PubMed

Curr Drug Metab. 2024 Jul 8. doi: 10.2174/0113892002289388240705113755. Online ahead of print.ABSTRACTBACKGROUND: The global obese population is rapidly increasing, urgently requiring the development of effective and safe weight-loss medications. The classic Chinese medicine formulation Lingguizhugan De-coction has exerted a significant anti-obesity effect. However, the underlying mechanism is still unclear.OBJECTIVE: This study aimed to explore the mechanism of LGZGD in the treatment of obesity based on the gut microbiota and its metabolites.METHODS: Three different dosages of LGZGD were gavaged to ob/ob mice for 8 weeks. Body mass and visceral fat mass were evaluated. Additionally, the changes in gut microbiota, fecal and plasma metabolites in mice after LGZGD treatment were analyzed by metagenomics and non-targeted metabolomics.RESULTS: The results demonstrated a significant anti-obesity effect of LGZGD treatment in ob/ob mice. Fur-thermore, the metagenomic analysis revealed that LGZGD reduced the ratio of Firmicutes / Bacteroidetes (F to B) in the gut, restored gut microbiota diversity, and identified 3 enriched KEGG pathways, including energy metabolism, lipid metabolism, and energy production and conversion pathways. Based on non-targeted metab-olomics analysis, 20 key metabolites in the feces and 30 key metabolites in the plasma responding to LGZGD treatment were identified, and the levels of Eicosapentaenoic acid (EPA) and Myristoleic acid (MA) might be the metabolites related to gut microbiota after LGZGD treatment. Their biological functions were mainly re-lated to the metabolism pathway.CONCLUSIONS: These findings suggested that LGZGD had therapeutic potential for obesity. The mechanism of LGZGD alleviating obesity was associated with improving dysbiosis of the gut microbiota. LDZGD affected gut microbiota-derived metabolites of EPA and MA and may act on energy metabolism pathways.PMID:38982915 | DOI:10.2174/0113892002289388240705113755

FEBS J. 2024 Jul 10. doi: 10.1111/febs.17221. Online ahead of print.ABSTRACTThe metabolic networks of microorganisms are remarkably robust to genetic and environmental perturbations. This robustness stems from redundancies such as gene duplications, isoenzymes, alternative metabolic pathways, and also from non-enzymatic reactions. In the oxidative branch of the pentose phosphate pathway (oxPPP), 6-phosphogluconolactone hydrolysis into 6-phosphogluconate is catalysed by 6-phosphogluconolactonase (Pgl) but in the absence of the latter, the oxPPP flux is thought to be maintained by spontaneous hydrolysis. However, in Δpgl Escherichia coli, an extracellular pathway can also contribute to pentose phosphate synthesis. This raises question as to whether the intracellular non-enzymatic reaction can compensate for the absence of 6-phosphogluconolactonase and, ultimately, on the role of 6-phosphogluconolactonase in central metabolism. Our results validate that the bypass pathway is active in the absence of Pgl, specifically involving the extracellular spontaneous hydrolysis of gluconolactones to gluconate. Under these conditions, metabolic flux analysis reveals that this bypass pathway accounts for the entire flux into the oxPPP. This alternative metabolic route-partially extracellular-sustains the flux through the oxPPP necessary for cell growth, albeit at a reduced rate in the absence of Pgl. Importantly, these findings imply that intracellular non-enzymatic hydrolysis of 6-phosphogluconolactone does not compensate for the absence of Pgl. This underscores the crucial role of Pgl in ensuring the efficient functioning of the oxPPP.PMID:38982839 | DOI:10.1111/febs.17221

Food Addit Contam Part B Surveill. 2024 Jul 9:1-14. doi: 10.1080/19393210.2024.2372426. Online ahead of print.ABSTRACTMaize grain samples collected from 129 small-scale farmers' stores in southern and southwestern Ethiopia were analysed by LC-MS/MS for a total of 218 mycotoxins and other fungal metabolites of which 15% were regulated mycotoxins. Mycotoxins produced by Penicillium, Aspergillus, and Fusarium accounted for 31%, 17%, and 12% of the metabolites, respectively. Most of the current samples were contaminated by masked and/or emerging mycotoxins with moniliformin being the most prevalent one, contaminating 93% of the samples. Each sample was co-contaminated by 3 to 114 mycotoxins/fungal metabolites. Zearalenone, fumonisin B1, and deoxynivalenol were the dominant mycotoxins, occurring in 78%, 61%, and 55% of the samples with mean concentrations of 243, 429, and 530 µg/kg, respectively. The widespread co-occurrence of several mycotoxins in the samples may pose serious health risks due to synergistic/additional effects.PMID:38982744 | DOI:10.1080/19393210.2024.2372426

