PubMed

Aging Cell. 2023 Apr 26:e13852. doi: 10.1111/acel.13852. Online ahead of print.ABSTRACTPerturbed metabolism of ammonia, an endogenous cytotoxin, causes mitochondrial dysfunction, reduced NAD+ /NADH (redox) ratio, and postmitotic senescence. Sirtuins are NAD+ -dependent deacetylases that delay senescence. In multiomics analyses, NAD metabolism and sirtuin pathways are enriched during hyperammonemia. Consistently, NAD+ -dependent Sirtuin3 (Sirt3) expression and deacetylase activity were decreased, and protein acetylation was increased in human and murine skeletal muscle/myotubes. Global acetylomics and subcellular fractions from myotubes showed hyperammonemia-induced hyperacetylation of cellular signaling and mitochondrial proteins. We dissected the mechanisms and consequences of hyperammonemia-induced NAD metabolism by complementary genetic and chemical approaches. Hyperammonemia inhibited electron transport chain components, specifically complex I that oxidizes NADH to NAD+ , that resulted in lower redox ratio. Ammonia also caused mitochondrial oxidative dysfunction, lower mitochondrial NAD+ -sensor Sirt3, protein hyperacetylation, and postmitotic senescence. Mitochondrial-targeted Lactobacillus brevis NADH oxidase (MitoLbNOX), but not NAD+ precursor nicotinamide riboside, reversed ammonia-induced oxidative dysfunction, electron transport chain supercomplex disassembly, lower ATP and NAD+ content, protein hyperacetylation, Sirt3 dysfunction and postmitotic senescence in myotubes. Even though Sirt3 overexpression reversed ammonia-induced hyperacetylation, lower redox status or mitochondrial oxidative dysfunction were not reversed. These data show that acetylation is a consequence of, but is not the mechanism of, lower redox status or oxidative dysfunction during hyperammonemia. Targeting NADH oxidation is a potential approach to reverse and potentially prevent ammonia-induced postmitotic senescence in skeletal muscle. Since dysregulated ammonia metabolism occurs with aging, and NAD+ biosynthesis is reduced in sarcopenia, our studies provide a biochemical basis for cellular senescence and have relevance in multiple tissues.PMID:37101412 | DOI:10.1111/acel.13852

Neuropharmacology. 2023 Apr 24:109562. doi: 10.1016/j.neuropharm.2023.109562. Online ahead of print.ABSTRACTEmerging evidence implicate the gut microbiota as a potential susceptibility factor in attention-deficit hyperactivity disorder (ADHD), a common multifactorial neurodevelopmental condition. However, little is known about the biochemical signature of ADHD, including the metabolic contribution of the microbiota via the gut-brain axis, and the relative contribution of genetics and environmental factors. Here, we perform unbiased metabolomic profiling of urine and fecal samples collected from a well-characterized Swedish twin cohort enriched for ADHD (33 ADHD, 79 non-ADHD), using 1H nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry. Our results highlight sex-specific patterns in the metabolic phenotype of individuals with ADHD. Specifically, the urine profile of males, but not females, with ADHD was characterized by greater excretion of hippurate, a product of microbial-host co-metabolism that can cross the blood-brain-barrier with bioactivity of potential relevance to ADHD. This trans-genomic metabolite was also negatively correlated with IQ in males and was significantly correlated with fecal metabolites associated with gut microbial metabolism. The fecal profile of ADHD individuals was characterized by increased excretion of stearoyl-linoleoyl-glycerol, 3,7-dimethylurate, and FAD and lower amounts of glycerol 3-phosphate, thymine, 2(1H)-quinolinone, aspartate, xanthine, hypoxanthine, and orotate. These changes were independent of ADHD medication, age, and BMI. Furthermore, our specific twins' models revealed that many of these gut metabolites had a stronger genetic influence than environmental. These findings suggest that metabolic disturbances in ADHD, involving combined gut microbial and host metabolic processes, may largely derive from gene variants previously linked to behavioral symptoms in this disorder.PMID:37100381 | DOI:10.1016/j.neuropharm.2023.109562

