PubMed

New Phytol. 2023 Oct 17. doi: 10.1111/nph.19324. Online ahead of print.ABSTRACTInduction of high photosynthetic capacity is a key acclimation response to high light (HL) for many herbaceous dicot plants; however, the signaling pathways that control this response remain largely unknown. Here, a systems biology approach was utilized to characterize the induction of high photosynthetic capacity in strongly and weakly acclimating Arabidopsis thaliana accessions. Plants were grown for 5 wk in a low light (LL) regime, and time-resolved photosynthetic physiological, metabolomic, and transcriptomic responses were measured during subsequent exposure to HL. The induction of high nitrogen (N) assimilation rates early in the HL shift was strongly predictive of the induction of photosynthetic capacity later in the HL shift. Accelerated N assimilation rates depended on the mobilization of existing organic acid (OA) reserves and increased de novo OA synthesis during the induction of high photosynthetic capacity. Enhanced sucrose biosynthesis capacity increased in tandem with the induction of high photosynthetic capacity, and increased starch biosynthetic capacity was balanced by increased starch catabolism. This systems analysis supports a model in which the efficient induction of N assimilation early in the HL shift begins the cascade of events necessary for the induction of high photosynthetic capacity acclimation in HL.PMID:37849025 | DOI:10.1111/nph.19324

Cancer Metab. 2023 Oct 17;11(1):17. doi: 10.1186/s40170-023-00319-x.ABSTRACTBACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, but if discovered at an early stage, the survival rate is high. The aim of this study was to identify novel markers predictive of future CRC risk using untargeted metabolomics.METHODS: This study included prospectively collected plasma samples from 902 CRC cases and 902 matched cancer-free control participants from the population-based Northern Sweden Health and Disease Study (NSHDS), which were obtained up to 26 years prior to CRC diagnosis. Using reverse-phase liquid chromatography-mass spectrometry (LC-MS), data comprising 5015 metabolic features were obtained. Conditional logistic regression was applied to identify potentially important metabolic features associated with CRC risk. In addition, we investigated if previously reported metabolite biomarkers of CRC risk could be validated in this study population.RESULTS: In the univariable analysis, seven metabolic features were associated with CRC risk (using a false discovery rate cutoff of 0.25). Two of these could be annotated, one as pyroglutamic acid (odds ratio per one standard deviation increase = 0.79, 95% confidence interval, 0.70-0.89) and another as hydroxytigecycline (odds ratio per one standard deviation increase = 0.77, 95% confidence interval, 0.67-0.89). Associations with CRC risk were also found for six previously reported metabolic biomarkers of prevalent and/or incident CRC: sebacic acid (inverse association) and L-tryptophan, 3-hydroxybutyric acid, 9,12,13-TriHOME, valine, and 13-OxoODE (positive associations).CONCLUSIONS: These findings suggest that although the circulating metabolome may provide new etiological insights into the underlying causes of CRC development, its potential application for the identification of individuals at higher risk of developing CRC is limited.PMID:37849011 | DOI:10.1186/s40170-023-00319-x

Life Sci. 2023 Oct 15:122180. doi: 10.1016/j.lfs.2023.122180. Online ahead of print.ABSTRACTAIMS: Obesity is the main cause of low-grade inflammation and oxidation, resulting in insulin resistance. This study aimed to investigate the effects of a seed peptide lunasin on glucose utilization in C2C12 myotubes and the metabolite profiles in obese mice.MAIN METHODS: C2C12 myotubes were challenged by palmitic acid (PA) to mimic the obese microenvironment and inflammation, cell vitality, and glucose utilization were determined. C57BL6/j mice were divided into low-fat diet (LF), high-fat diet (HF), and HF with intraperitoneally injected lunasin (HFL) groups. Glucose intolerance and metabolite profiles of the tissues were analyzed.KEY FINDINGS: In vitro, C2C12 myotubes treated with lunasin showed decreased proinflammatory cytokines and increased cell vitality under palmitic acid conditions. Lunasin improved glucose uptake and glucose transporter 4 expression by activating insulin receptor substrate-1, AKT, and AMPK phosphorylation. Next-generation sequencing revealed that lunasin regulates genes expression by promoting insulin secretion and decreasing oxidative stress. In vivo, HF mice showed increased tricarboxylic acid cycle and uric acid metabolites but decreased bile acids metabolites and specific amino acids. Lunasin intervention improved glucose intolerance and modulated metabolites associated with increased insulin sensitivity and decreased metabolic disorders.SIGNIFICANCE: This study is the first to reveal that lunasin is a promising regulator of anti-inflammation, anti-oxidation, and glucose utilization in myotubes and ameliorating glucose uptake and metabolite profiles in obese mice, contributing to glucose homeostasis and benefiting metabolic disorders.PMID:37848083 | DOI:10.1016/j.lfs.2023.122180

