PubMed

Alzheimers Dement. 2024 Dec;20 Suppl 2:e092421. doi: 10.1002/alz.092421.ABSTRACTBACKGROUND: Our Alzheimer Disease Metabolomics Consortium (ADMC), part of the Accelerating Medicines Partnership for AD (AMP-AD) and in partnership with AD Neuroimaging Initiative (ADNI), applied state-of-the-art metabolomics and lipidomics technologies combined with genomic and imaging data to map metabolic failures across the trajectory of the disease. Our studies confirmed that peripheral metabolic changes influenced by the exposome inform about cognitive changes, brain imaging changes, and ATN markers for disease confirming that peripheral and central changes are connected, in part through the metabolome.METHODS: To map the biochemical changes in AD, we used various targeted and untargeted metabolic platforms to profile ∼800 postmortem brain tissue, and ∼ 5000 blood samples.RESULTS: Recently, we built a comprehensive reference map of extensive AD-related metabolic changes in brain, spanning multiple AD-related traits, including neuropathological b-amyloid and tau tangle burden, as well as late-life cognitive performance. Using this resource, we extracted novel metabolic including bioenergetic pathways, cholesterol metabolism, neuroinflammation, broad impairment of osmoregulation, an imbalance between excitatory/inhibitory neurotransmitter ratios and identification of tau load as a potential driver of metabolic dysfunction in the AD brain, with minimal contributions from b-amyloid load. As AD and progressive supranuclear palsy (PSP) share the pathological feature of tauopathy and metabolic alterations, we compared their metabolomic profiles to identify shared biological pathways that could be targeted for therapeutic interventions. Our findings indicate that both diseases display oxidative stress, mitochondrial dysfunction, and tau-induced polyamine stress response.CONCLUSION: Overall, through our studies, (1) We identified biochemical processes altered in AD, with findings supported across both metabolomic and proteomic data, indicating multimodal deregulation. (2) Our research pinpointed widespread AD-related biochemical changes across various brain regions with differing levels of neuropathology. While there are many overlapping changes across the brain regions, each region also has its distinct metabolic alterations. (3) We identified biochemical processes disrupted by AD, with parallel findings in other neurodegenerative diseases, hinting at broader implications in neurodegenerative research. Currently, we are working on mapping widespread connections of the brain metabolome with various determinants of AD namely genome, gut microbiome, exposome, and linking with peripheral metabolic alterations in AD.PMID:39784050 | DOI:10.1002/alz.092421

Alzheimers Dement. 2024 Dec;20 Suppl 2:e091167. doi: 10.1002/alz.091167.ABSTRACTBACKGROUND: Alzheimer's disease (AD) pathogenesis is not restricted to amyloid-beta, Aβ, and tau pathologies but involves dysregulation in diverse cellular and molecular processes. Numerous metabolomic studies revealed plasma metabolite alterations in AD individuals compared to healthy controls. Nevertheless, plasma P-tau181, an established biomarker for AD diagnosis and prognosis, has been described to reflect initial multiple cortical region Aβ deposition in cognitively intact adults. The current study aims to identify plasma metabolites associated with plasma P-tau181 at the preclinical stage and better understand the associated biochemical mechanisms for AD pathogenesis.METHOD: In the current study, 100 older adults with no objective cognitive impairment, MoCA and MMSE ≥ 26, from the Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH) cohort, comprising 65 CI Aβ- (cognitively intact normal brain Aβ) and 35 CI Aβ+ (cognitively intact higher brain Aβ) individuals, were assessed for plasma P-tau181, via ultra-sensitive Quanterix Simoa technology, and plasma metabolites, via mass spectrometry-based BIOCRATES kit, and then investigated for associations, both before and after adjusting for confounding variables, in the study groups. Additionally, P-tau181-associated plasma metabolites were evaluated using the receiver operating characteristic (ROC) curves for the potential to classify brain Aβ status.RESULT: In the entire cohort, significant positive associations of plasma metabolites, including acylcarnitines, amino acid citrulline, and three biogenic amines (creatinine, kynurenine and SDMA), were observed with P-tau181 and similar associations, except for kynurenine, were detected in CI Aβ-. In contrast, in CI Aβ+, only acylcarnitine, AC(10:3), was found to have a positive association with P-tau181 and further, upon including AC(10:3), the AUC for P-tau181 (AUC=70.9%) potentially outperformed (AUC=76.2%), which additionally topped to 83.9% when combined with a base model (Abstract Figure).CONCLUSION: These findings suggest that the higher the plasma P-tau181, the higher the medium chain acylcarnitine, AC(10:3), in plasma in cognitively intact older adults at risk for AD, indicating a link between early Aβ pathology and fatty acid oxidation mediated energy metabolism pathway. Additionally, associated metabolite strengthens the significance of P-tau181 in classifying brain Aβ status in cognitively intact older adults. Therefore, plasma P-tau181-associated plasma metabolite may serve as potential predictive marker for preclinical AD pathogenesis.PMID:39783968 | DOI:10.1002/alz.091167