Inflamm Bowel Dis. 2024 Jul 9:izae124. doi: 10.1093/ibd/izae124. Online ahead of print.ABSTRACTBACKGROUND: Exclusive enteral nutrition (EEN) is an effective treatment for active Crohn's disease (CD). This study explored the immunostimulatory potential of a cell-free fecal filtrate and related this with changes in the fecal microbiota and metabolites in children with active CD undertaking treatment with EEN.METHODS: Production of tumor necrosis factor α (TNFα) from peripheral blood mononuclear cells was measured following their stimulation with cell-free fecal slurries from children with CD, before, during, and at completion of EEN. The metabolomic profile of the feces used was quantified using proton nuclear magnetic resonance and their microbiota composition with 16S ribosomal RNA sequencing.RESULTS: Following treatment with EEN, 8 (72%) of 11 patients demonstrated a reduction in fecal calprotectin (FC) >50% and were subsequently labeled FC responders. In this subgroup, TNFα production from peripheral blood mononuclear cells was reduced during EEN (P = .008) and reached levels like healthy control subjects. In parallel to these changes, the fecal concentrations of acetate, butyrate, propionate, choline, and uracil significantly decreased in FC responders, and p-cresol significantly increased. At EEN completion, TNFα production from peripheral blood mononuclear cells was positively correlated with butyrate (rho = 0.70; P = .016). Microbiota structure (β diversity) was influenced by EEN treatment, and a total of 28 microbial taxa changed significantly in fecal calprotectin responders. At EEN completion, TNFα production positively correlated with the abundance of fiber fermenters from Lachnospiraceae_UCG-004 and Faecalibacterium prausnitzii and negatively with Hungatella and Eisenbergiella tayi.CONCLUSIONS: This study offers proof-of concept data to suggest that the efficacy of EEN may result from modulation of diet-dependent microbes and their products that cause inflammation in patients with CD.PMID:38982655 | DOI:10.1093/ibd/izae124

Am J Physiol Cell Physiol. 2024 Jul 9. doi: 10.1152/ajpcell.00272.2024. Online ahead of print.ABSTRACTGlutamine is a critical amino acid that serves as an energy source, building block, and signaling molecule for the heart tissue and the immune system. However, the role of glutamine metabolism in regulating cardiac remodeling following myocardial infarction (MI) is unknown. In this study, we show in adult male mice that glutamine metabolism is altered both in the remote (contractile) area and in infiltrating macrophages in the infarct area after permanent left anterior descending artery occlusion. We found that metabolites related to glutamine metabolism were differentially altered in macrophages at days 1, 3, and 7 after MI using untargeted metabolomics. Glutamine metabolism in live cells was increased after MI relative to no MI controls. Gene expression in the remote area of the heart indicated a loss of glutamine metabolism. Glutamine administration improved LV function at days 1, 3, and 7 after MI, which was associated with improved contractile and metabolic gene expression. Conversely, administration of BPTES, a pharmacological inhibitor of glutaminase-1, worsened LV function after MI. Neither glutamine nor BPTES administration impacted gene expression or bioenergetics of macrophages isolated from the infarct area. Our results indicate that glutamine metabolism plays a critical role in maintaining LV contractile function following MI, and that glutamine administration improves LV function. Glutamine metabolism may also play a role in regulating macrophage function, but macrophages are not responsive to exogenous pharmacological manipulation of glutamine metabolism.PMID:38981605 | DOI:10.1152/ajpcell.00272.2024