Environ Pollut. 2023 Apr 24:121708. doi: 10.1016/j.envpol.2023.121708. Online ahead of print.ABSTRACTPerfluorooctane sulfonate (PFOS), one of the legacy per- and poly-fluoroalkyl substances (PFAS), is associated with multiple adverse health effects on children. However, much remains to be known about its potential impacts on intestinal immune homeostasis during early life. Our study found that PFOS exposure during pregnancy in rats significantly increased the maternal serum levels of interleukin-6 (IL-6) and zonulin, a gut permeability biomarker, and decreased gene expressions of Tight junction protein 1 (Tjp1) and Claudin-4 (Cldn4), the tight junction proteins, in maternal colons on gestation day 20 (GD20). Being exposed to PFOS during pregnancy and lactation in rats significantly decreased the body weight of pups and increased the offspring's serum levels of IL-6 and tumor necrosis factor-α (TNF-α) on postnatal day 14 (PND14), and induced a disrupted gut tight junction, manifested by decreased expressions of Tjp1 in pup's colons on PND14 and increased pup's serum concentrations of zonulin on PND28. By integrating high-throughput 16S rRNA sequencing and metabolomics, we demonstrated that early-life PFOS exposure altered the diversity and composition of gut microbiota that were correlated with the changed metabolites in serum. The altered blood metabolome was associated with increased proinflammatory cytokines in offspring. These changes and correlations were divergent at each developmental stage, and pathways underlying immune homeostasis imbalance were significantly enriched in the PFOS-exposed gut. Our findings provide new evidence for the developmental toxicity of PFOS and its underlying mechanism and explain in part the epidemiological observation of its immunotoxicity.PMID:37100370 | DOI:10.1016/j.envpol.2023.121708

Int J Biol Macromol. 2023 Apr 24:124569. doi: 10.1016/j.ijbiomac.2023.124569. Online ahead of print.ABSTRACTStylo (Stylosanthes guianensis) is a tropical forage and cover crop that possesses low phosphate (Pi) tolerance traits. However, the mechanisms underlying its tolerance to low-Pi stress, particularly the role of root exudates, remain unclear. This study employed an integrated approach using physiological, biochemical, multi-omics, and gene function analyses to investigate the role of stylo root exudates in response to low-Pi stress. Widely targeted metabolomic analysis revealed that eight organic acids and one amino acid (L-cysteine) were significantly increased in the root exudates of Pi-deficient seedlings, among which tartaric acid and L-cysteine had strong abilities to dissolve insoluble-P. Furthermore, flavonoid-targeted metabolomic analysis identified 18 flavonoids that were significantly increased in root exudates under low-Pi conditions, mainly belonging to the isoflavonoid and flavanone subclasses. Additionally, transcriptomic analysis revealed that 15 genes encoding purple acid phosphatases (PAPs) had upregulated expression in roots under low-Pi conditions. Among them, SgPAP10 was characterized as a root-secreted phosphatase, and overexpression of SgPAP10 enhanced organic-P utilization by transgenic Arabidopsis. Overall, these findings provide detailed information regarding the importance of stylo root exudates in adaptation to low-Pi stress, highlighting the plant's ability to release Pi from organic-P and insoluble-P sources through root-secreted organic acids, amino acids, flavonoids, and PAPs.PMID:37100319 | DOI:10.1016/j.ijbiomac.2023.124569

Int J Biol Macromol. 2023 Apr 24:124570. doi: 10.1016/j.ijbiomac.2023.124570. Online ahead of print.ABSTRACTAreca catechu is well known as a medicinal plant that has high nutritional and medicinal benefits. However, the metabolism and regulatory mechanism of B vitamins during areca nut development remain largely unclear. In this study, we obtained the metabolite profiles of six B vitamins during different areca nut developmental stages by targeted metabolomics. Furthermore, we obtained a panoramic expression profile of genes related to the biosynthetic pathway of B vitamins in areca nuts at different developmental stages using RNA-seq. In total, 88 structural genes related to B vitamin biosynthesis were identified. Furthermore, the integrated analysis of B vitamin metabolism data and RNA-seq data showed the key transcription factors regulating thiamine and riboflavin accumulation in areca nuts, including AcbZIP21, AcMYB84, and AcARF32. These results lay the foundation for understanding metabolite accumulation and the molecular regulatory mechanisms of B vitamins in A. catechu nut.PMID:37100313 | DOI:10.1016/j.ijbiomac.2023.124570