Alzheimers Dement. 2024 Dec;20 Suppl 8:e095342. doi: 10.1002/alz.095342.ABSTRACTBACKGROUND: Multi-omics integration can clarify molecular mechanisms contributing to Alzheimer's Disease (AD). We conducted a quantitative trait locus (QTL) analysis across three omics layers to identify genetic variants that regulate metabolomics, gene expression, and DNA methylation in AD.METHOD: We analyzed data from Caribbean Hispanic individuals from the Dominican Republic and New York with AD or family history of AD including: N = 750 with whole genome sequencing (WGS), RNA-sequencing, and DNA methylation (in blood), and N = 272 with untargeted metabolomics. Metabolites (N = 5,883) were measured using liquid chromatography coupled to high-resolution mass spectrometry. WGS data (7,588,678 variants) were normalized, aligned, and filtered for quality (BCFTools). Variants with a minor allele frequency greater than 5% were retained. The MatrixEQTL package in R was used for QTL analyses, adjusting for age, sex, and principal components for population substructure. Significant QTLs were declared at a false-discovery rate of 0.05 across all tests. Pathway analyses (clusterProfiler) and colocalization with known AD SNPs were completed to identify causal variants and genes in AD.RESULT: 19,336 SNP-metabolite combinations were statistically significant after adjusting for multiple comparisons (FDR<0.05). 16,421 unique SNPs were identified as QTLs for 60.9% of all metabolites. 68% of FDR-significant metabolomics QTLs overlapped with trans-expression QTLs with P<10-5. The most significant associations were between the metabolomics QTLs (P.FDR<0.05) and cardiovascular pathways including brain ischemia, angiogenesis, and cerebrovascular disease; neuronal pathways including synaptic organization/signaling, neuronal apoptosis, neurogenesis, gliogenesis, and axonogenesis; and AD endophenotypic pathways including cognition, learning and memory, amyloid-beta binding, and dementia. We additionally colocalized SNPs in the Bellenguez et al. 2022 AD GWAS (P<10-3) with metabolomics QTLs (P.FDR<0.05), identifying 24 unique colocalized genes. Notably, SPOCK3 associated with verbal memory (Debette et al., 2015), WWOX associated with Aβ42/Aβ40 ratio (Stevenson-Hoare et al., 2023), and CACNA2D3 associated with an AD subgroup (Mukherjee et al., 2018).CONCLUSION: We identified common genetic variants that regulate metabolite levels, many of which were found to overlap with known AD variants and were enriched in AD-relevant biological pathways. Our next steps include integrating QTLs of transcriptomic and epigenetic data to identify shared molecular pathways that underlie several omics layers leading to AD.PMID:39783736 | DOI:10.1002/alz.095342

Alzheimers Dement. 2024 Dec;20 Suppl 8:e095238. doi: 10.1002/alz.095238.ABSTRACTBACKGROUND: The mitochondrial translocator protein (TSPO) is a biomarker of inflammation associated with aging and Alzheimer's disease (AD). We have previously shown that TSPO plays a critical role in protective immune responses important in AD. Here we investigated the interaction between TSPO immunomodulatory function and aging in the hippocampus, a region severely affected in AD.METHOD: Using RNAseq, we investigated the role of TSPO in the aging hippocampal transcriptome. Multi-weighted co-expression network analysis (WGCNA) was used to determine the effect of TSPO deletion on aging and identify hub regulators of the molecular network in aging. We compared the TSPO-dependent aging transcriptome signature with drug gene expression signatures in a perturbational signature library called Connectivity Map (CMap). NMR metabolomics was used to determine the effect of TSPO in the context of aging and inflammation on brain metabolites.RESULT: Aging resulted in reversal of inflammatory transcriptional signatures in TSPO-KO hippocampus, with TSPO deletion drastically exacerbating inflammatory transcriptional responses in the aged whilst dampening inflammation in the young hippocampus. This TSPO-aging interaction was linked to transcriptional control of interferon regulatory factors. Drugs such as heat shock protein inhibitors and topoisomerase inhibitors were identified to phenocopy the transcriptional signature characterizing the inflammatory response in TSPO-dependent aging. Through NMR detection, we also noted the exclusive presence of methanediol, another form of formaldehyde, in the aged TSPOKO mice.CONCLUSION: The effect of TSPO in inflammatory responses is age-dependent, an interaction which we linked to transcriptional control of interferon regulatory factors. This TSPO-aging interaction is an important consideration in interpretation TSPO-targeted biomarker and therapeutic studies, as well as in vitro studies which cannot model the aging brain.PMID:39783652 | DOI:10.1002/alz.095238