Cancer Cell. 2024 Jul 8;42(7):1217-1238.e19. doi: 10.1016/j.ccell.2024.06.004.ABSTRACTAlthough genomic anomalies in glioblastoma (GBM) have been well studied for over a decade, its 5-year survival rate remains lower than 5%. We seek to expand the molecular landscape of high-grade glioma, composed of IDH-wildtype GBM and IDH-mutant grade 4 astrocytoma, by integrating proteomic, metabolomic, lipidomic, and post-translational modifications (PTMs) with genomic and transcriptomic measurements to uncover multi-scale regulatory interactions governing tumor development and evolution. Applying 14 proteogenomic and metabolomic platforms to 228 tumors (212 GBM and 16 grade 4 IDH-mutant astrocytoma), including 28 at recurrence, plus 18 normal brain samples and 14 brain metastases as comparators, reveals heterogeneous upstream alterations converging on common downstream events at the proteomic and metabolomic levels and changes in protein-protein interactions and glycosylation site occupancy at recurrence. Recurrent genetic alterations and phosphorylation events on PTPN11 map to important regulatory domains in three dimensions, suggesting a central role for PTPN11 signaling across high-grade gliomas.PMID:38981438 | DOI:10.1016/j.ccell.2024.06.004

Food Chem. 2024 Jul 4;459:140356. doi: 10.1016/j.foodchem.2024.140356. Online ahead of print.ABSTRACTPuffiness, a physiological disorder commonly observed during the ripening and post-harvest processes of fruits in Citrus reticulata, significantly affects the quality and shelf-life of citrus fruits. The complex array of factors contributing to puffiness has obscured the current understanding of its mechanistic basis. This study examined the puffing index (PI) of 12 citrus varieties at full ripeness, focusing on the albedo layer as a crucial tissue, and investigated the correlation between cellular structural characteristics, key primary metabolites and PI. The findings revealed that the cell gap difference and the number of lipid droplets were closely linked to PI. Chlorogenic acid, Ferulic acid, D-Galacturonic acid, D-Glucuronic acid, (9Z,11E)-Octadecadienoic acid, and 9(10)-EpOME were identified as pivotal primary metabolites for rind puffing. Determination of lignin, protopectin, cellulose and lipoxygenase content further validated the relationship between cell wall, lipid metabolism and rind puffing. This study furnishes novel insights into the mechanisms underlying puffing disorder.PMID:38981384 | DOI:10.1016/j.foodchem.2024.140356

Food Chem. 2024 Jul 6;459:140374. doi: 10.1016/j.foodchem.2024.140374. Online ahead of print.ABSTRACTThe sliced and dried hawthorn berries are easily infested by insects during storage. This study aimed to determine the effect of insect infestation on the quality of hawthorn berries and assess the change at metabolite level by analyzing physicochemical property and metabolomics profiling. A total of 184 shared differential metabolites were obtained, mainly including flavonoids, fatty acids, carboxylic acids and derivatives, and nitrogenous compounds. Through receiver operating characteristic curve assessment, 9 significant differential markers were screened out to distinguish insect infestation of hawthorn berries. Correlation analysis showed that the color, total organic acids, total phenolics, and total flavonoids were effective indicators for quality evaluation of insect infestation, and uric acid and hippuric acid can serve as biomarkers for the quality deterioration of hawthorn berries during storage. This study demonstrated that insect infestation could decrease the quality of hawthorn berries from macro and micro perspectives.PMID:38981382 | DOI:10.1016/j.foodchem.2024.140374

Food Chem. 2024 Jul 4;459:140346. doi: 10.1016/j.foodchem.2024.140346. Online ahead of print.ABSTRACTPhyllanthus emblica L. offers promising therapeutic potential for inflammatory diseases. This study revealed the molecular structure of a homogeneous polysaccharide purified from Phyllanthus emblica L. (PEP-1) and evaluated its anti-inflammatory effects on ulcerative colitis (UC) in mice. In the in vivo experiment, administered in varying dosages to dextran sulfate sodium (DSS)-induced UC models, PEP-1 significantly alleviated colonic symptoms, histological damages and reshaped the gut microbiota. Notably, it adjusted the Firmicutes/Bacteroidetes ratio and reduced pro-inflammatory species, closely aligning with shifts in the fecal metabolites and metabolic pathways such as the metabolism of pyrimidine, beta-alanine, and purine. These findings underscore the potential of PEP-1 as a therapeutic agent for UC, providing insights into the mechanisms through gut microbiota and metabolic modulation.PMID:38981378 | DOI:10.1016/j.foodchem.2024.140346

