PubMed

Curr Protoc. 2024 Mar;4(3):e1014. doi: 10.1002/cpz1.1014.ABSTRACTThis article presents a practical guide to mass spectrometry-based data-independent acquisition and label-free quantification for proteomics analysis applied to cerebrospinal fluid, offering a robust and scalable approach to probing the proteomic composition of the central nervous system. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Cerebrospinal fluid sample collection and preparation for mass spectrometry analysis Basic Protocol 2: Mass spectrometry sample analysis with data-independent acquisition Support Protocol: Data-dependent mass spectrometry and spectral library construction Basic Protocol 3: Analysis of mass spectrometry data.PMID:38506436 | DOI:10.1002/cpz1.1014

Arch Insect Biochem Physiol. 2024 Mar;115(3):e22104. doi: 10.1002/arch.22104.ABSTRACTAs a common defense mechanism in Hymenoptera, bee venom has complex components. Systematic and comprehensive analysis of bee venom components can aid in early evaluation, accurate diagnosis, and protection of organ function in humans in cases of bee stings. To determine the differences in bee venom composition and metabolic pathways between Apis cerana and Apis mellifera, proton nuclear magnetic resonance (1 H-NMR) technology was used to detect the metabolites in venom samples. A total of 74 metabolites were identified and structurally analyzed in the venom of A. cerana and A. mellifera. Differences in the composition and abundance of major components of bee venom from A. cerana and A. mellifera were mapped to four main metabolic pathways: valine, leucine and isoleucine biosynthesis; glycine, serine and threonine metabolism; alanine, aspartate and glutamate metabolism; and the tricarboxylic acid cycle. These findings indicated that the synthesis and metabolic activities of proteins or polypeptides in bee venom glands were different between A. cerana and A. mellifera. Pyruvate was highly activated in 3 selected metabolic pathways in A. mellifera, being much more dominant in A. mellifera venom than in A. cerana venom. These findings indicated that pyruvate in bee venom glands is involved in various life activities, such as biosynthesis and energy metabolism, by acting as a precursor substance or intermediate product.PMID:38506277 | DOI:10.1002/arch.22104

Food Funct. 2024 Mar 20. doi: 10.1039/d3fo05345h. Online ahead of print.ABSTRACTThis study aimed to elucidate the effect of tyrosol (TYR) on the amelioration of nonalcoholic fatty liver disease (NAFLD). Male C57BL/6J mice were fed a low-fat diet (LFD), a high-fat diet (HFD), or a HFD supplemented with 0.025% (w/w) TYR (TYR) for 16 weeks. Following a 16-week intervention, the TYR cohort exhibited diminished final body weight and hepatic lipid accumulation, compared to HFD fed mice. Liver metabolomics analysis revealed that TYR increased the hepatic levels of spermidine, taurine, linoleic acid, malic acid and eicosapentaenoic acid (EPA), indicating the beneficial effect of TYR on lipid homeostasis. Using molecular docking analysis and the luciferase assay, we found that TYR acts as a ligand and binds with peroxisome proliferator-activated receptor-α (PPARα), which plays a pivotal role in the modulation of hepatic lipid metabolism, thereby activating the transcription of downstream genes. Our results suggest that TYR alleviates NAFLD in HFD-fed mice probably by the modulation of the PPARα signaling pathway.PMID:38506160 | DOI:10.1039/d3fo05345h

J Cell Mol Med. 2024 Apr;28(7):e18194. doi: 10.1111/jcmm.18194.ABSTRACTNon-alcoholic steatohepatitis (NASH) is a severe form of fatty liver disease. If not treated, it can lead to liver damage, cirrhosis and even liver cancer. However, advances in treatment have remained relatively slow, and there is thus an urgent need to develop appropriate treatments. Hedan tablet (HDP) is used to treat metabolic syndrome. However, scientific understanding of the therapeutic effect of HDP on NASH remains limited. We used HDP to treat a methionine/choline-deficient diet-induced model of NASH in rats to elucidate the therapeutic effects of HDP on liver injury. In addition, we used untargeted metabolomics to investigate the effects of HDP on metabolites in liver of NASH rats, and further validated its effects on inflammation and lipid metabolism following screening for potential target pathways. HDP had considerable therapeutic, anti-oxidant, and anti-inflammatory effects on NASH. HDP could also alter the hepatic metabolites changed by NASH. Moreover, HDP considerable moderated NF-κB and lipid metabolism-related pathways. The present study found that HDP had remarkable therapeutic effects in NASH rats. The therapeutic efficacy of HDP in NASH mainly associated with regulation of NF-κB and lipid metabolism-related pathways via arachidonic acid metabolism, glycine-serine-threonine metabolism, as well as steroid hormone biosynthesis.PMID:38506086 | DOI:10.1111/jcmm.18194