Alzheimers Dement. 2024 Dec;20 Suppl 8:e095144. doi: 10.1002/alz.095144.ABSTRACTBACKGROUND: High fat diets are a risk factor for Alzheimer Dementia (AD) but little is known about the effect of acute high fat feeding on brain lipid metabolism. Previous studies suggest that diet results may differ by APOE genotype and sex. Here we examined cerebrospinal fluid (CSF) lipidomic profiles after high and low fat feeding in a group of older adults to ascertain how APOE and sex influenced post-prandial lipids.METHOD: As part of the Meal and Memory study (CT# NCT03070535), 78 healthy older adults (50% E4+, each E4 group 56% women) ingested high fat meal (HFM) and low fat meal (LFM) breakfasts 3-5 weeks apart after overnight fast. Plasma triglycerides (TG) were measured at 7 time points, and lumbar puncture was performed 4 hours post-meal. Lipidomics were performed on 250 ul of CSF on a Lipidyzer platform consisting of an AB Sciex 5500 MS/MS QTraps system equipped with a SelexION for differential mobility spectrometry (DMS). Multiple reaction monitoring was used to target 1,530 lipid species (across 20 lipid classes/subclasses) in positive and negative ionization modes with and without DMS, respectively. Lipids were analyzed using MetaboAnalyst 6.0 and SAS OnDemand (2021).RESULT: HFM expectedly increased plasma triglycerides (TG) (LFM peak TG 134±69 mg/dL, HFM peak TG 149±80, F 8.85, p = 0.004), results unaffected by E4 status or sex. No differences were found between the two meals for the 20 lipid classes or for individual lipid species in CSF. When examined by sex*APOE group, important baseline differences were noted in 10 of the 20 lipid classes. Furthermore, there were meal*group effects for phosphoserines (ANOVA F statistic 3.57, p = 0.024), with all groups except for E4+ men showing decreases in these lipids after HFM compared to LFM.CONCLUSION: Meals that produced predictable changes in plasma lipids did not change overall CSF lipids; however, changes were noted when analyzed by APOE*sex and further differed depending on whether the meal was high in fat. These findings suggest that diet or treatments that rely on brain lipid metabolism may need to be further stratified by APOE genotype and sex.PMID:39783594 | DOI:10.1002/alz.095144

Alzheimers Dement. 2024 Dec;20 Suppl 6:e086468. doi: 10.1002/alz.086468.ABSTRACTBACKGROUND: Abnormal glucose metabolism in AD brains correlates with cognitive deficits. The glucose changes are consistent with brain thiamine (vitamin B1) deficiency. In animals, thiamine deficiency causes multiple AD-like changes including memory loss, neuron loss, brain inflammation, enhanced phosphorylation of tau, exaggerated plaque formation and elevated advanced glycation end products (AGE). Increasing thiamine as much as 100 times with the thiamine prodrug benfotiamine diminishes all these changes. These results plus an outstanding safety profile stimulated a double-blind placebo-controlled pilot trial for 12 months with benfotiamine in mild AD patients (MMSE >20). Blood thiamine increased >100 fold compared to placebo. The decline in ADAS cog was diminished by 43% (p<0.125). Worsening of the CDR was 77% lower (p<0.034). Considerable data suggests that the thiamine dependent transketolase regulates AGE, which are elevated in AD. In the pilot trial, the benfotiamine reduced AGE (p<0.044). The following experiments sought to determine if other metabolites/lipids in serum can serve as biomarkers of the effects of benfotiamine.METHOD: Serum from a subset of patients on placebo and benfotiamine groups in the pilot trial was analyzed by LC-MS/MS in parallel for comparative metabolome and lipidome.RESULT: A total of 315 unique metabolites and 417 lipids species were confidently identified and quantified. Differences to benfotiamine treatment were found in 25 metabolites, including thiamine, tyrosine, tryptophan, lysine, and 22 lipid species, especially phosphatidylcholines and triglycerides. Ten of 11 metabolites and 14 of 15 lipid species reported in previous literature to reflect AD progression changed in the opposite direction after benfotiamine treatment. Enrichment pathway analyses show that significantly altered metabolites are involved in glucose metabolism and biosynthesis of aromatic amino acids.CONCLUSION: Benfotiamine reverses the changes of metabolites/lipids reflecting AD progression. Our ongoing NIH funded multicenter trial includes blood biomarkers of thiamine, amyloid, tau, inflammation, neurodegeneration, AGE, and extensive cognitive testing. A larger sample size is necessary to test whether metabolic biomarkers are useful for disease diagnosis, prognosis, and monitoring therapeutic efficacy. This research was partially funded by National Institute of Aging R01AG043679 (G.E.G), AG014930 (G.E.G, S.Z) and R01 AG076634 (GEG, HF, JAL).PMID:39782583 | DOI:10.1002/alz.086468

