PubMed

Phytomedicine. 2025 May 3;143:156826. doi: 10.1016/j.phymed.2025.156826. Online ahead of print.ABSTRACTBACKGROUND: Lung adenocarcinoma (LUAD) remains a leading cause of cancer mortality due to resistance, metastasis, and recurrence. Unlike conventional cytotoxic therapies, Xingxiao Pills (XXP), a classic traditional Chinese medicine formula, offers a complementary approach to treating LUAD, while its non-cytotoxic anti-cancer mechanisms remain unclear.PURPOSE: To investigate the effect and mechanism of XXP on LUAD progression and stemness via lipid metabolism regulation.METHOD: UHPLC-MS/MS was used to analyze the chemical constituents of XXP. The effects of XXP on LUAD cell proliferation, migration, invasion, and stemness were evaluated using CCK-8, Transwell, and tumor sphere assays. A LUAD xenograft model confirmed XXP's anti-tumor effects. Transcriptomics, metabolomics, ELISA, qRT-PCR, and Western blot were used to investigate the underlying mechanisms. Kaplan-Meier (KM) survival analysis and stemness index scores were performed for LUAD patients based on the TCGA dataset. Statistical analyses were performed using Student's t-test, ANOVA, and KM survival analysis (p< 0.05 considered significant).RESULTS: XXP inhibits LUAD progression in mouse and cell models by targeting lipid metabolism reprogramming. It suppresses FA synthesis, elongation, oxidation, and glycerophospholipid (GPL) metabolism while upregulating arachidonic acid (AA) metabolism. Mechanistic studies revealed that XXP attenuates tumor stemness by inhibiting PLA2G4A (cPLA2), lowering AA release, and disrupting SMO/GLI1/SOX2 signaling, an effect also observed with the cPLA2 inhibitor AACOCF3. KM analysis showed that higher PLA2G4A expression correlated with a worse 5-year prognosis in LUAD (p = 0.0047). The low GPL/high AA group (consistent with XXP's metabolic pattern) had better survival (p = 0.0028) and a lower stemness index (p< 0.0001) than the high GPL/low AA unrelated group.CONCLUSION: Xingxiao Pill modulates GPL and AA metabolism and downregulates the PLA2G4A (cPLA2)-AA/SMO/GLI1/SOX2 axis. Through this mechanism, XXP effectively inhibits tumor growth and stemness by targeting lipid metabolism.PMID:40339555 | DOI:10.1016/j.phymed.2025.156826

Phytomedicine. 2025 Apr 22;143:156695. doi: 10.1016/j.phymed.2025.156695. Online ahead of print.ABSTRACTBACKGROUND: The Huiyang Shengji Decoction (HYSJD) is a renowned compound herbal formula known for its ability to accelerate the healing of chronic wounds, including diabetic skin ulcers(DSU). However, the precise mechanisms remain to be further investigated.PURPOSE: The primary goal of this investigation was to evaluate the therapeutic impact of HYSJD extract on DSU in a murine model. Additionally, the study sought to decipher the intricate mechanisms driving the wound healing process, leveraging a comprehensive multi-omics analysis coupled with a network pharmacology framework.MATERIALS AND METHODS: The constituents of HYSJD were characterized utilizing liquid chromatography in conjunction with tandem mass spectrometry (LC-MS/MS). A model of DSU was developed in mice,A multi-faceted approach incorporating transcriptomics, pharmacological networking, and metabolomics was employed to investigate the mechanisms by which HYSJD promotes healing of DSU. Additionally, in vivo studies were executed to substantiate the proposed mechanisms of HYSJD.RESULTS: The application of HYSJD has demonstrated efficacy in accelerating the healing process of wounds in a DSU mouse model. Through transcriptomic profiling and pharmacological networking, Sinapine and Arginine were identified as the predominant bioactive constituents exerting their effects on DSU lesions. These elements were found to suppress cellular apoptosis and modulate signaling cascades associated with inflammatory responses. Metabolomic evaluations uncovered a set of 12 distinct metabolites and 7 metabolic routes that are influenced by HYSJD's intervention in DSU. Supplementary experimental data validated the capacity of HYSJD to regulate the NF-κB/STAT3/NLRP3 signaling axis, which in turn, manages inflammatory mediators in both wound tissue and serum, while also curbing cellular apoptosis.CONCLUSION: HYSJD augments the wound healing capability in diabetic mice by mitigating cellular apoptosis and diminishing inflammatory activity, attributable to its regulatory effect on the NF-κB/STAT3/NLRP3 signaling pathway.PMID:40339553 | DOI:10.1016/j.phymed.2025.156695