Angew Chem Weinheim Bergstr Ger. 2021 Mar 1;133(10):5121-5126. doi: 10.1002/ange.202015962. Epub 2021 Feb 1.ABSTRACTDer metallhaltige Wirkstoff BOLD‐100/KP1339 zeigte bereits vielversprechende Resultate in verschiedenen In vitro‐ und In vivo‐Tumormodellen sowie in klinischen Studien. Der detaillierte Wirkmechanismus wurde jedoch noch nicht komplett aufgeklärt. Als entscheidende Wirkstoffeffekte kristallisierten sich kürzlich die Stressinduktion im endoplasmatischen Retikulum (ER) und die damit einhergehende Modulierung von HSPA5 (GRP78) heraus. Das spontane und stabile Addukt zwischen BOLD‐100 und menschlichem Serumalbumin wurde als Immobilisierungsstrategie ausgewählt, um einen chemoproteomischen Ansatz auszuführen, der die ribosomalen Proteine RPL10, RPL24 und den Transkriptionsfaktor GTF2I als potentielle Interaktoren dieser Ru(III)‐Verbindung identifizierten. Dieses Ergebnis wurde mit proteomischen und transkriptomischen Profiling‐Experimenten kombiniert, was die Interpretation einer ribosomalen Beeinträchtigung sowie der Induktion von ER‐Stress unterstützte. Die Bildung von Polyribosomen und begleitende ER‐Schwellungen in behandelten Krebszellen wurden zudem durch TEM‐Messungen bestätigt. Somit scheint eine direkte Wechselwirkung von BOLD‐100 mit ribosomalen Proteinen die ER‐Stressinduktion und die Modulierung von GRP78 in Krebszellen zu begleiten.PMID:38505777 | PMC:PMC10947255 | DOI:10.1002/ange.202015962

Front Endocrinol (Lausanne). 2024 Mar 4;15:1182519. doi: 10.3389/fendo.2024.1182519. eCollection 2024.ABSTRACTBACKGROUND: Alzheimer's disease (AD) is increasing in prevalence, but effective treatments for its cognitive impairment remain severely limited. This study investigates the impact of ketone body production through dietary manipulation on memory in persons with mild cognitive impairment due to early AD and explores potential mechanisms of action.METHODS: We conducted a 12-week, parallel-group, controlled feasibility trial of a ketogenic diet, the modified Atkins diet (MAD), compared to a control diet in patients with cognitive impairments attributed to AD. We administered neuropsychological assessments, including memory tests, and collected blood samples at baseline and after 12 weeks of intervention. We performed untargeted lipidomic and targeted metabolomic analyses on plasma samples to detect changes over time.RESULTS: A total of 839 individuals were screened to yield 38 randomized participants, with 20 assigned to receive MAD and 18 assigned to receive a control diet. Due to attrition, only 13 in the MAD arm and nine in the control arm were assessed for the primary endpoint, with two participants meeting ketosis levels used to define MAD adherence criteria. The average change from baseline in the Memory Composite Score was 1.37 (95% CI: -0.87, 4.90) points higher in the MAD group compared to the control group. The effect size of the intervention on baseline MAD change was moderate (Cohen's D = 0.57, 95% CI: -0.67, 1.33). In the 15 participants (nine MAD, six control) assessed for lipidomic and metabolomic-lipidomics and metabolomics, 13 metabolites and 10 lipids showed significant changes from baseline to 12 weeks, including triacylglycerols (TAGs, 50:5, 52:5, and 52:6), sphingomyelins (SM, 44:3, 46:0, 46:3, and 48:1), acetoacetate, fatty acylcarnitines, glycerol-3-phosphate, and hydroxy fatty acids.CONCLUSIONS: Attrition was greatest between baseline and week 6. All participants retained at week 6 completed the study. Despite low rates of adherence by criteria defined a priori, lipidomic and metabolomic analyses indicate significant changes from baseline in circulating lipids and metabolites between MAD and control participants at 12-week postrandomization, and MAD participants showed greater, albeit nonsignificant, improvement in memory.PMID:38505743 | PMC:PMC10949529 | DOI:10.3389/fendo.2024.1182519

