Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

PubMed

Metabolic Effects of the SGLT2 Inhibitor Dapagliflozin in Heart Failure Across the Spectrum of Ejection Fraction

Fri, 18/10/2024 - 12:00
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

Ferroptosis Mediated Inflammation Promotes Pulmonary Hypertension

Fri, 18/10/2024 - 12:00
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

Metabolomics of 3D cell co-culture reveals alterations in energy metabolism at the cross-talk of colorectal cancer-adipocytes

Fri, 18/10/2024 - 12:00
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

Stemona alkaloid derivative induce ferroptosis of colorectal cancer cell by mediating carnitine palmitoyltransferase 1

Fri, 18/10/2024 - 12:00
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

Attractant potential of <em>Enterobacter cloacae</em> and its metabolites to <em>Bactrocera dorsalis</em> (Hendel)

Fri, 18/10/2024 - 12:00
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

Limitations in metabolic plasticity after traumatic injury are only moderately exacerbated by physical activity restriction

Fri, 18/10/2024 - 12:00
NPJ Metab Health Dis. 2024;2:4. doi: 10.1038/s44324-024-00006-5. Epub 2024 Apr 6.ABSTRACTFollowing traumatic musculoskeletal injuries, prolonged bedrest and loss of physical activity may limit muscle plasticity and drive metabolic dysfunction. One specific injury, volumetric muscle loss (VML), results in frank loss of muscle and is characterized by whole-body and cellular metabolic dysfunction. However, how VML and restricted physical activity limit plasticity of the whole-body, cellular, and metabolomic environment of the remaining uninjured muscle remains unclear. Adult mice were randomized to posterior hindlimb compartment VML or were age-matched injury naïve controls, then randomized to standard or restricted activity cages for 8-wks. Activity restriction in naïve mice resulted in ~5% greater respiratory exchange ratio (RER); combined with VML, carbohydrate oxidation was ~23% greater than VML alone, but lipid oxidation was largely unchanged. Activity restriction combined with VML increased whole-body carbohydrate usage. Together there was a greater pACC:ACC ratio in the muscle remaining, which may contribute to decreased fatty acid synthesis. Further, β-HAD activity normalized to mitochondrial content was decreased following VML, suggesting a diminished capacity to oxidize fatty acids. The muscle metabolome was not altered by the restriction of physical activity. The combination of VML and activity restriction resulted in similar (~91%) up- and down-regulated metabolites and/or ratios, suggesting that VML injury alone is regulating changes in the metabolome. Data supports possible VML-induced alterations in fatty acid metabolism are exacerbated by activity restriction. Collectively, this work adds to the sequala of VML injury, exhausting the ability of the muscle remaining to oxidize fatty acids resulting in a possible accumulation of triglycerides.PMID:39421399 | PMC:PMC11486518 | DOI:10.1038/s44324-024-00006-5

<em>Faecalibacterium prausnitzii</em> A2-165 metabolizes host- and media-derived chemicals and induces transcriptional changes in colonic epithelium in GuMI human gut microphysiological system

Fri, 18/10/2024 - 12:00
Microbiome Res Rep. 2024 May 22;3(3):30. doi: 10.20517/mrr.2024.14. eCollection 2024.ABSTRACTAim: Recently, a GuMI gut microphysiological system has been established to coculture oxygen-intolerant Faecalibacterium prausnitzii (F. prausnitzii) A2-165 with organoids-derived primary human colonic epithelium. This study aims to test if this GuMI system applies to different donors with different healthy states and uses metabolomics to reveal the role of gut microbes in modulating host- and diet-derived molecules in the gut lumen. Methods: Organoids-derived colonic monolayers were generated from an uninflamed region of diverticulitis, ulcerative colitis, and Crohn's disease patients and then integrated into the GuMI system to coculture with F. prausnitzii A2-165 for 2 to 4 days. Apical media was collected for metabolomic analysis. Targeted metabolomics was performed to profile 169 polar chemicals under three conditions: conventional static culture without bacteria, GuMI without bacteria, and GuMI with F. prausnitzii. The barrier function of monolayers was measured using transepithelial resistance. Results: GuMI successfully cocultured patient-derived monolayers and F. prausnitzii for up to 4 days, with active bacterial growth. Introducing flow and oxygen gradient significantly increases the barrier function, while exposure to F. prausnitzii slightly increases the barrier function. Targeted metabolomics screened 169 compounds and detected 76 metabolites, of which 70 significantly differed between at least two conditions. F. prausnitzii significantly modulates the levels of nucleosides, nucleobases, and amino acids on the apical side. Further analysis suggests that F. prausnitzii changes the mRNA level of 260 transcription factor genes in colonic epithelial cells. Conclusion: The GuMI physiomimetic system can maintain the coculture of F. prausnitzii and colonic epithelium from different donors. Together with metabolomics, we identified the modulation of F. prausnitzii in extracellular chemicals and colonic epithelial cell transcription in coculture with human colonic epithelium, which may reflect its function in gut lumen in vivo.PMID:39421254 | PMC:PMC11480719 | DOI:10.20517/mrr.2024.14