Proc Biol Sci. 2023 Oct 25;290(2009):20231476. doi: 10.1098/rspb.2023.1476. Epub 2023 Oct 18.ABSTRACTReef-building crustose coralline algae (CCA) are known to facilitate the settlement and metamorphosis of scleractinian coral larvae. In recent decades, CCA coverage has fallen globally and degrading environmental conditions continue to reduce coral survivorship, spurring new restoration interventions to rebuild coral reef health. In this study, naturally produced chemical compounds (metabolites) were collected from two pantropical CCA genera to isolate and classify those that induce coral settlement. In experiments using four ecologically important Caribbean coral species, we demonstrate the applicability of extracted, CCA-derived metabolites to improve larval settlement success in coral breeding and restoration efforts. Tissue-associated CCA metabolites induced settlement of one coral species, Orbicella faveolata, while metabolites exuded by CCA (exometabolites) induced settlement of three species: Acropora palmata, Colpophyllia natans and Orbicella faveolata. In a follow-up experiment, CCA exometabolites fractionated and preserved using two different extraction resins induced the same level of larval settlement as the unfractionated positive control exometabolites. The fractionated CCA exometabolite pools were characterized using liquid chromatography tandem mass spectrometry, yielding 145 distinct molecular subnetworks that were statistically defined as CCA-derived and could be classified into 10 broad chemical classes. Identifying these compounds can reveal their natural prevalence in coral reef habitats and facilitate the development of new applications to enhance larval settlement and the survival of coral juveniles.PMID:37848062 | DOI:10.1098/rspb.2023.1476

Cell. 2023 Oct 9:S0092-8674(23)01034-6. doi: 10.1016/j.cell.2023.09.013. Online ahead of print.ABSTRACTPost-acute sequelae of COVID-19 (PASC, "Long COVID") pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction. Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes.PMID:37848036 | DOI:10.1016/j.cell.2023.09.013

Cell Chem Biol. 2023 Oct 5:S2451-9456(23)00330-6. doi: 10.1016/j.chembiol.2023.09.011. Online ahead of print.ABSTRACTMultiple tyrosine kinase inhibitors (TKIs) are often developed for the same indication. However, their relative overall efficacy is frequently incompletely understood and they may harbor unrecognized targets that cooperate with the intended target. We compared several ROS1 TKIs for inhibition of ROS1-fusion-positive lung cancer cell viability, ROS1 autophosphorylation and kinase activity, which indicated disproportionately higher cellular potency of one TKI, lorlatinib. Quantitative chemical and phosphoproteomics across four ROS1 TKIs and differential network analysis revealed that lorlatinib uniquely impacted focal adhesion signaling. Functional validation using pharmacological probes, RNA interference, and CRISPR-Cas9 knockout uncovered a polypharmacology mechanism of lorlatinib by dual targeting ROS1 and PYK2, which form a multiprotein complex with SRC. Rational multi-targeting of this complex by combining lorlatinib with SRC inhibitors exhibited pronounced synergy. Taken together, we show that systems pharmacology-based differential network analysis can dissect mixed canonical/non-canonical polypharmacology mechanisms across multiple TKIs enabling the design of rational drug combinations.PMID:37848034 | DOI:10.1016/j.chembiol.2023.09.011

