PubMed

Fitoterapia. 2023 Sep 4:105667. doi: 10.1016/j.fitote.2023.105667. Online ahead of print.ABSTRACTEucommia ulmoides Oliv. is a deciduous tree which contains various chemical ingredients. The main objective was to document the active chemical ingredients of Eucommia ulmoides Oliv. and their metabolic profiles in vivo, with a view to providing an experimental and theoretical basis for clarifying the mechanisms underlying the pharmacological activity of Eucommia ulmoides Oliv. against rheumatoid arthritis. Eight main active constituents of Eucommia ulmoides Oliv. bark (pinoresinol glucopyranoside, aucubin, geniposidic acid, geniposide, genipin, chlorogenic acid, quercetin and betulinic acid) were quantified using high-performance liquid chromatography (HPLC). This paper additionally identified and characterized prototype metabolites via ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) combined with the Human Metabolome Database (HMDB) and literature comparisons. Ultra pressure liquid chromatography-mass spectrometry/ mass spectrometry (UPLC-MS/MS) was subsequently employed to quantify these components in blood over time and evaluate their pharmacokinetic characteristics. The anti-rheumatoid arthritis effects of genipin, pinoresinol glucopyranoside and their combinations were assessed using in vitro cellular assays. We identified and characterized a total of 53 ingredients from Eucommia ulmoides Oliv. bark and plasma samples, among which 20 were confirmed as prototype metabolites. Meanwhile, this paper derived and analyzed the metabolic cleavage pathway of 8 index ingredients. Six of these compounds displayed rapid entry into blood, with high plasma exposure and fast elimination rates. Data from the in vitro cellular assay showed that aucubin, pinoresinol glucopyranoside, genipin, and combinations of these compounds effectively inhibit MH7A cell proliferation, reduce NO release, and decrease inflammatory factor levels.PMID:37673275 | DOI:10.1016/j.fitote.2023.105667

Sci Total Environ. 2023 Sep 4:166830. doi: 10.1016/j.scitotenv.2023.166830. Online ahead of print.ABSTRACTMicrocystin-LR (MC-LR) produced by cyanobacteria blooms poses a serious risk to aquatic organisms. Rice straw-derived biochar (BC) is gradually being utilized as an effective adsorbent to remove water pollutants. In the present study, the combined toxicity of MC-LR and BC on hepatic antioxidant capacity and metabolic phenotype of zebrafish (Danio rerio) were conducted due to the increasing concern of eutrophication in aquatic environments. Female zebrafish were exposed to solutions of MC-LR (10 μg/L) and BC (100 μg/L) individually and in combination for 30 days. The results indicated that sub-chronic MC-LR exposure induced oxidative stress and metabolic disorders, with a significant elevation of several amino acids, glucose as well as unsaturated fatty acids. Metabolic pathway analysis showed that the ascorbate and aldarate metabolism and biosynthesis of unsaturated fatty acids were affected under MC-LR stress. Significantly increased MDA levels along with significantly decreased CAT and GPx activities were observed in the MC-LR group. Nevertheless, MDA levels, antioxidant enzyme activities, and the relevant gene expressions (cat1, nrf2a, HO-1, keap1a) returned to baseline in the co-exposure group. These findings revealed that MC-LR resulted in metabolic disorders of protein, sugar, and lipid related to energy production, and BC could relieve MC-LR-induced metabolic disorder and oxidative stress in the liver of zebrafish. However, the potential risk of BC-induced metabolic disorder should not be neglected. Our present results highlight the potential of BC as a tool for mitigating the negative impacts of MC-LR on aquatic organisms in blooms-contaminated water.PMID:37673272 | DOI:10.1016/j.scitotenv.2023.166830