Alzheimers Dement. 2024 Dec;20 Suppl 6:e090939. doi: 10.1002/alz.090939.ABSTRACTBACKGROUND: Non-human primates (NHP) serve as an important bridge for testing therapeutic agents that have been previously shown to be effective in transgenic mouse models. Our earlier published data using an NHP model of sporadic AD-related pathology that develops abundant cerebral amyloid angiopathy (CAA), squirrel monkeys (SQMs), indicates that chronic treatment with TLR9 agonist, class B CpG ODN, safely ameliorates CAA while promoting cognitive benefits. In the present study, we intended to delineate alterations in brain metabolome induced by chronic CpG ODN administration in order to provide further insight into CpG ODN immunomodulatory capabilities.METHOD: Global metabolomics analysis by HILIC-LC-MS was performed on frontal cortex tissue dissected from geriatric SQMs one month after the final CpG ODN or Vehicle (saline) injection. Tandem spectral (MS2) data was searched against the NIST/METLIN libraries for compound identification. Metabolite peak intensities were used for differential metabolite expression (p<0.05) and pathway analysis was performed using Metaboanalyst 5.0.RESULT: Differential metabolomics analyses revealed 151 putatively identified metabolites that were significantly altered in the brains of CpG ODN-treated SQMs. Amino acids were the largest group of metabolites altered, with decreased levels in the CpG ODN group compared to the saline controls. ROC analyses identified several metabolites strongly associated with CpG ODN treatment, including amino acids such as proline and branched chain amino acids valine, leucine, and isoleucine. Furthermore, trimethylamine N-oxide, a gut microbiome-derived metabolite previously implicated in AD, was the most downregulated metabolite in the brains of CpG ODN monkeys relative to saline controls. Enrichment analysis identified significantly altered pathways including: "Aminoacyl-tRNA biosynthesis", "Valine, leucine and isoleucine biosynthesis", and "Arginine biosynthesis."CONCLUSION: Overall, the brain metabolome in an NHP model of naturally occurring CAA pathology was assessed for the first time. We observed decreased levels of several AD-associated metabolites. These findings further develop our novel concept of immunomodulation in order to provide essential preclinical evidence for CpG ODN use as an effective drug for AD.PMID:39782456 | DOI:10.1002/alz.090939

Int J Biol Sci. 2025 Jan 1;21(2):823-841. doi: 10.7150/ijbs.101055. eCollection 2025.ABSTRACTThe TIRAP protein is an adaptor protein in TLR signaling which links TLR2 and TLR4 to the adaptor protein Myd88. The transcriptomic profiles of zebrafish larvae from a tirap, myd88 and tlr2 mutant and the corresponding wild type controls under unchallenged developmental conditions revealed a specific involvement of tirap in calcium homeostasis and myosin regulation. Metabolomic profiling showed that the tirap mutation results in lower glucose levels, whereas a tlr2 mutation leads to higher glucose levels. A tail-wounding zebrafish larval model was used to identify the role of tirap in leukocyte migration to tissue wounding. We found that more neutrophils were recruited to the wounded region in the tirap mutant larvae compared to the wild type controls, whereas there was no difference in macrophage recruitment. In contrast, published data show that tlr2 and myd88 mutants recruit fewer neutrophils and macrophages to the wounds. Based on cell tracking analysis, we demonstrate that the neutrophil migration speed is increased in the tirap mutant in contrast to neutrophil behavior in myd88 and tlr2 mutants. In conclusion, we show that tirap plays specialized roles distinct from tlr2 and myd88 in signaling, metabolic control, and in regulating neutrophil migration speed upon wounding.PMID:39781449 | PMC:PMC11705633 | DOI:10.7150/ijbs.101055