Mol Cell. 2023 Oct 10:S1097-2765(23)00755-4. doi: 10.1016/j.molcel.2023.09.028. Online ahead of print.ABSTRACTPurinosomes serve as metabolons to enhance de novo purine synthesis (DNPS) efficiency through compartmentalizing DNPS enzymes during stressed conditions. However, the mechanism underpinning purinosome assembly and its pathophysiological functions remains elusive. Here, we show that K6-polyubiquitination of the DNPS enzyme phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthetase (PAICS) by cullin-5/ankyrin repeat and SOCS box containing 11 (Cul5/ASB11)-based ubiquitin ligase plays a driving role in purinosome assembly. Upon several purinosome-inducing cues, ASB11 is upregulated by relieving the H3K9me3/HP1α-mediated transcriptional silencing, thus stimulating PAICS polyubiquitination. The polyubiquitinated PAICS recruits ubiquitin-associated protein 2 (UBAP2), a ubiquitin-binding protein with multiple stretches of intrinsically disordered regions, thereby inducing phase separation to trigger purinosome assembly for enhancing DNPS pathway flux. In human melanoma, ASB11 is highly expressed to facilitate a constitutive purinosome formation to which melanoma cells are addicted for supporting their proliferation, viability, and tumorigenesis in a xenograft model. Our study identifies a driving mechanism for purinosome assembly in response to cellular stresses and uncovers the impact of purinosome formation on human malignancies.PMID:37848033 | DOI:10.1016/j.molcel.2023.09.028

Cell Rep Methods. 2023 Oct 12:100615. doi: 10.1016/j.crmeth.2023.100615. Online ahead of print.ABSTRACTUnderstanding the effects of the microbiome on the host's metabolism is core to enlightening the role of the microbiome in health and disease. Herein, we develop the paradigm of in silico in vivo association pattern analyses, combining microbiome metabolome association studies with in silico constraint-based community modeling. Via theoretical dissection of confounding and causal paths, we show that in silico in vivo association pattern analyses allow for causal inference on microbiome-metabolome relations in observational data. We justify the corresponding theoretical criterion by structural equation modeling of host-microbiome systems, integrating deterministic microbiome community modeling into population statistics approaches. We show the feasibility of our approach on a published multi-omics dataset (n = 347), demonstrating causal microbiome-metabolite relations for 26 out of 54 fecal metabolites. In summary, we generate a promising approach for causal inference in metabolic host-microbiome interactions by integrating hypothesis-free screening association studies with knowledge-based in silico modeling.PMID:37848031 | DOI:10.1016/j.crmeth.2023.100615

Redox Biol. 2023 Oct 11;67:102930. doi: 10.1016/j.redox.2023.102930. Online ahead of print.ABSTRACTBenzo[α]pyrene (Bap) is recognized as a ubiquitous environmental pollutant among the polycyclic aromatic hydrocarbons (PAHs) class. Previous studies have shown that the hepatotoxicity of Bap is mainly caused by its metabolites, although it remains unclear whether Bap itself induces such damage. This study integrated metabolomics and chemical proteomics approaches to comprehensively identify the potential target proteins affected by Bap in liver cells. The results from the metabolomics showed that the significant changed metabolites were related with cellular redox homeostasis. CEllular Thermal Shift Assay (CETSA) showed that Bap induced protein thermal displacement of superoxide dismutase 3 (SOD3) and glutathione peroxidase 4 (GPX4), which are closely related to oxidative homeostasis. Further validation through in vitro CETSA and drug affinity response target stability (DARTS) revealed that Bap directly affected the stability of SOD3 and GPX4 proteins. The binding affinities of Bap to the potential target proteins were further evaluated using molecular docking, while the isothermal titration calorimetry (ITC) interaction measurements indicated nanomolar-level Kd values. Importantly, we found that Bap weakened the antioxidant capacity by destroying the activities of SOD3 and GPX4, which provided a new understanding of the mechanism of hepatotoxicity induced by Bap. Moreover, our provided workflow integrating metabolomics and label-free chemical proteomics, can be regarded as a practical way to identify the targets and inter-mechanisms for the various environmental compounds.PMID:37847980 | DOI:10.1016/j.redox.2023.102930

