PubMed

J Pediatr Gastroenterol Nutr. 2024 Aug 16. doi: 10.1002/jpn3.12351. Online ahead of print.ABSTRACTOBJECTIVE: In functional dyspepsia patients, duodenal mucosal eosinophilia has been associated with early satiety but is not present in all patients suggesting varied pathways to symptom generation. The objective of the current study was to explore metabolic differences comparing those with duodenal mucosal eosinophilia to those without eosinophilia.METHODS: This study was conducted utilizing an existing biorepository. Patients had plasma samples obtained at the time of endoscopy. All had undergone endoscopy for dyspepsia and reported early satiety. Two groups were identified including those with peak duodenal mucosal eosinophil densities above 30/high power field (N = 28) and those below 30 (N = 16). The fasting plasma samples were analyzed by liquid chromatography/high-resolution mass spectrometry. Significant differences between groups were determined.RESULTS: The eosinophilia group demonstrated significant elevations in several gamma-glutamyl amino acids. The eosinophilia group had elevations of metabolites associated with oxidative stress including glutathione metabolites (cysteinlyglycine and cys-gly oxidized), and metabolites related to nitric oxide synthesis (arginine, citrulline, ornithine, and dimethylarginine). Eosinophilia was also associated with alterations in lipid metabolism including several long-chain acylcarnitine conjugated fatty acids. Carnitine levels were lower in the eosinophilia group. Lastly, vanillymandelate, a derivative of norepinephrine and epinephrine was elevated in the eosinophilia group.CONCLUSIONS: In patients with dyspepsia and early satiety, duodenal mucosal eosinophilia is associated with metabolites levels which are consistent with increased oxidative stress and alterations in lipid metabolism. Eosinophilia was also associated with lower carnitine levels. These alterations may contribute to pathophysiology and represent therapeutic targets.PMID:39149805 | DOI:10.1002/jpn3.12351

Food Chem (Oxf). 2024 Jul 17;9:100214. doi: 10.1016/j.fochms.2024.100214. eCollection 2024 Dec 30.ABSTRACTThe by-products of the grain processing industry are a vital resource for the valorization methods in the food industry. In comparison to the whole grain, the broken kernels and seeds own similar nutrient and bioactive compounds having multifaceted health properties. This study aims to develop a nutritional bar by utilizing the by-products from barnyard millet and foxnut with added sweeteners. Furthermore, high-resolution mass spectrometry (HR-MS) metabolomics was carried out in positive and negative both ion modes to identify the major bioactive compounds formed in the matrix of the best-optimized valorized bar. The formulation of the bar having 15 % foxnut flour and the barnyard flour each, was elucidated highest rheological and sensory scores. A sum of 29 bioactive metabolites has been observed in the obtained metabolome. Major metabolites were palmitoyl serinol, glycitein, persin, bufagargarizin, apigenin, carvone, etc. covering a wide area in the mass spectrum. The therapeutic value of these compounds is heart health promotion, anti-inflammatory, anti-carcinogenic, anti-diabetic, anti-microbial, etc. This work highlights the bioactivity of the valorized nutritional bar employing robust and accurate tool of mass spectrometry. The developed snack is a functional food for the consumers.PMID:39149574 | PMC:PMC11324833 | DOI:10.1016/j.fochms.2024.100214

Front Nutr. 2024 Aug 1;11:1439094. doi: 10.3389/fnut.2024.1439094. eCollection 2024.ABSTRACTAging often accompanies cognitive and mood disturbances. Emerging evidence indicates that specific probiotics mitigate cognitive and mood dysfunctions. Strains within Lactococcus, a subgroup of probiotics, including Lactococcus lactis and Lactococcus cremoris are shown beneficial effects on brain functions via the gut microbiota-brain axis (GBA). Our previous study identified two Lactococcus strains (L. lactis WHH2078 and L. cremoris WHH2080) with the ability to promote the secretion of gut 5-hydroxytryptophan (5-HTP), the precursor of the GBA mediator 5-hydroxytryptamine (5-HT). In this study, the modulatory effects of WHH2078 and WHH2080 on cognitive and mood alternations were investigated in aged mice. Oral administration of WHH2078 and WHH2080 (1 × 109 CFU/mL/day) in aged mice (12-month-old) for 12 weeks significantly improved cognitive and depressive-and anxiety-like behaviors. The neuronal loss, the 5-HT metabolism dysfunction, and the neuroinflammation in the hippocampus of aged mice were restored by WHH2078 and WHH2080. the disturbances in the serum tryptophan metabolism in aged mice were unveiled by metabolomics, notably with decreased levels of 5-HT and 5-HTP, and increased levels of kynurenine, 3-hydroxykynurenine, and indolelactic acid, which were reversed by WHH2078 and WHH2080. Regarding the gut microbial community, WHH2078 and WHH2080 restored the increased abundance of Firmicutes, Desulfobacterota, and Deferribacterota and the decreased abundance of Bacteroidota and Actinobacteriota in aged mice. The beneficial effects of the two strains were linked to the modulation of 5-HT metabolism and gut microbiota. Our findings point to the potential role of Lactococcus strains with 5-HTP-promoting abilities as therapeutic approaches for age-related cognitive and mood disorders.PMID:39149553 | PMC:PMC11324604 | DOI:10.3389/fnut.2024.1439094

