PubMed

Mol Cell. 2024 Oct 14:S1097-2765(24)00782-2. doi: 10.1016/j.molcel.2024.09.026. Online ahead of print.ABSTRACTHepatocellular carcinoma (HCC) emerges from chronic inflammation, to which activation of hepatic stellate cells (HSCs) contributes by shaping a pro-tumorigenic microenvironment. Key to this process is p62, whose inactivation leads to enhanced hepatocarcinogenesis. Here, we show that p62 activates the interferon (IFN) cascade by promoting STING ubiquitination by tripartite motif protein 32 (TRIM32) in HSCs. p62, binding neighbor of BRCA1 gene 1 (NBR1) and STING, triggers the IFN cascade by displacing NBR1, which normally prevents the interaction of TRIM32 with STING and its subsequent activation. Furthermore, NBR1 also antagonizes STING by promoting its trafficking to the endosome-lysosomal compartment for degradation independent of autophagy. Of functional relevance, NBR1 deletion completely reverts the tumor-promoting function of p62-deficient HSCs by rescuing the inhibited STING-IFN pathway, thus enhancing anti-tumor responses mediated by CD8+ T cells. Therefore, NBR1 emerges as a synthetic vulnerability of p62 deficiency in HSCs by promoting the STING/IFN pathway, which boosts anti-tumor CD8+ T cell responses to restrain HCC progression.PMID:39423823 | DOI:10.1016/j.molcel.2024.09.026

J Pharm Biomed Anal. 2024 Oct 10;252:116509. doi: 10.1016/j.jpba.2024.116509. Online ahead of print.ABSTRACTIn this study, we prepared four derivatives of fucosylated chondroitin sulfate (FCS): full-length FCS (flFCS) from Holothuria leucospilota, low molecular weight FCS (lmFCS) derived from flFCS, and their de-branched counterparts, de-branched flFCS (d-flFCS) and de-branched lmFCS (d-lmFCS) via controlled acid treatment. Following structural verification using various analytical techniques, we applied targeted metabolomics to examine the impact of FCS on nutritional efficacy and its structure-activity relationship. Analysis of 225 plasma and feces samples from 75 mice revealed a positive correlation between metabolomic shifts and increased weight gain, underscoring FCS's potential to enhance nutrient absorption and promote growth. The observed linear relationship between the levels of short-chain fatty acids in plasma and feces suggests that FCS may facilitate catabolic activities in the gastrointestinal tract. The comparative study of different FCS derivatives on mouse growth and metabolic homeostasis regulation led to the conclusion that FCS exhibits greater biological activity with a higher degree of branching and larger molecular weight.PMID:39423606 | DOI:10.1016/j.jpba.2024.116509

J Chromatogr A. 2024 Oct 9;1737:465426. doi: 10.1016/j.chroma.2024.465426. Online ahead of print.ABSTRACTDicarboxylic acids (DCAs) are essential for intermediate metabolism and are implicated in multiple processes associated with various diseases. Several DCAs contribute to energy metabolism, impact mitochondrial function, and play a crucial role in body function. However, the low abundance of some DCAs in various body fluids makes their quantification particularly challenging. Therefore, an extremely sensitive method is required to determine DCA level fluctuations in biological samples in different diseases. We developed and optimized an LC-MS/MS method to quantify DCAs. We achieved charge reversal of the compounds from negative to positive ionization through chemical derivatization with dimethylaminophenacyl bromide (DmPABr) targeting the carboxyl group (R-COOH) under mild basic conditions. Derivatization enhanced sensitivity, mass fragmentation, and chromatographic separation for LC-tandem mass spectrometric quantification. The method was analytically optimized and demonstrated excellent linearity for individual DCAs (R2>0.99), as well as an exceptionally lower limit of detection (LLOD<266 fg) and lower limit of quantification (LLOQ<805 fg) for all DCAs. Furthermore, most derivatized DCAs were stable at room temperature and after ten repeated freeze-thaw cycles. After DCA extraction and quantification detection, we found differences in their distribution in plasma and urine. The rank order for DCAs in plasma is C4>C6>C7>C9>C5>C8>C22, whereas in the urine sample, the order is C4>C7>C6>C9>C5>C8>C10. For longer chains (C > 16), their proportions were >10x higher in plasma than in urine. Our optimized method using LC-MS/MS enables the quantification of DCAs with excellent sensitivity. The method will help in future studies investigating dicarboxylic acids' crucial role in health and biomarker discovery studies using targeted metabolomics.PMID:39423602 | DOI:10.1016/j.chroma.2024.465426

