PubMed

J Clin Endocrinol Metab. 2025 Jan 29:dgaf057. doi: 10.1210/clinem/dgaf057. Online ahead of print.ABSTRACTCONTEXT: PCOS pregnancies are linked to metabolic disorders affecting maternal and fetal outcomes, with maternal metabolites differing from those in normal pregnancies.OBJECTIVE: To investigate the metabolic communication at the maternal-fetal interface in PCOS pregnancies.DESIGN: Placenta and umbilical cord serum were analyzed using gas chromatography-mass spectrometry. In-depth analysis was performed with clinical characteristics.SETTING: Placenta and umbilical cord serum were analyzed using gas chromatography-mass spectrometry, alongside clinical characteristics.PARTICIPANTS: 45 uncomplicated PCOS pregnancies and 50 normal pregnancies.INTERVENTION(S): None.MAIN OUTCOME MEASURE(S): The metabolic characteristics at the maternal-fetal interface in PCOS pregnancies and the underlying mechanisms.RESULTS: A total of 79 metabolites in the placenta and 25 in umbilical cord serum showed significant differences between polycystic ovary syndrome (PCOS) and normal pregnancies. The 10 most significant placental metabolites were identified through receiver operating characteristic (ROC) analysis, 9 of which correlated significantly with maternal serum testosterone levels. Lasso regression analysis identified 4 key placental metabolite combinations: gamma-aminobutyric acid, proline, glycine, and isoleucine, achieving an area under the curve (AUC) of 93.24%. In umbilical cord serum, 6 metabolites differed significantly between PCOS and normal pregnancies, with the highest AUC reaching 76.07%, and 5 of these metabolites showed significant correlations with maternal serum testosterone levels. Nine differential metabolites were shared between the placenta and umbilical cord serum, which also shared metabolic pathways, including ABC transporters and aminoacyl-tRNA biosynthesis, potentially influencing maternal-fetal interactions.CONCLUSION: This study identifies the metabolomic profile and key pathways in maternal-fetal communication during PCOS pregnancies.PMID:39880380 | DOI:10.1210/clinem/dgaf057

Environ Pollut. 2025 Jan 27:125759. doi: 10.1016/j.envpol.2025.125759. Online ahead of print.ABSTRACTCr(VI) is widely used in industry and has high toxicity, making it one of the most common environmental pollutants. Long-term exposure to Cr(VI) can cause metabolic disorders and tissue damage. However, the effects of Cr(VI) on liver and gut microbes in fish have rarely been reported. In this study, 240 fish were randomly divided into 3 groups: the control group, low-dose Cr(VI) group (0.5 mg/L), and high-dose Cr(VI) group (2 mg/L). The mechanism by which Cr(VI) affects the enterohepatic axis of common carp was elucidated via multiomic analysis, serology, histomorphology, and physiological and biochemical indices. The results revealed that Cr(VI) stress led to hepatocyte damage, nuclear lysis, inflammatory cell infiltration, and vacuolated degeneration. The structure of the intestinal villi was severely damaged, and the length and width of the intestinal villi were significantly reduced. We also found that the accumulation of Cr(VI) in tissues increased in a concentration-dependent manner, and the content of Cr(VI) in each tissue increased in the order of gut > gill > liver > muscle. Multiple omics studies have revealed that chronic Cr(VI) stress leads to disturbances in the intestinal flora, with a significant reduction in the abundance of the beneficial bacterium Akkermansia and a significant increase in the abundance of the harmful bacterium Escherichia/Shigella. Intestinal injury and dysbiosis lead to an increase in blood LPS levels, further inducing metabolic disorders in the liver. The metabolites in the liver, including geniposide, leucine, C17 sphingosine, and 9,10-DiHODE, were significantly increased, whereas the beneficial metabolites, such as carnitine propionate and palmitoyl ethanolamide, were significantly reduced. In conclusion, our results suggest that chronic Cr(VI) stress leads to disturbances in gut microbial homeostasis and disturbed fatty acid and amino acid metabolism in the liver. LPS released into the bloodstream reaches the liver through the portal circulation, further exacerbating Cr(VI) stress-induced hepatotoxicity. This study revealed the mechanism of Cr(VI) toxicity to the liver-microbiota-gut axis of common carp. Our study provides new insights into the effects of Cr(VI) on the liver-microbiota-gut axis.PMID:39880355 | DOI:10.1016/j.envpol.2025.125759