J Ethnopharmacol. 2023 Apr 24:116555. doi: 10.1016/j.jep.2023.116555. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicines (TCMs) are often prepared in oral dosage forms, making TCMs interact with gut microbiota after oral administration, which could affect the therapeutic effect of TCM. Xiaoyao Pills (XYPs) are a commonly used TCM in China to treat depression. The biological underpinnings, however, are still in its infancy due to its complex chemical composition.AIM OF THE STUDY: The study aims to explore XYPs' underlying antidepressant mechanism from both in vivo and in vitro.MATERIALS AND METHODS: XYPs were composed of 8 herbs, including the root of Bupleurum chinense DC., the root of Angelica sinensis (Oliv.) Diels, the root of Paeonia lactiflora Pall., the sclerotia of Poria cocos (Schw.) Wolf, the rhizome of Glycyrrhiza uralensis Fisch., the leaves of Mentha haplocalyx Briq., the rhizome of Atractylis lanceavar. chinensis (Bunge) Kitam., and the rhizome of Zingiber officinale Roscoe, in a ratio of 5:5:5:5:4:1:5:5. The chronic unpredictable mild stress (CUMS) rat models were established. After that, the sucrose preference test (SPT) was carried out to evaluate if the rats were depressed. After 28 days of treatment, the forced swimming test and SPT were carried out to evaluate the antidepressant efficacy of XYPs. The feces, brain and plasma were taken out for 16SrRNA gene sequencing analysis, untargeted metabolomics and gut microbiota transformation analysis.RESULTS: The results revealed multiple pathways affected by XYPs. Among them, the hydrolysis of fatty acids amide in brain decreased most significant via XYPs treatment. Moreover, the XYPs' metabolites which mainly derived from gut microbiota (benzoic acid, liquiritigenin, glycyrrhetinic acid and saikogenin D were found in plasma and brain of CUMS rats and could inhibit the levels of FAAH in brain, which contributed to XYPs' antidepressant effect.CONCLUSIONS: The potential antidepressant mechanism of XYPs by untargeted metabolomics combined with gut microbiota-transformation analysis was revealed, which further support the theory of gut-brain axis and provide valuable evidence of the drug discovery.PMID:37100263 | DOI:10.1016/j.jep.2023.116555

Ecotoxicol Environ Saf. 2023 Apr 24;257:114943. doi: 10.1016/j.ecoenv.2023.114943. Online ahead of print.ABSTRACTThe hazardous potential of haloquinolines (HQLs) is becoming an issue of great concern due to its wide and long-term usage in many personal care products. We examined the growth inhibition, structure-activity relationship, and toxicity mechanism of 33 HQLs on Chlorella pyrenoidosa using the 72-h algal growth inhibition assay, three-dimensional quantitative structure-activity relationship (3D-QSAR), and metabolomics. We found that the IC50 (half maximal inhibitory concentration) values for 33 compounds ranged from 4.52 to > 150 mg·L-1, most tested compounds were toxic (1 mg·L-1 < IC50 < 10 mg·L-1) or harmful (10 mg·L-1 < IC50 < 100 mg·L-1) for the aquatic ecosystem. Hydrophobic properties of HQLs dominate their toxicity. Halogen atoms with large volume appear at the 2, 3, 4, 5, 6, and 7-positions of the quinoline ring to significantly increase the toxicity. In algal cells, HQLs can block diverse carbohydrates, lipids, and amino acid metabolism pathways, thereby resulting in energy usage, osmotic pressure regulation, membrane integrity, oxidative stress disorder, thus fatally damaging algal cells. Therefore, our results provide insight into the toxicity mechanism and ecological risk of HQLs.PMID:37099961 | DOI:10.1016/j.ecoenv.2023.114943