Front Microbiol. 2024 Mar 5;15:1358530. doi: 10.3389/fmicb.2024.1358530. eCollection 2024.ABSTRACTINTRODUCTION: Patients with COVID-19 have dysbiosis of the intestinal microbiota with altered metabolites in the stool. However, it remains unclear whether the differences among SARS-CoV-2 variants lead to differences in intestinal microbiota and metabolites. Thus, we compared the microbiome and metabolome changes for each SARS-CoV-2 variant in patients with COVID-19.MATERIALS AND METHODS: We conducted a multicenter observational study of patients with COVID-19 and performed fecal microbiome, metabolome, and calprotectin analyses and compared the results among the different SARS-CoV-2 variants.RESULTS: Twenty-one patients with COVID-19 were enrolled and stratified according to the SARS-CoV-2 strain: six with the Alpha, 10 with the Delta, and five with the Omicron variant. Fecal microbiome analysis showed that α-diversity was reduced in the order of the Omicron, Delta, and Alpha variants (p = 0.07). Linear discriminant analysis revealed differences in the abundance of short-chain fatty acid-producing gut microbiota for each SARS-CoV-2 variant. Fecal metabolome analysis showed that the Omicron and Delta variants had markedly reduced propionic and lactic acid levels compared to the Alpha strain (p < 0.05).CONCLUSION: The intestinal microbiota of patients with COVID-19 varies depending on the SARS-CoV-2 variant. Dysbiosis of the intestinal microbiota due to differences in SARS-CoV-2 variants causes a decrease in intestinal short-chain fatty acids.PMID:38505560 | PMC:PMC10948395 | DOI:10.3389/fmicb.2024.1358530

Front Microbiol. 2024 Mar 5;15:1337368. doi: 10.3389/fmicb.2024.1337368. eCollection 2024.ABSTRACTMeta-organisms encompassing the host and resident microbiota play a significant role in combatting diseases and responding to stress. Hence, there is growing traction to build a knowledge base about this ecosystem, particularly to characterize the bidirectional relationship between the host and microbiota. In this context, metabolomics has emerged as the major converging node of this entire ecosystem. Systematic comprehension of this resourceful omics component can elucidate the organism-specific response trajectory and the communication grid across the ecosystem embodying meta-organisms. Translating this knowledge into designing nutraceuticals and next-generation therapy are ongoing. Its major hindrance is a significant knowledge gap about the underlying mechanisms maintaining a delicate balance within this ecosystem. To bridge this knowledge gap, a holistic picture of the available information has been presented with a primary focus on the microbiota-metabolite relationship dynamics. The central theme of this article is the gut-brain axis and the participating microbial metabolites that impact cerebral functions.PMID:38505556 | PMC:PMC10949987 | DOI:10.3389/fmicb.2024.1337368

J Thorac Dis. 2024 Feb 29;16(2):1552-1564. doi: 10.21037/jtd-23-1326. Epub 2024 Feb 27.ABSTRACTLung cancer remains the leading cause of cancer mortality. Screening guidelines have been implemented in the past decade to aid in earlier detection of at-risk groups. Nevertheless, computed tomography (CT) scans, the principal screening modality in use today, are still low yield, with 3.6% of lung cancer confirmed amongst 39.1% of lesions detected over a 3-year period. They also carry relatively high false positive rates, between 9% and 27%, which can bear unnecessary financial and emotional costs to patients. As such, research efforts have been dedicated to the development of lung cancer screening adjuncts to improve detection reliability. We herein review several emerging technologies in this specific arena and their efficacy. These include plasma markers (microDNA, DNA methylation, and tumor-associated antibodies), breath/sputum biomarkers [volatile organic compounds (VOCs) and exhaled breath condensate (EBC)], proteomics, metabolomics, and machine learning, such as radiomics technology. We find that, across the board, they offer promising results in terms of non-invasive diagnostics, genetic sequencing for higher-risk individuals, and accessibility for a diverse cohort of patients. While these screening adjuncts are unlikely to completely replace the current standard of care at the moment, continued research into these technologies is crucial to improve and personalize the identification, treatment, and outcome of lung cancer patients in the near future.PMID:38505010 | PMC:PMC10944753 | DOI:10.21037/jtd-23-1326