Clin Epidemiol. 2025 Jan 3;17:1-6. doi: 10.2147/CLEP.S484953. eCollection 2025.NO ABSTRACTPMID:39781206 | PMC:PMC11705965 | DOI:10.2147/CLEP.S484953

JOR Spine. 2025 Jan 8;8(1):e70032. doi: 10.1002/jsp2.70032. eCollection 2025 Mar.ABSTRACTBACKGROUND: Intervertebral disc degeneration disease (IVDD) is a prevalent orthopedic condition that causes chronic lower back pain, imposing a substantial economic burden on patients and society. Despite its high incidence, the pathophysiological mechanisms of IVDD remain incompletely understood.OBJECTIVE: This study aimed to identify metabolomic alterations in IVDD patients and explore the key metabolic pathways and metabolites involved in its pathogenesis.METHODS: Serum samples from 20 IVDD patients and 20 healthy controls were analyzed using ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS). The identified metabolites were mapped to metabolic pathways using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database.RESULTS: Significant alterations were observed in metabolites such as 2-methyl-1,3-cyclohexadiene, stearoyl sphingomyelin, methylcysteine, L-methionine, and cis, cis-muconic acid. These metabolites were involved in pathways including glycine, serine, and threonine metabolism, cyanoamino acid metabolism, and the citrate cycle (TCA cycle).CONCLUSION: The identified metabolic alterations provide insights into the pathogenesis of IVDD and suggest potential therapeutic targets for future investigation.PMID:39781087 | PMC:PMC11707616 | DOI:10.1002/jsp2.70032

J Inflamm Res. 2025 Jan 3;18:17-30. doi: 10.2147/JIR.S500101. eCollection 2025.ABSTRACTPURPOSE: Serum uric acid (SUA) is primarily produced through the hydrolysis of purines in the liver, with its excretion largely handled by the kidneys. Urate transporter 1 (URAT1) inhibitors are known to enhance uric acid elimination via the kidneys, but they also increase the risk of kidney stone formation. Currently, xanthine oxidase (XO) inhibitors are the predominant uric-lowering medications on the market.METHODS: In this study, we utilized single-cell RNA sequencing, spatial metabolomics, plasma metabolomics, flow cytometry to explore the effects of Tigulixostat on uric acid level and hyperuricemic nephropathy (HN) in Uox-KO mouse model.RESULTS: In this study, we discovered that Tigulixostat (LC350189) more effectively reduced SUA levels and resulted in better renal outcomes compared to allopurinol, without inducing liver injury in urate oxidase knockout (Uox-KO) mice. Mechanistically, we found that Tigulixostat improved HN by promoting M2 macrophage polarization.CONCLUSION: These findings suggest Tigulixostat as a promising therapeutic option for managing hyperuricemia and related kidney conditions.PMID:39780982 | PMC:PMC11705990 | DOI:10.2147/JIR.S500101

Physiol Plant. 2025 Jan-Feb;177(1):e70038. doi: 10.1111/ppl.70038.ABSTRACTUnder changing climatic conditions, plant exposure to high-intensity UV-B can be a potential threat to plant health and all plant-derived human requirements, including food. It's crucial to understand how plants respond to high UV-B radiation so that proper measures can be taken to enhance tolerance towards high UV-B stress. We found that BBX22, a B-box protein-coding gene, is strongly induced within one hour of exposure to high-intensity UV-B. Our metabolomics data indicated that BBX22 promotes the accumulation of antioxidants like ascorbic acid and proline. These antioxidants play a vital role in shielding plants exposed to high UV-B from the detrimental effects of Reactive Oxygen Species (ROS), including DNA damage. Additionally, BBX22 promotes DNA damage repair by inducing the expression of DNA repair genes like UVR1 and UVR3. BBX22 directly binds to the promoter of UVR1 to regulate its expression. Furthermore, BBX22 indirectly induces the expression of UVR1 and UVR3 by enhancing the binding of HY5 to their promoters. Together, these results suggest a multi-pronged role of BBX22 in protection against high-intensity UV-B. Enhancing BBX22 levels or its orthologs in different plant species can potentially offer DNA damage protection and tolerance against intense UV radiation.PMID:39780752 | DOI:10.1111/ppl.70038