Biochem Biophys Res Commun. 2024 Oct 15;735:150837. doi: 10.1016/j.bbrc.2024.150837. Online ahead of print.ABSTRACTPURPOSE: Ulcerative colitis (UC) is a chronic, non-specific inflammatory condition of the colon, characterized by recurrent episodes and a notable lack of effective pharmacological treatments. Scutellarin, a natural component, exhibits appreciable pharmacological effects and therapeutic potential for various diseases. However, its effects on UC are not fully understood, and the precise mechanisms remain to be deciphered. This study aimed to assess the therapeutic efficacy of scutellarin and elucidate its underlying mechanisms in treating UC.METHODS: This study utilized dextran sulfate sodium (DSS)-induced mice to evaluate the therapeutic potential of scutellarin against UC and to elucidate the mechanisms involving the gut microbiota. An antibiotics cocktail (ABX) and fecal microbiota transplantation (FMT) were also used to determine the mechanistic role of the gut microbiota. An integrative approach combining fecal metabolomics and network pharmacology analysis was used to explore the gut microbiota-directed molecular mechanism.RESULTS: The results showed that scutellarin provided various therapeutic benefits in UC management, including alleviating weight loss, slowing disease progression, and reducing inflammatory damage in colon structures. The improved gut microbiota after scutellarin administration contributed to these effects. Fecal metabolome revealed that scutellarin selectively mitigated DSS-induced dysregulation of gut microbiota-derived metabolites, including glycolic acid, γ-aminobutyric acid, glutamate, tryptophan, xanthine, and β-hydroxypyruvate. Network pharmacology analysis, along with in vivo experimental verification, implicated the cAMP/PKA/NF-κB pathway in the action of these metabolites in treating UC, which may be the mechanism responsible for scutellarin's curative effects on UC.CONCLUSION: This study demonstrates the potential of scutellarin in alleviating UC by activating the cAMP/PKA/NF-κB pathway through gut microbiota-derived metabolites, highlighting scutellarin as a promising therapeutic agent for UC.PMID:39423571 | DOI:10.1016/j.bbrc.2024.150837

Food Chem. 2024 Oct 15;464(Pt 1):141624. doi: 10.1016/j.foodchem.2024.141624. Online ahead of print.ABSTRACTFoods fried in olive oil received great attention due to its bioactive profile, antioxidants, high stability, and health benefits. However, several chemical alterations contribute to olive oil degradation during deep-frying (DF), and negatively modify its safety and quality. Therefore, measuring the quality indices of olive oil is a vital topic. The classical chemical approaches are destructive and use toxic chemicals, thus, a harmless and real-time analytical technique has become increasingly critical. This review highlights the recent advances of spectroscopic technologies (STs) stand-alone or integrated with chemometrics to provide reliable, rapid, low-cost, sustainable, multi-parametric, and eco-friendly method for monitoring the quality and safety of olive oil during thermal processing, moreover, the limitations of STs are included. The present review offers fundamental insights regarding the degradation of deep-fried olive oil and provides recent evidence in spectroscopy that can be used as consistent method, providing more benefits for the consumers and food industry.PMID:39423542 | DOI:10.1016/j.foodchem.2024.141624

Food Chem. 2024 Oct 10;464(Pt 1):141584. doi: 10.1016/j.foodchem.2024.141584. Online ahead of print.ABSTRACTGrape fruit are harvested in the late summer or early fall and need to be stored at low temperatures to prevent enfeeblement and prolong their shelf-life. This study aimed to determine the effects of abscisic acid (ABA), brassinolide (BR) and ABA + BR (ABR) treatment on the berry quality of 'Shine Muscat' under low temperatures. ABA and BR maintained fruit appearance, cellular structure, weight, firmness. ABR treatments reduced the loss of fruit aroma. Furthermore, the transcriptome and metabolome analysis revealed that ABA, BR, and ABR treatments maintained the quality of fruits during the low temperatures period by influencing chlorophyll metabolism, carotenoid metabolism, flavonoid metabolism, unsaturated fatty acid, and terpene metabolism. These findings identify key genes and metabolites for ABA and BR-induced maintenance of grape fruit quality during cold storage, expanding our understanding of postharvest storage quality maintenance of grape fruit at the transcript and metabolic levels.PMID:39423526 | DOI:10.1016/j.foodchem.2024.141584