Front Plant Sci. 2024 Mar 5;15:1292054. doi: 10.3389/fpls.2024.1292054. eCollection 2024.ABSTRACTPlants intricately deploy defense systems to counter diverse biotic and abiotic stresses. Omics technologies, spanning genomics, transcriptomics, proteomics, and metabolomics, have revolutionized the exploration of plant defense mechanisms, unraveling molecular intricacies in response to various stressors. However, the complexity and scale of omics data necessitate sophisticated analytical tools for meaningful insights. This review delves into the application of artificial intelligence algorithms, particularly machine learning and deep learning, as promising approaches for deciphering complex omics data in plant defense research. The overview encompasses key omics techniques and addresses the challenges and limitations inherent in current AI-assisted omics approaches. Moreover, it contemplates potential future directions in this dynamic field. In summary, AI-assisted omics techniques present a robust toolkit, enabling a profound understanding of the molecular foundations of plant defense and paving the way for more effective crop protection strategies amidst climate change and emerging diseases.PMID:38504888 | PMC:PMC10948452 | DOI:10.3389/fpls.2024.1292054

Front Plant Sci. 2024 Mar 5;15:1336513. doi: 10.3389/fpls.2024.1336513. eCollection 2024.ABSTRACTMost food crops are susceptible to necrotrophic bacteria that cause rotting and wilting diseases in fleshy organs and foods. All varieties of cultivated potato (Solanum tuberosum L.) are susceptible to diseases caused by Pectobacterium species, but resistance has been demonstrated in wild potato relatives including S. chacoense. Previous studies demonstrated that resistance is in part mediated by antivirulence activity of phytochemicals in stems and tubers. Little is known about the genetic basis of antivirulence traits, and the potential for inheritance and introgression into cultivated potato is unclear. Here, the metabolites and genetic loci associated with antivirulence traits in S. chacoense were elucidated by screening a sequenced S. tuberosum x S. chacoense recombinant inbred line (RIL) population for antivirulence traits of its metabolite extracts. Metabolite extracts from the RILs exhibited a quantitative distribution for two antivirulence traits that were positively correlated: quorum sensing inhibition and exo-protease inhibition, with some evidence of transgressive segregation, supporting the role of multiple loci and metabolites regulating these resistance-associated systems. Metabolomics was performed on the highly resistant and susceptible RILs that revealed 30 metabolites associated with resistance, including several alkaloids and terpenes. Specifically, several prenylated metabolites were more abundant in resistant RILs. We constructed a high-density linkage map with 795 SNPs mapped to 12 linkage groups, spanning a length of 1,507 cM and a density of 1 marker per 1.89 cM. Genetic mapping of the antivirulence and metabolite data identified five quantitative trait loci (QTLs) related to quorum sensing inhibition that explained 8-28% of the phenotypic variation and two QTLs for protease activity inhibition that explained 14-19% of the phenotypic variation. Several candidate genes including alkaloid, and secondary metabolite biosynthesis that are related to disease resistance were identified within these QTLs. Taken together, these data support that quorum sensing inhibition and exo-protease inhibition assays may serve as breeding targets to improve resistance to nectrotrophic bacterial pathogens in potato and other plants. The identified candidate genes and metabolites can be utilized in marker assisted selection and genomic selection to improve soft- rot and blackleg disease resistance.PMID:38504885 | PMC:PMC10949924 | DOI:10.3389/fpls.2024.1336513

Oncoimmunology. 2024 Mar 17;13(1):2308940. doi: 10.1080/2162402X.2024.2308940. eCollection 2024.ABSTRACTPreclinical evidence indicates potent antitumor properties of local anesthetics. Numerous underlying mechanisms explaining such anticancer effects have been identified, suggesting direct cytotoxic as well as indirect immunemediated effects that together reduce the proliferative, invasive and migratory potential of malignant cells. Although some retrospective and correlative studies support these findings, prospective randomized controlled trials have not yet fully confirmed the antineoplastic activity of local anesthetics, likely due to the intricate methodology required for mitigating confounding factors. This trial watch aims at compiling all published preclinical and clinical research, along with completed and ongoing trials, that explore the potential antitumor effects of local anesthetics.PMID:38504848 | PMC:PMC10950281 | DOI:10.1080/2162402X.2024.2308940