J Lipid Res. 2025 Jan 27:100750. doi: 10.1016/j.jlr.2025.100750. Online ahead of print.ABSTRACTThe environmental pollutant cadmium (Cd) poses a threat to human health through consumption of contaminated foodstuffs culminating in chronic nephrotoxicity. Mitochondrial dysfunction and excessive reactive oxygen species (ROS) are key to Cd cellular toxicity. Cd-lipid interactions have been less considered. We hypothesized Cd binding to the inner mitochondrial membrane (IMM) phospholipid cardiolipin (CL) and membrane rigidification underlies defective electron transfer by disrupted respiratory supercomplexes (SCs). In Cd-treated rat kidney cortex (rKC) mitoplasts, laurdan (lipid-water interface) and diphenylhexatriene (hydrophobic core) revealed increased and decreased membrane fluidity, respectively. Laurdan-loaded pure CL or IMM biomimetic (40mol% POPC, 35mol% DOPE, 20mol% TOCL, 5mol% SAPI) nanoliposomes were rigidified by 25μM Cd, which was confirmed in live-cell imaging of laurdan or di-4-ANEPPDHQ loaded human proximal convoluted tubule (HPCT) cells. Blue native gel electrophoresis evidenced ∼30% loss of I+III2+IVn SC formation after 5μM Cd for 6h in HPCTs, which was reversed by CL-binding drug MTP-131/SS-31/elamipretide (0.1μM), yet α-tocopherol-insensitive. Moreover, MTP131 attenuated Cd-induced H2O2 (∼30%) and cytochrome c release (∼25%), but not osmotic swelling, in rKC mitochondria as well as Cd-induced ROS (∼25%) in HPCTs. MTP-131 binding to IMM biomimetic nanoliposomes decreased zeta potential, prevented Cd-induced liposome size increase, and membrane rigidification reported by laurdan. Heterologous CRLS1 expression reversed Cd (5μM, 24h) cytotoxicity (∼25%) by MTT assay, Cd (5μM, 3h)-induced ROS and mitochondrial membrane rigidification by Cd (1μM, 1h) in HPCT cells. In summary, we report a novel mechanism for Cd toxicity in which Cd-CL interactions cause IMM rigidification, thereby disrupting correct SC assembly and increasing ROS.PMID:39880166 | DOI:10.1016/j.jlr.2025.100750

Biochim Biophys Acta Bioenerg. 2025 Jan 27:149542. doi: 10.1016/j.bbabio.2025.149542. Online ahead of print.ABSTRACTCircadian rhythms driven by biological clocks regulate physiological processes in all living organisms by anticipating daily geophysical changes, thus enhancing environmental adaptation. Time-resolved serial multi-omic analyses in vivo, ex vivo, and in synchronized cell cultures have revealed rhythmic changes in the transcriptome, proteome, and metabolome, involving up to 50 % of the mammalian genome. Mitochondrial oxidative metabolism is central to cellular bioenergetics, and many nuclear genes encoding mitochondrial proteins exhibit both circadian and ultradian oscillatory expression. However, studies on mitochondrial DNA (mtDNA) gene expression remain incomplete. Using a well-established in vitro synchronization protocol, we investigated the time-resolved expression of mtDNA genes coding for respiratory chain complex subunits, revealing a rhythmic profile dependent on BMAL1, the master circadian clock transcription factor. Additionally, the expression of genes coding for key mitochondrial biogenesis transcription factors, PGC1a, NRF1, and TFAM, showed BMAL1-dependent circadian oscillations. Notably, LC3-II, involved in mitophagy, displayed a similar in-phase circadian expression, thereby maintaining stable respiratory chain complex levels. Moreover, we found that simultaneous mitochondrial biogenesis and degradation occur in a coordinated manner with cycles in organelle dynamics, leading to rhythmic changes in mitochondrial fission and fusion. This study provides new insights into circadian clock regulation of mitochondrial turnover, emphasizing the importance of temporal regulation in cellular metabolism. Understanding these mechanisms opens potential therapeutic avenues for targeting mitochondrial dysfunctions and related metabolic disorders.PMID:39880150 | DOI:10.1016/j.bbabio.2025.149542