J Magn Reson. 2023 Apr 8;351:107429. doi: 10.1016/j.jmr.2023.107429. Online ahead of print.ABSTRACTIn NMR-based untargeted metabolomic studies, 1H NMR spectra are usually divided into equal bins/buckets to diminish the effects of peak shift caused by sample status or instrument instability, and to reduce the number of variables used as input for the multivariate statistical analysis. It was noticed that the peaks near bin boundaries may cause significant changes in integral values of adjacent bins, and the weaker peak may be obscured if it is allocated in the same bin with intense peaks. Several efforts have been taken to improve the performance of binning. Here we propose an alternative method, named P-Bin, based on the combination of the classic peak-picking and binning procedures. The location of each peak defined by peak-picking is used as the center of the individual bin. P-Bin is expected to keep all spectral information associated with the peaks and significantly reduce the data size as the spectral regions without peaks are not considered. In addition, both peak-picking and binning are routine procedures, making P-Bin easy to be implemented. To verify the performance, two sets of experimental data from human plasma and Ganoderma lucidum (G. lucidum) extracts were processed using the conventional binning method and the proposed method, before the principal component analysis (PCA) and the orthogonal projection to latent structures discriminant analysis (OPLS-DA). The results indicate that the proposed method has improved both the clustering performance of PCA score plots and the interpretability of OPLS-DA loading plots, and P-Bin could be an improved version of data preparation for metabonomic study.PMID:37099854 | DOI:10.1016/j.jmr.2023.107429

Genome Biol. 2023 Apr 26;24(1):95. doi: 10.1186/s13059-023-02945-6.ABSTRACTBACKGROUND: Apple is an economically important fruit crop. Changes in metabolism accompanying human-guided evolution can be revealed using a multiomics approach. We perform genome-wide metabolic analysis of apple fruits collected from 292 wild and cultivated accessions representing various consumption types.RESULTS: We find decreased amounts of certain metabolites, including tannins, organic acids, phenolic acids, and flavonoids as the wild accessions transition to cultivated apples, while lysolipids increase in the "Golden Delicious" to "Ralls Janet" pedigree, suggesting better storage. We identify a total of 222,877 significant single-nucleotide polymorphisms that are associated with 2205 apple metabolites. Investigation of a region from 2.84 to 5.01 Mb on chromosome 16 containing co-mapping regions for tannins, organic acids, phenolic acids, and flavonoids indicates the importance of these metabolites for fruit quality and nutrition during breeding. The tannin and acidity-related genes Myb9-like and PH4 are mapped closely to fruit weight locus fw1 from 3.41 to 3.76 Mb on chromosome 15, a region under selection during domestication. Lysophosphatidylethanolamine (LPE) 18:1, which is suppressed by fatty acid desaturase-2 (FAD2), is positively correlated to fruit firmness. We find the fruit weight is negatively correlated with salicylic acid and abscisic acid levels. Further functional assays demonstrate regulation of these hormone levels by NAC-like activated by Apetala3/Pistillata (NAP) and ATP binding cassette G25 (ABCG25), respectively.CONCLUSIONS: This study provides a metabolic perspective for selection on fruit quality during domestication and improvement, which is a valuable resource for investigating mechanisms controlling apple metabolite content and quality.PMID:37101232 | DOI:10.1186/s13059-023-02945-6

Orphanet J Rare Dis. 2023 Apr 26;18(1):95. doi: 10.1186/s13023-023-02683-9.ABSTRACTBACKGROUND: Inherited Metabolic Disorders (IMDs) are rare diseases where one impaired protein leads to a cascade of changes in the adjacent chemical conversions. IMDs often present with non-specific symptoms, a lack of a clear genotype-phenotype correlation, and de novo mutations, complicating diagnosis. Furthermore, products of one metabolic conversion can be the substrate of another pathway obscuring biomarker identification and causing overlapping biomarkers for different disorders. Visualization of the connections between metabolic biomarkers and the enzymes involved might aid in the diagnostic process. The goal of this study was to provide a proof-of-concept framework for integrating knowledge of metabolic interactions with real-life patient data before scaling up this approach. This framework was tested on two groups of well-studied and related metabolic pathways (the urea cycle and pyrimidine de-novo synthesis). The lessons learned from our approach will help to scale up the framework and support the diagnosis of other less-understood IMDs.METHODS: Our framework integrates literature and expert knowledge into machine-readable pathway models, including relevant urine biomarkers and their interactions. The clinical data of 16 previously diagnosed patients with various pyrimidine and urea cycle disorders were visualized on the top 3 relevant pathways. Two expert laboratory scientists evaluated the resulting visualizations to derive a diagnosis.RESULTS: The proof-of-concept platform resulted in varying numbers of relevant biomarkers (five to 48), pathways, and pathway interactions for each patient. The two experts reached the same conclusions for all samples with our proposed framework as with the current metabolic diagnostic pipeline. For nine patient samples, the diagnosis was made without knowledge about clinical symptoms or sex. For the remaining seven cases, four interpretations pointed in the direction of a subset of disorders, while three cases were found to be undiagnosable with the available data. Diagnosing these patients would require additional testing besides biochemical analysis.CONCLUSION: The presented framework shows how metabolic interaction knowledge can be integrated with clinical data in one visualization, which can be relevant for future analysis of difficult patient cases and untargeted metabolomics data. Several challenges were identified during the development of this framework, which should be resolved before this approach can be scaled up and implemented to support the diagnosis of other (less understood) IMDs. The framework could be extended with other OMICS data (e.g. genomics, transcriptomics), and phenotypic data, as well as linked to other knowledge captured as Linked Open Data.PMID:37101200 | DOI:10.1186/s13023-023-02683-9