Phytomedicine. 2025 May 1;143:156821. doi: 10.1016/j.phymed.2025.156821. Online ahead of print.ABSTRACTBACKGROUND: Streptococcus suis is a zoonotic pathogen that causes meningitis, septicaemia, endocarditis, arthritis, and pneumonia in human beings. With the increasing prevalence of S. suis infections and a general decline in the effectiveness of antibiotics, the development of novel drugs that have effect on S. suis is extremely urgent. Emodin, a natural anthraquinone derivative of Rheum palmatum L., Reynoutria japonica Houtt., Polygonum multiflorum Thunb. and Cassia obtusifolia L., has been reported to exert anti-S. suis effect; however, the specific mechanism of the anti-S. suis action by targeting β-ketoacyl-acyl carrier protein synthase Ⅱ (FabF) in the fatty acid synthesis pathway remains unexplored.PURPOSE: We sought to reveal the potential role of emodin to prevent S. suis infection, investigate its mechanism of anti-S. suis action, and provide further evidence of emodin as an alternative to traditional antibiotic agents.METHODS: The in vitro anti-S. suis properties of emodin were assessed through minimum inhibitory concentration (MIC) assays, and time-kill assays. Subsequently, the mechanisms underlying emodin's mode of action at the molecular level by targeting FabF were elucidated using molecular docking, site-directed mutagenesis, bio-layer interferometry assays, and cellular thermal shift assays. Finally, metabolomics, cell membrane phospholipid content assay and biochemical parameters assays were used to detect emodin disrupting cell membrane integrity and function by affecting fatty acid biosynthesis.RESULTS: In this study, we have identified that emodin inhibits S. suis by suppressing free fatty acids (FFAs) synthesis and disrupting phospholipid production by targeting FabF, a key enzyme in the fatty acid biosynthesis pathway. This interference compromises the integrity and functionality of the cell membranes of S. suis. Emodin also triggers the dissipation of the proton motive force, accelerates the tricarboxylic acid cycle, and enhances cellular respiration, ultimately leading to S. suis cell death.CONCLUSION: This study suggested that emodin inhibits the growth of S. suis via targeting FabF and the inhibition of fatty acid biosynthesis through enzyme-targeted drug design. This represents a novel strategy for developing antimicrobial agents against S. suis and addressing the challenge of antibiotic resistance.PMID:40339548 | DOI:10.1016/j.phymed.2025.156821

Spectrochim Acta A Mol Biomol Spectrosc. 2025 May 4;340:126340. doi: 10.1016/j.saa.2025.126340. Online ahead of print.ABSTRACTThe high-throughput capability of attenuated total reflection mid-infrared spectroscopy (ATR-MIRS) makes it a promising analytical technique for rapid and green mycotoxin screening. In ATR-MIRS, changes in samples induced by mycotoxigenic fungi are correlated with mycotoxin concentrations obtained through reference analysis. Due to its indirect nature, limited research has explored the applicability of this technique for complex sample sets. We demonstrate that ATR-MIRS can effectively screen for deoxynivalenol (DON) contamination in wheat samples collected across two countries over multiple years. A total of 320 naturally contaminated samples from Austria and France were analyzed to develop screening models. Partial least squares discriminant analysis (PLS-DA) was used to classify samples as compliant or non-compliant with the European Commission (EC) limit of 1000 µg/kg DON in unprocessed wheat. Model performance during repeated nested cross-validation exhibited a true positive rate ranging from 0.32 to 1. This variability was primarily influenced by sample splitting, as well as by dataset balancing and spectral preprocessing approaches. These findings underscore the critical importance of sample selection when developing chemometric models for mycotoxin screening. Analysis of variable importance in projection (VIP) scores revealed that classification into compliant or non-compliant is based on wavenumbers associated with dissolved proteins and carbohydrates in the MIRS spectra. Overall, our results demonstrate the feasibility of using ATR-MIRS to assess DON contamination in complex, multiyear wheat sample sets while adhering to regulatory limits. Additionally, this study highlights the potential of MIRS for investigating the effects of mycotoxigenic fungi on wheat composition during the development of DON screening models.PMID:40339401 | DOI:10.1016/j.saa.2025.126340