Mol Cell Proteomics. 2025 Jan 27:100920. doi: 10.1016/j.mcpro.2025.100920. Online ahead of print.ABSTRACTUnder stress conditions, cells reprogram their molecular machineries to mitigate damage and promote survival. Ubiquitin signaling is globally increased during oxidative stress, controlling protein fate and supporting stress defenses at several subcellular compartments. However, the rules driving subcellular ubiquitin localization to promote concerted response mechanisms remain understudied. Here, we show that K63-linked polyubiquitin chains, known to promote proteasome-independent pathways, accumulate primarily in non-cytosolic compartments during oxidative stress induced by sodium arsenite in mammalian cells. Our subcellular ubiquitin proteomic analyses of non-cytosolic compartments expanded 2.5-fold the pool of proteins (2,494) and provided a comprehensive number of sites (10,157) known to be ubiquitinated during arsenite stress, suggesting their involvement in a myriad of cellular pathways. Moreover, subcellular proteome analyses revealed proteins that are recruited to non-cytosolic compartments under stress, including a significant enrichment of helper ubiquitin-binding adaptors of the ATPase VCP that processes ubiquitinated substrates for downstream signaling. We further show that VCP recruitment to non-cytosolic compartments under arsenite stress occurs in a ubiquitin-dependent manner mediated by its adaptor NPLOC4. Additionally, we show that VCP and NPLOC4 activities are critical to sustain low levels of non-cytosolic K63-linked ubiquitin chains, supporting a cyclical model of ubiquitin conjugation and removal that is disrupted by reactive oxygen species. This work deepens our understanding of the role of localized ubiquitin and VCP signaling in the basic mechanisms of stress response and highlights new pathways and molecular players that are essential to reshape the composition and function of the human subcellular proteome under dynamic environments.PMID:39880084 | DOI:10.1016/j.mcpro.2025.100920

J Ethnopharmacol. 2025 Jan 27:119418. doi: 10.1016/j.jep.2025.119418. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Xinbao pill (XBP) is a renowned Chinese patent medicine, primarily efficacious in warming and nourishing the heart and kidneys, supplementing Qi to boost Yang, and promoting blood circulation to remove blood stasis. XBP has been utilized for the treatment of chronic heart failure (CHF) for nearly 30 years, but the lack of clarity regarding the active ingredients of XBP against CHF has hindered its clinical application and further promotion.AIM OF THE STUDY: To comprehensively elucidate the efficacy-specific ingredients and potential mechanism of XBP against CHF.METHODS: The efficacy, chemical profiling and pharmacokinetics of XBP was assessed in a CHF model rat. The anti-CHF mechanism of the mixture of the likely active ingredients was clarified by targeted metabolomics and western blotting analysis.RESULTS: XBP alleviated CHF by enhancing cardiac function, reducing NT-pro BNP, mitigating myocardial damage and degrading extracellular collagen. Following XBP administration, ginsenosides exposed relatively abundant in sham or CHF rats. Ginsenoside Rg1 and notoginsenoside R1 showed downward trends in AUC0-t values in CHF group, accompanied by increasing trends in Vz/F values. Moreover, CHF rats presented significantly elevated levels of ginsenoside Rg1, ginsenoside Rg2 and notoginsenoside R1 in heart. The mixture of ginsenoside Rg1, ginsenoside Rg2 and notoginsenoside R1 demonstrated remarkable efficacy in ameliorating CHF as XBP did. Notably, these three compounds were predominantly localized in mitochondria and exhibited significant potential to enhance mitochondrial homeostasis by inhibiting heme synthesis pathway-mediated decomposition of succinyl CoA.CONCLUSIONS: Our research provides valuable insights that ginsenoside Rg1, ginsenoside Rg2 and notoginsenoside R1 may constitute the anti-CHF active ingredients of XBP for facilitating mitochondrial homeostasis by the suppression of heme synthesis to increase succinyl CoA.PMID:39880064 | DOI:10.1016/j.jep.2025.119418