Mar Pollut Bull. 2024 Jul 8;205:116674. doi: 10.1016/j.marpolbul.2024.116674. Online ahead of print.ABSTRACTFluorene is a coastal sediment pollutant with high ecological risk. Perinereis aibuhitensis is an ecotoxicological model used for polycyclic aromatic hydrocarbon bioremediation; however, the effects of fluorene on the physiological metabolism of P. aibuhitensis and its corresponding responses remain unclear. This study explored the tolerance and defense responses of P. aibuhitensis in sediments with different fluorene concentrations using histology, ecological biomarkers, and metabolic responses. Metabolomics analyses revealed that P. aibuhitensis has high tolerance to fluorene in sediments. Fluorene stress disrupted the normal metabolism of the P. aibuhitensis body wall, resulting in excessive glycosphospholipid and stearamide accumulation and elevated oxygen consumption rates. To mitigate this, P. aibuhitensis has adopted tail cutting, yellowing, and modulation of metabolite contents in the body wall. This study provides novel insights into the potential ecological risk of fluorene pollution in marine sediments and proposes the use of P. aibuhitensis in the bioremediation of fluorene-contaminated sediments.PMID:38981191 | DOI:10.1016/j.marpolbul.2024.116674

Curr Opin Chem Biol. 2024 Jul 8;81:102498. doi: 10.1016/j.cbpa.2024.102498. Online ahead of print.NO ABSTRACTPMID:38981158 | DOI:10.1016/j.cbpa.2024.102498

Sci Rep. 2024 Jul 9;14(1):15796. doi: 10.1038/s41598-024-66893-2.ABSTRACTThe clinical diagnosis of biliary atresia (BA) poses challenges, particularly in distinguishing it from cholestasis (CS). Moreover, the prognosis for BA is unfavorable and there is a dearth of effective non-invasive diagnostic models for detection. Therefore, the aim of this study is to elucidate the metabolic disparities among children with BA, CS, and normal controls (NC) without any hepatic abnormalities through comprehensive metabolomics analysis. Additionally, our objective is to develop an advanced diagnostic model that enables identification of BA. The plasma samples from 90 children with BA, 48 children with CS, and 47 NC without any liver abnormalities children were subjected to metabolomics analysis, revealing significant differences in metabolite profiles among the 3 groups, particularly between BA and CS. A total of 238 differential metabolites were identified in the positive mode, while 89 differential metabolites were detected in the negative mode. Enrichment analysis revealed 10 distinct metabolic pathways that differed, such as lysine degradation, bile acid biosynthesis. A total of 18 biomarkers were identified through biomarker analysis, and in combination with the exploration of 3 additional biomarkers (LysoPC(18:2(9Z,12Z)), PC (22:5(7Z,10Z,13Z,16Z,19Z)/14:0), and Biliverdin-IX-α), a diagnostic model for BA was constructed using logistic regression analysis. The resulting ROC area under the curve was determined to be 0.968. This study presents an innovative and pioneering approach that utilizes metabolomics analysis to develop a diagnostic model for BA, thereby reducing the need for unnecessary invasive examinations and contributing to advancements in diagnosis and prognosis for patients with BA.PMID:38982277 | DOI:10.1038/s41598-024-66893-2