Synth Syst Biotechnol. 2024 Jul 16;9(4):842-852. doi: 10.1016/j.synbio.2024.07.002. eCollection 2024 Dec.ABSTRACTThe Antarctic fungus Geomyces sp. WNF-15A can produce high-quality red pigments (AGRP) with good prospects for the use in food and cosmetic area. However, efficient AGRP synthesis relies on low-temperature and thus limits its industrial development. Here genome sequencing and comparative analysis were performed on the wild-type versus to four mutants derived from natural mutagenesis and transposon insertion mutation. Eleven mutated genes were identified from 2309 SNPs and 256 Indels. A CRISPR-Cas9 gene-editing system was established for functional analysis of these genes. Deficiency of scaffold1.t692 and scaffold2.t704 with unknown functions highly improved AGRP synthesis at all tested temperatures. Of note, the two mutants produced comparable levels of AGRP at 20 °C to the wild-type at 14 °C. They also broke the normal-temperature limitation and effectively synthesized AGRP at 25 °C. Comparative metabolomic analysis revealed that deficiency of scaffold1.t692 improved AGRP synthesis by regulation of global metabolic pathways especially downregulation of the competitive pathways. Knockout of key genes responsible for the differential metabolites confirmed the metabolomic results. This study shows new clues for cold-adaptive regulatory mechanism of polar fungi. It also provides references for exploitation and utilization of psychrotrophic fungal resources.PMID:39149535 | PMC:PMC11326490 | DOI:10.1016/j.synbio.2024.07.002

Res Sq [Preprint]. 2024 Jul 31:rs.3.rs-4669838. doi: 10.21203/rs.3.rs-4669838/v1.ABSTRACTBackground Chronic low back pain (CLBP) and fibromyalgia (FM) are leading causes of suffering, disability, and social costs. Current pharmacological treatments do not target molecular mechanisms driving CLBP and FM, and no validated biomarkers are available, hampering the development of effective therapeutics. Omics research has the potential to substantially advance our ability to develop mechanism-specific therapeutics by identifying pathways involved in the pathophysiology of CLBP and FM, and facilitate the development of diagnostic, predictive, and prognostic biomarkers. We will conduct a blood and urine multi-omics study in comprehensively phenotyped and clinically characterized patients with CLBP and FM. Our aims are to identify molecular pathways potentially involved in the pathophysiology of CLBP and FM that would shift the focus of research to the development of target-specific therapeutics, and identify candidate diagnostic, predictive, and prognostic biomarkers. Methods We are conducting a prospective cohort study of adults ≥18 years of age with CLBP (n=100) and FM (n=100), and pain-free controls (n=200). Phenotyping measures include demographics, medication use, pain-related clinical characteristics, physical function, neuropathiccomponents (quantitative sensory tests and DN4 questionnaire), pain facilitation (temporal summation), and psychosocial function as moderator. Blood and urine samples are collected to analyze metabolomics, lipidomics and proteomics. We will integrate the overall omics data to identify common mechanisms and pathways, and associate multi-omics profiles to pain-related clinical characteristics, physical function, indicators of neuropathic pain, and pain facilitation, with psychosocial variables as moderators. Discussion Our study addresses the need for a better understanding of the molecular mechanisms underlying chronic low back pain and fibromyalgia. Using a multi-omics approach, we hope to identify converging evidence for potential targets of future therapeutic developments, as well as promising candidate biomarkers for further investigation by biomarker validation studies. We believe that accurate patient phenotyping will be essential for the discovery process, as both conditions are characterized by high heterogeneity and complexity, likely rendering molecular mechanisms phenotype specific.PMID:39149502 | PMC:PMC11326421 | DOI:10.21203/rs.3.rs-4669838/v1

