PubMed

Biomed Chromatogr. 2024 Mar 6:e5851. doi: 10.1002/bmc.5851. Online ahead of print.ABSTRACTXixin-Ganjiang herb pair (XGHP) is a classic combination for warming the lungs to dissolve phlegm and is often used to treat a variety of chronic lung diseases; it can treat the syndrome of cold phlegm obstruction of lungs. First, ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to examine the composition of XGHP, and network pharmacology was used to predict its potential core targets and signaling pathways in the current study. Second, a rat model of chronic obstructive pulmonary disease (COPD) was established for assessing the anti-COPD activity of XGHP, and metabolomics was used to explore the biomarkers and metabolic pathways. Finally, the sample was validated using molecular docking and Western blotting. The integration of metabolomics and network pharmacology results identified 11 targets, 3 biomarkers, 3 pathways, and 2 metabolic pathways. Western blotting showed that XGHP effectively regulated the expression of core proteins via multiple signaling pathways (downregulation of toll-like receptor 4 [TLR4] and upregulation of serine/threonine-protein kinase 1 [p-AKT1] and nitric oxide synthase 3 [NOS3]). Molecular docking results showed that the 10 potentially active components of XGHP have good affinity with tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), matrix metalloproteinase 9 (MMP-9), TLR4, p-AKT1, and NOS3. Our findings suggest that XGHP may regulate glucolipid metabolism, improve energy supply, and inhibit inflammatory responses (TNF-α, IL-6, and MMP-9) via the PI3K-Akt signaling pathway and HIF-1 signaling pathway in the management of COPD.PMID:38449348 | DOI:10.1002/bmc.5851

Front Immunol. 2024 Feb 20;15:1354479. doi: 10.3389/fimmu.2024.1354479. eCollection 2024.ABSTRACTINTRODUCTION: The inflammatory response after spinal cord injury (SCI) is an important contributor to secondary damage. Infiltrating macrophages can acquire a spectrum of activation states, however, the microenvironment at the SCI site favors macrophage polarization into a pro-inflammatory phenotype, which is one of the reasons why macrophage transplantation has failed.METHODS: In this study, we investigated the therapeutic potential of the macrophage secretome for SCI recovery. We investigated the effect of the secretome in vitro using peripheral and CNS-derived neurons and human neural stem cells. Moreover, we perform a pre-clinical trial using a SCI compression mice model and analyzed the recovery of motor, sensory and autonomic functions. Instead of transplanting the cells, we injected the paracrine factors and extracellular vesicles that they secrete, avoiding the loss of the phenotype of the transplanted cells due to local environmental cues.RESULTS: We demonstrated that different macrophage phenotypes have a distinct effect on neuronal growth and survival, namely, the alternative activation with IL-10 and TGF-β1 (M(IL-10+TGF-β1)) promotes significant axonal regeneration. We also observed that systemic injection of soluble factors and extracellular vesicles derived from M(IL-10+TGF-β1) macrophages promotes significant functional recovery after compressive SCI and leads to higher survival of spinal cord neurons. Additionally, the M(IL-10+TGF-β1) secretome supported the recovery of bladder function and decreased microglial activation, astrogliosis and fibrotic scar in the spinal cord. Proteomic analysis of the M(IL-10+TGF-β1)-derived secretome identified clusters of proteins involved in axon extension, dendritic spine maintenance, cell polarity establishment, and regulation of astrocytic activation.DISCUSSION: Overall, our results demonstrated that macrophages-derived soluble factors and extracellular vesicles might be a promising therapy for SCI with possible clinical applications.PMID:38444856 | PMC:PMC10912310 | DOI:10.3389/fimmu.2024.1354479