Dtsch Med Wochenschr. 2025 Feb;150(4):157-162. doi: 10.1055/a-2303-3368. Epub 2025 Jan 29.ABSTRACTThe gastrointestinal microbiome influences physiological functions and is altered in a variety of diseases. The causality of "dysbiosis" in the pathogenesis is not always proven; association studies are often involved. Patients with IBD, bacteria, fungi, bacteriophages, and archaea show disease-typical patterns associated with metabolome disturbances. Fecal microbiome transfer (FMT) for treating various diseases is the subject of numerous clinical studies. Currently, recurrent Clostridioides difficile infection (rCDI) is the only confirmed indication recommended in medical guidelines. In Germany, the FMT is subject to the Medicines Act and may only be carried out as part of individual healing attempts or clinical studies. For patient safety, repeated donor screening, ideally with the construction of a chair bench, is necessary. This significantly limits the nationwide availability of the FMT in Germany. Microbiota-based therapeutics prepared from the stool of tested donors have recently been approved by the US Food and Drug Administration (FDA) for the prevention of rCDI. More microbiome-based medicines can be expected in the future.PMID:39879970 | DOI:10.1055/a-2303-3368

Clinics (Sao Paulo). 2025 Jan 28;80:100522. doi: 10.1016/j.clinsp.2024.100522. Online ahead of print.ABSTRACTThe objective of the present study was to evaluate biochemical quantitative metabolites in peripheral blood serum samples of Juvenile Idiopathic Arthritis (JIA) patients and healthy controls. A cross-sectional study included 33 post-pubertal JIA (21 without and 12 with Methotrexate (MTX) women and 28 age-matched healthy controls. Metabolomic analyses based on targeted electrospray ionization tandem mass spectrometry were used to identify possible biochemical pathway modifications in serum from JIA patients. The mean current age (p = 0.065) was similar in JIA patients and healthy controls. Current MTX use in all subtypes of JIA patients was associated with an increase in concentrations of free carnitine [21.74 (12.7‒35.2) vs. 27.49 (14.5‒41.3) µM/L, p = 0.02], suggesting an enhanced mitochondrial metabolism and intestinal absorptive function. In contrast, a decreased mitochondrial metabolism was observed in polyarticular and systemic JIA subtypes, with a decrease of several acylcarnitines' concentrations (p < 0.05). In conclusion, the present study identified a distinctive pattern of serum metabolic signatures in JIA patients under MTX therapy. Our findings indicate that MTX use is associated with a more efficient mitochondrial function.PMID:39879909 | DOI:10.1016/j.clinsp.2024.100522

Plant Physiol Biochem. 2025 Jan 21;220:109544. doi: 10.1016/j.plaphy.2025.109544. Online ahead of print.ABSTRACTCadmium (Cd) pollution is a growing concern worldwide, because it threatens human health through the food chain. Woody plants, such as the pioneer species black locust (Robinia pseudoacacia L.), are widely used in phytoremediation of Cd-contaminated soils, but strongly differ in Cd tolerance. Nitric oxide (NO), a highly reactive gas of biogenic and anthropogenic origin, has been shown to protect plants to Cd exposure. We investigated the protective mechanism of NO against Cd toxicity in black locust using physiological, transcriptomic and metabolomic approaches. We studied the correlation between cell wall traits, genes, and metabolites. The findings indicated that NO improved the growth of black locust under Cd exposure and elevated the fraction of Cd in the cell wall. NO increased cell wall thickness by stimulating the biosynthesis of pectin, cellulose, hemicellulose, and lignin. Transcriptomic and metabolomic analyses demonstrated that NO upregulated genes related to root cell wall biosynthesis and increased the accumulation of related metabolites, thereby increasing the Cd resistance of black locust. Our results elucidated a molecular mechanism underlying NO-mediated Cd tolerance in black locust and provided novel insights for phytoremediation of Cd-polluted soils by woody plants.PMID:39879830 | DOI:10.1016/j.plaphy.2025.109544