Sci Total Environ. 2023 Sep 4:166833. doi: 10.1016/j.scitotenv.2023.166833. Online ahead of print.ABSTRACTPerfluorohexanesulfonic acid (PFHxS) is a short-chain perfluoroalkyl substance widely used to replace the banned perfluorooctanesulfonic acid (PFOS) in various industrial and household products. It can be found in the environment and human bodies; however, its potential toxicities are not well studied. Zebrafish have been extensively used as a model for studying toxicants, and currently, two studies have reported on the toxicity of PFHxS in zebrafish from different approaches. Ulhaq and Tse (J Hazard Mater. 2023; 457: 131722) conducted general biological experiments and applied transcriptomics to demonstrate that PFHxS at a concentration of 5 μM could affect glucose and fatty acid metabolism, leading to oxidative stress, developmental defects, and cell cycle arrest. Xu et al. (Sci Total Environ. 2023; 887: 163770) employed metabolomics and showed that concentrations of various metabolites changed after exposure to 3 and 10 μM PFHxS. As we observed a match between the metabolomics data and our biochemistry experimental findings, we integrated the two studies, which enabled us to unfold the possible mechanism of the deregulated metabolites. We identified 22 differential expressed genes (DEGs) in the tricarboxylic acid (TCA) cycle, 17 DEGs in glcyolytic process, including the critical glucokinase under the carbon metabolism. Besides, genes likes aldehyde dehydrogenases, and histone-lysine N-methyltransferases that participate in lipid peroxidation and amino metabolism respectively were spotted. Lastly, we further strengthen our discoveries by undergoing the gene set enrichment analysis. This article could provide insights into the toxicity of PFHxS, as well as prospects for environmental studies.PMID:37673246 | DOI:10.1016/j.scitotenv.2023.166833

Plant Sci. 2023 Sep 4:111858. doi: 10.1016/j.plantsci.2023.111858. Online ahead of print.ABSTRACTThe Sirex noctilio's climatic adaption and rapid proliferation have caused Pinus mortality worldwide. The infestation combines the early effect of female S. noctilio gland secretion and the spreading symbiotic fungus Amylostereum areolatum. 'Lipidomics' is the study of all non-water-soluble components of the metabolome. Most of these non-water-soluble compounds correspond to lipids which can provide information about a biological activity, an organelle, an organism, or a disease. Using HPLC-MS/MS based lipidomics, 122 lipids were identified in P. radiata needles during S. noctilio infestation. Phosphatidic acids, N-acylethanolamines, and phosphatidylinositol-ceramides accumulated in infested trees could suggest a high level of phospholipases activities. The phosphatidylcholines were the most down-regulated species during infection, which could also suggest that they may be used as a substrate for up-regulated lipids. The accumulation of very long-chain fatty acids and long-chain fatty acids during the infestation could imply the tree defence response to create a barrier in the drilled zone to avoid larvae development and fungus proliferation. Also, the growth arrest phase of the trees during the prolonged infestation suggests a resistance response, regulated by the accumulation of NAE, which potentially shifts the tree energy to respond to the infestation.PMID:37673219 | DOI:10.1016/j.plantsci.2023.111858

Int J Biol Macromol. 2023 Sep 4:126702. doi: 10.1016/j.ijbiomac.2023.126702. Online ahead of print.ABSTRACTβ-Carotene functions in plant growth and development and plays an important role in resisting abiotic stress, such as drought and salt stress. The specific function and mechanism by which β-carotene responds to waterlogging stress, however, remain elusive. In this study, we found that β-carotene content and lycopene cyclase (TgLCYB1) expression, both in leaves and roots of Torreya grandis, were increased under waterlogging treatment. Subcellular localization assays indicated that TgLCYB1 was localized in the chloroplasts. Phenotypic, physiological, and metabolome analysis showed that overexpression of TgLCYB1 enhanced the tolerance of tomato plants to waterlogging stress. Furthermore, application of a LCYB enzyme inhibitor, 2-(4-chlorophenylthio)-triethylamine hydrochloride, markedly enhanced the sensitivity of T. grandis to waterlogging stress. In addition, yeast one-hybrid assay, the dual luciferase assay system, and real-time quantitative PCR indicated that waterlogging stress induced TgWRKY22 to increase TgLCYB1 expression by binding to the TgLCYB1 promoter. Collectively, our results indicated that TgWRKY22 positively regulated TgLCYB1 expression to improve the activities of antioxidant enzyme and increase the levels of some key metabolites, thereby relieving waterlogging-induced oxidative damage, and consequently modulating the waterlogging stress response. This study contributes to a more comprehensive understanding of carotenoid functions and the role LCYB genes play in plant stress response.PMID:37673161 | DOI:10.1016/j.ijbiomac.2023.126702