Adv Protein Chem Struct Biol. 2024;139:221-261. doi: 10.1016/bs.apcsb.2023.11.006. Epub 2024 Feb 15.ABSTRACTBioinformatics is an interconnected subject of science dealing with diverse fields including biology, chemistry, physics, statistics, mathematics, and computer science as the key fields to answer complicated physiological problems. Key intention of bioinformatics is to store, analyze, organize, and retrieve essential information about genome, proteome, transcriptome, metabolome, as well as organisms to investigate the biological system along with its dynamics, if any. The outcome of bioinformatics depends on the type, quantity, and quality of the raw data provided and the algorithm employed to analyze the same. Despite several approved medicines available, cardiovascular disorders (CVDs) and cancers comprises of the two leading causes of human deaths. Understanding the unknown facts of both these non-communicable disorders is inevitable to discover new pathways, find new drug targets, and eventually newer drugs to combat them successfully. Since, all these goals involve complex investigation and handling of various types of macro- and small- molecules of the human body, bioinformatics plays a key role in such processes. Results from such investigation has direct human application and thus we call this filed as translational bioinformatics. Current book chapter thus deals with diverse scope and applications of this translational bioinformatics to find cure, diagnosis, and understanding the mechanisms of CVDs and cancers. Developing complex yet small or long algorithms to address such problems is very common in translational bioinformatics. Structure-based drug discovery or AI-guided invention of novel antibodies that too with super-high accuracy, speed, and involvement of considerably low amount of investment are some of the astonishing features of the translational bioinformatics and its applications in the fields of CVDs and cancers.PMID:38448136 | DOI:10.1016/bs.apcsb.2023.11.006

Food Res Int. 2024 Apr;181:114117. doi: 10.1016/j.foodres.2024.114117. Epub 2024 Feb 9.ABSTRACTThe inoculation of S. cerevisiae can address the excessive acidity in Suanyu, but its influence on the microbial community structure has not been documented. In this study, the microbiota succession, and metabolites of Suanyu with the inoculation of acid-reducing S. cerevisiae L7 were explored. The findings revealed that the addition of S. cerevisiae L7 elevated the pH, and decreased the microbial α-diversity. In Suanyu, the dominant bacterial genera were Lactiplantibacillus and Bacillus, while the dominant fungal genera were Meyerozyma and Saccharomyces. Following the inoculation of S. cerevisiae L7, the relative abundance of Lactiplantibacillus decreased from 21 % to 13 %. Meanwhile, the growth of fungi such as Meyerozyma and Candida was suppressed. The rise in Saccharomyces had a significant impact on various pathways related to amino acid and carbohydrate metabolism, causing the accumulation of flavor compounds. This study sheds more lights on the methods for manipulating microbial community structure in fermented food.PMID:38448112 | DOI:10.1016/j.foodres.2024.114117

Food Res Int. 2024 Apr;181:114120. doi: 10.1016/j.foodres.2024.114120. Epub 2024 Feb 8.ABSTRACTMonoterpenes are typical aroma components in muscat grapes and wines, closely related to its geographical origins. However, the mechanism underlying the geographical differences of monoterpenes remains to be elucidated, especially in the Chinese viticulture regions. This study investigated the diversity of six Chinese viticultural vineyards (YT, XF, SS, XX, WW and CL) in the monoterpene composition of Vitis vinifera L. cv.'Muscat Hamburg' grapes and the resulted wines. Monoterpenes were analyzed by HS-SPME- GC-MS. The total amount of free and bound monoterpenes varied dramatically between grapes of different vineyards, and their contents were obviously higher in YT region grapes. The OAVs for 18 monoterpenes of grapes from the YT vineyard were relative higher than those of other regions, and the floral odor could distinguish grapes from different regions. The total free monoterpenes were highest in the YT region wine. Concentrations of total bound monoterpenes ranged from 711.13 μg/L (XF region) to 1078.30 μg/L (CL region). A correlation analysis showed that all monoterpenes showeda positive correlation with mean relative humidity, sum rainfall, and a negative correlation with sum duration of sunshine and mean temperature. This study would provide some new insights to understand the geographical differences of monoterpenes, and the results would facilitate the effective viticultural treatment of grapes to improve the quality of the aroma.PMID:38448101 | DOI:10.1016/j.foodres.2024.114120