Wound Repair Regen. 2025 Jan-Feb;33(1):e13251. doi: 10.1111/wrr.13251.ABSTRACTAs the number of patients requiring organ transplants continues to rise exponentially, there is a dire need for therapeutics, with repair and regenerative properties, to assist in alleviating this medical crisis. Over the past decade, there has been a shift from conventional stem cell treatments towards the use of the secretome, the protein and factor secretions from cells. These components may possess novel druggable targets and hold the key to profoundly altering the field of regenerative medicine. Despite the progress in this field, clinical translation of secretome-containing products is limited by several challenges including but not limited to ensuring batch-to-batch consistency, the prevention of further heterogeneity, production of sufficient secretome quantities, product registration, good manufacturing practice protocols and the pharmacokinetic/pharmacodynamic profiles of all the components. Despite this, the secretome may hold the key to unlocking the regenerative blockage scientists have encountered for years. This review critically analyses the secretome derived from different cell sources and used in several tissues for tissue regeneration. Furthermore, it provides an overview of the current delivery strategies and the future perspectives for the secretome as a potential therapeutic. The success and possible shortcomings of the secretome are evaluated.PMID:39780313 | DOI:10.1111/wrr.13251

Sci Rep. 2025 Jan 8;15(1):1263. doi: 10.1038/s41598-025-85304-8.ABSTRACTWhile the effect of time-of-day (morning versus evening) on hormones, lipids and lipolysis has been studied in relation to meals and exercise, there are no studies that have investigated the effects of time-of-day on ice bath induced hormone and lipidome responses. In this crossover-designed study, a group of six women and six men, 26 ± 5 years old, 176 ± 7 cm tall, weighing 75 ± 10 kg, and a BMI of 23 ± 2 kg/m2 had an ice bath (8-12 °C for 5 min) both in the morning and evening on separate days. Absence from intense physical exercise, nutrient intake and meal order was standardized in the 24 h prior the ice baths to account for confounders such as diet or exercise. We collected venous blood samples before and after (5 min and 30 min) the ice baths to measure hormones (noradrenaline, adrenaline, and cortisol) and lipid levels in plasma via liquid chromatography mass spectrometry shotgun lipidomics. We found that ice baths in the morning increase plasma fatty acids more than in the evening. Overall plasma lipid composition significantly differed in-between the morning and evening, and only in the morning ice bathing is accompanied by significantly increased plasma fatty acids from 5.1 ± 2.2% to 6.0 ± 2.4% (P = 0.029) 5 min after and to 6.3 ± 3.1% (P = 0.008) 30 min after. Noradrenaline was not affected by time-of-day and increased significantly immediately after the ice baths in the morning by 127 ± 2% (pre: 395 ± 158 pg/ml, post 5 min: 896 ± 562 pg/ml, P = 0.025) and in the evening by 144 ± 2% (pre: 385 ± 146 pg/ml, post 5 min: 937 ± 547 pg/ml, P = 0.015). Cortisol was generally higher in the morning than in the evening (pre: 179 ± 108 pg/ml versus 91 ± 59 pg/ml, P = 0.013; post 5 min: 222 ± 96 pg/ml versus 101 ± 52 pg/ml, P = 0.001; post 30 min: 190 ± 96 pg/ml versus 98 ± 54 pg/ml, P = 0.009). There was no difference in the hormonal and lipidome response to an ice bath between women and men. The main finding of the study was that noradrenaline, adrenaline, cortisol and plasma lipidome responses are similar after an ice bath in the morning and evening. However, ice baths in the morning increase plasma fatty acids more than in the evening.PMID:39779795 | DOI:10.1038/s41598-025-85304-8

Food Res Int. 2025 Jan;200:115493. doi: 10.1016/j.foodres.2024.115493. Epub 2024 Dec 4.ABSTRACTIn this work, the lipidomic analysis on polar components of almond, coconut, and soy beverages was performed by liquid chromatography quadrupole time-of-flight mass spectrometry. A comparison with bovine milk was also performed. A total of 30 subclasses of polar lipids, belonging mainly to glycerophospholipids and sphingolipids, and a total of 572 molecular species were identified. Coconut showed various kinds of sphingolipids, belonging to hexosylceramides and sulfatides. Soy is particularly rich in molecular species of phospholipids. Fatty acids with chain length from 16 to 18 were the most common in almond. Numerous species of sphingomyelins were found in bovine milk, differently from plant-based beverages. Furthermore, a principal component analysis based on the polar lipid data was applied to discriminate samples, with 21 molecular species identified as biomarkers. This research opens interesting perspectives on vegetable beverages as bovine milk alternatives, especially in vegetarian and vegan diets.PMID:39779134 | DOI:10.1016/j.foodres.2024.115493