Phytomedicine. 2024 Oct 11;135:156138. doi: 10.1016/j.phymed.2024.156138. Online ahead of print.ABSTRACTBACKGROUND: Atherosclerosis is a disease marked by the development of lipid lesions within the endothelium and continues to be a prominent contributor to global mortality. Shexiang Baoxin pill (SBP) has been employed in the management of numerous cardiovascular diseases, but the complex mechanisms by which it operates remain obscure. This research was conducted to determine the potential impact of SBP on atherosclerosis and the underlying regulatory mechanism involved.METHOD: Network pharmacology was utilized to predict the key drug-disease targets, and a nontargeted metabolomic assay was applied to identify the key metabolites and metabolic pathways. A mouse atherosclerosis model was constructed to clarify the protective effect of SBP on atherosclerosis, and in vivo and in vitro tests were performed to verify the analysis results and clarify the mechanism through which SBP affects atherosclerosis.RESULTS: The results show that SBP can exert a protective effect in vivo by decreasing lipid levels, plaque formation and endothelial damage. Network pharmacology and metabolomics revealed that MAPK3, AKT1 and STAT3 were the hub targets and that trimethylamine n-oxide (TMAO) was the pivotal metabolite. Due to the atherogenic effect of TMAO, the corresponding protective effect of SBP was investigated in vitro. SBP inhibited TMAO-induced endothelial cell apoptosis and oxidative stress and counteracted the upregulation of MAPK3, AKT1, and STAT3 expression. Molecular docking and enzymatic inhibition suggested that the active components of SBP could bind stably to key target proteins.CONCLUSION: Taken together, based on the integrated metabolomics and network pharmacology, our findings suggest that SBP may be implicated in TMAO-induced atherosclerosis by affecting endothelial function and bile acid synthesis. We observed that SBP may ameliorate atherosclerosis by regulating TMAO levels through multiple pathways, which may provide a novel direction and insight for SBP involved in cardiovascular protection by mediating the gut-heart axis.PMID:39423481 | DOI:10.1016/j.phymed.2024.156138

J Alzheimers Dis. 2024;101(s1):S299-S315. doi: 10.3233/JAD-240680.ABSTRACTDrug repurposing is a methodology used to identify new clinical indications for existing drugs developed for other indications and has been successfully applied in the treatment of numerous conditions. Alzheimer's disease (AD) may be particularly well-suited to the application of drug repurposing methods given the absence of effective therapies and abundance of multi-omic data that has been generated in AD patients recently that may facilitate discovery of candidate AD drugs. A recent focus of drug repurposing has been in the application of pharmacoepidemiologic approaches to drug evaluation. Here, real-world clinical datasets with large numbers of patients are leveraged to establish observational efficacy of candidate drugs for further evaluation in disease models and clinical trials. In this review, we provide a selected overview of methods for drug repurposing, including signature matching, network analysis, molecular docking, phenotypic screening, semantic network, and pharmacoepidemiological analyses. Numerous methods have also been applied specifically to AD with the aim of nominating novel drug candidates for evaluation. These approaches, however, are prone to numerous limitations and potential biases that we have sought to address in the Drug Repurposing for Effective Alzheimer's Medicines (DREAM) study, a multi-step framework for selection and validation of potential drug candidates that has demonstrated the promise of STAT3 inhibitors and re-evaluated evidence for other drug candidates, such as phosphodiesterase inhibitors. Taken together, drug repurposing holds significant promise for development of novel AD therapeutics, particularly as the pace of data generation and development of analytical methods continue to accelerate.PMID:39422962 | DOI:10.3233/JAD-240680