Plant Physiol Biochem. 2025 Jan 23;220:109551. doi: 10.1016/j.plaphy.2025.109551. Online ahead of print.ABSTRACTThe radionuclide contamination of the environment is an abiotic stress factor that influences biological systems. Plants growing in contaminated areas for many generations provide a unique opportunity to study adaptive strategies aimed at maintaining homeostasis under elevated radiation levels. Using non-targeted metabolomics approaches, we investigated the metabolomic profiles of Achillea millefolium L. plants from the Chernobyl exclusion zone. Amino acid biosynthesis pathways (arginine, glycine, serine, threonine, and proline) and metabolites associated with nitrogen mobilization, cell wall response to injury, photosynthetic efficiency, and defence responses were highly affected in plants from contaminated plots. Our results suggest that these changes may be involved in the adaptive strategies of A. millefolium plant to chronic radiation exposure.PMID:39879828 | DOI:10.1016/j.plaphy.2025.109551

J Pharm Biomed Anal. 2025 Jan 21;257:116668. doi: 10.1016/j.jpba.2025.116668. Online ahead of print.ABSTRACTBile acids (BAs) are essential signaling molecules that engage in host and gut microbial metabolism, playing a crucial role in maintaining organismal stability. Liquid chromatography-mass spectrometry (LC-MS) is a widely employed technique for metabolite analysis in biological samples due to its high sensitivity, excellent specificity, and low detection limits. This method has emerged as the mainstream approach for the detection and analysis of BAs. Pseudo-targeted analysis combines the advantages of both untargeted and targeted metabolomics methodologies. In this study, we developed a comprehensive and rapid method for detecting and analyzing BAs using LC-MS technology, applied to liver samples from bile duct-ligated (BDL) mice exhibiting liver fibrosis. A self-constructed database containing 488 BAs was established, and raw data from universal metabolome standard (UMS) were acquired using UHPLC-Q/TOF-MS. A total of 172 BA compounds were characterized, including 74 free BAs and 158 BAs were successfully detected using the high-coverage assay established with UHPLC-QQQ-MS. This assay was employed in the BDL liver fibrosis mouse model, where statistical analysis tools identified 20 differential BAs in the livers of affected mice. The development of this rapid method signifies a substantial advancement in the field, illustrating its utility in identifying differential BAs and enhancing our understanding of liver fibrosis. Furthermore, the high-coverage assay's ability to accurately analyze a diverse range of BAs could substantially aid in diagnosing and treating liver diseases.PMID:39879819 | DOI:10.1016/j.jpba.2025.116668

J Pharm Biomed Anal. 2025 Jan 27;257:116700. doi: 10.1016/j.jpba.2025.116700. Online ahead of print.ABSTRACTTrametes robiniophila Murr. (Huaier) is a traditional medicinal fungus known for its pharmacological properties, including heat-clearing, detoxifying, anti-inflammatory, and antitumor effects. Our previous research has demonstrated its antiviral activity, but the exact therapeutic mechanisms remain unclear. This study aims to explore the mechanisms of 50 % methanol extract of Huaier (HME) in treating influenza using 16S rRNA high-throughput sequencing and metabolomics techniques. The results showed that the HME significantly reduced the lung index and viral load in the lungs of influenza-infected mice, alleviated pathological damage in lung tissues, and downregulated the expression levels of inflammatory cytokines Interleukin-6 (IL-6), Tumor Necrosis Factor-α (TNF-α) and Interferon-γ (IFN-γ) in lung tissues. Furthermore, the HME enhanced the diversity of gut microbiota in infected mice, significantly increasing the relative abundance of beneficial bacteria, such as Alistipes and Alloprevotella. Through non-targeted metabolomic analysis of mouse feces, 45 potential biomarkers were identified. Meanwhile, the low-dose of HME was able to restore the disrupted metabolic levels. Analysis of gut microbiota and biomarker pathways revealed that HME primarily affects nicotinate and nicotinamide metabolism, which may be the key mechanism for its intervention in influenza. In addition, Spearman correlation analysis showed that most biomarkers were significantly associated with pharmacodynamics and the Alloprevotella.PMID:39879816 | DOI:10.1016/j.jpba.2025.116700