Sci Rep. 2024 Jul 9;14(1):15813. doi: 10.1038/s41598-024-66878-1.ABSTRACTPreschool children with recurrent wheezing are a heterogeneous population with many underlying biological pathways that contribute to clinical presentations. Although the morbidity of recurrent wheezing in preschool children is significant, biological studies in this population remain quite limited. To address this gap, this study performed untargeted plasma metabolomic analyses in 68 preschool children with recurrent wheezing to identify metabolomic endotypes of wheezing. K-means cluster analysis was performed on metabolomic dataset including a total of 1382 named and unnamed metabolites. We identified three metabolomic clusters which differed in symptom severity, exacerbation occurrence, and variables associated with social disadvantage. Metabolites that distinguished the clusters included those involved in fatty acid metabolism, fatty acids (long chain monounsaturated fatty acids, long chain polyunsaturated fatty acids, and long chain saturated fatty acids), lysophospholipids, phosphatidylcholines, and phosphatidylethanolamines. Pathway analyses identified pathways of interest in each cluster, including steroid metabolism, histidine metabolism, sphingomyelins, and sphingosines, among others. This study highlights the biologic complexity of recurrent wheezing in preschool children and offers novel metabolites and pathways that may be amenable to future study and intervention.PMID:38982241 | DOI:10.1038/s41598-024-66878-1

Sci Rep. 2024 Jul 9;14(1):15829. doi: 10.1038/s41598-024-65947-9.ABSTRACTMetabolomics is the study of small molecules (metabolites), within cells, tissues and biofluids. Maternal metabolites can provide important insight into the health and development of both mother and fetus throughout pregnancy. This study assessed metabolic profiles in the maternal circulation prior to and at the time of diagnosis of preeclampsia and fetal growth restriction. Maternal plasma samples were collected from two independent cohorts: (1) Established disease cohort: 50 participants diagnosed with early-onset preeclampsia (< 34 weeks' gestation), 14 with early-onset fetal growth restriction, and 25 gestation-matched controls. (2) Prospective cohort, collected at 36 weeks' gestation before diagnosis: 17 participants later developed preeclampsia, 49 delivered infants with fetal growth restriction (birthweight < 5th centile), and 72 randomly selected controls. Metabolic evaluation was performed by Metabolomics Australia on the Agilent 6545 QTOF Mass Spectrometer. In the established disease cohort, 77 metabolites were altered in circulation from participants with preeclampsia - increased L-cysteine (3.73-fold), L-cystine (3.28-fold), L-acetylcarnitine (2.57-fold), and carnitine (1.53-fold) (p < 0.05). There were 53 metabolites dysregulated in participants who delivered a fetal growth restriction infant-including increased levulinic acid, citric acid (1.93-fold), and creatine (1.14-fold) (p < 0.05). In the prospective cohort, 30 metabolites were altered in participants who later developed preeclampsia at term - reduced glutaric acid (0.85-fold), porphobilinogen (0.77-fold) and amininohippuric acid (0.82-fold) (p < 0.05) was observed. There were 5 metabolites altered in participants who later delivered a fetal growth restriction infant - including reduced 3-methoxybenzenepropanoic acid (p < 0.05). Downstream pathway analysis revealed aminoacyl-tRNA biosynthesis to be most significantly altered in the established cohort in preeclampsia (13/48 hits, p < 0.001) and fetal growth restriction (7/48 hits, p < 0.001). The predictive cohort showed no significant pathway alterations. This study observed altered metabolites in maternal plasma collected before and after diagnosis of a preeclampsia or fetal growth restriction. While a significant number of metabolites were altered with established disease, few changes were observed in the predictive cohort. Thus, metabolites measured in this study may not be useful as predictors of preeclampsia or fetal growth restriction.PMID:38982217 | DOI:10.1038/s41598-024-65947-9

NPJ Parkinsons Dis. 2024 Jul 9;10(1):130. doi: 10.1038/s41531-024-00713-2.ABSTRACTThe metabolic profile predating the onset of Parkinson's disease (PD) remains unclear. We aim to investigate the metabolites associated with incident and prevalent PD and their predictive values in the UK Biobank participants with metabolomics and genetic data at the baseline. A panel of 249 metabolites was quantified using a nuclear magnetic resonance analytical platform. PD was ascertained by self-reported history, hospital admission records and death registers. Cox proportional hazard models and logistic regression models were used to investigate the associations between metabolites and incident and prevalent PD, respectively. Area under receiver operating characteristics curves (AUC) were used to estimate the predictive values of models for future PD. Among 109,790 participants without PD at the baseline, 639 (0.58%) individuals developed PD after one year from the baseline during a median follow-up period of 12.2 years. Sixty-eight metabolites were associated with incident PD at nominal significance (P < 0.05), spanning lipids, lipid constituent of lipoprotein subclasses and ratios of lipid constituents. After multiple testing corrections (P < 9 × 10-4), polyunsaturated fatty acids (PUFA) and omega-6 fatty acids remained significantly associated with incident PD, and PUFA was shared by incident and prevalent PD. Additionally, 14 metabolites were exclusively associated with prevalent PD, including amino acids, fatty acids, several lipoprotein subclasses and ratios of lipids. Adding these metabolites to the conventional risk factors yielded a comparable predictive performance to the risk-factor-based model (AUC = 0.766 vs AUC = 0.768, P = 0.145). Our findings suggested metabolic profiles provided additional knowledge to understand different pathways related to PD before and after its onset.PMID:38982064 | DOI:10.1038/s41531-024-00713-2