Food Res Int. 2024 Apr;181:114116. doi: 10.1016/j.foodres.2024.114116. Epub 2024 Feb 9.ABSTRACTCantonese soy sauce (CSS) is an important Chinese condiment due to its distinctive flavor. Microorganisms play a significant role in the flavor formation of CSS during fermentation. However, the correlation between microbes and flavor compounds as well as the potential fermentation mechanism remained poorly uncovered. Here we revealed the dynamic changes of microbial structure and characteristics metabolites as well as their correlation of CSS during the fermentation process. Metagenomics sequencing analysis showed that Tetragenococcus halophilus, Weissella confusa, Weissella paramesenteroides, Aspergillus oryzae, Lactiplantibacillus plantarum, Weissella cibaria were top six dominant species from day 0 to day 120. Sixty compounds were either positively or tentatively identified through untargeted metabolomics profile and they were 27 peptides, amino acids and derivatives, 8 carbohydrates and conjugates, 14 organic acids and derivatives, 5 amide compounds, 3 flavonoids and 3 nucleosides. Spearman correlation coefficient indicated that Tetragenococcus halophilus, Zygosaccharomyces rouxii, Pediococcus pentosaceus and Aspergillus oryzae were significantly related with the formation of taste amino acids and derivatives, peptides and functional substances. Additionally, the metabolisms of flavor amino acids including 13 main free amino acids were also profiled. These results provided valuable information for the production practice in the soy sauce industry.PMID:38448100 | DOI:10.1016/j.foodres.2024.114116

Food Res Int. 2024 Apr;181:114094. doi: 10.1016/j.foodres.2024.114094. Epub 2024 Feb 2.ABSTRACTThe detailed dynamics of small molecular nonvolatile chemical and bacterial diversities, as well as their relationship are still unclear in the manufacturing process of Keemun black tea (KMBT). Herein, mass spectrometry-based untargeted metabolomics, Feature-based Molecular Networking (FBMN) and bacterial DNA amplicon sequencing were used to investigate the dense temporal samples of the manufacturing process. For the first time, we reveal that the pyrogallol-type catechins are oxidized asynchronously before catechol-type catechins during the black tea processing. Rolling is the key procedure for forming the small molecular nonvolatile metabolite profile (SMNMetProf), increasing the metabolite richness, and then shaping the bacterial community structure in the KMBT manufacturing process, which decreases both molecular weight and molecular polarity of the small molecular nonvolatile metabolites. The SMNMetProf of black tea is formed by the endogenous enzymatic oxidation of tea leaves, rather than bacterial fermentation.PMID:38448096 | DOI:10.1016/j.foodres.2024.114094

J Zhejiang Univ Sci B. 2024 Mar 6:1-12. doi: 10.1631/jzus.B2300579. Online ahead of print.ABSTRACTPheochromocytomas and paragangliomas (PPGLs) cause symptoms by altering the circulation levels of catecholamines and peptide hormones. Currently, the diagnosis of PPGLs relies on diagnostic imaging and the detection of catecholamines. In this study, we used ultra-performance liquid chromatography (UPLC)/quadrupole time-of-flight mass spectrometry (Q-TOF MS) analysis to identify and measure the perioperative differential metabolites in the plasma of adrenal pheochromocytoma patients. We identified differentially expressed genes by comparing the transcriptomic data of pheochromocytoma with the normal adrenal medulla. Through conducting two steps of metabolomics analysis, we identified 111 differential metabolites between the healthy group and the patient group, among which 53 metabolites were validated. By integrating the information of differential metabolites and differentially expressed genes, we inferred that the cysteine-methionine, pyrimidine, and tyrosine metabolism pathways were the three main metabolic pathways altered by the neoplasm. The analysis of transcription levels revealed that the tyrosine and cysteine-methionine metabolism pathways were downregulated in pheochromocytoma, whereas the pyrimidine pathway showed no significant difference. Finally, we developed an optimized diagnostic model of two metabolites, L-dihydroorotic acid and vanylglycol. Our results for these metabolites suggest that they may serve as potential clinical biomarkers and can be used to supplement and improve the diagnosis of pheochromocytoma.PMID:38448048 | DOI:10.1631/jzus.B2300579