Clin Transl Med. 2024 Oct;14(10):e70045. doi: 10.1002/ctm2.70045.ABSTRACTBACKGROUND: Liver cancer (LC) is among the deadliest cancers worldwide, with existing treatments showing limited efficacy. This study aimed to elucidate the role and underlying mechanisms of pyrroline-5-carboxylate reductase 1 (PYCR1) as a potential therapeutic target in LC.METHODS: Immunohistochemistry and Western blot were used to analyse the expression of PYCR1 in LC cells and tissues. EdU assays, colony-forming assays, scratch wound healing assays, Transwell assays, nude mouse xenograft models and nude mouse lung metastasis models were used to detect the growth and metastasis abilities of LC cells. Transcriptome sequencing was used to search for downstream target genes regulated by PYCR1, and metabolomics was used to identify the downstream metabolites regulated by PYCR1. ChIP assays were used to analyse the enrichment of H3K18 lactylation in the IRS1 promoter region.RESULTS: We found that the expression of PYCR1 was significantly increased in HCC and that this high expression was associated with poor prognosis in HCC patients. Knockout or inhibition of PYCR1 inhibited HCC cell proliferation, migration and invasion both in vivo and in vitro. In addition, we revealed that knocking out or inhibiting PYCR1 could inhibit glycolysis in HCC cells and reduce H3K18 lactylation of the IRS1 histone, thereby inhibiting IRS1 expression.CONCLUSIONS: Our findings identify PYCR1 as a pivotal regulator of LC progression that influences tumour cell metabolism and gene expression. By demonstrating the potential of targeting PYCR1 to inhibit LC cell proliferation and metastasis, this study identified PYCR1 as a promising therapeutic target for LC.HIGHLIGHTS: Pyrroline-5-carboxylate reductase 1 (PYCR1) promotes the proliferation and metastasis of liver cancer (LC) cells. The expression of PYCR1 in LC is regulated by DNA methylation. Knocking down or inhibiting PYCR1 inhibits glycolysis as well as the PI3K/AKT/mTOR and MAPK/ERK pathways in LC cells. PYCR1 regulates the transcriptional activity of IRS1 by affecting H3K18 lactylation in its promoter region.PMID:39422696 | DOI:10.1002/ctm2.70045

Chemistry. 2024 Oct 18:e202403278. doi: 10.1002/chem.202403278. Online ahead of print.ABSTRACTWe developed a single cell amine analysis approach utilizing isobarically multiplexed samples of 6 individual cells along with analyte abundant carrier. This methodology was applied for absolute quantitation of amino acids and untargeted relative quantitation of amines in a total of 108 individual cells using nanoflow LC with high-resolution mass spectrometry. Together with individually determined cell sizes, this provides quantification of intracellular concentrations within individual cells. The targeted method was partially validated for 10 amino acids with limits of detection in low attomoles, linear calibration range covering analyte amounts typically from 30 amol to 120 fmol, and correlation coefficients (R) above 0.99. This was applied with cell sizes recorded during dispensing to determine millimolar intracellular amino acid concentrations. The untargeted approach yielded 249 features that were detected in at least 25% of the single cells, providing modest cell type separation on principal component analysis. Using Greedy forward selection with regularized least squares, a sub-selection of 100 features explaining most of the difference was determined. These features were annotated using MS2 from analyte standards and accurate mass with library search. The approach provides accessible, sensitive, and high-throughput method with the potential to be expanded also to other forms of ultrasensitive analysis.PMID:39422672 | DOI:10.1002/chem.202403278

mSystems. 2024 Oct 18:e0064324. doi: 10.1128/msystems.00643-24. Online ahead of print.ABSTRACTGut microbiota and associated metabolites have been linked to breast carcinogenesis. Evidences demonstrate blood microbiota primarily originates from the gut and may act as a biomarker for breast cancer. We aimed to characterize the microbiota-gut microbial metabolites cross-talk in blood and develop a composite diagnostic panel for breast cancer. We performed 16S rRNA gene sequencing and metabolomics profiling on blood samples from 107 breast cancer cases and 107 age-paired controls. We found that the alpha diversity of the blood microbiota was decreased in breast cancer compared to controls. There were significantly different profiles of microbiota and gut microbial metabolites in blood between these two groups, with nine bacterial genera and four gut microbial metabolites increased in patients, while thirty-nine bacterial genera and two gut microbial metabolites increased in controls. Some breast cancer-associated gut microbial metabolites were linked to differential blood microbiota, and a composite microbiota-metabolite diagnostic panel was further developed with an area under the curve of 0.963 for breast cancer. This study underscored the pivotal role of microbiota and gut microbial metabolites in blood and their interactions for breast carcinogenesis, as well as the potential of a composite diagnostic panel as a non-invasive biomarker for breast cancer.IMPORTANCEOur integrated analysis demonstrated altered profiles of microbiota and gut microbial metabolites in blood for breast cancer patients. The extensive correlation between microbiota and gut microbial metabolites in blood assisted the understanding of the pathogenesis of breast cancer. The good performance of a composite microbiota-gut microbial metabolites panel in blood suggested a non-invasive approach for breast cancer detection and a novel strategy for better diagnosis and prevention of breast cancer in the future.PMID:39422470 | DOI:10.1128/msystems.00643-24