Biomed Chromatogr. 2024 Jul 9:e5948. doi: 10.1002/bmc.5948. Online ahead of print.ABSTRACTEpimedium is a traditional Chinese medicine with a wide range of clinical applications; however, there have been numerous reports of adverse reactions in recent years. The most common side effect of Epimedium is liver injury. In this study, the liquid chromatography-mass spectrometry (LC-MS) method has been established to study the components of Epimedium and to identify the components absorbed into the blood of rats. Bioinformatics was used to screen out potential toxic components, and the integrating metabolomics method was used to explore the molecular mechanism of Epimedium-induced liver injury. The chemical constituents of Epimedium were identified by LC-MS, and 62 compounds were obtained, including 57 flavonoids, four organic acids and one alkaloid. The toxicity network of "Epimedium-component-target-liver injury" was constructed using bioinformatics research methods, and then the key hepatotoxic component icaritin was identified. Integrating metabolomics was used to investigate the changes in the metabolic profile of L-02 cells with different durations of icaritin administration compared with the control group, and 106 different metabolites were obtained. A total of 14 potential biomarkers significantly associated with cell survival were screened by Pearson correlation analysis combined with the L-02 cell survival rate. Our study preliminarily revealed the mechanism of hepatotoxicity induced by Epimedium.PMID:38981997 | DOI:10.1002/bmc.5948

Rheumatol Int. 2024 Jul 9. doi: 10.1007/s00296-024-05628-y. Online ahead of print.ABSTRACTSystemic sclerosis is a rare autoimmune condition leading to incurable complications. Therefore fast and precise diagnosis is crucial to prevent patient death and to maintain quality of life. Unfortunately, currently known biomarkers do not meet this need. To address this problem researchers use diverse approaches to elucidate the underlying aberrations. One of the methods applied is metabolomics. This modern technique enables a comprehensive assessment of multiple compound concentrations simultaneously. As it has been gaining popularity, we found it necessary to summarize metabolomic studies presented so far in a narrative review. We found 11 appropriate articles. All of the researchers found significant differences between patients and control groups, whereas the reported findings were highly inconsistent. Additionally, we have found the investigated groups in most studies were scarcely described, and the inclusion/exclusion approach was diverse. Therefore, further study with meticulous patient assessment is necessary.PMID:38981905 | DOI:10.1007/s00296-024-05628-y

J Chromatogr A. 2024 Jul 8;1730:465145. doi: 10.1016/j.chroma.2024.465145. Online ahead of print.ABSTRACTIn recent years, target-specific affinity recognition systems based on Fe3O4-based composites have proven to be an effective method for screening natural products. Herbal medicines contain a wide range of natural products and are considered to be a major source for the development of novel drugs. However, the process of isolating and obtaining these bioactive components for the production of novel drugs is complex. Meanwhile, the complexity and diversity of herbal constituents have posed a great challenge to the screening studies of herbal active ingredients. Currently, traditional extraction and screening studies of active ingredients in herbal medicine include extraction and chromatographic separation technology development, serum medicinal chemistry, metabolomics and computerized virtual screening. In order to achieve integrated targeting of Fe3O4 for extraction and separation of natural products from herbs, various Fe3O4-based composites need to be synthesized so that the composites can be further functionalized and modified. Composites such as Fe3O4@SiO2, Fe3O4-based magnetic graphene oxide and Fe3O4-based magnetic carbon nanotubes were used to achieve targeted extraction and isolation of natural products from herbal medicines. The main extraction techniques involved based on these Fe3O4-based composites are molecularly imprinted techniques, immobilized ligand fishing techniques, and cell membrane-coated bionanotechnology methods. This article will present recent advances in the synthesis and modification of Fe3O4 composites and their applications for the extraction of natural products in conjunction with molecular imprinting, immobilization-targeted fishing, and cell-membrane-coated biomimetic techniques, as well as the future goals and challenges of functionalized modification of Fe3O4 composites for the targeted extraction of natural products, like protein overexpression modification, doping of fluorescent substances and genetic engineering development. A deeper understanding of the multi-level, multidisciplinary, and applied studies in materials science and phytochemistry will be provided by this article.PMID:38981147 | DOI:10.1016/j.chroma.2024.465145