J Invest Dermatol. 2024 Mar 4:S0022-202X(24)00161-1. doi: 10.1016/j.jid.2024.02.005. Online ahead of print.NO ABSTRACTPMID:38447865 | DOI:10.1016/j.jid.2024.02.005

Sci Total Environ. 2024 Mar 4:171462. doi: 10.1016/j.scitotenv.2024.171462. Online ahead of print.ABSTRACTThe damage caused by petroleum hydrocarbon pollution to soil and groundwater environment is becoming increasingly significant. The vadose zone is the only way for petroleum hydrocarbon pollutants to leak from surface into groundwater. The spatial distribution characteristics of indigenous microorganisms in vadose zone, considering presence of capillary zones, have rarely been reported. To explore the spatial distribution characteristics of indigenous microorganisms in vadose zone contaminated by petroleum hydrocarbons, a one-dimensional column migration experiment was conducted using n-hexadecane as characteristic pollutant. Soil samples were collected periodically from different heights during experiment. Corresponding environmental factors were monitored online. The microbial community structure and spatial distribution characteristics of the cumulative relative abundance were systematically analyzed using 16S rRNA sequencing. In addition, the microbial degradation mechanism of n-hexadecane was analyzed using metabolomics. The results showed that presence of capillary zone had a strong retarding effect on n-hexadecane infiltration. Leaked pollutants were mainly concentrated in areas with strong capillary action. Infiltration and displacement of NAPL-phase pollutants were major driving force for change in moisture content (θ) and electric conductivity (EC) in vadose zone. The degradation by microorganisms results in a downward trend in potential of hydrogen (pH) and oxidation-reduction potential (ORP). Five petroleum hydrocarbon-degrading bacterial phyla and 11 degradable straight-chain alkane bacterial genera were detected. Microbial degradation was strong in the area near edge of capillary zone and locations of pollutant accumulation. Mainly Sphingomonas and Nocardioides bacteria were involved in microbial degradation of n-hexadecane. Single-end oxidation involved microbial degradation of n-hexadecane (C16H34). The oxygen consumed, hexadecanoic acid (C16H32O2) produced during this process, and release of hydrogen ions (H+) were the driving factors for reduction of ORP and pH. The vadose zone in this study considered presence of capillary zone, which was more in line with actual contaminated site conditions compared with previous studies. This study systematically elucidated vertical distribution characteristics of petroleum hydrocarbon pollutants and spatiotemporal variation characteristics of indigenous microorganisms in vadose zone considered presence of capillary zone. In addition, the n-hexadecane degradation mechanism was elucidated using metabolomics. This study provides theoretical support for development of natural attenuation remediation measures for petroleum-hydrocarbon-contaminated soil and groundwater.PMID:38447732 | DOI:10.1016/j.scitotenv.2024.171462

Sci Total Environ. 2024 Mar 4:171447. doi: 10.1016/j.scitotenv.2024.171447. Online ahead of print.ABSTRACTDi-(2-ethylhexyl) phthalate (DEHP) is an extensively used phthalate esters (PAEs) that raise growing ecotoxicological concerns due to detrimental effects on living organisms and ecosystems. This study performed hepatotoxic investigations on crucian carp under chronic low-dosage (CLD) exposure to DEHP at environmentally relevant concentrations (20-500 μg/L). The results demonstrated that the CLD exposure induced irreversible damage to the liver tissue. Multi-omics (transcriptomics and metabolomics) analyses revealed the predominant toxicological mechanisms underlying DEHP-induced hepatotoxicity by inhibiting energy production pathways and the up-regulation of the purine metabolism. Disruption of metabolic pathways led to excessive reactive oxygen species (ROS) production and subsequent oxidative stress. The adverse metabolic effects were exacerbated by an interplay between oxidative stress and endoplasmic reticulum stress. This study not only provides new mechanistic insights into the ecotoxicological effects of DEHP under chronic low-dosage exposure, but also suggests a potential strategy for further ecological risk assessment of PAEs.PMID:38447714 | DOI:10.1016/j.scitotenv.2024.171447