Mol Cancer. 2025 Jan 8;24(1):6. doi: 10.1186/s12943-024-02202-9.ABSTRACTBACKGROUND: Intratumor-resident bacteria represent an integral component of the tumor microenvironment (TME). Microbial dysbiosis, which refers to an imbalance in the bacterial composition and bacterial metabolic activities, plays an important role in regulating breast cancer development and progression. However, the impact of specific intratumor-resident bacteria on tumor progression and their underlying mechanisms remain elusive.METHODS: 16S rDNA gene sequencing was used to analyze the cancerous and paracancerous tissues from breast cancer patients. The mouse models of bearing 4T1 cell tumors were employed to assess the influence of bacterial colonization on tumor growth. Tissue infiltration of regulatory T (Treg) cells and CD8+ T cells was evaluated through immunohistochemistry and flow cytometric analysis. Comparative metabolite profiling in mice tumors was conducted using targeted metabolomics. Differential genes of tumor cells stimulated by bacteria were analyzed by transcriptomics and validated by qPCR assay.RESULTS: We found that Sphingobacterium displayed high abundance in cancerous tissues. Intra-tumoral colonization of Sphingobacterium multivorum (S. multivorum) promoted tumor progression in 4T1 tumor-bearing mice. Moreover, S. multivorum diminished the therapeutic efficacy of αPD-1 mAb, which was associated with the increase of regulatory T cell (Treg) infiltration, and decrese of the CD8+ T cell infiltration. Targeted metabolomics revealed a conspicuous reduction of propionylcarnitine in tumors colonized by S. multivorum Furthermore, the combination of metabolite propionylcarnitine and S. multivorum shown to suppress tumor growth compared that in S. multivorum alone in vivo. Mechanistically, S. multivorum promoted the secretion of chemokines CCL20 and CXCL8 from tumor cells. CCL20 secreted into the TME facilitated the recruitment of Treg cells and reduced CD8+ T cell infiltration, thus promoting tumor immune escape.CONCLUSIONS: This study reveals S. multivorum suppresses immune surveillance within the TME, thereby promoting breast cancer progression.PMID:39780177 | DOI:10.1186/s12943-024-02202-9

BMC Plant Biol. 2025 Jan 9;25(1):34. doi: 10.1186/s12870-025-06060-5.ABSTRACTBACKGROUND: Space-induced plant mutagenesis, driven by cosmic radiation, offers a promising approach for the selective breeding of new plant varieties. By leveraging the unique environment of outer space, we successfully induced mutagenesis in 'Deqin' alfalfa and obtained a fast-growing mutant. However, the molecular mechanisms underlying its rapid growth remain poorly unexplored.RESULTS: Comparative analyses of transcriptomics, proteomics, and hormone profiles were conducted in root, stem, and leaf tissues of both mutant and non-mutagenic materials. Targeted plant hormone showed notable increases in the levels of 3-indolebutyric, indole-3-acetic, and 3-indolepropionic acids in the mutant, with percentage increases of 33.55%, 32.49%, and 30.39%, respectively. Zeatin-riboside and dihydrozeatin riboside levels increased by 164.92% and 25.86%, while giberellin (GA) 7, GA3, and GA1 levels increased by 219.52%, 68.74%, and 40.98%. Non-mutagenic materials sprayed with exogenous 3-indolebutyric acid, zeatin-riboside, and GA7 exhibited significant growth acceleration. Transcriptomics identified 49,095 annotated genes, with 2,009, 1,889, and 1,760 upregulated and 2,082, 2,035, and 1,499 downregulated in the leaves, stems, and roots, respectively. Twenty-two genes related to plant hormone biosynthesis showed significant alterations. Screening through weighted correlation network analysis revealed ten candidate genes, four of which were associated with photosynthesis and starch and sucrose metabolism. Integrated analysis of targeted plant hormone metabolomics and transcriptomics indicated that plant hormone signal transduction played a crucial role. Proteomics revealed 479 differentially accumulated proteins, of which 174 were upregulated and 305 were downregulated. Integrated proteomics and transcriptomics showed that photosynthesis, starch and sucrose metabolism, carbon metabolism, and carbon fixation in photosynthetic organisms promoted the rapid growth of the mutants. By integrating multi-omics data, we elucidated the synergistic effects of pathways such as hormone signal transduction and tryptophan metabolism on the rapid growth of the mutants.CONCLUSION: This study demonstrated the significance of plant hormones in the rapid growth of the mutants and identified key genes and metabolic pathways. Our findings provide valuable information for the genetic improvement of alfalfa varieties and serve as a reference for achieving rapid growth in other plants.PMID:39780091 | DOI:10.1186/s12870-025-06060-5