Cell Metab. 2023 Sep 5;35(9):1530-1547.e8. doi: 10.1016/j.cmet.2023.08.002.ABSTRACTNon-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic dysfunction for which effective interventions are lacking. To investigate the effects of resistant starch (RS) as a microbiota-directed dietary supplement for NAFLD treatment, we coupled a 4-month randomized placebo-controlled clinical trial in individuals with NAFLD (ChiCTR-IOR-15007519) with metagenomics and metabolomics analysis. Relative to the control (n = 97), the RS intervention (n = 99) resulted in a 9.08% absolute reduction of intrahepatic triglyceride content (IHTC), which was 5.89% after adjusting for weight loss. Serum branched-chain amino acids (BCAAs) and gut microbial species, in particular Bacteroides stercoris, significantly correlated with IHTC and liver enzymes and were reduced by RS. Multi-omics integrative analyses revealed the interplay among gut microbiota changes, BCAA availability, and hepatic steatosis, with causality supported by fecal microbiota transplantation and monocolonization in mice. Thus, RS dietary supplementation might be a strategy for managing NAFLD by altering gut microbiota composition and functionality.PMID:37673036 | DOI:10.1016/j.cmet.2023.08.002

J Hazard Mater. 2023 Sep 1;460:132305. doi: 10.1016/j.jhazmat.2023.132305. Online ahead of print.ABSTRACTMicroplastics (MPs) pose a significant environmental concern, particularly for terrestrial fauna. In this study, earthworms were used as a model organism to investigate the ecotoxicological effects of short-term exposure to virgin MPs on changes in metabolome and gut microbiota. High-throughput untargeted metabolomics showed significant internal reactions in the earthworms' metabolic processes due to MPs exposure, even when no visible stress signs, such as changes in growth or mortality rates, were present. Earthworms exposed to different concentrations of polyethylene (PE) MP exhibited significant disruption in 39 and 199 molecular features related to energy and lipid metabolism, anti-inflammatory, cell signaling, and membrane integrity. The activities of enzymes and transport proteins in earthworms were dysregulated when exposed to PE. Changes in the gut microbiota's community structure and complexity were observed in response to PE MPs exposure. Despite the relative stability in alpha-diversity and relative abundance, shifts in beta-diversity and network analysis in the PE-exposed group were indicative of an adaptive response to MPs. Earthworms exhibited resilience or adaptation in response to MPs exposure, potentially maintaining their functionality. This study provides preliminary insights into the impact of MPs on soil invertebrates like earthworms and highlights the need for further exploration of long-term effects and underlying molecular mechanisms.PMID:37672993 | DOI:10.1016/j.jhazmat.2023.132305

Ecotoxicol Environ Saf. 2023 Sep 4;264:115442. doi: 10.1016/j.ecoenv.2023.115442. Online ahead of print.ABSTRACTPolyamines (PAs) are small aliphatic nitrogenous bases with strong biological activity that participate in plant stress response signaling and the alleviation of damage from stress. Herein, the effects of the PA-producing bacterium Bacillus megaterium N3 and PAs on the immobilization of Cd and inhibition of Cd absorption by spinach and the underlying mechanisms were studied. A solution test showed that strain N3 secreted spermine and spermidine in the presence of Cd. Both strain N3 and the PAs (spermine+spermidine) immobilized Cd and increased the pH of the solution. Untargeted metabolomics results showed that strain N3 secreted PAs, N1-acetylspermidine, 3-indolepropionic acid, indole-3-acetaldehyde, cysteinyl-gamma-glutamate, and choline, which correlated with plant growth promotion and Cd immobilization. A pot experiment showed that rhizosphere soil inoculation with strain N3 and PAs improved spinach dry weight and reduced spinach Cd absorption compared with the control. These positive effects were likely due to the increase in rhizosphere soil pH and NH4+-N and PA contents, which can be attributed primarily to Cd immobilization. Moreover, inoculation with strain N3 more effectively inhibited the absorption of Cd by spinach than spraying PAs, mainly because strain N3 enabled a better relative abundance of bacteria (Microvirga, Pedobacter, Bacillus, Brevundimonas, Pseudomonas, Serratia, Devosid, and Aminobacter), that have been reported to have the ability to resist heavy metals and produce PAs. Strain N3 regulated the structure of rhizosphere functional bacterial communities and inhibited Cd uptake by spinach. These results provide a theoretical basis for the prevention of heavy metal absorption by vegetables using PA-producing bacteria.PMID:37672938 | DOI:10.1016/j.ecoenv.2023.115442