Gene. 2024 Mar 4:148313. doi: 10.1016/j.gene.2024.148313. Online ahead of print.ABSTRACTAdenosine kinase deficiency (OMIM #614300) is a type of inborn errors of metabolism with multiorgan symptoms primarily neurological disorders, hepatic impairment, global developmental delay, and mild dysmorphism. The genetic causes of adenosine kinase deficiency are homozygous or compound heterozygous loss-of-function variants of ADK. To date, fewer than 25 cases of adenosine kinase deficiency have been reported worldwide and none have been reported in China. In this research, trio whole-exome sequencing (Trio-WES) identified a novel homozygous ADK (NM_001123.4) out-of-frame deletion, c.518_519delCA (p.Thr173Serfs*15), in a Chinese patient with rare phenotypes of sepsis, metabolites disruption and neutrophil dysfunction. This variant was dysfunctional, with marked reduction of ADK level in both the patient's peripheral blood and cells transfected with the corresponding variant. Additionally, metabolomics detected by high-throughput mass spectrometry showed disturbances in the methionine (Met) and energy pathway. RNA sequencing (RNA-seq) of the patient's peripheral blood suggested a defective anti-inflammatory response characterized by impaired neutrophil activation, migration, and degranulation, which might be the primary cause for the sepsis. To our knowledge, we identified the first Chinese patient of adenosine kinase deficiency with a novel homozygous out-of-frame deletion in ADK causing multiorgan disorders, metabolites disruption, rare phenotypes of sepsis, and neutrophil dysfunction. Our findings broaden the genetic spectrum and pathogenic mechanisms of adenosine kinase deficiency.PMID:38447681 | DOI:10.1016/j.gene.2024.148313

J Ethnopharmacol. 2024 Mar 4:118009. doi: 10.1016/j.jep.2024.118009. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: According to traditional Chinese medicine (TCM) theory, cholestasis belongs to category of jaundice. Artemisia capillaris Thunb. has been widely used for the treatment of jaundice in TCM. The polysaccharides are the one of main active components of the herb, but its effects on cholestasis remain unclear.AIM OF THE STUDY: To investigate the protective effect and mechanism of Artemisia capillaris Thunb. polysaccharide (APS) on cholestasis and liver injury.MATERIALS AND METHODS: The amelioration of APS on cholestasis was evaluated in an alpha-naphthyl isothiocyanate (ANIT)-induced mice model. Then nuclear Nrf2 knockout mice, mass spectrometry, 16s rDNA sequencing, metabolomics, and molecular biotechnology methods were used to elucidate the associated mechanisms of APS against cholestatic liver injury.RESULTS: Treatment with low and high doses of APS markedly decreased cholestatic liver injury of mice. Mechanistically, APS promoted nuclear translocation of hepatic nuclear factor erythroid 2-related factor (Nrf2), upregulated downstream bile acid (BA) efflux transporters and detoxifying enzymes expression, improved BA homeostasis, and attenuated oxidative liver injury; however, these effects were annulled in Nrf2 knock-out mice. Furthermore, APS ameliorated the microbiota dysbiosis of cholestatic mice and selectively increased short-chain fatty acid (SCFA)-producing bacteria growth. Fecal microbiota transplantation of APS also promoted hepatic Nrf2 activation, increased BA efflux transporters and detoxifying enzymes expression, ameliorated intrahepatic BA accumulation and cholestatic liver injury. Non-targeted metabolomics and in vitro microbiota culture confirmed that APS significantly increased the production of a microbiota-derived SCFA (butyric acid), which is also able to upregulate Nrf2 expression.CONCLUSIONS: These findings indicate that APS can ameliorate cholestasis by modulating gut microbiota and activating the Nrf2 pathway, representing a novel therapeutic approach for cholestatic liver disease.PMID:38447617 | DOI:10.1016/j.jep.2024.118009