Food Chem. 2025 Jan 27;473:143069. doi: 10.1016/j.foodchem.2025.143069. Online ahead of print.ABSTRACTAn attempt was made here to a complemental analytical tool for classical MSI approach. OLE-LC-MS/MS imaging was proposed to plot the spatial-resolved metabolome through deploying mint leaf as a proof-of-concept. A dried leaf underwent chemical composition characterization using OLE-LC-Qtof-MS. Another dried leaf was cut into small pieces, and all pieces were successively packed into a suitable cartridge to undergo OLE-LC-SRM measurements. Fifty-two compounds were observed and identified. Special attention was paid onto isomeric identification using fragment ion intensity ranking style, e.g., 3-O-caffeoylquinic acid vs. 4-O-caffeoylquinic acid. Thereof, 23 abundant ones were involved for relatively quantitative analysis. Quantitative settings were optimized using online ER-MS program. Following spatial metabolome imaging, regioselective distributions were observed for most concerned metabolites. Particularly, isomer-specific occurrences were observed for luteolin-7-O-glucuronide and luteolin-3'-O-glucuronide. Together, OLE-LC-MS/MS is alternative for spatial metabolome imaging due to the advantages at isomeric separation, identification confidence, and quantitative accuracy.PMID:39879757 | DOI:10.1016/j.foodchem.2025.143069

Food Chem. 2025 Jan 27;473:143055. doi: 10.1016/j.foodchem.2025.143055. Online ahead of print.ABSTRACTApple polyphenols (APP) can reduce obesity. However, the effects of APP on abdominal subcutaneous adipose tissue (aSAT) at metabolic level were unclear. In this study, 5-week APP intervenes were conducted on 10-week high-fat diet (HFD) feeding mice with doses of 200 and 500 mg/kg b.w./day, followed by ultra-high-performance liquid chromatography-mass spectrometry based untargeted metabolomics analysis. As expected, APP obviously reversed aSAT weight and index, as well as activities of myeloperoxidase, glutathione peroxidase, superoxide dismutase and catalase. Euclidean distance between HFD and normal chow diet (NCD) group was shortened. 64 and 127 differential metabolites were found in 200 and 500 mg/kg b.w./day group, with 12 and 13 changed pathways, respectively. Specifically, APP restored glycolysis, tricarboxylic acid cycle, amino acid metabolism, and lipid metabolism as dose-dependent manner. Finally, glucose-6-phosphate, xanthine and tyrosine were selected as critical junctures. Collectively, these findings underscore the potential of APP in reversing molecular alterations in aSAT.PMID:39879748 | DOI:10.1016/j.foodchem.2025.143055

J Nat Prod. 2025 Jan 29. doi: 10.1021/acs.jnatprod.4c01051. Online ahead of print.ABSTRACTA structurally novel metabolite, fatuamide A (1), was discovered from a laboratory cultured strain of the marine cyanobacterium Leptolyngbya sp., collected from Faga'itua Bay, American Samoa. A bioassay-guided approach using NCI-H460 human lung cancer cells directed the isolation of fatuamide A, which was obtained from the most cytotoxic fraction. The planar structure of fatuamide A was elucidated by integrated NMR and MS/MS analysis, and a combination of bioinformatic and computational approaches was used to deduce the absolute configuration at its eight stereocenters. A putative hybrid PKS/NRPS biosynthetic gene cluster responsible for fatuamide A production was identified from the sequenced genomic DNA of the cultured cyanobacterium. The biosynthetic gene cluster possessed elements that suggested fatuamide A binds metals, and this metallophore property was demonstrated by native metabolomics and indicated a preference for binding copper. The producing strain was found to be highly resistant to toxicity from elevated copper concentrations in culture media.PMID:39879528 | DOI:10.1021/acs.jnatprod.4c01051

