0485

Sci Adv. 2023 Aug 11;9(32):eadg4017. doi: 10.1126/sciadv.adg4017. Epub 2023 Aug 11.ABSTRACTObesity is associated with cognitive decline. Recent observations in mice propose an adipose tissue (AT)-brain axis. We identified 188 genes from RNA sequencing of AT in three cohorts that were associated with performance in different cognitive domains. These genes were mostly involved in synaptic function, phosphatidylinositol metabolism, the complement cascade, anti-inflammatory signaling, and vitamin metabolism. These findings were translated into the plasma metabolome. The circulating blood expression levels of most of these genes were also associated with several cognitive domains in a cohort of 816 participants. Targeted misexpression of candidate gene ortholog in the Drosophila fat body significantly altered flies memory and learning. Among them, down-regulation of the neurotransmitter release cycle-associated gene SLC18A2 improved cognitive abilities in Drosophila and in mice. Up-regulation of RIMS1 in Drosophila fat body enhanced cognitive abilities. Current results show previously unidentified connections between AT transcriptome and brain function in humans, providing unprecedented diagnostic/therapeutic targets in AT.PMID:37566655 | DOI:10.1126/sciadv.adg4017

Metabolomics. 2023 Aug 11;19(8):74. doi: 10.1007/s11306-023-02036-4.ABSTRACTINTRODUCTION: Fecal samples are highly complex and heterogeneous, containing materials at various stages of digestion. The heterogeneity and complexity of feces make stool metabolomics inherently challenging. The level of homogenization influences the outcome of the study, affecting the metabolite profiles and reproducibility; however, there is no consensus on how fecal samples should be prepared to overcome the topographical discrepancy and obtain data representative of the stool as a whole.OBJECTIVES: Various combinations of homogenization conditions were compared to investigate the effects of bead size, addition of solvents and the differences between wet-frozen and lyophilized feces.METHODS: The homogenization parameters were systematically altered to evaluate the solvent usage, bead size, and whether lyophilization is required in homogenization. The metabolic coverage and reproducibility were compared among the different conditions.RESULTS: The current work revealed that a combination of mechanical and chemical lysis obtained by bead-beating with a mixture of big and small sizes of beads in an organic solvent is an effective way to homogenize fecal samples with adequate reproducibility and metabolic coverage. Lyophilization is required when bead-beating is not available.CONCLUSIONS: A comprehensive and systematical evaluation of various fecal matter homogenization conditions provides a profound understanding for the effects of different homogenization methods. Our findings would be beneficial to assist with standardization of fecal sample homogenization protocol.PMID:37566260 | DOI:10.1007/s11306-023-02036-4

Plant Foods Hum Nutr. 2023 Aug 11. doi: 10.1007/s11130-023-01088-0. Online ahead of print.ABSTRACTThis study presents the metabolic profiling of potato powders obtained through various processing procedures and commercially available potato powders. The metabolic fingerprinting was conducted using 1H NMR-based metabolomics coupled with machine learning projections. The results indicate hot air-dried potatoes have higher fumarate, glucose, malate, asparagine, choline, gamma aminobutyric acid (GABA), alanine, lactate, threonine, and fatty acids. In comparison, steam-cooked potatoes have higher levels of phenylalanine, sucrose, proline, citrate, glutamate, and valine. Moreover, the contents of metabolites in processed potatoes in this study were higher than those found in commercial potato powders, regardless of the drying or cooking methods used. The results indicate that a new processing technique may be developed to improve the nutritional value of potatoes.PMID:37566209 | DOI:10.1007/s11130-023-01088-0

Cells. 2023 Aug 5;12(15):2006. doi: 10.3390/cells12152006.ABSTRACTPleural mesothelioma (PM) is an aggressive malignancy that develops in a unique tumor microenvironment (TME). However, cell models for studying the TME in PM are still limited. Here, we have generated and characterized novel human telomerase reverse transcriptase (hTERT)-transduced mesothelial cell and mesothelioma-associated fibroblast (Meso-CAF) models and investigated their impact on PM cell growth. Pleural mesothelial cells and Meso-CAFs were isolated from tissue of pneumothorax and PM patients, respectively. Stable expression of hTERT was induced by retroviral transduction. Primary and hTERT-transduced cells were compared with respect to doubling times, hTERT expression and activity levels, telomere lengths, proteomes, and the impact of conditioned media (CM) on PM cell growth. All transduced derivatives exhibited elevated hTERT expression and activity, and increased mean telomere lengths. Cell morphology remained unchanged, and the proteomes were similar to the corresponding primary cells. Of note, the CM of primary and hTERT-transduced Meso-CAFs stimulated PM cell growth to the same extent, while CM derived from mesothelial cells had no stimulating effect, irrespective of hTERT expression. In conclusion, all new hTERT-transduced cell models closely resemble their primary counterparts and, hence, represent valuable tools to investigate cellular interactions within the TME of PM.PMID:37566084 | DOI:10.3390/cells12152006