BMC Plant Biol. 2023 Apr 27;23(1):223. doi: 10.1186/s12870-023-04238-3.ABSTRACTBACKGROUND: Foxtail millet (Setaria italica) harbors the small diploid genome (~ 450 Mb) and shows the high inbreeding rate and close relationship to several major foods, feed, fuel and bioenergy grasses. Previously, we created a mini foxtail millet, xiaomi, with an Arabidopsis-like life cycle. The de novo assembled genome data with high-quality and an efficient Agrobacterium-mediated genetic transformation system made xiaomi an ideal C4 model system. The mini foxtail millet has been widely shared in the research community and as a result there is a growing need for a user-friendly portal and intuitive interface to perform exploratory analysis of the data.RESULTS: Here, we built a Multi-omics Database for Setaria italica (MDSi, http://sky.sxau.edu.cn/MDSi.htm ), that contains xiaomi genome of 161,844 annotations, 34,436 protein-coding genes and their expression information in 29 different tissues of xiaomi (6) and JG21 (23) samples that can be showed as an Electronic Fluorescent Pictograph (xEFP) in-situ. Moreover, the whole-genome resequencing (WGS) data of 398 germplasms, including 360 foxtail millets and 38 green foxtails and the corresponding metabolic data were available in MDSi. The SNPs and Indels of these germplasms were called in advance and can be searched and compared in an interactive manner. Common tools including BLAST, GBrowse, JBrowse, map viewer, and data downloads were implemented in MDSi.CONCLUSION: The MDSi constructed in this study integrated and visualized data from three levels of genomics, transcriptomics and metabolomics, and also provides information on the variation of hundreds of germplasm resources that can satisfies the mainstream requirements and supports the corresponding research community.PMID:37101150 | DOI:10.1186/s12870-023-04238-3

BMC Plant Biol. 2023 Apr 26;23(1):221. doi: 10.1186/s12870-023-04230-x.ABSTRACTBACKGROUND: Rhizome is vital for carbon and nitrogen metabolism of the whole plant. However, the effect of carbon and nitrogen in the rhizome on rhizome expansion remains unclear.RESULTS: Three wild Kentucky bluegrass (Poa pratensis L.) germplasms with different rhizome expansion capacity (strong expansion capacity, 'YZ'; medium expansion capacity, 'WY'; and weak expansion capacity, 'AD') were planted in the field and the rhizomes number, tiller number, rhizome dry weight, physiological indicators and enzyme activity associated carbon and nitrogen metabolisms were measured. Liquid chromatography coupled to mass spectrometry (LC-MS) was utilized to analyze the metabolomic of the rhizomes. The results showed that the rhizome and tiller numbers of the YZ were 3.26 and 2.69-fold of that of the AD, respectively. The aboveground dry weight of the YZ was the greatest among all three germplasms. Contents of soluble sugar, starch, sucrose, NO3--N, and free amino acid were significantly higher in rhizomes of the YZ than those of the WY and AD (P < 0.05). The activities of glutamine synthetase (GS), glutamate dehydrogenase (GDH) and sucrose phosphate synthase (SPS) of the YZ were the highest among all three germplasm, with values of 17.73 A·g- 1 h- 1, 5.96 µmol·g- 1 min- 1, and 11.35 mg·g- 1 h- 1, respectively. Metabolomics analyses revealed that a total of 28 differentially expressed metabolites (DEMs) were up-regulated, and 25 DEMs were down-regulated in both comparison groups (AD vs. YZ group and WY vs. YZ group). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis demonstrated that metabolites related to histidine metabolism, tyrosine metabolism, tryptophan metabolism, and phenylalanine metabolism were associated with rhizomes carbon and nitrogen metabolism.CONCLUSIONS: Overall, the results suggest that soluble sugar, starch, sucrose, NO3--N, and free amino acid in rhizome are important to and promote rhizome expansion in Kentucky bluegrass, while tryptamine, 3-methylhistidine, 3-indoleacetonitrile, indole, and histamine may be key metabolites in promoting carbon and nitrogen metabolism of rhizome.PMID:37101108 | DOI:10.1186/s12870-023-04230-x