Sci Adv. 2025 Jan 31;11(5):eadr8837. doi: 10.1126/sciadv.adr8837. Epub 2025 Jan 29.ABSTRACTThe Epstein-Barr virus (EBV) infects nearly 90% of adults globally and is linked to over 200,000 annual cancer cases. Immunocompromised individuals from conditions such as primary immune disorders, HIV, or posttransplant immunosuppressive therapies are particularly vulnerable because of EBV's transformative capability. EBV remodels B cell metabolism to support energy, biosynthetic precursors, and redox equivalents necessary for transformation. Most EBV-driven metabolic pathways center on mitochondria. However, how EBV regulates B cell mitochondrial function and metabolic fluxes remains unclear. Here, we show that EBV boosts cardiolipin (CL) biosynthesis, essential for mitochondrial cristae biogenesis, via EBV nuclear antigen 2/MYC-induced CL enzyme transactivation. Pharmacological and CRISPR genetic analyses underscore the essentiality of CL biosynthesis in EBV-transformed B cells. Metabolomic and isotopic tracing highlight CL's role in sustaining respiration, one-carbon metabolism, and aspartate synthesis. Disrupting CL biosynthesis destabilizes mitochondrial matrix enzymes pivotal to these pathways. We demonstrate EBV-induced CL metabolism as a therapeutic target, offering synthetic lethal strategies against EBV-associated B cell malignancies.PMID:39879311 | DOI:10.1126/sciadv.adr8837

Sci Adv. 2025 Jan 31;11(5):eads0535. doi: 10.1126/sciadv.ads0535. Epub 2025 Jan 29.ABSTRACTKetogenesis is a dynamic metabolic conduit supporting hepatic fat oxidation particularly when carbohydrates are in short supply. Ketone bodies may be recycled into anabolic substrates, but a physiological role for this process has not been identified. Here, we use mass spectrometry-based 13C-isotope tracing and shotgun lipidomics to establish a link between hepatic ketogenesis and lipid anabolism. Unexpectedly, mouse liver and primary hepatocytes consumed ketone bodies to support fatty acid biosynthesis via both de novo lipogenesis (DNL) and polyunsaturated fatty acid (PUFA) elongation. While an acetoacetate intermediate was not absolutely required for ketone bodies to source DNL, PUFA elongation required activation of acetoacetate by cytosolic acetoacetyl-coenzyme A synthetase (AACS). Moreover, AACS deficiency diminished free and esterified PUFAs in hepatocytes, while ketogenic insufficiency depleted PUFAs and increased liver triacylglycerols. These findings suggest that hepatic ketogenesis influences PUFA metabolism, representing a molecular mechanism through which ketone bodies could influence systemic physiology and chronic diseases.PMID:39879309 | DOI:10.1126/sciadv.ads0535

PLoS Biol. 2025 Jan 29;23(1):e3002998. doi: 10.1371/journal.pbio.3002998. eCollection 2025 Jan.ABSTRACTUbiquitin-conjugating enzymes (E2s) are key for protein turnover and quality control via ubiquitination. Some E2s also physically interact with the proteasome, but it remains undetermined which E2s maintain proteostasis during aging. Here, we find that E2s have diverse roles in handling a model aggregation-prone protein (huntingtin-polyQ) in the Drosophila retina: while some E2s mediate aggregate assembly, UBE2D/effete (eff) and other E2s are required for huntingtin-polyQ degradation. UBE2D/eff is key for proteostasis also in skeletal muscle: eff protein levels decline with aging, and muscle-specific eff knockdown causes an accelerated buildup in insoluble poly-ubiquitinated proteins (which progressively accumulate with aging) and shortens lifespan. Mechanistically, UBE2D/eff is necessary to maintain optimal proteasome function: UBE2D/eff knockdown reduces the proteolytic activity of the proteasome, and this is rescued by transgenic expression of human UBE2D2, an eff homolog. Likewise, human UBE2D2 partially rescues the lifespan and proteostasis deficits caused by muscle-specific effRNAi and re-establishes the physiological levels of effRNAi-regulated proteins. Interestingly, UBE2D/eff knockdown in young age reproduces part of the proteomic changes that normally occur in old muscles, suggesting that the decrease in UBE2D/eff protein levels that occurs with aging contributes to reshaping the composition of the muscle proteome. However, some of the proteins that are concertedly up-regulated by aging and effRNAi are proteostasis regulators (e.g., chaperones and Pomp) that are transcriptionally induced presumably as part of an adaptive stress response to the loss of proteostasis. Altogether, these findings indicate that UBE2D/eff is a key E2 ubiquitin-conjugating enzyme that ensures protein quality control and helps maintain a youthful proteome composition during aging.PMID:39879147 | DOI:10.1371/journal.pbio.3002998