bioRxiv [Preprint]. 2024 Aug 10:2024.08.09.607377. doi: 10.1101/2024.08.09.607377.ABSTRACTMicroRNA-1 (miR-1) is the most abundant miRNA in adult skeletal muscle. To determine the function of miR-1 in adult skeletal muscle, we generated an inducible, skeletal muscle-specific miR-1 knockout (KO) mouse. Integration of RNA-sequencing (RNA-seq) data from miR-1 KO muscle with Argonaute 2 enhanced crosslinking and immunoprecipitation sequencing (AGO2 eCLIP-seq) from human skeletal muscle identified miR-1 target genes involved with glycolysis and pyruvate metabolism. The loss of miR-1 in skeletal muscle induced cancer-like metabolic reprogramming, as shown by higher pyruvate kinase muscle isozyme M2 (PKM2) protein levels, which promoted glycolysis. Comprehensive bioenergetic and metabolic phenotyping combined with skeletal muscle proteomics and metabolomics further demonstrated that miR-1 KO induced metabolic inflexibility as a result of pyruvate oxidation resistance. While the genetic loss of miR-1 reduced endurance exercise performance in mice and in C. elegans, the physiological down-regulation of miR-1 expression in response to a hypertrophic stimulus in both humans and mice causes a similar metabolic reprogramming that supports muscle cell growth. Taken together, these data identify a novel post-translational mechanism of adult skeletal muscle metabolism regulation mediated by miR-1.PMID:39149347 | PMC:PMC11326265 | DOI:10.1101/2024.08.09.607377

Heliyon. 2024 Jul 18;10(14):e34835. doi: 10.1016/j.heliyon.2024.e34835. eCollection 2024 Jul 30.ABSTRACTTo investigate the alleviating effect and mechanism of the docosahexaenoic acid-enriched phosphatidylserine (DHA-PS) on bisphenol A (BPA)-induced liver injury in mice, the murine liver injury model was established by gavage of BPA (5 mg/kg) or co-administration of BPA and DHA-PS (50 mg/kg or 100 mg/kg) for 6 weeks. The results showed that after administration of 100 mg/kg DHA-PS, the liver index, serum levels of AST, ALT, TC, TG, NEFA, and LDL-C in mice were significantly decreased, while HDL-C was significantly increased. The LPS, IL-6, IL-1β, TNF-α, and MDA levels in liver tissues were effectively down-regulated, and IL-10, SOD, GSH-Px, and CAT levels were effectively up-regulated. The H&E and Oil Red O staining results showed that liver damage was notably repaired and lipid deposition was notably reduced after DHA-PS administration. Furthermore, metabolomics and immunohistochemical studies revealed that DHA-PS mainly regulates glycerophospholipid metabolism and the SIRT1-AMPK pathway to improve metabolic disorders of the liver caused by BPA. Therefore, DHA-PS could potentially alleviate BPA-induced murine liver injury through suppressing inflammation and oxidative stress, and modulating lipid metabolism disorders.PMID:39148994 | PMC:PMC11325772 | DOI:10.1016/j.heliyon.2024.e34835

medRxiv [Preprint]. 2024 Aug 8:2024.08.07.24311628. doi: 10.1101/2024.08.07.24311628.ABSTRACTBACKGROUND: Posttraumatic stress disorder (PTSD) is characterized by severe distress and associated with cardiometabolic diseases. Studies in military and clinical populations suggest dysregulated metabolomic processes may be a key mechanism. Prior work identified and validated a metabolite-based distress score (MDS) linked with depression and anxiety and subsequent cardiometabolic diseases. Here, we assessed whether PTSD shares metabolic alterations with depression and anxiety and also if additional metabolites are related to PTSD.METHODS: We leveraged plasma metabolomics data from three subsamples nested within the Nurses' Health Study II, including 2835 women with 2950 blood samples collected across three timepoints (1996-2014) and 339 known metabolites consistently assayed by mass spectrometry-based techniques. Trauma and PTSD exposures were assessed in 2008 and characterized as follows: lifetime trauma without PTSD, lifetime PTSD in remission, and persistent PTSD symptoms. Associations between the exposures and the MDS or individual metabolites were estimated within each subsample adjusting for potential confounders and combined in random-effects meta-analyses.RESULTS: Persistent PTSD symptoms were associated with higher levels of the previously developed MDS for depression and anxiety. Out of 339 metabolites, we identified nine metabolites (primarily elevated glycerophospholipids) associated with persistent symptoms (false discovery rate<0.05). No metabolite associations were found with the other PTSD-related exposures.CONCLUSIONS: As the first large-scale, population-based metabolomics analysis of PTSD, our study highlighted shared and distinct metabolic differences linked to PTSD versus depression or anxiety. We identified novel metabolite markers associated with PTSD symptom persistence, suggesting further connections with metabolic dysregulation that may have downstream consequences for health.PMID:39148851 | PMC:PMC11326341 | DOI:10.1101/2024.08.07.24311628