J Tradit Chin Med. 2024 Apr;44(2):303-314. doi: 10.19852/j.cnki.jtcm.20230510.001.ABSTRACTOBJECTIVE: To investigate the impact of Yemazhui (Herba Eupatorii Lindleyani, HEL) against lipopolysaccharide (LPS)-induced acute lung injury (ALI) and explore its underlying mechanism in vivo.METHODS: The chemical constituents of HEL were analyzed by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry method. Then, HEL was found to suppress LPS-induced ALI in vivo. Six-week-old male Sprague-Dawley rats were randomly divided into 6 groups: control, LPS, Dexamethasone (Dex), HEL low dose 6 g/kg (HEL-L), HEL medium dose 18 g/kg (HEL-M) and HEL high dose 54 g/kg (HEL-H) groups. The model rats were intratracheally injected with 3 mg/kg LPS to establish an ALI model. Leukocyte counts, lung wet/dry weight ratio, as well as myeloperoxidase (MPO) activity were determined followed by the detection with hematoxylin and eosin staining, enzyme linked immunosorbent assay, quantitative real time polymerase chain reaction, western blotting, immunohistochemistry, and immunofluorescence. Besides, to explore the effect of HEL on ALI-mediated intestinal flora, we performed 16s rRNA sequencing analysis of intestinal contents.RESULTS: HEL attenuated LPS-induced inflammation in lung tissue and intestinal flora disturbance. Mechanism study indicated that HEL suppressed the lung coefficient and wet/dry weight ratio of LPS-induced ALI in rats, inhibited leukocytes exudation and MPO activity, and improved the pathological injury of lung tissue. In addition, HEL reduced the expression of tumor necrosis factor-alpha, interleukin-1beta (IL-1β) and interleukin-6 (IL-6) in bronchoalveolar lavage fluid and serum, and inhibited nuclear displacement of nuclear factor kappa-B p65 (NF-κBp65). And 18 g/kg HEL also reduced the expression levels of toll-like receptor 4 (TLR4), myeloid differentiation factor 88, NF-κBp65, phosphorylated inhibitor kappa B alpha (phospho-IκBα), nod-like receptor family pyrin domain-containing 3 protein (NLRP3), IL-1β, and interleukin-18 (IL-18) in lung tissue, and regulated intestinal flora disturbance.CONCLUSIONS: In summary, our findings revealed that HEL has a protective effect on LPS-induced ALI in rats, and its mechanism may be related to inhibiting TLR4/ NF-κB/NLRP3 signaling pathway and improving intestinal flora disturbance.PMID:38504536 | DOI:10.19852/j.cnki.jtcm.20230510.001

J Tradit Chin Med. 2024 Apr;44(2):260-267. doi: 10.19852/j.cnki.jtcm.20240203.003.ABSTRACTOBJECTIVE: To explore the anti-inflammatory components and mechanism of the non-volatile ingredients of patchouli.METHODS: High performance liquid chromatography-heated electron spray ionization-high resolution mass spectroscope (HPLC-HESI-HRMS) was used to analyze the chemical constituents of the non-volatile ingredients of patchouli. The anti-inflammatory activity of ingredients was evaluated using lipopolysaccharide (LPS) induced RAW264.7 cell inflammation model, and the anti-inflammatory mechanism was investigated using multivariate statistical analysis of cell metabolomics.RESULTS: The non-volatile ingredients of patchouli were characterized by HPLC-HESI-HRMS, and 36 flavonoids and 18 other components were identified. These ingredients of patchouli not only had a good protective effect on the LPS-induced inflammation model of RAW264.7 cells, but also regulated the expression levels of arginine, L-leucine, cholesterol, fructose and sorbitol by down-regulating arginine metabolism, aminoacyl-tRNA biosynthesis, polyol/sorbitol pathway, so as to reduce inflammation and reduce cell damage.CONCLUSION: The non-volatile ingredients of patchouli had good anti-inflammatory effect and exerted its curative effect by regulating endogenous metabolic pathway to reduce inflammatory response.PMID:38504532 | DOI:10.19852/j.cnki.jtcm.20240203.003