Plant Physiol Biochem. 2023 Oct 13;204:108085. doi: 10.1016/j.plaphy.2023.108085. Online ahead of print.ABSTRACTThe traditional Chinese herb Rubus chingii Hu (R. chingii) is widely used in clinical practice due to its beneficial effects. Flavonoids are the important class of pharmacological substances in R. chingii, however, the molecular mechanism underlying the differences in active flavonoid contents in R. chingii at different developmental stages remain poorly understood. In this experiment, we selected four developmental stages (GG, GY, YR, RR) of R. chingii as the research material. We studied the untargeted and targeted metabolic profiles of flavonoids in different periods of R. chingii, combining full-length and comparative transcriptome analyses. Functional analyses were conducted on genes implicated in flavonoid differences. GG and RR displayed relatively higher and lower contents of flavonols, flavones, flavanols, flavanones, and isoflavonoid, respectively. RNA-seq analyses showed structural genes such as RcPAL, RcC4H, Rc4CL, RcCHS, RcCHI, RcF3H, RcF3'H, and RcFLS in flavonoid biosynthesis pathway were upregulated in GG, which were essential for the accumulation flavanones, flavones, and flavonols (effective components). qRT-PCR analyses investigated that six structural genes RcCHI, RcF3H, 2 RcCHS, and 2 Rc4CL, two TFs RcMYB308 and RcMYB123 had a consistent expression pattern with which in transcriptome. Also, an interaction network showed that the RcMYB308 could positively regulate Ka3R, Qu, Qu3G, AS, Hy, Ti through RcF3H. Furthermore, Subcellular localization analysis revealed that RcMYB308 was localization to the nucleus. In tobacco, RcMYB308 was overexpressed, resulting in higher flavonoids, RcF3H, RcF3'H, RcCHI, and RcFLS. RcMYB308 upregulated RcF3H in dual-luciferase assays. These results provide new insights for further understanding the molecular mechanism regulating flavonol biosynthesis in R. chingii fruit, and also provide a potential MYB regulator for molecular breeding of R. chingii.PMID:37847976 | DOI:10.1016/j.plaphy.2023.108085

BMC Oral Health. 2023 Oct 17;23(1):763. doi: 10.1186/s12903-023-03527-5.ABSTRACTBACKGROUND: Long-term antiretroviral therapy (ART) perpetually suppresses HIV load and has dramatically altered the prognosis of HIV infection, such that HIV is now regarded as a chronic disease. Side effects of ART in Patients With HIV (PWH), has introduced new challenges including "metabolic" (systemic) and oral complications. Furthermore, inflammation persists despite great viral load suppression and normal levels of CD4+ cell count. The impact of ART on the spectrum of oral diseases among PWH is often overlooked relative to other systemic complications. There is paucity of data on oral complications associated with ART use in PWH. This is in part due to limited prospective longitudinal studies designed to better understand the range of oral abnormalities observed in PWH on ART.METHODS: We describe here the study design, including processes associated with subject recruitment and retention, study visit planning, oral health assessments, bio-specimen collection and preprocessing procedures, and data management and statistical plan.DISCUSSION: We present a procedural roadmap that could be modelled to assess the extent and progression of oral diseases associated with ART in PWH. We also highlight the rigors and challenges associated with our ongoing participant recruitment and retention. A rigorous prospective longitudinal study requires proper planning and execution. A great benefit is that large data sets are collected and biospecimen repository can be used to answer more questions in future studies including genetic, microbiome and metabolome-based studies.TRIAL REGISTRATION: National Institute of Health Clinical Trials Registration (NCT) #: NCT04645693.PMID:37848867 | DOI:10.1186/s12903-023-03527-5