Front Plant Sci. 2024 Aug 1;15:1322261. doi: 10.3389/fpls.2024.1322261. eCollection 2024.ABSTRACTThe dramatic decrease in atmospheric CO2 concentration during Oligocene was proposed as directly linked to C4 evolution. However, it remains unclear how the decreased CO2 concentration directly facilitate C4 evolution, besides its role as a selection pressure. We conducted a systematic transcriptomics and metabolomics analysis under short-term low CO2 condition and found that Arabidopsis grown under this condition showed 1) increased expression of most genes encoding C4-related enzymes and transporters; 2) increased expression of genes involved in photorespiration and pathways related to carbon skeleton generation for ammonium refixation; 3) increased expression of genes directly involved in ammonium refixation. Furthermore, we found that in vitro treatment of leaves with NH4 + induced a similar pattern of changes in C4 related genes and genes involved in ammonium refixation. These data support the view that Arabidopsis grown under short-term low CO2 conditions rewired its metabolism to supply carbon skeleton for ammonium recycling, during which process the expression of C4 genes were up-regulated as a result of a hitchhiking process. This study provides new insights into the adaptation of the C3 model plant Arabidopsis under low CO2 conditions and suggests that low CO2 can facilitate the evolution of C4 photosynthesis beyond the commonly assumed role of being a selection pressure.PMID:39148616 | PMC:PMC11324553 | DOI:10.3389/fpls.2024.1322261

Front Plant Sci. 2024 Aug 1;15:1440663. doi: 10.3389/fpls.2024.1440663. eCollection 2024.ABSTRACTINTRODUCTION: Salt stress is a major abiotic stress that affects crop growth and productivity. Choline Chloride (CC) has been shown to enhance salt tolerance in various crops, but the underlying molecular mechanisms in rice remain unclear.METHODS: To investigate the regulatory mechanism of CC-mediated salt tolerance in rice, we conducted morpho-physiological, metabolomic, and transcriptomic analyses on two rice varieties (WSY, salt-tolerant, and HHZ, salt-sensitive) treated with 500 mg·L-1 CC under 0.3% NaCl stress.RESULTS: Our results showed that foliar application of CC improved morpho-physiological parameters such as root traits, seedling height, seedling strength index, seedling fullness, leaf area, photosynthetic parameters, photosynthetic pigments, starch, and fructose content under salt stress, while decreasing soluble sugar, sucrose, and sucrose phosphate synthase levels. Transcriptomic analysis revealed that CC regulation combined with salt treatment induced changes in the expression of genes related to starch and sucrose metabolism, the citric acid cycle, carbon sequestration in photosynthetic organs, carbon metabolism, and photosynthetic antenna proteins in both rice varieties. Metabolomic analysis further supported these findings, indicating that photosynthesis, carbon metabolism, and carbon fixation pathways were crucial in CC-mediated salt tolerance.DISCUSSION: The combined transcriptomic and metabolomic data suggest that CC treatment enhances rice salt tolerance by activating distinct transcriptional cascades and phytohormone signaling, along with multiple antioxidants and unique metabolic pathways. These findings provide a basis for further understanding the mechanisms of metabolite synthesis and gene regulation induced by CC in rice in response to salt stress, and may inform strategies for improving crop resilience to salt stress.PMID:39148614 | PMC:PMC11324541 | DOI:10.3389/fpls.2024.1440663