mBio. 2024 Oct 18:e0175824. doi: 10.1128/mbio.01758-24. Online ahead of print.ABSTRACTVirulence screens have indicated potential roles during Streptococcus pneumoniae infection for the one-carbon metabolism pathway component Fhs and proline synthesis mediated by ProABC. To define how these metabolic pathways affect S. pneumoniae virulence, we have investigated the phenotypes, transcription, and metabolic profiles of Δfhs and ΔproABC mutants. S. pneumoniae capsular serotype 6B BHN418 Δfhs and ΔproABC mutant strains had strongly reduced virulence in mouse sepsis and pneumonia models but could colonize the nasopharynx. Both mutant strains grew normally in complete media but had markedly impaired growth in chemically defined medium, human serum, and human cerebrospinal fluid. The BHN418 ΔproABC strain also had impaired growth under conditions of osmotic and oxidative stress. The virulence role of proABC was strain specific, as the D39 ΔproABC strain could still cause septicemia and grow in serum. Compared to culture in broth, in serum, the BHN418 Δfhs and ΔproABC strains showed considerable derangement in global gene transcription that affected multiple but different metabolic pathways for each mutant strain. Metabolic data suggested that Δfhs had an impaired stringent response, and when cultured in sera, BHN418 Δfhs and ΔproABC were under increased oxidative stress and had altered lipid profiles. Loss of proABC also affected carbohydrate metabolism and the accumulation of peptidoglycan synthesis precursors in the BHN418 but not the D39 background, linking this phenotype to the conditional virulence phenotype. These data identify the S. pneumoniae metabolic functions affected by S. pneumoniae one-carbon metabolism and proline biosynthesis, and the role of these genetic loci for establishing systemic infection.IMPORTANCERapid adaptation to grow within the physiological conditions found in the host environment is an essential but poorly understood virulence requirement for systemic pathogens such as Streptococcus pneumoniae. We have now demonstrated an essential role for the one-carbon metabolism pathway and a conditional role depending on strain background for proline biosynthesis for S. pneumoniae growth in serum or cerebrospinal fluid, and therefore for systemic virulence. RNAseq and metabolomic data demonstrated that the loss of one-carbon metabolism or proline biosynthesis has profound but differing effects on S. pneumoniae metabolism in human serum, identifying the metabolic processes dependent on each pathway during systemic infection. These data provide a more detailed understanding of the adaptations required by systemic bacterial pathogens in order to cause infection and demonstrate that the requirement for some of these adaptations varies between strains from the same species and could therefore underpin strain variations in virulence potential.PMID:39422467 | DOI:10.1128/mbio.01758-24

Plant Cell. 2024 Oct 18:koae282. doi: 10.1093/plcell/koae282. Online ahead of print.ABSTRACTThe banana (Musa spp.) peel undergoes rapid softening during ripening, leading to finger drop and a shortened shelf life. The regulatory mechanism behind this process remains to be elucidated. In this study, we confirmed the role of peel softening in banana finger drop and uncovered the underlying transcriptional regulatory network. Cell wall-related (CWR) genes were substantially upregulated in both the peel and finger drop zone during ethylene-induced ripening. Transcriptome analysis and genome-wide profiling of chromatin accessibility and transcription factor (TF) binding revealed that two key regulators of fruit ripening, Musa acuminata NAC-like, Activated by apetala3/Pistillata1 (MaNAP1) and MaMADS1, regulate CWR genes by directly binding to their promoters or by targeting other ripening-related TFs to form a hierarchical regulatory network. Notably, MaNAP1 and MaMADS1 were directly targeted by ETHYLENE INSENSITIVE3 (MaEIN3), and MaNAP1 and MaMADS1 associated with tissue-specific histone modifications, enabling them to integrate MaEIN3-mediated ethylene signaling and undergo epigenetic regulation. Overexpression of MaNAP1, MaMADS1 or other identified regulatory TFs upregulated CWR genes and promoted peel softening. Our findings unveil a MaNAP1-MaMADS1-centered regulatory cascade governing banana peel softening and finger drop, offering potential targets for enhancing banana texture and shelf life.PMID:39422253 | DOI:10.1093/plcell/koae282