Sci Rep. 2023 Oct 17;13(1):17666. doi: 10.1038/s41598-023-41176-4.ABSTRACTPapillary thyroid carcinoma (PTC) is the most common endocrine malignancy with a rapidly increasing incidence. The pathogenesis of PTC is unclear, but metabolic and lipidomic reprogramming may play a role in tumor growth. We applied ultra-performance liquid chromatography-tandem mass spectrometry to perform widely targeted metabolomics and lipidomics on plasma samples from 94 patients with PTC and 100 healthy controls. We identified 113 differential metabolites and 236 differential lipids, mainly involved in branched-chain amino acid metabolism, glutamate and glutamine metabolism, tricarboxylic acid cycle, and lipid metabolism. We also screened three potential metabolite biomarkers: sebacic acid, L-glutamine, and indole-3-carboxaldehyde. These biomarkers showed excellent diagnostic performance for PTC in both discovery and validation cohorts, with areas under the receiver operating characteristic curves of 0.994 and 0.925, respectively. Our findings reveal distinct metabolic and lipidomic features of PTC and provide novel targets for diagnosis and treatment.PMID:37848492 | DOI:10.1038/s41598-023-41176-4

Nat Commun. 2023 Oct 17;14(1):6558. doi: 10.1038/s41467-023-42227-0.ABSTRACTThe neurofilament (NF) cytoskeleton is critical for neuronal morphology and function. In particular, the neurofilament-light (NF-L) subunit is required for NF assembly in vivo and is mutated in subtypes of Charcot-Marie-Tooth (CMT) disease. NFs are highly dynamic, and the regulation of NF assembly state is incompletely understood. Here, we demonstrate that human NF-L is modified in a nutrient-sensitive manner by O-linked-β-N-acetylglucosamine (O-GlcNAc), a ubiquitous form of intracellular glycosylation. We identify five NF-L O-GlcNAc sites and show that they regulate NF assembly state. NF-L engages in O-GlcNAc-mediated protein-protein interactions with itself and with the NF component α-internexin, implying that O-GlcNAc may be a general regulator of NF architecture. We further show that NF-L O-GlcNAcylation is required for normal organelle trafficking in primary neurons. Finally, several CMT-causative NF-L mutants exhibit perturbed O-GlcNAc levels and resist the effects of O-GlcNAcylation on NF assembly state, suggesting a potential link between dysregulated O-GlcNAcylation and pathological NF aggregation. Our results demonstrate that site-specific glycosylation regulates NF-L assembly and function, and aberrant NF O-GlcNAcylation may contribute to CMT and other neurodegenerative disorders.PMID:37848414 | DOI:10.1038/s41467-023-42227-0

J Matern Fetal Neonatal Med. 2023 Dec;36(2):2270761. doi: 10.1080/14767058.2023.2270761. Epub 2023 Oct 17.ABSTRACTBackground: Macrosomia is a common disorder that occurs during pregnancy. We investigated the comprehensive metabolite profiles of pregnant maternal and fetal sera in normoglycemic macrosomia in a Chinese population. Methods: Forty pregnant women and their fetuses were included in the study (twenty macrosomia patients and twenty normal-weight controls). Maternal and umbilical cord serum metabolites were identified using ultra-performance liquid chromatography coupled with tandem mass spectrometry. Results: In total, 203 metabolites were identified. Lipids and lipid-like molecules were the predominant metabolites. Fifty-three metabolites with significant differences were obtained in the maternal samples. In the macrosomia group, the levels of docosahexaenoic acid, eicosapentaenoic acid, and arachidonic acid were significantly higher than those in the control group. Umbilical cord serum samples were obtained for 24 different metabolites. The maternal-fetal gradient of polyunsaturated fatty acids was decreased in the macrosomia group. Aconitic acid, citric acid, isocitric acid, 2-methylhexanoic acid, and 12-hydroxystearic acid were the common differential metabolites in the maternal and umbilical cord serum samples. Conclusion: There were obvious metabolic abnormalities in the sera of pregnant women and fetuses with macrosomia. Lipids and lipid-like molecules were the predominant differential metabolites but had different classifications in the maternal and umbilical cord serum. These results may provide new insights into the long-term metabolic disorders associated with macrosomia.PMID:37848386 | DOI:10.1080/14767058.2023.2270761