Cell Death Differ. 2023 Apr 26. doi: 10.1038/s41418-023-01153-w. Online ahead of print.ABSTRACTApoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.PMID:37100955 | DOI:10.1038/s41418-023-01153-w

Osteoporos Int. 2023 Apr 26. doi: 10.1007/s00198-023-06763-1. Online ahead of print.ABSTRACTOlder adults with type 2 diabetes mellitus have an increased risk of fracture despite a paradoxically higher average bone mineral density. This study identified additional markers of fracture risk in this at-risk population. Non-esterified fatty acids and the amino acids glutamine/glutamate and asparagine/aspartate were associated with incident fractures.PURPOSE: Type 2 diabetes mellitus (T2D) is associated with an increased risk of fracture despite a paradoxically higher bone mineral density. Additional markers of fracture risk are needed to identify at-risk individuals.METHOD: The MURDOCK study is an ongoing study, initiated in 2007, of residents in central North Carolina. At enrollment, participants completed health questionnaires and provided biospecimen samples. In this nested case-control analysis, incident fractures among adults with T2D, age ≥ 50 years, were identified by self-report and electronic medical record query. Fracture cases were matched 1:2 by age, gender, race/ethnicity, and BMI to those without incident fracture. Stored sera were analyzed for conventional metabolites and targeted metabolomics (amino acids and acylcarnitines). The association between incident fracture and metabolic profile was assessed using conditional logistic regression, controlled for multiple confounders including tobacco and alcohol use, medical comorbidities, and medications.RESULTS: 107 incident fractures were identified with 210 matched controls. Targeted metabolomics analysis included 2 amino acid factors, consisting of: 1) the branched chain amino acids, phenylalanine and tyrosine; and 2) glutamine/glutamate, asparagine/aspartate, arginine, and serine [E/QD/NRS]. After controlling for multiple risk factors, E/QD/NRS was significantly associated with incident fracture (OR 2.50, 95% CI: 1.36-4.63). Non-esterified fatty acids were associated with lower odds of fracture (OR 0.17, 95% CI: 0.03-0.87). There were no associations with fracture among other conventional metabolites, acylcarnitine factors, nor the other amino acid factors.CONCLUSION: Our results indicate novel biomarkers, and suggest potential mechanisms, of fracture risk among older adults with T2D.PMID:37100949 | DOI:10.1007/s00198-023-06763-1

Nature. 2023 Apr 26. doi: 10.1038/s41586-023-06017-4. Online ahead of print.ABSTRACTInflammation is a complex physiological process triggered in response to harmful stimuli1. It involves cells of the immune system capable of clearing sources of injury and damaged tissues. Excessive inflammation can occur as a result of infection and is a hallmark of several diseases2-4. The molecular bases underlying inflammatory responses are not fully understood. Here we show that the cell surface glycoprotein CD44, which marks the acquisition of distinct cell phenotypes in the context of development, immunity and cancer progression, mediates the uptake of metals including copper. We identify a pool of chemically reactive copper(II) in mitochondria of inflammatory macrophages that catalyses NAD(H) redox cycling by activating hydrogen peroxide. Maintenance of NAD+ enables metabolic and epigenetic programming towards the inflammatory state. Targeting mitochondrial copper(II) with supformin (LCC-12), a rationally designed dimer of metformin, induces a reduction of the NAD(H) pool, leading to metabolic and epigenetic states that oppose macrophage activation. LCC-12 interferes with cell plasticity in other settings and reduces inflammation in mouse models of bacterial and viral infections. Our work highlights the central role of copper as a regulator of cell plasticity and unveils a therapeutic strategy based on metabolic reprogramming and the control of epigenetic cell states.PMID:37100912 | DOI:10.1038/s41586-023-06017-4