Br J Nutr. 2024 Oct 18:1-11. doi: 10.1017/S0007114524001934. Online ahead of print.ABSTRACTTo improve the interpretation and utilisation of blood lipids, ketones and acylcarnitine concentrations as biomarkers in clinical assessments, more information is needed on their dynamic alterations in response to dietary intake and fasting. The aim of this intervention study was to characterise the changes in serum lipid, ketone and acylcarnitine concentrations 24 h after a standardised breakfast meal. Thirty-four healthy subjects (eighteen males and sixteen females) aged 20-30 years were served a breakfast meal (∼500 kcal, 36 E% fat, 46 E% carbohydrates, 16 E% protein, 2E% fibre), after which they consumed only water for 24 h. Blood samples were drawn before and at thirteen standardised timepoints after the meal. Metabolite concentrations were plotted as a function of time since the completion of the breakfast meal. Results demonstrated that concentrations of HDL-cholesterol and LDL-cholesterol decreased until ∼2 h (-4 % for both), while TAG concentrations peaked at 3 h (+27 %). Acetoacetate and β-hydroxybutyrate were highest 24 h after the meal (+433 and +633 %, respectively). Acetylcarnitine, butyrylcarnitine, hexanoylcarnitine, octanoylcarnitine, decanoylcarnitine and dodecanoylcarnitine reached the lowest values at 60 min (decreases ranging from -47 to -70 %), before increasing and peaking at 24 h after the meal (increases ranging from +86 to +120 %). Our findings suggest that distinguishing between fasting and non-fasting blood samples falls short of capturing the dynamics in lipid, ketone, carnitine and acylcarnitine concentrations. To enhance the utility of serum acylcarnitine analyses, we strongly recommend accounting for the specific time since the last meal at the time of blood sampling.PMID:39422147 | DOI:10.1017/S0007114524001934

J Agric Food Chem. 2024 Oct 18. doi: 10.1021/acs.jafc.4c05558. Online ahead of print.ABSTRACTPhenazine-1-carboxamide (PCN) has been exploited as a successful biopesticide due to its broad-spectrum antifungal activity. We engineered a PCN-overproducing Pseudomonas chlororaphis strain through overexpressing shikimate pathway genes (aroB, aroQ, aroE, and phzC) and deleting negative regulatory genes (relA, fleQ, and pykF). The optimized strain produced 1.92 g/L PCN with a yield of 0.11 g/g glycerol, the highest titer ever reported by using minimal media. To gain deeper insights into the underlying regulatory network, the final strain and the parental strain were examined using three distinct omic data sets. 13C-metabolic flux analysis revealed a substantial flux reconfiguration in the optimized strain, including the activation of the EDEMP cycle, the PP pathway, the glyoxylate shunt, and the shikimate pathway. Metabolomic results indicated that central carbon was rerouted to the shikimate pathway. Transcriptomic data identified global gene expression changes. This study forms the basis for further engineering of strains to achieve outstanding performance.PMID:39422022 | DOI:10.1021/acs.jafc.4c05558