Elife. 2023 Oct 17;12:e92465. doi: 10.7554/eLife.92465. Online ahead of print.ABSTRACTJuvenile undernutrition has lasting effects on adult metabolism of the affected individuals, but it is unclear how adult physiology is shaped over evolutionary time by natural selection driven by juvenile undernutrition. We combined RNAseq, targeted metabolomics and genomics to study the consequences of evolution under juvenile undernutrition for metabolism of reproductively active adult females of Drosophila melanogaster. Compared to Control populations maintained on standard diet, Selected populations maintained for over 230 generations on a nutrient-poor larval diet evolved major changes in adult gene expression and metabolite abundance, in particular affecting amino-acid and purine metabolism. The evolved differences in adult gene expression and metabolite abundance between Selected and Control populations were positively correlated with the corresponding differences previously reported for Selected versus Control larvae. This implies that genetic variants affect both stages similarly. Even when well fed, the metabolic profile of Selected flies resembled that of flies subject to starvation. Finally, Selected flies had lower reproductive output than Controls even when both were raised under the conditions under which the Selected populations evolved. These results imply that evolutionary adaptation to juvenile undernutrition has large pleiotropic consequences for adult metabolism, and that they are costly rather than adaptive for adult fitness. Thus, juvenile and adult metabolism do not appear to evolve independently from each other even in a holometabolous species where the two life stages are separated by a complete metamorphosis.PMID:37847744 | DOI:10.7554/eLife.92465

Proc Natl Acad Sci U S A. 2023 Oct 31;120(44):e2304933120. doi: 10.1073/pnas.2304933120. Epub 2023 Oct 17.ABSTRACTTravel can induce motion sickness (MS) in susceptible individuals. MS is an evolutionary conserved mechanism caused by mismatches between motion-related sensory information and past visual and motion memory, triggering a malaise accompanied by hypolocomotion, hypothermia, hypophagia, and nausea. Vestibular nuclei (VN) are critical for the processing of movement input from the inner ear. Motion-induced activation of VN neurons recapitulates MS-related signs. However, the genetic identity of VN neurons mediating MS-related autonomic and aversive responses remains unknown. Here, we identify a central role of cholecystokinin (CCK)-expressing VN neurons in motion-induced malaise. Moreover, we show that CCK VN inputs onto the parabrachial nucleus activate Calca-expressing neurons and are sufficient to establish avoidance to novel food, which is prevented by CCK-A receptor antagonism. These observations provide greater insight into the neurobiological regulation of MS by identifying the neural substrates of MS and providing potential targets for treatment.PMID:37847729 | DOI:10.1073/pnas.2304933120

Glycobiology. 2023 Oct 17:cwad085. doi: 10.1093/glycob/cwad085. Online ahead of print.ABSTRACTAberrant glycosylation is a hallmark of cancer and is not just a consequence, but also a driver of a malignant phenotype. In prostate cancer, changes in fucosylated and sialylated glycans are common and this has important implications for tumour progression, metastasis, and immune evasion. Glycans hold huge translational potential and new therapies targeting tumour-associated glycans are currently being tested in clinical trials for several tumour types. Inhibitors targeting fucosylation and sialylation have been developed and show promise for cancer treatment, but translational development is hampered by safety issues related to systemic adverse effects. Recently, potent metabolic inhibitors of sialylation and fucosylation were designed that reach higher effective concentrations within the cell, thereby rendering them useful tools to study sialylation and fucosylation as potential candidates for therapeutic testing. Here, we investigated the effects of global metabolic inhibitors of fucosylation and sialylation in the context of prostate cancer progression. We find that these inhibitors effectively shut down the synthesis of sialylated and fucosylated glycans to remodel the prostate cancer glycome with only minor apparent side effects on other glycan types. Our results demonstrate that treatment with inhibitors targeting fucosylation or sialylation decreases prostate cancer cell growth and downregulates the expression of genes and proteins important in the trajectory of disease progression. We anticipate our findings will lead to the broader use of metabolic inhibitors to explore the role of fucosylated and sialylated glycans in prostate tumour pathology and may pave the way for the development of new therapies for prostate cancer.PMID:37847613 | DOI:10.1093/glycob/cwad085