DETECTING MULTIPLE REPLICATING SIGNALS USING ADAPTIVE FILTERING PROCEDURES

Fri, 18/10/2024 - 12:00
Ann Stat. 2022 Aug;50(4):1890-1909. doi: 10.1214/21-aos2139. Epub 2022 Aug 25.ABSTRACTReplicability is a fundamental quality of scientific discoveries: we are interested in those signals that are detectable in different laboratories, different populations, across time etc. Unlike meta-analysis which accounts for experimental variability but does not guarantee replicability, testing a partial conjunction (PC) null aims specifically to identify the signals that are discovered in multiple studies. In many contemporary applications, for example, comparing multiple high-throughput genetic experiments, a large number M of PC nulls need to be tested simultaneously, calling for a multiple comparisons correction. However, standard multiple testing adjustments on the M PC p -values can be severely conservative, especially when M is large and the signals are sparse. We introduce AdaFilter, a new multiple testing procedure that increases power by adaptively filtering out unlikely candidates of PC nulls. We prove that AdaFilter can control FWER and FDR as long as data across studies are independent, and has much higher power than other existing methods. We illustrate the application of AdaFilter with three examples: microarray studies of Duchenne muscular dystrophy, single-cell RNA sequencing of T cells in lung cancer tumors and GWAS for metabolomics.PMID:39421244 | PMC:PMC11486506 | DOI:10.1214/21-aos2139

Comparative transcriptomic and metabolomic analysis reveals mechanisms of selenium-regulated anthocyanin synthesis in waxy maize (Zea mays L.)

Fri, 18/10/2024 - 12:00
Front Plant Sci. 2024 Oct 3;15:1466756. doi: 10.3389/fpls.2024.1466756. eCollection 2024.ABSTRACTAnthocyanins in maize (Zea mays L.) kernels determine the plant's color and can enhance its resistance. Selenium (Se) significantly impacts plant growth, development, and secondary metabolic regulation. However, the molecular mechanisms by which Se regulates anthocyanin synthesis in waxy corn remain unclear. This study employed integrated transcriptomic and metabolomic analyses to investigate the mechanisms through which selenium influences anthocyanin synthesis in yellow and purple waxy corn. The results showed that maize varieties with higher anthocyanin content had higher selenium enrichment capacity in their kernels. Under selenium stress, HN2025 exhibited 1,904 more differentially expressed genes (DEGs) and 140 more differential metabolites compared to HN5. The expression levels of anthocyanin synthesis-related genes and transcription factors such as phenylalanine ammonia-lyase, flavonoid 3-hydroxylase (F3H), dihydroflavonol reductase (DFR), chalcone synthase (CHS), cinnamate-4-hydroxylase (C4H), anthocyanin 5,3-O-glucosyltransferases, and anthocyanidin reductase, MYB, and bHLH were strongly induced in HN2025. Metabolomic analysis revealed significant enrichment in anthocyanin biosynthesis, flavonoid and flavonol biosynthesis, glutathione metabolism, phenylalanine biosynthesis, and phenylalanine metabolism under selenium treatment. Three up-regulated PAL genes and one C4H gene were significantly enriched with DAMs in phenylalanine metabolism, phenylpropanoid biosynthesis, flavonoid biosynthesis, and anthocyanin biosynthesis, resulting in significant differences between HN5 and HN2025 in selenium-induced anthocyanin metabolism-related pathways. These findings provide a theoretical basis for understanding the effects of selenium on the molecular regulatory mechanisms of anthocyanin biosynthesis in maize kernels.PMID:39421142 | PMC:PMC11484008 | DOI:10.3389/fpls.2024.1466756