Circ Heart Fail. 2024 Oct 18:e011980. doi: 10.1161/CIRCHEARTFAILURE.124.011980. Online ahead of print.ABSTRACTBACKGROUND: Mechanisms of benefit with SGLT2is (sodium-glucose cotransporter-2 inhibitors) in heart failure (HF) remain incompletely characterized. Dapagliflozin alters ketone and fatty acid metabolism in HF with reduced ejection fraction though similar effects have not been observed in HF with preserved ejection fraction. We explore whether metabolic effects of SGLT2is vary across the left ventricular ejection fraction spectrum and their relationship with cardiometabolic end points in 2 randomized trials of dapagliflozin in HF.METHODS: Metabolomic profiling of 61 metabolites was performed in 527 participants from DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients With HF With Reduced Ejection Fraction) and PRESERVED-HF (Dapagliflozin in PRESERVED Ejection Fraction HF; 12-week, placebo-controlled trials of dapagliflozin in HF with reduced ejection fraction and HF with preserved ejection fraction, respectively). Linear regression was used to assess changes in principal components analysis-defined metabolite factors with treatment from baseline to 12 weeks, as well as the relationship between changes in metabolite clusters and HF-related end points.RESULTS: The mean age was 66±11 years, 43% were female, and 33% were self-identified as Black. Two principal components analysis-derived metabolite factors (which were comprised of ketone and short-/medium-chain acylcarnitines) increased with dapagliflozin compared with placebo. Ketosis (defined as 3-hydroxybutyrate >500 μM) was achieved in 4.5% with dapagliflozin versus 1.2% with placebo (P=0.03). There were no appreciable treatment effects on amino acids, including branched-chain amino acids. Increases in several acylcarnitines were consistent across LVEF (Pinteraction>0.10), whereas the ketogenic effect diminished at higher LVEF (Pinteraction=0.01 for 3-hydroxybutyrate). Increases in metabolites reflecting mitochondrial dysfunction (particularly long-chain acylcarnitines) and aromatic amino acids and decreases in branched-chain amino acids were associated with worse HF-related outcomes in the overall cohort, with consistency across treatment and LVEF.CONCLUSIONS: SGLT2is demonstrate common (fatty acid) and distinct (ketogenic) metabolic signatures across the LVEF spectrum. Changes in key pathways related to fatty acid and amino acid metabolism are associated with HF-related end points and may serve as therapeutic targets across HF subtypes.REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifiers: NCT03030235 and NCT02653482.PMID:39421941 | DOI:10.1161/CIRCHEARTFAILURE.124.011980

Circ Res. 2024 Oct 18. doi: 10.1161/CIRCRESAHA.123.324138. Online ahead of print.ABSTRACTBACKGROUND: Mitochondrial dysfunction, characterized by impaired lipid metabolism and heightened reactive oxygen species generation, results in lipid peroxidation and ferroptosis. Ferroptosis is an inflammatory mode of cell death that promotes complement activation and macrophage recruitment. In pulmonary arterial hypertension (PAH), pulmonary arterial endothelial cells exhibit cellular phenotypes that promote ferroptosis. Moreover, there is ectopic complement deposition and inflammatory macrophage accumulation in the pulmonary vasculature. However, the effects of ferroptosis inhibition on these pathogenic mechanisms and the cellular landscape of the pulmonary vasculature are incompletely defined.METHODS: Multiomics and physiological analyses evaluated how ferroptosis inhibition-modulated preclinical PAH. The impact of adeno-associated virus 1-mediated expression of the proferroptotic protein ACSL (acyl-CoA synthetase long-chain family member) 4 on PAH was determined, and a genetic association study in humans further probed the relationship between ferroptosis and pulmonary hypertension.RESULTS: Ferrostatin-1, a small-molecule ferroptosis inhibitor, mitigated PAH severity in monocrotaline rats. RNA-sequencing and proteomics analyses demonstrated that ferroptosis was associated with PAH severity. RNA-sequencing, proteomics, and confocal microscopy revealed that complement activation and proinflammatory cytokines/chemokines were suppressed by ferrostatin-1. In addition, ferrostatin-1 combatted changes in endothelial, smooth muscle, and interstitial macrophage abundance and gene activation patterns as revealed by deconvolution RNA-sequencing. Ferroptotic pulmonary arterial endothelial cell damage-associated molecular patterns restructured the transcriptomic signature and mitochondrial morphology, promoted the proliferation of pulmonary artery smooth muscle cells, and created a proinflammatory phenotype in monocytes in vitro. Adeno-associated virus 1-Acsl4 induced an inflammatory PAH phenotype in rats. Finally, single-nucleotide polymorphisms in 6 ferroptosis genes identified a potential link between ferroptosis and pulmonary hypertension severity in the Vanderbilt BioVU repository.CONCLUSIONS: Ferroptosis promotes PAH through metabolic and inflammatory mechanisms in the pulmonary vasculature.PMID:39421926 | DOI:10.1161/CIRCRESAHA.123.324138