Adv Sci (Weinh). 2024 Jul 9:e2406333. doi: 10.1002/advs.202406333. Online ahead of print.ABSTRACTMortality rates due to lung cancer are high worldwide. Although PD-1 and PD-L1 immune checkpoint inhibitors boost the survival of patients with non-small-cell lung cancer (NSCLC), resistance often arises. The Warburg Effect, which causes lactate build-up and potential lysine-lactylation (Kla), links immune dysfunction to tumor metabolism. The role of non-histone Kla in tumor immune microenvironment and immunotherapy remains to be clarified. Here, global lactylome profiling and metabolomic analyses of samples from patients with NSCLC is conducted. By combining multi-omics analysis with in vitro and in vivo validation, that intracellular lactate promotes extracellular lipolysis through lactyl-APOC2 is revealed. Mechanistically, lactate enhances APOC2 lactylation at K70, stabilizing it and resulting in FFA release, regulatory T cell accumulation, immunotherapy resistance, and metastasis. Moreover, the anti-APOC2K70-lac antibody that sensitized anti-PD-1 therapy in vivo is developed. This findings highlight the potential of anti lactyl-APOC2-K70 approach as a new combination therapy for sensitizing immunotherapeutic responses.PMID:38981044 | DOI:10.1002/advs.202406333

J Clin Endocrinol Metab. 2024 Jul 9:dgae468. doi: 10.1210/clinem/dgae468. Online ahead of print.ABSTRACTCONTEXT: Mild autonomous cortisol secretion (MACS) is diagnosed based on post-dexamethasone cortisol>1.8 mcg/dL. Scarce evidence exists on steroid circadian secretion and steroid metabolome in MACS.OBJECTIVE: To characterize 24-hour (h) urine steroid metabolome in patients with MACS and determine circadian differences in urine steroid profiling and cortisol concentrations in patients with MACS versus referent subjects.DESIGN: Cross-sectional study, 2018-2023.SETTING: Referral center.PARTICIPANTS: Patients with MACS and age-, sex-, BMI-, and menopausal status-matched referent subjects.MEASUREMENTS: Urine was collected over 24h period as separate day- and night-time collections. High-resolution mass spectrometry assay was used to measure 25 steroids. A subgroup of patients and referent subjects were admitted for every 2h serum measurements of free and total cortisol.OUTCOMES: Steroids, sums, and ratios.RESULTS: Patients with MACS (n=72) had lower mcg/24h median androgens (2084 vs 3283, P<0.001), higher glucocorticoids (15754 vs 12936, P<0.001), and higher glucocorticoid/androgen ratio (8.7 vs 3.9, P<0.001), compared to referent subjects. Patients also had lower steroid day/night ratios compared to referent subjects, reflecting a higher relative nocturnal steroid production in MACS. In a subgroup of 12 patients with MACS and 10 referent subjects, the 24-hour area under the curves for total and free cortisol were similar. However, evening mean total (5.3 vs 4.0 mcg/dL, P=0.056) and free (0.2 vs 0.1 mcg/dL, P=0.035) cortisol was higher in patients vs referent subjects.CONCLUSION: Patients with MACS demonstrate an abnormal urine steroid metabolome, with a high glucocorticoid to androgen ratio, and a higher nocturnal steroid production.PMID:38981002 | DOI:10.1210/clinem/dgae468