FASEB J. 2023 Nov;37(11):e23241. doi: 10.1096/fj.202300870RR.ABSTRACTCementum, a constituent part of periodontal tissues, has important adaptive and reparative functions. It serves to attach the tooth to alveolar bone and acts as a barrier delimit epithelial growth and bacteria evasion. A dynamic and highly responsive cementum is essential for maintaining occlusal relationships and the integrity of the root surface. It is a thin layer of mineralized tissue mainly produced by cementoblasts. Cementoblasts are osteoblast-like cells essential for the restoration of periodontal tissues. In recent years, glucose metabolism has been found to be critical in bone remodeling and osteoblast differentiation. However, the glucose metabolism of cementoblasts remains incompletely understood. First, immunohistochemistry staining and in vivo tracing with 18 F-fluorodeoxyglucose (18 F-FDG) revealed significantly higher glucose metabolism in cementum formation. To test the bioenergetic pathways of cementoblast differentiation, we compared the bioenergetic profiles of mineralized and unmineralized cementoblasts. As a result, we observed a significant increase in the consumption of glucose and production of lactate, coupled with the higher expression of glycolysis-related genes. However, the expression of oxidative phosphorylation-related genes was downregulated. The verified results were consistent with the RNA sequencing results. Likewise, targeted energy metabolomics shows that the levels of glycolytic metabolites were significantly higher in the mineralized cementoblasts. Seahorse assays identified an increase in glycolytic flux and reduced oxygen consumption during cementoblast mineralization. Apart from that, we also found that lactate dehydrogenase A (LDHA), a key glycolysis enzyme, positively regulates the mineralization of cementoblasts. In summary, cementoblasts mainly utilized glycolysis rather than oxidative phosphorylation during the mineralization process.PMID:37847512 | DOI:10.1096/fj.202300870RR

Cancer Res. 2023 Oct 17. doi: 10.1158/0008-5472.CAN-23-3169. Online ahead of print.ABSTRACTAdvances in mass spectrometry allow for broader applications of metabolomics in research and clinical applications. In a recent issue of Nature Metabolism, Voorde and colleagues utilized metabolite profiling to investigate the metabolism of colorectal cancer (CRC) in mouse models, organoids and patients. This study underscores the utility of metabolomics in distinguishing CRC, offering potential for its use in precision medicine. It also revealed a pivotal role for adenosylhomocysteinase in the methionine cycle and highlighted its potential as a therapeutic target.PMID:37847509 | DOI:10.1158/0008-5472.CAN-23-3169

Anal Methods. 2023 Oct 17. doi: 10.1039/d3ay01527k. Online ahead of print.ABSTRACTAccurate detection of vitamins is critically important for clinical diagnosis, metabolomics and epidemiological studies. However, the amounts of different vitamins vary dramatically in human serum. It is a challenge to achieve simultaneous detection of multiple vitamins rapidly. Herein, we developed and validated a sensitive and specific method using ultra high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) for simultaneous quantification of 7 fat-soluble vitamins (FSVs) across their physiological concentrations in serum for the first time, which was subjected to protein precipitation, liquid-liquid extraction to an organic phase, evaporation to dryness and reconstitution with acetonitrile. In the present procedure, retinol (vitamin A), ergocalciferol (25-OH-D2), cholecalciferol (25-OH-D3), α-tocopherol (vitamin E), phylloquinone (vitamin K1), menatetrenone-4 (MK-4), and menaquinone-7 (MK-7) were detected in one analytical procedure for the first time within 5.0 min by triple quadrupole tandem mass spectrometry. The limit of quantification (LOQ) for vitamin A was 10.0 ng mL-1, LOQs for 25-OH-D2 and 25-OH-D3 were 1.0 ng mL-1, LOQ for vitamin E was 100.0 ng mL-1, and LOQs for vitamin K1, MK-4 and MK-7 were 0.10 ng mL-1, respectively, with a correlation (R2) of 0.995-0.999. Recoveries ranged from 80.5% to 118.5% and the intra-day and inter-day coefficients of variance (CVs) were 0.72-8.89% and 3.2-9.0% respectively. The method was validated according to the European Medicines Agency (EMA) and U.S. Food and Drug guidelines and C62-A on bioanalytical methods, and was used for clinical routine determination.PMID:37847399 | DOI:10.1039/d3ay01527k