Front Med (Lausanne). 2024 Oct 3;11:1436866. doi: 10.3389/fmed.2024.1436866. eCollection 2024.ABSTRACTINTRODUCTION: Colorectal cancer (CRC) is the third most incident and the second most lethal malignant tumor. Despite the recognized association between obesity and CRC, further clarification is necessary regarding the lipids that are overexpressed during the development of CRC. In this scenario, the combination of metabolomics and a three-dimensional (3D) co-culture model involving CRC tumor cells and lipids can enhance the knowledge of energy metabolism modifications at the cross-talk between colorectal cancer and adipocytes. This study aimed to screen potential metabolites in the three dimensional (3D) co-culture of CRC and adipocytes by investigating the metabolome composition of this co-culture released into the extracellular space, which is known as the secretome.METHODS: Pre-adipocyte cells (3T3-L1), human colon carcinoma (HT-29), and the 3D co-culture (3T3-L1 + HT-29) were cultured for the secretome obtention. Then, ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) was employed to analyze the metabolomics of each secretome.RESULTS: Overall, 3.731 molecules were detected independent of the cell culture. When comparing the three cultures, 105 molecules presented a statistically significant difference in abundance between groups. Among these molecules, 16 were identified, with a particular emphasis on six lipids (PG 20:0, octadecenal, 3-Hydroxytetracosanoyl-CoA, 9,10-dihydroxy-octadecenoic acid, palmitoleic acid, and PA 18:4) and one amino acid derivative (acetylglutamic acid), which presented significant scores during the partial least-squares discriminant analysis (PLS-DA).DISCUSSION: Although it is too early to determine the possible impact of such molecules in a CRC microenvironment, these results open new avenues for further studies on the energy metabolism at the cross-talk of colorectal cancer adipocytes.PMID:39421865 | PMC:PMC11484090 | DOI:10.3389/fmed.2024.1436866

Front Chem. 2024 Oct 3;12:1478674. doi: 10.3389/fchem.2024.1478674. eCollection 2024.ABSTRACTAccumulation of acylcarnitines is a characteristic feature of various metabolic disorders affecting fatty acid metabolism. Despite extensive research, no specific molecules have been identified to induce ferroptosis through the regulation of acylcarnitine metabolism. In this study, acylcarnitine accumulation was identified based on cell metabolomics study after the treatment with Stemona alkaloid derivative (SA-11), which was proved to induce ferroptosis in our previous research. Furthermore, the CPT-1 level was proved to significantly increase, while the CPT-2 level indicated no significant difference, which resulted in the accumulation of acylcarnitine. Besides, the ferroptosis-inducing ability of SA-11 was significantly enhanced by the addition of exogenous acylcarnitine, presumably due to the production of additional ROS. This hypothesis was corroborated by the observation of increased ROS levels in HCT-116 cells treated with SA-11 compared to the control group. These findings suggest that targeting acylcarnitine metabolism, particularly through CPT-1, may offer a novel therapeutic strategy for cancer treatment by enhancing ferroptosis induction.PMID:39421605 | PMC:PMC11484037 | DOI:10.3389/fchem.2024.1478674

Front Physiol. 2024 Oct 3;15:1465946. doi: 10.3389/fphys.2024.1465946. eCollection 2024.ABSTRACTOBJECTIVE: Bactrocera dorsalis (Hendel) has a wide host range. It has been the most important quarantine pest in many countries or regions. Currently, chemical control and bait trapping are mainly used in the monitoring, prevention, and control of B. dorsalis. However, chemical control will cause pollution of the environment and drug resistance of insects. Methyl eugenol, the main attractant currently used, can only attract males of B. dorsalis.METHODS: This study focused on the attractant function and active substances of one key intestinal bacterium, Enterobacter cloacae, which was isolated from B. dorsalis.RESULTS: First, the attraction of the E. cloacae autoclaved supernatant to male and female adults of 0, 6, and 15 days post-emergence was confirmed using a Y-type olfactometer. Subsequently, through metabolome sequencing and bioassays, L-prolinamide was identified and confirmed as the most effective attractant for B. dorsalis. Finally, the synergistic effect of L-prolinamide with the sex attractant ME was validated through field experiments. This study confirmed the attraction effect of E. cloacae on B. dorsalis and also proved the attraction effect of L-prolinamide, the metabolite of E. cloacae, on B. dorsalis. This laid a theoretical foundation for the development of a new attractant and safe, green, and efficient prevention and control technology of B. dorsalis.PMID:39421438 | PMC:PMC11484074 | DOI:10.3389/fphys.2024.1465946