Commun Med (Lond). 2025 Jan 9;5(1):11. doi: 10.1038/s43856-024-00682-w.ABSTRACTBACKGROUND: Alzheimer's disease (AD) is a major neurodegenerative disorder with significant environmental factors, including diet and lifestyle, influencing its onset and progression. Although previous studies have suggested that certain diets may reduce the incidence of AD, the underlying mechanisms remain unclear.METHOD: In this post-hoc analysis of a randomized crossover study of 20 elderly adults, we investigated the effects of a modified Mediterranean ketogenic diet (MMKD) on the plasma lipidome in the context of AD biomarkers, analyzing 784 lipid species across 47 classes using a targeted lipidomics platform.RESULTS: Here we identified substantial changes in response to MMKD intervention, aside from metabolic changes associated with a ketogenic diet, we identified a a global elevation across all plasmanyl and plasmenyl ether lipid species, with many changes linked to clinical and biochemical markers of AD. We further validated our findings by leveraging our prior clinical studies into lipid related changeswith AD (n = 1912), and found that the lipidomic signature with MMKD was inversely associated with the lipidomic signature of prevalent and incident AD.CONCLUSIONS: Intervention with a MMKD was able to alter the plasma lipidome in ways that contrast with AD-associated patterns. Given its low risk and cost, MMKD could be a promising approach for prevention or early symptomatic treatment of AD.PMID:39779882 | DOI:10.1038/s43856-024-00682-w

Nat Microbiol. 2025 Jan 8. doi: 10.1038/s41564-024-01910-8. Online ahead of print.ABSTRACTTo overtake competitors, microbes produce and secrete secondary metabolites that kill neighbouring cells and sequester nutrients. This metabolite-mediated competition probably evolved in complex microbial communities in the presence of viral pathogens. We therefore hypothesized that microbes secrete natural products that make competitors sensitive to phage infection. We used a binary-interaction screen and chemical characterization to identify a secondary metabolite (coelichelin) produced by Streptomyces sp. that sensitizes its soil competitor Bacillus subtilis to phage infection in vitro. The siderophore coelichelin sensitized B. subtilis to a panel of lytic phages (SPO1, SP10, SP50, Goe2) via iron sequestration, which prevented the activation of B. subtilis Spo0A, the master regulator of the stationary phase and sporulation. Metabolomics analysis revealed that other bacterial natural products may also provide phage-mediated competitive advantages to their producers. Overall, this work reveals that synergy between natural products and phages can shape the outcomes of competition between microbes.PMID:39779880 | DOI:10.1038/s41564-024-01910-8

Nat Microbiol. 2025 Jan 8. doi: 10.1038/s41564-024-01882-9. Online ahead of print.ABSTRACTSepsis is a major cause of morbidity and mortality, but our understanding of the mechanisms underlying survival or susceptibility is limited. Here, as pathogens often subvert host defence mechanisms, we hypothesized that this might influence the outcome of sepsis. We used microbiota analysis, faecal microbiota transplantation, antibiotic treatment and caecal metabolite analysis to show that gut-microbiota-derived tryptophan metabolites including indoles increased host survival in a mouse model of Serratia marcescens sepsis. Infection in macrophage-specific aryl hydrocarbon receptor (AhR) knockout mice revealed that AhR activation induced transcriptional reprogramming in macrophages and increased bacterial clearance and host survival. However, culture supernatants from multiple bacterial pathogens inhibited AhR activation in vitro. We showed that the secreted siderophore, enterobactin, inhibited AhR activation in vitro and increased sepsis mortality in vivo. By contrast, oral or systemic tryptophan supplementation increased survival. These findings show that sepsis survival depends upon the interplay between pathogen inhibition and the activation of AhR by a microbiota-derived metabolite.PMID:39779878 | DOI:10.1038/s41564-024-01882-9