Acta Pharmacol Sin. 2023 Sep 6. doi: 10.1038/s41401-023-01147-x. Online ahead of print.ABSTRACTGut microbiota disturbance and systemic inflammation have been implicated in the degeneration of dopaminergic neurons in Parkinson's disease (PD). How the alteration of gut microbiota results in neuropathological events in PD remains elusive. In this study, we explored whether and how environmental insults caused early neuropathological events in the substantia nigra (SN) of a PD mouse model. Aged (12-month-old) mice were orally administered rotenone (6.25 mg·kg-1·d-1) 5 days per week for 2 months. We demonstrated that oral administration of rotenone to ageing mice was sufficient to establish a PD mouse model and that microglial activation and iron deposition selectively appeared in the SN of the mice prior to loss of motor coordination and dopaminergic neurons, and these events could be fully blocked by microglial elimination with a PLX5622-formulated diet. 16 S rDNA sequencing analysis showed that the gut microbiota in rotenone-treated mice was altered, and mice receiving faecal microbial transplantation (FMT) from ageing mice treated with rotenone for 2 months exhibited the same pathology in the SN. We demonstrated that C-X-C motif chemokine ligand-1 (CXCL1) was an essential molecule, as intravenous injection of CXCL1 mimicked almost all the pathology in serum and SN induced by oral rotenone and FMT. Using metabolomics and transcriptomics analyses, we identified the PPAR pathway as a key pathway involved in rotenone-induced neuronal damage. Inhibition of the PPARγ pathway was consistent in the above models, whereas its activation by linoleic acid (60 mg·kg-1·d-1, i.g. for 1 week) could block these pathological events in mice intravenously injected with CXCL1. Altogether, these results reveal that the altered gut microbiota resulted in neuroinflammation and iron deposition occurring early in the SN of ageing mice with oral administration of rotenone, much earlier than motor symptoms and dopaminergic neuron loss. We found that CXCL1 plays a crucial role in this process, possibly via PPARγ signalling inhibition. This study may pave the way for understanding the "brain-gut-microbiota" molecular regulatory networks in PD pathogenesis. The aged C57BL/6 male mice with rotenone intragastric administration showed altered gut microbiota, which caused systemic inflammation, PPARγ signalling inhibition and neuroinflammation, brain iron deposition and ferroptosis, and eventually dopaminergic neurodegeneration in PD.PMID:37674043 | DOI:10.1038/s41401-023-01147-x

Nat Commun. 2023 Sep 6;14(1):5471. doi: 10.1038/s41467-023-41283-w.ABSTRACTGut dysbiosis contributes to Alzheimer's disease (AD) pathogenesis, and Bacteroides strains are selectively elevated in AD gut microbiota. However, it remains unknown which Bacteroides species and how their metabolites trigger AD pathologies. Here we show that Bacteroides fragilis and their metabolites 12-hydroxy-heptadecatrienoic acid (12-HHTrE) and Prostaglandin E2 (PGE2) activate microglia and induce AD pathogenesis in neuronal C/EBPβ transgenic mice. Recolonization of antibiotics cocktail-pretreated Thy1-C/EBPβ transgenic mice with AD patient fecal samples elicits AD pathologies, associated with C/EBPβ/Asparaginyl endopeptidase (AEP) pathway upregulation, microglia activation, and cognitive disorders compared to mice receiving healthy donors' fecal microbiota transplantation (FMT). Microbial 16S rRNA sequencing analysis shows higher abundance of proinflammatory Bacteroides fragilis in AD-FMT mice. Active components characterization from the sera and brains of the transplanted mice revealed that both 12-HHTrE and PGE2 activate primary microglia, fitting with poly-unsaturated fatty acid (PUFA) metabolites enrichment identified by metabolomics. Strikingly, recolonization with live but not dead Bacteroides fragilis elicited AD pathologies in Thy1-C/EBPβ transgenic mice, so did 12-HHTrE or PGE2 treatment alone. Collectively, our findings support a causal role for Bacteroides fragilis and the PUFA metabolites in activating microglia and inducing AD pathologies in Thy1- C/EBPβ transgenic mice.PMID:37673907 | DOI:10.1038/s41467-023-41283-w