Res Vet Sci. 2025 May 3;191:105682. doi: 10.1016/j.rvsc.2025.105682. Online ahead of print.ABSTRACTMicroRNAs (miRNAs) are a class of endogenous non-coding small RNAs that are widely found in organisms and play an important regulatory role in various biological processes, especially immune and inflammatory responses. However, the function of miR-320b in the inflammatory responses of bovine mammary epithelial cells (bMECs) remains to be elucidated. In this study, we examined the miR-320b mimic transduction group (miR-320b_mimic) and negative control mimic transduction group (NC_mimic) of lipopolysaccharide-treated bMECs using data-independent acquisition (DIA) proteomics and untargeted metabolomics. Subsequently, we performed a joint analysis of the sequencing data. Proteomic analysis identified 330 differentially abundant proteins (DAPs) primarily related to PPAR, ferroptosis, arachidonic acid metabolism, IL-17, and complement and coagulation cascades. Metabolome analysis identified 128 and 66 differentially accumulated metabolites (DAMs) in the positive and negative ion mode primarily involved in linoleic acid metabolism, cholesterol metabolism, AMPK, MAPK, and chemokine. Integrated metabolomics and proteomics analysis revealed the co-enrichment of DAPs and DAMs in choline metabolism in cancer, endocrine resistance, glycerophospholipid metabolism, primary bile acid biosynthesis, and the ferroptosis signaling pathways. The results of quantitative real-time PCR (RT-qPCR) showed that compared with the NC_mimic group, mRNA expression levels of COX-2, IL-12 A, iNOS, MAPK1, and MAPK14 genes were significantly down-regulated, and the mRNA expression levels of PPARγ, CEBPα, CEBPβ, FABP4, and LPL genes were significantly up-regulated in the miR-320b_mimic group. These results provide crucial insights into the molecular regulatory functions of miR-320b and offer valuable data for further research on molecular breeding aimed at enhancing mastitis resistance in bovine animals.PMID:40339219 | DOI:10.1016/j.rvsc.2025.105682

J Pharm Biomed Anal. 2025 May 3;263:116942. doi: 10.1016/j.jpba.2025.116942. Online ahead of print.ABSTRACTPostmenopausal osteoporosis (PMOP) was caused by significant deviations in gut microbiota and metabolites. Gushudan (GSD), a small traditional Chinese medicine formula, exerted therapeutic effects including kidney-nourishing and bone-strengthening properties. The therapeutic mechanism of GSD in alleviating kidney-yang deficiency syndrome and secondary osteoporosis was systematically investigated through metabolomics and network pharmacology. However, the mechanisms and impact on gut microbiota through which GSD mitigated PMOP remained to be elucidated. In this study, fecal metabolomics was integrated with gut microbiota analysis to comprehensively investigate modification in intestinal flora and metabolic profiles in PMOP rat models from the gut-bone axis framework. Therefore, the GC-MS-based method integrating non-targeted and targeted metabolomics was established to analyze fecal metabolites. The comprehensive analysis of gut microbial communities was performed using 16S rRNA on fecal samples. In the result, 20 potential biomarkers were successfully identified in the non-targeted metabolomics analysis. Subsequently, 12 metabolites related to amino acid metabolism, energy metabolism and bile acid biosynthesis were quantitatively. Then, ten gut microorganisms with significant changes were discovered through 16S rRNA. Furthermore, alterations in fecal metabolites demonstrated a significant correlation with dysbiosis within the gut microorganisms such as [Ruminococcus]_torques_group, Elusimicrobium, Intestinimonas and Papillibacter. GSD effectively modulated abnormal levels of metabolites such as glycine, lactic acid, succinic acid, cholesterol and deoxycholic acid. Specifically, GSD improved the abundance of [Ruminococcus]_torques_group, Elusimicrobium, Intestinimonas. In conclusion, the gut-bone axis was validated as a novel framework, and gut microbiota modulation was further identified as a promising therapeutic target for the prevention of PMOP.PMID:40339206 | DOI:10.1016/j.jpba.2025.116942