Sci Rep. 2023 Apr 26;13(1):6828. doi: 10.1038/s41598-023-34132-9.ABSTRACTDietary restriction (DR) has been a very important discovery in modern aging biology research. Its remarkable anti-aging effect has been proved in a variety of organisms, including members of Lepidoptera, but mechanisms by which DR increases longevity are not fully understood. By using the silkworm (Bombyx mori), a model of lepidopteran insect, we established a DR model, isolated hemolymph from fifth instar larvae and employed LC-MS/MS metabolomics to analyze the effect of DR on the endogenous metabolites of silkworm, and tried to clarify the mechanism of DR to prolong lifespan. We identified the potential biomarkers by analyzing the metabolites of the DR and control groups. Then, we constructed relevant metabolic pathways and networks with MetaboAnalyst. DR significantly prolonged the lifespan of silkworm. The differential metabolites between the DR and control groups were mainly organic acids (including amino acid), and amines. These metabolites are involved in metabolic pathways such as amino acid metabolism. Further analysis showed that, the levels of 17 amino acids were significantly changed in the DR group, indicating that the prolonged lifespan was mainly due to changes in amino acid metabolism. Furthermore, we identified 41 and 28 unique differential metabolites in males and females, respectively, demonstrating sex differences in biological responses to DR. The DR group showed higher antioxidant capacity and lower lipid peroxidation and inflammatory precursors, with differences between the sexes. These results provide evidence for various DR anti-aging mechanisms at the metabolic level and novel reference for the future development of DR-simulating drugs or foods.PMID:37100857 | DOI:10.1038/s41598-023-34132-9

Carcinogenesis. 2023 Apr 26:bgad024. doi: 10.1093/carcin/bgad024. Online ahead of print.ABSTRACTNonmelanoma skin cancer (NMSC) is the most common cancer in the world. Environmental exposure to carcinogens is one of the major causes of NMSC initiation and progression. In the current study, we utilized a two-stage skin carcinogenesis mouse model generated by sequential exposure to cancer-initiating agent benzo[a]pyrene (BaP) and promoting agent 12-O-tetra-decanoylphorbol-13-acetate (TPA), to study epigenetic, transcriptomic, and metabolic changes at different stages during the development of NMSC. BaP caused significant alterations in DNA methylation and gene expression profiles in skin carcinogenesis, as evidenced by DNA-seq and RNA-seq analysis. Correlation analysis between differentially expressed genes and differentially methylated regions found that the mRNA expression of oncogenes leucine rich repeat LGI family member 2 (Lgi2), kallikrein related peptidase 13 (Klk13), and SRY-Box transcription factor (Sox5) are correlated with the promoter CpG methylation status, indicating BaP/TPA regulates these oncogenes through regulating their promoter methylation at different stages of NMSC. Pathway analysis identified that the modulation of macrophage-stimulating protein-recepteur d'origine nantais (MSP-RON) and high-mobility group box 1 (HMGB1) signaling pathways, superpathway of melatonin degradation, melatonin degradation 1, sirtuin signaling, and actin cytoskeleton signaling pathways are associated with the development of NMSC. The metabolomic study showed BaP/TPA regulated cancer-associated metabolisms like pyrimidine and amino acid metabolisms/metabolites and epigenetic-associated metabolites, such as S-adenosylmethionine, methionine, and 5-methylcytosine, indicating a critical role in carcinogen-mediated metabolic reprogramming and its consequences on cancer development. Altogether, this study provides novel insights integrating methylomic, transcriptomic, and metabolic signaling pathways that could benefit future skin cancer treatment and interception studies.PMID:37100755 | DOI:10.1093/carcin/bgad024