Nat Commun. 2023 Sep 6;14(1):5195. doi: 10.1038/s41467-023-40798-6.ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy in need of new therapeutic options. Using unbiased analyses of super-enhancers (SEs) as sentinels of core genes involved in cell-specific function, here we uncover a druggable SE-mediated RNA-binding protein (RBP) cascade that supports PDAC growth through enhanced mRNA translation. This cascade is driven by a SE associated with the RBP heterogeneous nuclear ribonucleoprotein F, which stabilizes protein arginine methyltransferase 1 (PRMT1) to, in turn, control the translational mediator ubiquitin-associated protein 2-like. All three of these genes and the regulatory SE are essential for PDAC growth and coordinately regulated by the Myc oncogene. In line with this, modulation of the RBP network by PRMT1 inhibition reveals a unique vulnerability in Myc-high PDAC patient organoids and markedly reduces tumor growth in male mice. Our study highlights a functional link between epigenetic regulation and mRNA translation and identifies components that comprise unexpected therapeutic targets for PDAC.PMID:37673892 | DOI:10.1038/s41467-023-40798-6

Cell Death Discov. 2023 Sep 6;9(1):335. doi: 10.1038/s41420-023-01633-5.ABSTRACTAllicin exhibits various pharmacological activities and has been suggested to be beneficial in the treatment of stroke. However, the underlying mechanisms are largely unknown. Here, we confirmed that allicin protected the brain from cerebral injury, which could be ascribed to its anti‑apoptotic and anti‑inflammatory effects, as well as the regulation of lipid metabolism, using proteomics and metabolomics analysis. Our results suggested that allicin could significantly ameliorate behavioral characteristics, cerebral infarct area, cell apoptosis, inflammatory factors, and lipid metabolic-related factors (arachidonic acid, 15-hydroperoxy-eicosatetraenoic acid (15S-HPETE), palmitoylcarnitine, and acylcarnitine) by recalibrating astrocyte homeostasis in mice with photothrombotic stroke (PT). In astrocytes, allicin significantly increased glutathione peroxidase 1 (GPX1) levels and inhibited the arachidonic acid-related pathway, which was also observed in the brains of mice with PT. Allicin was proven to inhibit hypoxia-induced astrocyte apoptosis by increasing GPX1 expression, activating proto-oncogene tyrosine-protein kinase Src (Src)- protein kinase B (AKT)-extracellular signal-regulated kinase (ERK) phosphorylation, and decreasing lipid peroxidation. Thus, we concluded that allicin significantly prevented and ameliorated ischemic stroke by increasing GPX1 levels to complete the complex physiological process.PMID:37673878 | DOI:10.1038/s41420-023-01633-5

Mol Nutr Food Res. 2023 Sep 6:e2300052. doi: 10.1002/mnfr.202300052. Online ahead of print.ABSTRACTSCOPE: Although many beneficial health effects are attributed to polyphenols their influence on the human metabolome has not been elucidated yet. The ubiquitous occurrence of polyphenols in the human diet demands comprehensive knowledge about physiological and toxicological effects of these compounds on human cells.METHODS AND RESULTS: The human hepatocarcinogenic cell line HepG2 is used to elucidate the effects of 13 polyphenols and three respective phenolic degradation products on the human metabolome using HPLC-MS/MS. To investigate structure-activity-relationships, structurally related examples of polyphenols from different compound classes are selected. The analysis of catechins points toward a relation between the degree of hydroxylation and the extent of metabolic effects particularly on the urea cycle and the pentose phosphate pathway (PPP). A correlation between the modulation of the PPP and the stability of the compounds is demonstrated, which may be caused by reactive oxygen species (ROS). The incubation of flavones and alkenylbenzenes demonstrates reduced activity of methoxylated compounds and no impact of the B-ring position.CONCLUSION: In general, polyphenols induce a multitude of metabolic effects, for example, on energy metabolism, PPP, and urea cycle. These metabolic alterations may be related to the widely reported bioactivity of these compounds such as the anticarcinogenic effects.PMID:37672806 | DOI:10.1002/mnfr.202300052