Front Pharmacol. 2024 Aug 1;15:1419609. doi: 10.3389/fphar.2024.1419609. eCollection 2024.ABSTRACTINTRODUCTION: Snakebites are acute systemic toxic diseases caused by snake venom entering the body through wounds. Failure to use antivenom immediately and difficulty in obtaining antivenoms are frequently responsible for worsening disease. Traditional Chinese medicine is commonly used to supplement and replace antivenom in treating snakebites. The Jidesheng snake pill (JDS) is a widely used traditional Chinese medicine that has achieved good clinical therapeutic effects; however, its mechanism remains unclear. Therefore, metabolomics techniques were employed to explore the pathophysiological mechanisms of JDS treatment of Agkistrodon halys (Ah) snake venom-poisoned mice.METHODS: The Ah group mouse model was established by intramuscular injection of Ah venom into the hind legs of the mice. The Ah venom + JDS group model was established using JDS after the affected area was treated with Ah venom. Hematoxylin and eosin (HE) staining was used to evaluate the severity of gastrocnemius injury. Quantitative polymerase chain reaction (qPCR) was utilized to detect the mRNA expression of vascular cell adhesion molecule-1 (VCAM-1), muscle-specific creatine kinase (CKM), thrombin antithrombin complex (TAT), and tumor necrosis factor-alpha (TNF-α). Gas chromatography-mass spectrometry (GC-MS) was performed with multivariate statistical analysis to provide new insights into the global metabolic profile of Ah venom-poisoned mice.RESULTS: HE staining revealed increased red cell necrosis, local hemorrhage, and neutrophil infiltration in the Ah venom group than in the control group. Several compounds were identified, including lipids, amino acids, peptides, and organooxygen. Eighty differential metabolites were screened between the control group and the Ah venom group, and 24 were screened between the Ah venom and JDS groups. The mechanism of Ah venom poisoning in mice may involve aminoacyl-tRNA biosynthesis, various amino acid metabolism disorders, tricarboxylic acid circulation disorders, and abnormal fatty acid metabolism. JDS may reduce symptoms by affecting long-chain fatty acid and amino acid metabolism and promoting nicotinamide-nicotinamide metabolism.CONCLUSION: Our results suggest that metabolomics has huge prospects for elucidating the pathophysiology of Agkistrodon haly venom poisoning and therapeutic mechanisms of JDS.PMID:39148553 | PMC:PMC11324443 | DOI:10.3389/fphar.2024.1419609

Front Pharmacol. 2024 Jul 30;15:1431085. doi: 10.3389/fphar.2024.1431085. eCollection 2024.ABSTRACTIntroduction: Glioblastoma, which affects a large number of patients every year and has an average overall lifespan of around 14.6 months following diagnosis stands out as the most lethal primary invasive brain tumor. Currently, surgery, radiation, and chemotherapy with temozolomide (TMZ) are the three major clinical treatment approaches. However, the ability to treat patients effectively is usually limited by TMZ resistance. Naringin, a bioflavonoid with anti-cancer, antioxidant, metal-chelating, and lipid-lowering effects, has emerged as a promising therapeutic option. Methods: To explore the targets and pathways of naringin and TMZ in glioblastoma network pharmacology, cell line-based ELISA, flow cytometry, immunocytochemistry, western blotting, and LC-HRMS based metabolomics study were used. Results: The findings through the network pharmacology suggested that the key targets of naringin in the chemosensitization of glioblastoma would be Poly [ADP-ribose] polymerase 1 (PARP-1), O-6-Methylguanine-DNA Methyltransferase (MGMT), and caspases. The functional enrichment analysis revealed that these targets were significantly enriched in important pathways such as p53 signaling, apoptosis, and DNA sensing. Further, the results of the in-vitro study in U87-MG and T98-G glioblastoma cells demonstrated that TMZ and naringin together significantly reduced the percentage of viability and inhibited the DNA repair enzymes PARP-1 and MGMT, and PI3K/AKT which led to chemosensitization and, in turn, induced apoptosis, which was indicated by increased p53, caspase-3 expression and decreased Bcl2 expression. Additionally, a metabolomics study in T98-G glioblastoma cells using liquid chromatography high-resolution mass spectrometry (LC-HRMS) revealed downregulation of C8-Carnitine (-2.79), L-Hexanoylcarnitine (-4.46), DL-Carnitine (-2.46), Acetyl-L-carnitine (-3.12), Adenine (-1.3), Choline (-2.07), Propionylcarnitine (-1.69), Creatine (-1.33), Adenosine (-0.84), Spermine (-1.42), and upregulation of Palmitic Acid (+1.03) and Sphingosine (+0.89) in the naringin and TMZ treatment groups. Discussion: In conclusion, it can be said that naringin in combination with TMZ chemosensitized TMZ antiglioma response and induced apoptosis in tumor cells.PMID:39148542 | PMC:PMC11325085 | DOI:10.3389/fphar.2024.1431085