Vaccine. 2023 Apr 24:S0264-410X(23)00459-0. doi: 10.1016/j.vaccine.2023.04.045. Online ahead of print.ABSTRACTThe live attenuated temperature sensitive vaccine strain MS-H (Vaxsafe® MS, Bioproperties Pty. Ltd., Australia) is widely used to control disease associated with M. synoviae infection in commercial poultry. MS-H was derived from a field strain (86079/7NS) through N-methyl-N'-nitro-N-nitrosoguanidine (NTG)-induced mutagenesis. Whole genomic sequence analysis of the MS-H and comparison with that of the 86079/7NS have found that MS-H contains 32 single nucleotide polymorphisms (SNPs). Three of these SNPs, found in the obgE, oppF and gapdh genes, have been shown to be prone to reversion under field condition, albeit at a low frequency. Three MS-H reisolates containing the 86079/7NS genotype in obgE (AS2), obgE and oppF (AB1), and obgE, oppF and gapdh (TS4), appeared to be more immunogenic and transmissible compared to MS-H in chickens. To investigate the influence of these reversions in the in vitro fitness of M. synoviae, the growth kinetics and steady state metabolite profiles of the MS-H reisolates, AS2, AB1 and TS4, were compared to those of the vaccine strain. Steady state metabolite profiling of the reisolates showed that changes in ObgE did not significantly influence the metabolism, while changes in OppF was associated with significant alterations in uptake of peptides and/or amino acids into the M. synoviae cell. It was also found that GAPDH plays a role in metabolism of the glycerophospholipids as well as an arginine deiminase (ADI) pathway. This study underscores the role of ObgE, OppF and GAPDH in M. synoviae metabolism, and suggests that the impaired fitness arising from variations in ObgE, OppF and GAPDH contributes to attenuation of MS-H.PMID:37100722 | DOI:10.1016/j.vaccine.2023.04.045

Tree Physiol. 2023 Apr 26:tpad046. doi: 10.1093/treephys/tpad046. Online ahead of print.ABSTRACTMichelia compressa (Maxim.) Sarg. is one of the important timber trees in Taiwan province, P. R. China. Michelia 'Zhongshanhanxiao' is a group of variants found among the progeny of M. compressa that exhibit higher growth rates compared with normal individuals, with significantly increased stem diameter and height, as well as enlarged leaves and flowers. However, the molecular mechanisms fostering the growth advantage and morphological variations are unknown and deserve further study. Through analyzing the transcriptome, metabolome and physiological processes of leaves, we identified remarkable differences in gene expression and metabolic profiles between Michelia 'Zhongshanhanxiao' and both the maternal M. compressa and its normal progeny. These differences were widely associated with plant-pathogen interaction, phenylpropanoid biosynthesis, cyanoamino acid metabolism, carbon fixation in photosynthetic organisms and plant hormone signal transduction. Additionally, physiological measurements showed that Michelia 'Zhongshanhanxiao' possesses stronger photosynthetic capacity and higher plant hormone contents. These results suggest that the heterosis of Michelia 'Zhongshanhanxiao' is regulated by candidates related to cell division, resistance to pathogens and accumulation of organic compounds. The findings of this study provide crucial information on the molecular mechanisms underlying the growth advantages conferred by heterosis in trees.PMID:37099801 | DOI:10.1093/treephys/tpad046

Plant Physiol. 2023 Apr 26:kiad236. doi: 10.1093/plphys/kiad236. Online ahead of print.ABSTRACTGlandular trichomes (GTs) are outgrowths of plant epidermal cells that secrete and store specialized secondary metabolites that protect plants against biotic and abiotic stresses and have economic importance for human use. While extensive work has been done to understand the molecular mechanisms of trichome organogenesis in Arabidopsis (Arabidopsis thaliana), which forms unicellular, non-glandular trichomes (NGTs), little is known about the mechanisms of GT development or regulation of secondary metabolites in plants with multicellular GTs. Here, we identified and functionally characterized genes associated with GT organogenesis and secondary metabolism in GTs of cucumber (Cucumis sativus). We developed a method for effective separation and isolation of cucumber GTs and NGTs. Transcriptomic and metabolomic analyses showed that flavonoid accumulation in cucumber GTs is positively associated with increased expression of related biosynthesis genes. We identified 67 GT development-related genes, the functions of 7 of which were validated by virus-induced gene silencing. We further validated the role of cucumber ECERIFERUM1 (CsCER1) in GT organogenesis by overexpression and RNA interference transgenic approaches. We further show that the transcription factor TINY BRANCHED HAIR (CsTBH) serves as a central regulator of flavonoid biosynthesis in cucumber glandular trichomes. Work from this study provides insight into the development of secondary metabolite biosynthesis in multi-cellular glandular trichomes.PMID:37099480 | DOI:10.1093/plphys/kiad236