J Nat Prod. 2023 Sep 6. doi: 10.1021/acs.jnatprod.3c00310. Online ahead of print.ABSTRACTThe integration of NMR-metabolomic and genomic analyses can provide enhanced identification of structural properties as well as key biosynthetic information, thus achieving the targeted discovery of new natural products. For this purpose, NMR-based metabolomic profiling of the marine-derived Streptomyces sp. S063 (CGMCC 14582) was performed, by which N-methylated peptides possessing unusual negative 1H NMR chemical shift values were tracked. Meanwhile, genome mining of this strain revealed the presence of an unknown NRPS gene cluster (len) with piperazic-acid-encoding genes (lenE and lenF). Under the guidance of the combined information, two cyclic decapeptides, lenziamides D1 (1) and B1 (2), were isolated from Streptomyces sp. S063, which contains piperazic acids with negative 1H NMR values. The structures of 1 and 2 were determined by extensive spectroscopic analysis combined with Marfey's method and ECD calculations. Furthermore, we provided a detailed model of lenziamide (1 and 2) biosynthesis in Streptomyces sp. S063. In the cytotoxicity evaluation, 1 and 2 showed moderate growth inhibition against the human cancer cells HEL, H1975, H1299, and drug-resistant A549-taxol with IC50 values of 8-24 μM.PMID:37672645 | DOI:10.1021/acs.jnatprod.3c00310

Sci Adv. 2023 Sep 8;9(36):eadh2023. doi: 10.1126/sciadv.adh2023. Epub 2023 Sep 6.ABSTRACTPrevious studies have revealed a role for proline metabolism in supporting cancer development and metastasis. In this study, we show that many cancer cells respond to loss of attachment by accumulating and secreting proline. Detached cells display reduced proliferation accompanied by a general decrease in overall protein production and de novo amino acid synthesis compared to attached cells. However, proline synthesis was maintained under detached conditions. Furthermore, while overall proline incorporation into proteins was lower in detached cells compared to other amino acids, there was an increased production of the proline-rich protein collagen. The increased excretion of proline from detached cells was also shown to be used by macrophages, an abundant and important component of the tumor microenvironment. Our study suggests that detachment induced accumulation and secretion of proline may contribute to tumor progression by supporting increased production of extracellular matrix and providing proline to surrounding stromal cells.PMID:37672588 | DOI:10.1126/sciadv.adh2023

J Mol Med (Berl). 2023 Sep 6. doi: 10.1007/s00109-023-02362-z. Online ahead of print.ABSTRACTInvestigating the cross talk of different omics layers is crucial to understand molecular pathomechanisms of metabolic diseases like obesity. Here, we present a large-scale association meta-analysis of genome-wide whole blood and peripheral blood mononuclear cell (PBMC) gene expressions profiled with Illumina HT12v4 microarrays and metabolite measurements from dried blood spots (DBS) characterized by targeted liquid chromatography tandem mass spectrometry (LC-MS/MS) in three large German cohort studies with up to 7706 samples. We found 37,295 associations comprising 72 amino acids (AA) and acylcarnitine (AC) metabolites (including ratios) and 8579 transcripts. We applied this catalogue of associations to investigate the impact of associating transcript-metabolite pairs on body mass index (BMI) as an example metabolic trait. This is achieved by conducting a comprehensive mediation analysis considering metabolites as mediators of gene expression effects and vice versa. We discovered large mediation networks comprising 27,023 potential mediation effects within 20,507 transcript-metabolite pairs. Resulting networks of highly connected (hub) transcripts and metabolites were leveraged to gain mechanistic insights into metabolic signaling pathways. In conclusion, here, we present the largest available multi-omics integration of genome-wide transcriptome data and metabolite data of amino acid and fatty acid metabolism and further leverage these findings to characterize potential mediation effects towards BMI proposing candidate mechanisms of obesity and related metabolic diseases. KEY MESSAGES: Thousands of associations of 72 amino acid and acylcarnitine metabolites and 8579 genes expand the knowledge of metabolome-transcriptome associations. A mediation analysis of effects on body mass index revealed large mediation networks of thousands of obesity-related gene-metabolite pairs. Highly connected, potentially mediating hub genes and metabolites enabled insight into obesity and related metabolic disease pathomechanisms.PMID:37672078 | DOI:10.1007/s00109-023-02362-z