Food Chem X. 2024 Jul 15;23:101651. doi: 10.1016/j.fochx.2024.101651. eCollection 2024 Oct 30.ABSTRACTCocoa can undergo an alkalization process to enhance its color and solubility. It reduces astringency and alters its composition, particularly in the phenolic compound content, which is related to cocoa health benefits. This study aimed to investigate the impact of alkalization on the composition of seven commercial cocoa powders. A liquid chromatography-based metabolomic approach was employed to assess the metabolic differences between alkalized and non-alkalized cocoa powders. Supervised orthogonal partial least squares discriminant analysis (OPLS-DA) was used to identify the most discriminating variables between groups. A feature-based molecular network (FBMN) was used to explore the chemical space. Three hundred forty-seven metabolites were obtained as the most discriminant, among which 60 were tentatively annotated. Phenolic compounds, lysophosphatidylethanolamines, amino acids, and their derivatives were significantly reduced in alkalized cocoas. In contrast, fatty acids and their derivatives significantly increased with alkalization. Despite the variability among commercial cocoas, chemometrics allowed the elucidation of alterations induced specifically by alkalization in their composition.PMID:39148527 | PMC:PMC11324845 | DOI:10.1016/j.fochx.2024.101651

J Biochem Mol Toxicol. 2024 Sep;38(9):e23807. doi: 10.1002/jbt.23807.ABSTRACTCancer is a deadly disease that affects a cell's metabolism and surrounding tissues. Understanding the fundamental mechanisms of metabolic alterations in cancer cells would assist in developing cancer treatment targets and approaches. From this perspective, metabolomics is a great analytical tool to clarify the mechanisms of cancer therapy as well as a useful tool to investigate cancer from a distinct viewpoint. It is a powerful emerging technology that detects up to thousands of molecules in tissues and biofluids. Like other "-omics" technologies, metabolomics involves the comprehensive investigation of micromolecule metabolites and can reveal important details about the cancer state that is otherwise not apparent. Recent developments in metabolomics technologies have made it possible to investigate cancer metabolism in greater depth and comprehend how cancer cells utilize metabolic pathways to make the amino acids, nucleotides, and lipids required for tumorigenesis. These new technologies have made it possible to learn more about cancer metabolism. Here, we review the cellular and systemic effects of cancer and cancer treatments on metabolism. The current study provides an overview of metabolomics, emphasizing the current technologies and their use in clinical and translational research settings.PMID:39148273 | DOI:10.1002/jbt.23807

Clin Pharmacol Ther. 2024 Aug 15. doi: 10.1002/cpt.3414. Online ahead of print.ABSTRACTThe inhibition of renal transport proteins organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATE1, MATE2-K), and organic anion transporters (OAT1, OAT3) causes clinically relevant drug-drug interactions (DDI). Endogenous biomarkers could be used to improve risk prediction of such renal DDIs. While a number of biomarkers for renal DDIs have been described so far, multiple criteria for valid biomarkers have frequently not been investigated, for example, specificity, metabolism, or food effects. Therefore, there is a need for novel biomarkers of renal DDIs. Here, we investigated the global metabolomic effects following the administration of two classical inhibitors of renal transport proteins [cimetidine (OCT2/MATEs), probenecid (OATs)] in human plasma and urine of healthy volunteers. Additionally, we investigated metabolomic effects of two inhibitors of other transporters [verapamil (P-glycoprotein), rifampin (organic anion transporting polypeptides)] as controls. This analysis shows that both cimetidine and probenecid affect compounds involved in caffeine metabolism, carnitines, and sulfates. Hierarchical cluster analysis of the effects of all four inhibitors on endogenous compounds identified multiple promising new sensitive and specific biomarker candidates for OCT2/MATE- or OAT-mediated DDIs. For OCT2/MATEs, 5-amino valeric acid betaine (median log2-fold change of estimated renal elimination: -3.62) presented itself as a promising candidate. For OATs, estimated renal elimination of 7-methyluric acid and cinnamoylglycine (median log2-fold changes -3.10 and -1.92, respectively) was both sensitive and specific. This study provides comprehensive information on metabolomic effects of transport protein inhibition in humans and identifies putative new sensitive and specific biomarkers for renal transporter-mediated DDIs.PMID:39148267 | DOI:10.1002/cpt.3414