Proc Natl Acad Sci U S A. 2025 May 13;122(19):e2412854122. doi: 10.1073/pnas.2412854122. Epub 2025 May 8.ABSTRACTCancer cells frequently reprogram one-carbon metabolic pathways to fulfill their vigorous demands of biosynthesis and antioxidant defense for survival and proliferation. Dysfunction of oncogenes or tumor suppressor genes is critically involved in this process, but the precise mechanisms by which cancer cells actively trigger one-carbon metabolic alterations remain incompletely elucidated. Here, by using untargeted metabolomic analysis, we identify the oncoprotein SE translocation (SET) as a key regulator of one-carbon metabolism in cancer cells. SET physically interacts with mitochondrial SHMT2 and facilitates SHMT2 enzymatic activity. Loss of SET profoundly suppresses serine-derived one-carbon metabolic flux, whereas reexpression of ectopic SET leads to the opposite effect. Notably, although the presence of SHMT2 is critical for SET-mediated one-carbon metabolic alterations, the depletion of SHMT2 alone is insufficient to antagonize SET-induced tumor growth, probably due to functional compensation by its cytosolic isozyme SHMT1 upon SHMT2 knockdown. Instead, pharmacological targeting of cellular SHMT (including both SHMT1 and SHMT2) activity results in dramatic suppression of SET-induced tumor growth. Moreover, by using a Kras/Lkb1 mutation-driven lung tumor mouse model, we demonstrate that the loss of SET compromises both tumor formation and intratumoral SHMT2 enzymatic activity. Clinically, the overexpression of SET and SHMT2 is observed in lung tumors, both of which correlate with poor prognosis. Our study reveals a SET-SHMT2 axis in regulating serine-derived one-carbon metabolism and uncovers one-carbon metabolic reprogramming as a mechanism for SET-driven tumorigenesis.PMID:40339130 | DOI:10.1073/pnas.2412854122

PLoS One. 2025 May 8;20(5):e0323222. doi: 10.1371/journal.pone.0323222. eCollection 2025.ABSTRACTBACKGROUND: Long-term alcohol intake has toxic effects on osteoblasts and osteoclasts, resulting in decreased bone density, which directly disrupts the composition of the gut microbiota and affects bone metabolism and immune activity. The effects of alcohol on the bones may be closely related to sex. This study investigated the effects of long-term alcohol consumption on bone status in different sexes by examining the gut microbiota, bone metabolism, and immune activity.METHODS: Young male and female rats were administered a Bio-Serv liquid diet containing 5% alcohol. The effects of alcohol metabolism capacity, bone morphology, bone formation, bone resorption, bone marrow immune activity, gut microbiota, and metabolite differences were analyzed in male and female rats using hematoxylin and eosin staining, micro-computed tomography, enzyme-linked immunosorbent assay, western blotting, 16S rRNA sequencing, and untargeted metabolomics.RESULTS: Chronic alcohol consumption resulted in excessive osteoclast activation and decreased bone mineral density. Furthermore, alcohol reduced bone metabolism and formation while increasing bone resorption. Bone loss was significantly more severe in female rats than in male rats, indicating that the effects of alcohol on rat bones are related to sex. Chronic alcohol consumption also led to polarization of bone marrow immunoreactivity toward the M1 phenotype. In addition, chronic alcohol consumption affected the composition of gut microbiota, reduced the richness and diversity of intestinal microbiota, and decreased the ratio of Firmicutes/Bacteroidetes. Long-term alcohol consumption also affected fecal metabolites, and 754 differentially expressed metabolites were identified.CONCLUSIONS: Chronic alcohol consumption increased bone resorption, inhibited bone formation, and affected bone marrow immunoreactivity in young male and female rats. Alcohol can also affect gut microbiota composition and fecal metabolism. Female rats were more susceptible to alcohol, possibly because young female rats have a lower alcohol metabolism, immunomodulatory capacity, and gut microbiota diversity than young male rats.PMID:40338892 | DOI:10.1371/journal.pone.0323222