Cells. 2023 Aug 4;12(15):1998. doi: 10.3390/cells12151998.ABSTRACTMulti-omics has the promise to provide a detailed molecular picture of biological systems. Although obtaining multi-omics data is relatively easy, methods that analyze such data have been lagging. In this paper, we present an algorithm that uses probabilistic graph representations and external knowledge to perform optimal structure learning and deduce a multifarious interaction network for multi-omics data from a bacterial community. Kefir grain, a microbial community that ferments milk and creates kefir, represents a self-renewing, stable, natural microbial community. Kefir has been shown to have a wide range of health benefits. We obtained a controlled bacterial community using the two most abundant and well-studied species in kefir grains: Lentilactobacillus kefiri and Lactobacillus kefiranofaciens. We applied growth temperatures of 30 °C and 37 °C and obtained transcriptomic, metabolomic, and proteomic data for the same 20 samples (10 samples per temperature). We obtained a multi-omics interaction network, which generated insights that would not have been possible with single-omics analysis. We identified interactions among transcripts, proteins, and metabolites, suggesting active toxin/antitoxin systems. We also observed multifarious interactions that involved the shikimate pathway. These observations helped explain bacterial adaptation to different stress conditions, co-aggregation, and increased activation of L. kefiranofaciens at 37 °C.PMID:37566077 | DOI:10.3390/cells12151998

Cells. 2023 Aug 3;12(15):1993. doi: 10.3390/cells12151993.ABSTRACTRetinoid X receptor (RXR) heterodimerizes with the PPAR nuclear hormone receptor and regulates its downstream events. We investigated the effects of RXR agonists (LG100754, bexarotene, AGN194204, and LG101506) on lenalidomide's anti-myeloma activity, T cell functions, and the level of glucose and lipids in vivo. Genetic overexpression and CRISPR/Cas9 knockout experiments were conducted in multiple myeloma (MM) cell lines and Jurkat T cell lines to determine the roles of CRBN in RXR-agonist mediated effects. A xenograft mouse model of MM was established to determine the combination effect of LG100754 and lenalidomide. The combination of RXR agonists and lenalidomide demonstrated synergistic activity in increasing CRBN expression and killing myeloma cells. Mechanistically, the RXR agonists reduced the binding of PPARs to the CRBN promoter, thereby relieving the repressor effect of PPARs on CRBN transcription. RXR agonists downregulated the exhaustion markers and increased the activation markers of Jurkat T cells and primary human T cells. Co-administration of LG100754 and lenalidomide showed enhanced anti-tumor activity in vivo. LG100754 retained its glucose- and lipid-lowering effects. RXR agonists demonstrate potential utility in enhancing drug sensitivity and T-cell function in the treatment of myeloma.PMID:37566072 | DOI:10.3390/cells12151993

Cells. 2023 Jul 25;12(15):1925. doi: 10.3390/cells12151925.ABSTRACTIn contracting muscles, carbohydrates and fatty acids serve as energy substrates; the predominant utilization depends on the workload. Here, we investigated the contribution of non-mitochondrial and mitochondrial metabolic pathways in response to repeated training in a polygenic, paternally selected marathon mouse model (DUhTP), characterized by exceptional running performance and an unselected control (DUC), with both lines descended from the same genetic background. Both lines underwent three weeks of high-speed treadmill training or were sedentary. Both lines' muscles and plasma were analyzed. Muscle RNA was sequenced, and KEGG pathway analysis was performed. Analyses of muscle revealed no significant selection-related differences in muscle structure. However, in response to physical exercise, glucose and fatty acid oxidation were stimulated, lactate dehydrogenase activity was reduced, and lactate formation was inhibited in the marathon mice compared with trained control mice. The lack of lactate formation in response to exercise appears to be associated with increased lipid mobilization from peripheral adipose tissue in DUhTP mice, suggesting a specific benefit of lactate avoidance. Thus, results from the analysis of muscle metabolism in born marathon mice, shaped by 35 years (140 generations) of phenotype selection for superior running performance, suggest increased metabolic flexibility in male marathon mice toward lipid catabolism regulated by lactate dehydrogenase.PMID:37566003 | DOI:10.3390/cells12151925