J Exp Clin Cancer Res. 2024 Aug 16;43(1):227. doi: 10.1186/s13046-024-03154-0.ABSTRACTBACKGROUND: The failure of proper recognition of the intricate nature of pathophysiology in colorectal cancer (CRC) has a substantial effect on the progress of developing novel medications and targeted therapy approaches. Imbalances in the processes of lipid oxidation and biosynthesis of fatty acids are significant risk factors for the development of CRC. Therapeutic intervention that specifically targets the peroxisome proliferator-activated receptor gamma (PPARγ) and its downstream response element, in response to lipid metabolism, has been found to promote the growth of tumors and has shown significant clinical advantages in cancer patients.METHODS: Clinical CRC samples and extensive in vitro and in vivo experiments were carried out to determine the role of ZDHHC6 and its downstream targets via a series of biochemical assays, molecular analysis approaches and lipid metabolomics assay, etc. RESULTS: To study the effect of ZDHHC6 on the progression of CRC and identify whether ZDHHC6 is a palmitoyltransferase that regulates fatty acid synthesis, which directly palmitoylates and stabilizes PPARγ, and this stabilization in turn activates the ACLY transcription-related metabolic pathway. In this study, we demonstrate that PPARγ undergoes palmitoylation in its DNA binding domain (DBD) section. This lipid-related modification enhances the stability of PPARγ protein by preventing its destabilization. As a result, palmitoylated PPARγ inhibits its degradation induced by the lysosome and facilitates its translocation into the nucleus. In addition, we have identified zinc finger-aspartate-histidine-cysteine 6 (ZDHHC6) as a crucial controller of fatty acid biosynthesis. ZDHHC6 directly interacts with and adds palmitoyl groups to stabilize PPARγ at the Cys-313 site within the DBD domain of PPARγ. Consequently, this palmitoylation leads to an increase in the expression of ATP citrate lyase (ACLY). Furthermore, our findings reveals that ZDHHC6 actively stimulates the production of fatty acids and plays a role in the development of colorectal cancer. However, we have observed a significant reduction in the cancer-causing effects when the expression of ZDHHC6 is inhibited in in vivo trials. Significantly, in CRC, there is a strong positive correlation between the high expression of ZDHHC6 and the expression of PPARγ. Moreover, this high expression of ZDHHC6 is connected with the severity of CRC and is indicative of a poor prognosis.CONCLUSIONS: We have discovered a mechanism in which lipid biosynthesis is controlled by ZDHHC6 and includes the signaling of PPARγ-ACLY in the advancement of CRC. This finding provides a justification for targeting lipid synthesis by blocking ZDHHC6 as a potential therapeutic approach.PMID:39148124 | DOI:10.1186/s13046-024-03154-0

Acta Diabetol. 2024 Aug 15. doi: 10.1007/s00592-024-02338-6. Online ahead of print.ABSTRACTAIMS: To investigate immunometabolic associations of CD4+ T cell phenotypes with gestational diabetes mellitus (GDM).METHODS: A nested case-control study was conducted comprising 53 pairs of GDM patients and matched controls within a prospective cohort. Metabolomic signatures related to both CD4+ T cell phenotypes and glycemic traits among pregnant women were investigated by weighted gene co-expression network analysis (WGCNA). Multivariable-adjusted generalized linear models were used to explore the associations of CD4+ T cell phenotypes and selected metabolites with GDM. Mediation analysis was conducted to evaluate the mediating effect of selected metabolites on the relationship between CD4+ T cell phenotypes and glycemic traits.RESULTS: Higher levels of Treg cells (OR per SD increment (95%CI): 0.57 (0.34, 0.95), p = 0.031) and increased expression of Foxp3 (OR per SD increment (95%CI): 0.59 (0.35, 0.97), p = 0.039) and GATA3 (OR per SD increment (95%CI): 0.42 (0.25, 0.72), p = 0.002) were correlated with a decreased risk of GDM. Plasma pyruvaldehyde, S-adenosylhomocysteine (SAH), bergapten, and 9-fluorenone mediated the association between Tregs and fasting plasma glucose (FPG), with mediation proportions of 46.9%, 39.6%, 52.4%, and 56.9%, respectively.CONCLUSIONS: Treg cells and Foxp3 expressions were inversely associated with GDM risk, with potential metabolic mechanisms involving metabolites such as pyruvaldehyde and SAH.PMID:39147954 | DOI:10.1007/s00592-024-02338-6