Prev Chronic Dis. 2025 May 8;22:E18. doi: 10.5888/pcd22.240220.ABSTRACTINTRODUCTION: Peripheral artery disease (PAD) and dyslipidemia are both independent predictors of cardiovascular disease, but the association between individual lipid species and subclinical PAD, assessed by ankle-brachial index (ABI), is lacking in large-scale longitudinal studies.METHODS: We used liquid chromatography-mass spectrometry to repeatedly measure 1,542 lipid species from 1,886 American Indian adults attending 2 clinical examinations (mean ~5 years apart) in the Strong Heart Family Study. We used generalized estimating equation models to identify baseline lipid species associated with change in ABI and the Cox frailty regression to examine whether lipids associated with change in ABI were also associated with incident coronary heart disease (CHD). We also examined the longitudinal association between change in lipid species and change in ABI and the cross-sectional association of individual lipids with ABI. All models were adjusted for age, sex, body mass index, smoking, alcohol use, hypertension, estimated glomerular filtration rate, diabetes, and lipid-lowering medication.RESULTS: Baseline levels of 120 lipid species, including glycerophospholipids, glycerolipids, fatty acids, and sphingomyelins, were associated with change in ABI. Among these, higher baseline levels of 3 known lipids (phosphatidylinositol[16:0/20:4], triacylglycerol[48:2], triacylglycerol[55:1]) were associated with a lower risk of CHD (hazard ratios [95% CIs] ranged from 0.67 [0.46-0.99] to 0.76 [0.58-0.99]), while cholesterol was associated with a higher risk of CHD (hazard ratio [95% CI] = 1.37 [1.00-1.87]). Longitudinal changes in 32 lipids were significantly associated with change in ABI during 5-year follow-up. Plasma levels of glycerophospholipids, triacylglycerols, and glycosylceramides were significantly associated with ABI in the cross-sectional analysis.CONCLUSION: Altered plasma lipidome is significantly associated with subclinical PAD in American Indians beyond traditional risk factors. If validated, the identified lipid species may serve as novel biomarkers for PAD in this high-risk but understudied population.PMID:40338792 | DOI:10.5888/pcd22.240220

Med Microbiol Immunol. 2025 May 8;214(1):21. doi: 10.1007/s00430-025-00831-5.ABSTRACTClostridium innocuum, a member of the human gut microbiome with intrinsic resistance to vancomycin, has been increasingly associated with inflammatory bowel diseases (IBD). Clinical observations indicate that co-infection with Clostridioides difficile and C. innocuum could lead to poorer clinical remission in ulcerative colitis; however, the pathogenic mechanism of C. innocuum remains unclear. Here, we investigated the effects of vancomycin and C. difficile on C. innocuum secretomes and the functions of the modified secretomes on C. innocuum pathogenicity. The results indicated that, compared to co-culturing with C. difficile, vancomycin was more effective in stimulating the secretion of proteins without a signal peptide, whereas C. difficile was better at promoting the secretion of classical secretory proteins. Based on these results, we further analyzed the effects of three abundant classical secretory proteins on C. innocuum virulence utilizing recombinant proteins. The results demonstrated that the NlpC/P60-containing protein (NlpC/P60) can enhance C. innocuum biofilm formation and adherence to HT-29 cells. Additionally, NlpC/P60, D-Ala-D-Ala carboxypeptidase, and a polysaccharide deacetylase were able to stimulate IL-8 production of HT-29 cells and TNF-α production of Raw264.7 macrophages. Additionally, recombinant NlpC/P60 and polysaccharide deacetylase exhibited cytotoxicity on Raw264.7 cells at 48 h. As the production of IL-8 and TNF-α is closely associated with IBD development, it is suggested that C. innocuum secretomes, under the influence of vancomycin or C. difficile, could contribute to IBD progression by enhancing inflammation and host-pathogen interactions.PMID:40338351 | DOI:10.1007/s00430-025-00831-5

Int J Syst Evol Microbiol. 2025 May;75(5). doi: 10.1099/ijsem.0.006783.ABSTRACTStrain MCT is a strictly anaerobic, homoacetogenic bacterium with the ability to utilize methyl chloride as the sole energy source. It was tentatively assigned to the genus Acetobacterium as 'Acetobacterium dehalogenans'. Due to sequence ambiguities, it was not possible to determine the 16S rRNA gene sequence of this strain by direct sequencing of a PCR-amplified DNA segment. Whole-genome sequencing revealed significant heterogeneity amongst the five rRNA operons detected in this strain, with maximum sequence differences between the individual 16S rRNA genes exceeding 1.4%, compared to <0.8% in related species. Genome comparisons identified strain MCT as most closely related to Acetobacterium malicum MuME1T, with a digital DNA-DNA hybridization value of 71.9% and an average nucleotide identity score of 96.59%, indicating that the strains belong to the same species. Both strains share the ability to utilize malate, a key feature of A. malicum, but differ in the utilization of methanol and glucose. Chemotaxonomic analyses also revealed distinct fatty acid and polar lipid patterns. Based on these findings, we propose the classification of strain 'Acetobacterium dehalogenans' MCT (=DSM 11527T=NBRC 117038T) as A. malicum subsp. dehalogenans subsp. nov. This automatically establishes A. malicum subsp. malicum subsp. nov., with MuME1T (=DSM 4132T=ATCC 51201T) as the type strain.PMID:40338649 | DOI:10.1099/ijsem.0.006783