BMC Pediatr. 2024 Mar 19;24(1):196. doi: 10.1186/s12887-024-04633-1.ABSTRACTBACKGROUND: Ifosfamide is a major anti-cancer drug in children with well-known renal toxicity. Understanding the mechanisms underlying this toxicity could help identify children at increased risk of toxicity.METHODS: The IFOS01 study included children undergoing ifosfamide-based chemotherapy for Ewing sarcoma or rhabdomyosarcoma. A fully evaluation of renal function was performed during and after chemotherapy. Proton nuclear magnetic resonance (NMR) and conventional biochemistry were used to detect early signs of ifosfamide-induced tubulopathy. The enzymatic activity of aldehyde dehydrogenase (ALDH) was measured in the peripheral blood lymphocytes as a marker of ifosfamide-derived chloroacetaldehyde detoxification capacity. Plasma and urine concentrations of ifosfamide and dechloroethylated metabolites were quantified.RESULTS: The 15 participants received a median total ifosfamide dose of 59 g/m2 (range: 24-102), given over a median of 7 cycles (range: 4-14). All children had acute proximal tubular toxicity during chemotherapy that was reversible post-cycle, seen with both conventional assays and NMR. After a median follow-up of 31 months, 8/13 children presented overall chronic toxicity among which 7 had decreased glomerular filtration rate. ALDH enzymatic activity showed high inter- and intra-individual variations across cycles, though overall activity looked lower in children who subsequently developed chronic nephrotoxicity. Concentrations of ifosfamide and metabolites were similar in all children.CONCLUSIONS: Acute renal toxicity was frequent during chemotherapy and did not allow identification of children at risk for long-term toxicity. A role of ALDH in late renal dysfunction is possible so further exploration of its enzymatic activity and polymorphism should be encouraged to improve the understanding of ifosfamide-induced nephrotoxicity.PMID:38504218 | DOI:10.1186/s12887-024-04633-1

BMC Genomics. 2024 Mar 19;25(1):291. doi: 10.1186/s12864-024-10202-8.ABSTRACTBACKGROUND: Thymus mongolicus (family Lamiaceae) is a Thyme subshrub with strong aroma and remarkable environmental adaptability. Limited genomic information limits the use of this plant.RESULTS: Chromosome-level 605.2 Mb genome of T. mongolicus was generated, with 96.28% anchored to 12 pseudochromosomes. The repetitive sequences were dominant, accounting for 70.98%, and 32,593 protein-coding genes were predicted. Synteny analysis revealed that Lamiaceae species generally underwent two rounds of whole genome duplication; moreover, species-specific genome duplication was identified. A recent LTR retrotransposon burst and tandem duplication might play important roles in the formation of the Thymus genome. Using comparative genomic analysis, phylogenetic tree of seven Lamiaceae species was constructed, which revealed that Thyme plants evolved recently in the family. Under the phylogenetic framework, we performed functional enrichment analysis of the genes on nodes that contained the most gene duplication events (> 50% support) and of relevant significant expanded gene families. These genes were highly associated with environmental adaptation and biosynthesis of secondary metabolites. Combined transcriptome and metabolome analyses revealed that Peroxidases, Hydroxycinnamoyl-CoA shikimate/quinate hydroxycinnamoyl transferases, and 4-coumarate-CoA ligases genes were the essential regulators of the phenylpropanoid-flavonoid pathway. Their catalytic products (e.g., apigenin, naringenin chalcone, and several apigenin-related compounds) might be responsible for the environmental tolerance and aromatic properties of T. mongolicus.CONCLUSION: This study enhanced the understanding of the genomic evolution of T. mongolicus, enabling further exploration of its unique traits and applications, and contributed to the understanding of Lamiaceae genomics and evolutionary biology.PMID:38504151 | DOI:10.1186/s12864-024-10202-8

Nat Metab. 2024 Mar 19. doi: 10.1038/s42255-024-00997-x. Online ahead of print.ABSTRACTMitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD+) levels are hallmarks of skeletal muscle ageing and sarcopenia1-3, but it is unclear whether these defects result from local changes or can be mediated by systemic or dietary cues. Here we report a functional link between circulating levels of the natural alkaloid trigonelline, which is structurally related to nicotinic acid4, NAD+ levels and muscle health in multiple species. In humans, serum trigonelline levels are reduced with sarcopenia and correlate positively with muscle strength and mitochondrial oxidative phosphorylation in skeletal muscle. Using naturally occurring and isotopically labelled trigonelline, we demonstrate that trigonelline incorporates into the NAD+ pool and increases NAD+ levels in Caenorhabditis elegans, mice and primary myotubes from healthy individuals and individuals with sarcopenia. Mechanistically, trigonelline does not activate GPR109A but is metabolized via the nicotinate phosphoribosyltransferase/Preiss-Handler pathway5,6 across models. In C. elegans, trigonelline improves mitochondrial respiration and biogenesis, reduces age-related muscle wasting and increases lifespan and mobility through an NAD+-dependent mechanism requiring sirtuin. Dietary trigonelline supplementation in male mice enhances muscle strength and prevents fatigue during ageing. Collectively, we identify nutritional supplementation of trigonelline as an NAD+-boosting strategy with therapeutic potential for age-associated muscle decline.PMID:38504132 | DOI:10.1038/s42255-024-00997-x