Sci Rep. 2024 Aug 15;14(1):18949. doi: 10.1038/s41598-024-69985-1.ABSTRACTSecondhand vaping exposure is an emerging public health concern that remains understudied. In this study, saliva and exhaled emissions from ENDS users (secondhand) and non-ENDS users (baseline) were collected, firsthand emissions were generated using an automated ENDS aerosol generation system programmed to simulate puffing topography profiles collected from ENDS users. Particulate concentrations and sizes along with volatile organic compounds were characterized. We revealed puffing topography metrics as potential mediators of firsthand and secondhand particle and chemical exposures, as well as metabolic and respiratory health outcomes. Particle deposition modeling revealed that while secondhand emissions displayed smaller deposited mass, total and pulmonary particle deposition fractions were higher than firsthand deposition levels, possibly due to smaller secondhand emission particle diameters. Lastly, untargeted metabolomic profiling of salivary biomarkers of lung injury due to firsthand ENDS exposures revealed potential early indicators of respiratory distress that may also be relevant in bystanders exposed to secondhand vaping scenarios. By leveraging system toxicology, we identified 10 metabolites, including leukotriene D4, that could potentially serve as biomarkers for ENDS use, exposure estimation, and the prediction of vaping-related disease. This study highlights characterization of vaping behavior is an important exposure component in advancing our understanding of potential health effects in ENDS users and bystanders.PMID:39147784 | DOI:10.1038/s41598-024-69985-1

Nat Commun. 2024 Aug 15;15(1):7048. doi: 10.1038/s41467-024-51244-6.ABSTRACTPlants possess cell surface-localized immune receptors that detect microbe-associated molecular patterns (MAMPs) and initiate defenses that provide effective resistance against microbial pathogens. Many MAMP-induced signaling pathways and cellular responses are known, yet how pattern-triggered immunity (PTI) limits pathogen growth in plants is poorly understood. Through a combined metabolomics and genetics approach, we discovered that plant-exuded proline is a virulence-inducing signal and nutrient for the bacterial pathogen Pseudomonas syringae, and that MAMP-induced depletion of proline from the extracellular spaces of Arabidopsis leaves directly contributes to PTI against P. syringae. We further show that MAMP-induced depletion of extracellular proline requires the amino acid transporter Lysine Histidine Transporter 1 (LHT1). This study demonstrates that depletion of a single extracellular metabolite is an effective component of plant induced immunity. Given the important role for amino acids as nutrients for microbial growth, their depletion at sites of infection may be a broadly effective means for defense against many pathogens.PMID:39147739 | DOI:10.1038/s41467-024-51244-6

Nat Commun. 2024 Aug 15;15(1):7020. doi: 10.1038/s41467-024-51181-4.ABSTRACTMechanosensitive PIEZO2 ion channels play roles in touch, proprioception, and inflammatory pain. Currently, there are no small molecule inhibitors that selectively inhibit PIEZO2 over PIEZO1. The TMEM120A protein was shown to inhibit PIEZO2 while leaving PIEZO1 unaffected. Here we find that TMEM120A expression elevates cellular levels of phosphatidic acid and lysophosphatidic acid (LPA), aligning with its structural resemblance to lipid-modifying enzymes. Intracellular application of phosphatidic acid or LPA inhibits PIEZO2 but not PIEZO1 activity. Extended extracellular exposure to the non-hydrolyzable phosphatidic acid and LPA analog carbocyclic phosphatidic acid (ccPA) also inhibits PIEZO2. Optogenetic activation of phospholipase D (PLD), a signaling enzyme that generates phosphatidic acid, inhibits PIEZO2 but not PIEZO1. Conversely, inhibiting PLD leads to increased PIEZO2 activity and increased mechanical sensitivity in mice in behavioral experiments. These findings unveil lipid regulators that selectively target PIEZO2 over PIEZO1, and identify the PLD pathway as a regulator of PIEZO2 activity.PMID:39147733 | DOI:10.1038/s41467-024-51181-4