Clin J Am Soc Nephrol. 2025 May 1;20(5):595-597. doi: 10.2215/CJN.0000000720. Epub 2025 Apr 14.NO ABSTRACTPMID:40338634 | DOI:10.2215/CJN.0000000720

Int Microbiol. 2025 May 8. doi: 10.1007/s10123-025-00668-1. Online ahead of print.ABSTRACTAgricultural sustainability is vital to meet the growing global demand for food; therefore, the search for more sustainable options to replace traditional chemical products has gained attention due to their benefits. The sector has applied innovative microbial consortium approaches as a niche for exploring new bioproducts and metabolic pathways through microbial interactions. Thus, this study sought to select two endophytic bacterial strains with biocontrol activity to study their metabolic interactions in culture. For this, co-cultivation and axenic culture assays were carried out to evaluate the inhibition of Corynespora cassiicola, Sclerotinia sclerotiorum, Moniliophthora perniciosa, and Colletotrichum truncatum. After the production of antiphytopathogenic compound tests, two strains were selected: P. putida MG36 and B. amyloliquefaciens SS14. These bacteria were cultivated under three distinct conditions: axenic cultivation of SS14, axenic cultivation of MG36, and co-cultivation. The metabolites were extracted and analyzed by liquid chromatography coupled with mass spectrometry (UHPLC-MS/MS). The results showed that both strains exhibited significant antifungal activity. B. amyloliquefaciens SS14 demonstrated 65% inhibition against C. truncatum, while P. putida MG36 showed 58% inhibition against S. sclerotiorum. Analysis of the chemical profiles revealed the presence of exclusive and shared metabolites, such as iturin A4 (antifungal lipopeptide) and macrolactin A (bioactive polyketide), under different culture conditions. In conclusion, P. putida MG36 and B. amyloliquefaciens SS14 show promise as biocontrol agents against phytopathogens, contributing to more sustainable agricultural practices.PMID:40338459 | DOI:10.1007/s10123-025-00668-1

Foods. 2025 Apr 3;14(7):1262. doi: 10.3390/foods14071262.ABSTRACTEffects of low temperature (LT, 20 °C) combined with nitrogen-modified atmosphere (MA, 95% N2) storage (LT + MA) on quality, microstructure, and metabolome characteristics of high moisture content (15.5%) during 180 days of storage were investigated to explore a potential preservation technique for high moisture rice. The results showed that after 180 days of storage, the fatty acid value, malondialdehyde content, and amylose content of rice under LT + MA storage were 53.33%, 72.93%, and 91.85% of those under conventional storage (CS, conventional atmosphere, 30 °C, RH 65%), respectively. The color, pasting properties, and scanning electron microscopy (SEM) of the LT + MA treatment were found to be markedly superior to those of the CS treatment. In addition, the differential metabolites sucrose, trehalose-6P, trehalose, 3,7-Di-O-methylquercetin (DMQ), rutin, and vitexin 2″-O-rhamnoside (VOR) were screened to assess for sensitivity to changes in storage conditions. The study demonstrated that the LT + MA effectively suppressed the escalation of FAV, MDA content, and amylose content. In addition, it was observed to inhibit the deterioration of color and pasting properties while concurrently maintaining the polygonal shape of rice starch granules. Furthermore, the differential metabolites of non-targeted metabolomics indicated that the LT + MA group exhibited superior efficacy in retarding rice aging.PMID:40338278 | DOI:10.3390/foods14071262