Talanta. 2024 Feb 22;272:125801. doi: 10.1016/j.talanta.2024.125801. Online ahead of print.ABSTRACTThe objective of this study is to evaluate the influence of mixed L. acidophilus LA-5 and enrichment with microalgae (C. vulgaris and A. platensis) on metabolomic formation in a brined cheese matrix. Microbiological, compositional, and metabolomic characterization were investigated during the ripening. It was found that the nutritional quality indices of the samples were based on amino acid and fatty acid characterization. Fifty-six metabolomics including fatty acids, amino acids, organic acids, minerals, and vitamins were detected using the HPLC-DAD, GC-MS, and ICP-OES-based methods. The results indicated that the enrichment with probiotic strain and microalgae led to an increase in the nutritional quality indices such as EAAI, NI, BV, MUFA/SFA, h/H, and DFA. The chemometric analysis (e.g. HCA and PCA) presented the variance between the cheese samples based on their attributes. The identification of cheese metabolomics throughout the ripening could be used for a better understanding of the functional ingredients-cheese matrix relationships and as a directive approach for novel dairy products in other metabolomic-related studies.PMID:38447466 | DOI:10.1016/j.talanta.2024.125801

Phytomedicine. 2024 Feb 19;127:155467. doi: 10.1016/j.phymed.2024.155467. Online ahead of print.ABSTRACTThe death and disability caused by myocardial infarction is a health problem that needs to be addressed worldwide, and poor cardiac repair and fibrosis after myocardial infarction seriously affect patient recovery. Postmyocardial infarction repair by M2 macrophages is of great significance for ventricular remodeling. Quercitrin (Que) is a common flavonoid in fruits and vegetables that has antioxidant, anti-inflammatory, antitumor and other effects, but whether it has a role in the treatment of myocardial infarction is unclear. In this study, we constructed a mouse myocardial infarction model and administered Que. We found through cardiac ultrasound that Que administration improved cardiac ejection fraction and reduced ventricular remodeling. Staining of heart sections and detection of fibrosis marker protein levels revealed that Que administration slowed fibrosis after myocardial infarction. Flow cytometry showed that the proportion of M2 macrophages in the mouse heart was increased and that the expression levels of M2 macrophage markers were increased in the Que-treated group. Finally, we identified by metabolomics that Que reduces glycolysis, increases aerobic phosphorylation, and alters arginine metabolic pathways, polarizing macrophages toward the M2 phenotype. Our research lays the foundation for the future application of Que in myocardial infarction and other cardiovascular diseases.PMID:38447360 | DOI:10.1016/j.phymed.2024.155467

J Chromatogr B Analyt Technol Biomed Life Sci. 2024 Mar 1;1236:124063. doi: 10.1016/j.jchromb.2024.124063. Online ahead of print.ABSTRACTHigh blood pressure is a serious human health problem and one of the leading risk factors for fatal complications in cardiovascular disease. The ZXT granules were prepared based on the Zhengan-Xifeng-Tang (ZXT) decoction. However, the therapeutic effects of ZXT granules on spontaneous hypertension and the metabolic pathways in which they may intervene are unclear. The aim of this study was to investigate the antihypertensive effect of ZXT granules on spontaneously hypertensive rats (SHR) and to analyze the metabolic pathway of intervention through chemical composition characterization, pharmacodynamics, and serum metabolomics analysis. After eight weeks of administration, serum and aortic arch samples were collected for biochemical, histopathology and serum metabolomics analysis to assess the effect of ZXT granules on SHR. The results showed that ZXT granules reduced aortic arch injury and blood pressure in SHR rats. Serum data from rats in each group was collected using LC-MS and 74 potential biomarkers were identified that showed significant differences between the model and control groups. Of these, 18 potential biomarkers were found to be deregulated after intervention with ZXT granules. These 18 potential differential metabolic markers are primarily involved in bile acid biosynthesis, arachidonic acid metabolism pathway, and fatty acid degradation. The results demonstrated that ZXT granules significantly affected blood lipids, aortic arch, and metabolic disorders in SHR rats. ZXT granules offer a new possibility for effective and convenient treatment of hypertensive patients.PMID:38447242 | DOI:10.1016/j.jchromb.2024.124063