Expert Rev Mol Diagn. 2023 Sep 6:1-12. doi: 10.1080/14737159.2023.2254884. Online ahead of print.ABSTRACTBACKGROUND: Aberrant methylation and metabolic perturbations may deepen our understanding of hepatocarcinogenesis and help identify novel biomarkers for diagnosing hepatocellular carcinoma (HCC). We aimed to develop an HCC model based on a multi-omics.RESEARCH DESIGN AND METHODS: Four hundred patient samples (200 with HCC and 200 with hepatitis B virus-related liver disease (HBVLD)) were subjected to liquid chromatography-mass spectrometry and multiplex bisulfite sequencing. Integrative analysis of clinical data, CpG data, and metabolome for the 20 complete imputation datasets within a for-loopwas used to identify biomarker.RESULTS: Totally, 1,140 metabolites were annotated, of which 125 were differentially expressed. Lipid metabolism reprogramming in HCC, resulting in phosphatidylcholines (PC) significantly downregulated, partly due to the altered mitochondrial beta-oxidation of fatty acids with diverse chain lengths. Age, sex, serum-fetoprotein levels, cg05166871,cg14171514, cg18772205, PC (O-16:0/20:3(8Z, 11Z, 14Z)), and PC (16:1(9Z)/P-18:0) were used to develop the HCC model. The model presented a good diagnostic and an acceptable predictive performance. The cumulative incidence of HCC in low- and high-risk groups of HBVLD patients were 1.19% and 21.40%, respectively (p = 0.0039).CONCLUSIONS: PCs serve as potential plasma biomarkers and help identify patients with HBVLD at risk of HCC who should be screened for early diagnosis and intervention.PMID:37672012 | DOI:10.1080/14737159.2023.2254884

Gut Microbes. 2023 Dec;15(2):2252764. doi: 10.1080/19490976.2023.2252764.ABSTRACTThe microbiome-gut-brain axis plays a crucial role in many neurological diseases, including mild cognitive impairment. Sleep deprivation (SD) induces cognitive decline accompanied by alterations in the gut microbiota. However, the role of gut microbiota alterations in SD-induced cognitive dysfunction and the underlying mechanisms remain unclear. Here, we found that dysbiosis of the gut microbiota following pretreatment with broad-spectrum antibiotics worsens SD-induced cognitive impairment in mice. Fecal microbiota transplantation from SD mice to healthy mice induced cognitive impairment. Additionally, the abundance of Akkermansia muciniphila (A. muciniphila) in the mouse gut microbiota was significantly reduced after 7 days of SD. A. muciniphila pretreatment alleviated cognitive dysfunction and prevented synaptic reduction in the hippocampus in SD mice. A. muciniphila pretreatment inhibited extensive microglial activation and synaptic engulfment in the hippocampus of SD mice. Metabolomics analysis revealed that A. muciniphila pretreatment increased the serum acetate and butanoic acid levels in SD mice. Finally, pretreatment with short-chain fatty acids (SCFAs) inhibited microglial synaptic engulfment and prevented neuronal synaptic loss in SD mice and primary microglia-neuron co-culture following LPS stimulation. Together, our findings illustrate that gut dysbiosis plays an essential role in SD-induced cognitive impairment by activating microglial engulfment at synapses. A. muciniphila supplementation may be a novel preventative strategy for SD-induced cognitive dysfunction, by increasing SCFAs production and maintaining microglial homeostasis.PMID:37671803 | DOI:10.1080/19490976.2023.2252764