Appl Environ Microbiol. 2025 May 8:e0221124. doi: 10.1128/aem.02211-24. Online ahead of print.ABSTRACTAmmonia nitrogen posed a significant threat to aquatic animals in aquaculture environments, and the substantial potential of microorganisms in removing ammonia nitrogen had garnered considerable attention. This study identified a marine yeast, Pichia kudriavzevii HJ2, which effectively removed ammonia nitrogen. By combining transcriptomics and metabolomics, the ammonia nitrogen transformation mechanism of HJ2 was elucidated. HJ2 achieved 100% ammonia nitrogen removal efficiency within 1 day of fermentation at 35°C with 300 mg/L ammonia nitrogen and 73.56% removal efficiency within 36 h with 600 mg/L ammonia nitrogen. Transcriptomics revealed that exposure to 600 mg/L ammonia nitrogen resulted in 541 up-regulated genes and 567 down-regulated genes in the HJ2 strain. Differentially expressed genes (DEGs) were primarily involved in the tricarboxylic acid (TCA) cycle and amino acid metabolism. Metabolomics revealed that HJ2 facilitated the production of 383 up-regulated metabolites and suppressed 137 down-regulated metabolites when exposed to 600 mg/L ammonia nitrogen. Integrating transcriptomics and metabolomics analyses showed that HJ2 removed ammonia nitrogen by sensing its presence in the extracellular environment, activating the TCA cycle, enhancing amino acid metabolism and nucleotide metabolism, and promoting its robust growth and reproduction. Amino acid metabolism played an important role in the ammonia transformation mechanism of HJ2. The result was confirmed by the increased activity of glutamate dehydrogenase (GDH) and aspartate aminotransferase (GOT). Up-regulated nitrogen metabolites such as L-glutamate, L-aspartic acid, spermidine, and trigonelline were produced. The results of enzyme activity tests, construction of overexpressing strains, and adding exogenous amino acid experiments demonstrated that HJ2 could utilize GDH and GOT ammonia assimilation pathways.IMPORTANCEAmmonia nitrogen removal ability was a universal characteristic among the ammonia-oxidizing bacteria or archaea. Recently, yeast strains from the genus Pichia were found to have ammonia nitrogen removal ability. However, the mechanism of ammonia nitrogen removal in Pichia had not been reported. In the study, the ammonia nitrogen removal efficiency of Pichia kudriavzevii HJ2 was identified, and the mechanisms by which HJ2 transformed ammonia nitrogen into non-toxic organic nitrogen were elucidated, offering potential solutions to pollution challenges in aquaculture and helping minimize resource waste. The study offered new insights into the transformation mechanism of microbial ammonia nitrogen removal and its environmentally friendly application.PMID:40338088 | DOI:10.1128/aem.02211-24

J Infect Dis. 2025 May 8:jiaf240. doi: 10.1093/infdis/jiaf240. Online ahead of print.ABSTRACTBACKGROUND: High-resolution metabolomics has shown promise for identifying blood-based biomarkers of tuberculosis (TB). We sought to discover a metabolic signature to detect pulmonary TB disease and monitor treatment response.METHODS: Plasma from Ethiopian persons with pulmonary TB at diagnosis (n=82) was compared to household contacts with TB symptoms (n=104) and 2, 6, and 12 months after treatment initiation. Participants were divided into training and test sets for model building, with additional validation using independent cohorts from the countries of Georgia (n=89) and South Africa (n=85). Signatures were further evaluated in non-human primates infected with M. tuberculosis (Mtb).RESULTS: Among the metabolites that most significantly differed in concentration, tryptophan and retinol were significantly decreased in persons with TB disease (45.2 uM vs 62.5 uM and 4.1 uM vs 8.2 uM respectively), while kynurenine was significantly increased (2.1 uM vs 1.6 uM; q<0.0001 for all). A signature that included the kynurenine/tryptophan ratio and retinol showed excellent classification for TB disease (AUC=0.97). The signature had an AUC of 0.97 in HIV+ and 0.95 in HIV- persons with TB disease from South Africa and 0.93 in TB patients from Georgia. In Ethiopian participants, signature scores decreased after 2 (0.85 to 0.42) and 6 months of TB treatment (0.42 to 0.18; p<0.0001 for both) to similar levels as controls. Plasma retinol also declined in NHPs infected with Mtb 15-16 weeks after infection (5.9 uM vs 3.6 uM; p<0.001).CONCLUSIONS: The plasma Kyn/Trp ratio and retinol represents a promising metabolic signature that could advance TB diagnostics.PMID:40338044 | DOI:10.1093/infdis/jiaf240

Comb Chem High Throughput Screen. 2025 May 7. doi: 10.2174/0113862073365403250423070858. Online ahead of print.ABSTRACTBACKGROUND: This study aimed to explore the mechanism of moxibustion in the knee by combining osteoarthritis metabolomics and network pharmacology.METHODS: A rat knee osteoarthritis (KOA) model was established by intra-articular injection of papain. The efficacy of moxibustion in KOA rats was evaluated by swelling degree, pathological progress, and mobility loss of knee joint. On this basis, the metabolic mechanism of moxibustion in relieving knee osteoarthritis was analyzed by metabolomics analysis.RESULTS: Moxibustion significantly reduced joint swelling and inflammation in the knee joint of KOA rats. Sixteen metabolites and nine metabolic pathways were found to be associated with the mechanism of action of moxibustion in metabolomics analysis results. According to network pharmacology, 3186 KOA disease targets, 158 drug targets, and 89 intersecting targets were obtained. The key targets included MAPK-3, AKT-1, RELA, MAPK-8, MAPK-14, etc. Signal pathways were found to be involved in mechanisms of moxibustion in knee osteoarthritis, such as alanine, aspartate, and glutamate metabolism, cysteine and methionine metabolism, and arginine and proline metabolism.CONCLUSION: The mechanism of moxibustion in knee osteoarthritis may involve alanine, aspartate, and glutamate metabolism, cysteine and methionine metabolism, arginine and proline metabolism, amino tRNA biosynthesis, and D-glutamine and D-glutamate metabolism signaling pathways with MAPK-3, AKT-1, RELA, MAPK-8, and MAPK-14 as core targets. More precise mechanisms need to be verified by further systematic molecular biology experiments.PMID:40337969 | DOI:10.2174/0113862073365403250423070858