Eur J Nucl Med Mol Imaging. 2025 Jan 29. doi: 10.1007/s00259-025-07091-8. Online ahead of print.ABSTRACTPURPOSE: Advancements of deep learning in medical imaging are often constrained by the limited availability of large, annotated datasets, resulting in underperforming models when deployed under real-world conditions. This study investigated a generative artificial intelligence (AI) approach to create synthetic medical images taking the example of bone scintigraphy scans, to increase the data diversity of small-scale datasets for more effective model training and improved generalization.METHODS: We trained a generative model on 99mTc-bone scintigraphy scans from 9,170 patients in one center to generate high-quality and fully anonymized annotated scans of patients representing two distinct disease patterns: abnormal uptake indicative of (i) bone metastases and (ii) cardiac uptake indicative of cardiac amyloidosis. A blinded reader study was performed to assess the clinical validity and quality of the generated data. We investigated the added value of the generated data by augmenting an independent small single-center dataset with synthetic data and by training a deep learning model to detect abnormal uptake in a downstream classification task. We tested this model on 7,472 scans from 6,448 patients across four external sites in a cross-tracer and cross-scanner setting and associated the resulting model predictions with clinical outcomes.RESULTS: The clinical value and high quality of the synthetic imaging data were confirmed by four readers, who were unable to distinguish synthetic scans from real scans (average accuracy: 0.48% [95% CI 0.46-0.51]), disagreeing in 239 (60%) of 400 cases (Fleiss' kappa: 0.18). Adding synthetic data to the training set improved model performance by a mean (± SD) of 33(± 10)% AUC (p < 0.0001) for detecting abnormal uptake indicative of bone metastases and by 5(± 4)% AUC (p < 0.0001) for detecting uptake indicative of cardiac amyloidosis across both internal and external testing cohorts, compared to models without synthetic training data. Patients with predicted abnormal uptake had adverse clinical outcomes (log-rank: p < 0.0001).CONCLUSIONS: Generative AI enables the targeted generation of bone scintigraphy images representing different clinical conditions. Our findings point to the potential of synthetic data to overcome challenges in data sharing and in developing reliable and prognostic deep learning models in data-limited environments.PMID:39878897 | DOI:10.1007/s00259-025-07091-8

Biofactors. 2025 Jan-Feb;51(1):e2156. doi: 10.1002/biof.2156.ABSTRACTAtherosclerosis is a major cause of morbidity and mortality worldwide; in Israel, ischemic heart disease is the second leading cause of death for both genders aged 45 and above. Atherosclerosis involves stiffening of the arteries due to the accumulation of lipids and oxidized lipids on the blood vessel walls, triggering the development of artery plaque. Coronary artery disease (CAD) is the most common manifestation of atherosclerosis. The prevalence of CAD in the general population remains high, despite efforts to improve the identification of risk factors and preventive treatments. The discovery of new biomarkers is vital to improving the diagnosis of CAD and its risk factors. We aimed to identify novel biomarkers that could provide an early diagnosis of coronary artery atherosclerotic plaques, their type, and the percentage of stenosis. We used an untargeted metabolomics approach to identify potential biomarkers that could enable highly sensitive and specific CAD detection. The study consisted of 109 patients who underwent cardiac computed tomography angiography at the Cardiology Department of Ziv Medical Center. Fifty-four patients were diagnosed with coronary atherosclerotic plaques (CAD group), and 55 without plaques used control. Untargeted metabolomics using LC-MS/MS revealed 2560 metabolites in the patients' serum: 106 showed statistically significant upregulation in the serum of the CAD group compared with the healthy control group (p < 0.05). These metabolites belonged to the following chemical families: acyl-carnitines, cyclodipeptides, lysophosphatidylcholine, and primary bile acids. In contrast, 98 metabolites displayed statistically significant downregulation in the serum of the CAD group compared with the control group, belonging to the following chemical families: GABA amino acids and derivatives (inhibitory neurotransmitters), lipids, and secondary bile acids. Our comprehensive untargeted serum metabolomic analysis revealed biomarkers that can be used for the diagnosis of patients with CAD. Further cohort studies with a larger number of participants are needed to validate the detected biomarkers.PMID:39878362 | DOI:10.1002/biof.2156