Hum Reprod. 2023 Sep 6:dead177. doi: 10.1093/humrep/dead177. Online ahead of print.ABSTRACTSTUDY QUESTION: Are human ovarian aging and the age-related female fertility decline caused by oxidative stress and mitochondrial dysfunction in oocytes?SUMMARY ANSWER: We found oxidative damage in oocytes of advanced maternal age, even at the primordial follicle stage, and confirmed mitochondrial dysfunction in such oocytes, which likely resulted in the use of alternative energy sources.WHAT IS KNOWN ALREADY: Signs of reactive oxygen species-induced damage and mitochondrial dysfunction have been observed in maturing follicles, and even in early stages of embryogenesis. However, although recent evidence indicates that also primordial follicles have metabolically active mitochondria, it is still often assumed that these follicles avoid oxidative phosphorylation to prevent oxidative damage in dictyate arrested oocytes. Data on the influence of ovarian aging on oocyte metabolism and mitochondrial function are still limited.STUDY DESIGN, SIZE, DURATION: A set of 39 formalin-fixed and paraffin-embedded ovarian tissue biopsies were divided into different age groups and used for immunofluorescence analysis of oxidative phosphorylation activity and oxidative damage to proteins, lipids, and DNA. Additionally, 150 immature oocytes (90 germinal vesicle oocytes and 60 metaphase I oocytes) and 15 cumulus cell samples were divided into different age groups and used for targeted metabolomics and lipidomics analysis.PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovarian tissues used for immunofluorescence microscopy were collected through PALGA, the nationwide network, and registry of histo- and cytopathology in The Netherlands. Comprehensive metabolomics and lipidomics were performed by liquid-liquid extraction and full-scan mass spectrometry, using oocytes and cumulus cells of women undergoing ICSI treatment based on male or tubal factor infertility, or fertility preservation for non-medical reasons.MAIN RESULTS AND THE ROLE OF CHANCE: Immunofluorescence imaging on human ovarian tissue indicated oxidative damage by protein and lipid (per)oxidation already at the primordial follicle stage. Metabolomics and lipidomics analysis of oocytes and cumulus cells in advanced maternal-age groups demonstrated a shift in the glutathione-to-oxiglutathione ratio and depletion of phospholipids. Age-related changes in polar metabolites suggested a decrease in mitochondrial function, as demonstrated by NAD+, purine, and pyrimidine depletion, while glycolysis substrates and glutamine accumulated, with age. Oocytes from women of advanced maternal age appeared to use alternative energy sources like glycolysis and the adenosine salvage pathway, and possibly ATP which showed increased production in cumulus cells.LIMITATIONS, REASONS FOR CAUTION: The immature oocytes used in this study were all subjected to ovarian stimulation with high doses of follicle-stimulating hormones, which might have concealed some age-related differences.WIDER IMPLICATIONS OF THE FINDINGS: Further studies on how to improve mitochondrial function, or lower oxidative damage, in oocytes from women of advanced maternal age, for instance by supplementation of NAD+ precursors to promote mitochondrial biogenesis, are warranted. In addition, supplementing the embryo medium of advanced maternal-age embryos with such compounds could be a treatment option worth exploring.STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Amsterdam UMC. The authors declare to have no competing interests.TRIAL REGISTRATION NUMBER: N/A.PMID:37671592 | DOI:10.1093/humrep/dead177

PeerJ. 2023 Sep 1;11:e15856. doi: 10.7717/peerj.15856. eCollection 2023.ABSTRACTBACKGROUND: Ambient fine particulate matter ≤ 2.5 µm (PM2.5) air pollution exposure has been identified as a global health threat, the epidemiological evidence suggests that PM2.5 increased the risk of chronic kidney disease (CKD) among the diabetes mellitus (DM) patients. Despite the growing body of research on PM2.5 exposure, there has been limited investigation into its impact on the kidneys and the underlying mechanisms. Past studies have demonstrated that PM2.5 exposure can lead to lipid metabolism disorder, which has been linked to the development and progression of diabetic kidney disease (DKD).METHODS: In this study, db/db mice were exposed to different dosage PM2.5 for 8 weeks. The effect of PM2.5 exposure was analysis by assessment of renal function, pathological staining, immunohistochemical (IHC), quantitative real-time PCR (qPCR) and liquid chromatography with tandem mass spectrometry (LC-MS/MS) based metabolomic analyses.RESULTS: The increasing of Oil Red staining area and adipose differentiation related protein (ADRP) expression detected by IHC staining indicated more ectopic lipid accumulation in kidney after PM2.5 exposure, and the increasing of SREBP-1 and the declining of ATGL detected by IHC staining and qPCR indicated the disorder of lipid synthesisandlipolysis in DKD mice kidney after PM2.5 exposure. The expressions of high mobility group nucleosome binding protein 1 (HMGN1) and kidney injury molecule 1 (KIM-1) that are associated with kidney damage increased in kidney after PM2.5 exposure. Correlation analysis indicated that there was a relationship between HMGN1-KIM-1 and lipid metabolic markers. In addition, kidneys of mice were analyzed using LC-MS/MS based metabolomic analyses. PM2.5 exposure altered metabolic profiles in the mice kidney, including 50 metabolites. In conclusion the results of this study show that PM2.5 exposure lead to abnormal renal function and further promotes renal injury by disturbance of renal lipid metabolism and alter metabolic profiles.PMID:37671359 | PMC:PMC10476618 | DOI:10.7717/peerj.15856