BMC Genomics. 2024 Mar 6;25(1):254. doi: 10.1186/s12864-024-10118-3.ABSTRACTBACKGROUND: Neddylation, an important post-translational modification (PTM) of proteins, plays a crucial role in follicular development. MLN4924 is a small-molecule inhibitor of the neddylation-activating enzyme (NAE) that regulates various biological processes. However, the regulatory mechanisms of neddylation in rabbit ovarian cells have not been emphasized. Here, the transcriptome and metabolome profiles in granulosa cells (GCs) treated with MLN4924 were utilized to identify differentially expressed genes, followed by pathway analysis to precisely define the altered metabolisms.RESULTS: The results showed that 563 upregulated and 910 downregulated differentially expressed genes (DEGs) were mainly enriched in pathways related to cancer, cell cycle, PI3K-AKT, progesterone-mediated oocyte maturation, and PPAR signaling pathway. Furthermore, we characterized that MLN4924 inhibits PPAR-mediated lipid metabolism, and disrupts the cell cycle by promoting the apoptosis and proliferation of GCs. Importantly, we found the reduction of several metabolites in the MLN4924 treated GCs, including glycerophosphocholine, arachidic acid, and palmitic acid, which was consistent with the deregulation of PPAR signaling pathways. Furthermore, the increased metabolites included 6-Deoxy-6-sulfo-D-glucono-1,5-lactone and N-Acetyl-D-glucosaminyldiphosphodolichol. Combined with transcriptome data analyses, we identified genes that strongly correlate with metabolic dysregulation, particularly those related to glucose and lipid metabolism. Therefore, neddylation inhibition may disrupt the energy metabolism of GCs.CONCLUSIONS: These results provide a foundation for in-depth research into the role and molecular mechanism of neddylation in ovary development.PMID:38448814 | DOI:10.1186/s12864-024-10118-3

Nat Med. 2024 Mar 6. doi: 10.1038/s41591-024-02899-7. Online ahead of print.NO ABSTRACTPMID:38448791 | DOI:10.1038/s41591-024-02899-7

Nat Metab. 2024 Mar 6. doi: 10.1038/s42255-024-01005-y. Online ahead of print.ABSTRACTThe post-translational modification lysine succinylation is implicated in the regulation of various metabolic pathways. However, its biological relevance remains uncertain due to methodological difficulties in determining high-impact succinylation sites. Here, using stable isotope labelling and data-independent acquisition mass spectrometry, we quantified lysine succinylation stoichiometries in mouse livers. Despite the low overall stoichiometry of lysine succinylation, several high-stoichiometry sites were identified, especially upon deletion of the desuccinylase SIRT5. In particular, multiple high-stoichiometry lysine sites identified in argininosuccinate synthase (ASS1), a key enzyme in the urea cycle, are regulated by SIRT5. Mutation of the high-stoichiometry lysine in ASS1 to succinyl-mimetic glutamic acid significantly decreased its enzymatic activity. Metabolomics profiling confirms that SIRT5 deficiency decreases urea cycle activity in liver. Importantly, SIRT5 deficiency compromises ammonia tolerance, which can be reversed by the overexpression of wild-type, but not succinyl-mimetic, ASS1. Therefore, lysine succinylation is functionally important in ammonia metabolism.PMID:38448615 | DOI:10.1038/s42255-024-01005-y

Nature. 2024 Mar 6. doi: 10.1038/s41586-024-07148-y. Online ahead of print.ABSTRACTGenome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1-7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8-11. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases.PMID:38448586 | DOI:10.1038/s41586-024-07148-y