Environ Sci Technol. 2024 Mar 19. doi: 10.1021/acs.est.4c00375. Online ahead of print.ABSTRACTSoil microbes, the main driving force of terrestrial biogeochemical cycles, facilitate soil organic matter turnover. However, the influence of the soil fauna on microbial communities remains poorly understood. We investigated soil microbiota dynamics by introducing competition and predation among fauna into two soil ecosystems with different fertilization histories. The interactions significantly affected rare microbial communities including bacteria and fungi. Predation enhanced the abundance of C/N cycle-related genes. Rare microbial communities are important drivers of soil functional gene enrichment. Key rare microbial taxa, including SM1A02, Gammaproteobacteria, and HSB_OF53-F07, were identified. Metabolomics analysis suggested that increased functional gene abundance may be due to specific microbial metabolic activity mediated by soil fauna interactions. Predation had a stronger effect on rare microbes, functional genes, and microbial metabolism compared to competition. Long-term organic fertilizer application increased the soil resistance to animal interactions. These findings provide a comprehensive understanding of microbial community dynamics under soil biological interactions, emphasizing the roles of competition and predation among soil fauna in terrestrial ecosystems.PMID:38504110 | DOI:10.1021/acs.est.4c00375

Nat Commun. 2024 Mar 19;15(1):2463. doi: 10.1038/s41467-024-46837-0.ABSTRACTMetabolic changes precede malignant histology. However, it remains unclear whether detectable characteristic metabolome exists in esophageal squamous cell carcinoma (ESCC) tissues and biofluids for early diagnosis. Here, we conduct NMR- and MS-based metabolomics on 1,153 matched ESCC tissues, normal mucosae, pre- and one-week post-operative sera and urines from 560 participants across three hospitals, with machine learning and WGCNA. Aberrations in 'alanine, aspartate and glutamate metabolism' proved to be prevalent throughout the ESCC evolution, consistently identified by NMR and MS, and reflected in 16 serum and 10 urine metabolic signatures in both discovery and validation sets. NMR-based simplified panels of any five serum or urine metabolites outperform clinical serological tumor markers (AUC = 0.984 and 0.930, respectively), and are effective in distinguishing early-stage ESCC in test set (serum accuracy = 0.994, urine accuracy = 0.879). Collectively, NMR-based biofluid screening can reveal characteristic metabolic events of ESCC and be feasible for early detection (ChiCTR2300073613).PMID:38504100 | DOI:10.1038/s41467-024-46837-0

Nat Commun. 2024 Mar 19;15(1):2359. doi: 10.1038/s41467-024-46132-y.ABSTRACTGenetic mechanisms of blood pressure (BP) regulation remain poorly defined. Using kidney-specific epigenomic annotations and 3D genome information we generated and validated gene expression prediction models for the purpose of transcriptome-wide association studies in 700 human kidneys. We identified 889 kidney genes associated with BP of which 399 were prioritised as contributors to BP regulation. Imputation of kidney proteome and microRNAome uncovered 97 renal proteins and 11 miRNAs associated with BP. Integration with plasma proteomics and metabolomics illuminated circulating levels of myo-inositol, 4-guanidinobutanoate and angiotensinogen as downstream effectors of several kidney BP genes (SLC5A11, AGMAT, AGT, respectively). We showed that genetically determined reduction in renal expression may mimic the effects of rare loss-of-function variants on kidney mRNA/protein and lead to an increase in BP (e.g., ENPEP). We demonstrated a strong correlation (r = 0.81) in expression of protein-coding genes between cells harvested from urine and the kidney highlighting a diagnostic potential of urinary cell transcriptomics. We uncovered adenylyl cyclase activators as a repurposing opportunity for hypertension and illustrated examples of BP-elevating effects of anticancer drugs (e.g. tubulin polymerisation inhibitors). Collectively, our studies provide new biological insights into genetic regulation of BP with potential to drive clinical translation in hypertension.PMID:38504097 | DOI:10.1038/s41467-024-46132-y