Anal Chem. 2025 May 8. doi: 10.1021/acs.analchem.4c06697. Online ahead of print.ABSTRACTTemporal metabolic dynamics are difficult to capture but are critical to understanding biology. We developed an automated liquid chromatography-mass spectrometry system that collects time-resolved metabolomics data from cultured cells, enabling sub-minute sequential sampling, broad metabolite coverage, robust metabolite identification, and parallel monitoring of up to 72 experimental conditions. Using this system, we identified temporal metabolic phenotypes of Escherichia coli and Proteus mirabilis that could not be captured from single time points.PMID:40337904 | DOI:10.1021/acs.analchem.4c06697

JCI Insight. 2025 May 8;10(9):e186629. doi: 10.1172/jci.insight.186629. eCollection 2025 May 8.ABSTRACTNonsyndromic cleft lip with palate (nsCLP) is a common birth defect disease. Current diagnostic methods comprise fetal ultrasound images, which are mainly limited by fetal position and technician skills. We aimed to identify reliable maternal serum lipid biomarkers to diagnose nsCLP. Eight-feature selection methods were used to assess the dysregulated lipids from untargeted lipidomics in a discovery cohort. The robust rank aggregation algorithm was applied on these selected lipids. The data were subsequently processed using 7 classification models to retrieve a panel of 35 candidate lipid biomarkers. Potential lipid biomarkers were evaluated using targeted lipidomics in a validation cohort. Seven classification models and multivariate analyses were constructed to identify the lipid biomarkers for nsCLP. The diagnostic model achieved high performance with 3 lipids in determining nsCLP. A panel of 3 lipid biomarkers showed great potential for nsCLP diagnosis. FA (20:4) and LPC (18:0) were also significantly downregulated in early serum samples from the nsCLP group in the additional validation cohort. We demonstrate the applicability and robustness of a machine-learning algorithm to analyze lipidomic data for efficient and reliable biomarker screening.PMID:40337862 | DOI:10.1172/jci.insight.186629

JCI Insight. 2025 May 8;10(9):e187911. doi: 10.1172/jci.insight.187911. eCollection 2025 May 8.ABSTRACTPathologic implications of dysregulated pulmonary vascular metabolism to pulmonary arterial hypertension (PAH) are increasingly recognized, but their clinical applications have been limited. We hypothesized that metabolite quantification across the pulmonary vascular bed in connective tissue disease-associated (CTD-associated) PAH would identify transpulmonary gradients of pathobiologically relevant metabolites, in an exercise stage-specific manner. Sixty-three CTD patients with established or suspected PAH underwent exercise right heart catheterization. Using mass spectrometry-based metabolomics, metabolites were quantified in plasma samples simultaneously collected from the pulmonary and radial arteries at baseline and during resistance-free wheeling, peak exercise, and recovery. We identified uptake and excretion of metabolites across the pulmonary vascular bed, unique and distinct from single vascular site analysis. We demonstrated the physiological relevance of metabolites previously shown to promote disease in animal models and end-stage human lung tissues, including acylcarnitines, glycolytic intermediates, and tryptophan catabolites. Notably, pulmonary vascular metabolite handling was exercise stage specific. Transpulmonary metabolite gradients correlated with hemodynamic endpoints largely during free-wheeling. Glycolytic intermediates demonstrated physiologic significance at peak exercise, including net uptake of lactate in those with more advanced disease. Contribution of pulmonary vascular metabolism to CTD-PAH pathogenesis and therapeutic candidacy of metabolism modulation must be considered in the context of physiologic stress.PMID:40337861 | DOI:10.1172/jci.insight.187911