Mechanism of ginsenoside Rb<sub>3</sub> against OGD/R damage based on metabonomic and PCR array analyses

Fri, 18/10/2024 - 12:00
Biomed Rep. 2024 Oct 9;21(6):187. doi: 10.3892/br.2024.1875. eCollection 2024 Dec.ABSTRACTIn order to study the mechanisms of ginsenoside Rb3 (G-Rb3) against oxygen-glucose deprivation/reoxygenation (OGD/R) injury in HT22 cells based on metabolomics and PCR array, HT22 cells were randomly divided into control group, model group, G-Rb3 high-dose group (10 µmol/l) and G-Rb3 low-dose group (5 µmol/l). Except for the control group, which was left untreated, the remaining groups were incubated with 10 mmol/l Na2S2O4 in sugar-free DMEM medium for 2 h and then replaced with serum-free high-sugar DMEM medium for 2 h in order to replicate in vitro OGD/R model. Trypan blue staining was used to detect the cell viability; flow cytometry was used to detect apoptosis; western blotting was used to detect the protein expression levels of Bax, Bcl-2 and caspase-3. The metabolomics were used to analyze the differential metabolites of G-Rb3 affecting OGD/R in order to find the relevant metabolic pathways. PCR array assay was performed to identify the expression of the differential genes. G-Rb3 could inhibit HT22 apoptosis according to the result of cell morphology, trypan blue staining and flow cytometry. The levels of Bax and caspase-3 protein expression were decreased, whereas the level of Bcl-2 protein expression was increased after the treatment of G-Rb3. Metabolomics results showed that a total of 31 differential metabolites between OGD/R group and G-Rb3 group, such as guanosine level, was downregulated, the levels of enalaprilat and sorbitol were upregulated, affecting ABC transporters, galactose metabolism, citrate cycle and other related metabolic pathways; according to the result of PCR array, it was observed that G-Rb3 significantly downregulated Trp63, Trp73, Dapk1, Casp14 and Cd70 pro-apoptotic genes. In conclusion, G-Rb3 has a significant protective effect on the OGD/R model simulated in vitro, and the mechanism may be related to the inhibition of apoptosis by affecting metabolites.PMID:39420925 | PMC:PMC11484189 | DOI:10.3892/br.2024.1875

Berberine alters the gut microbiota metabolism and impairs spermatogenesis

Fri, 18/10/2024 - 12:00
Acta Biochim Biophys Sin (Shanghai). 2024 Oct 17. doi: 10.3724/abbs.2024174. Online ahead of print.ABSTRACTBerberine (BBR) is used to treat diarrhea clinically. However, its reproductive toxicity is unclear. This study aims to investigate the impact of BBR on the male reproductive system. Intragastric BBR administration for 14 consecutive days results in a significant decrease in the serum testosterone concentration, epididymal sperm concentration, mating rate and fecundity of male mice. Testicular treatment with testosterone propionate (TP) partially reverses the damage caused by BBR to the male reproductive system. Mechanistically, the decrease in Muribaculaceae abundance in the gut microbiota of mice is the principal cause of the BBR-induced decrease in the sperm concentration. Both fecal microbiota transplantation (FMT) and polyethylene glycol (PEG) treatment demonstrate that Muribaculaceae is necessary for spermatogenesis. The intragastric administration of Muribaculaceae intestinale to BBR-treated mice restores the sperm concentration and testosterone levels. Metabolomic analysis reveals that BBR affects arginine and proline metabolism, of which ornithine level is downregulated. Combined analysis via 16S rRNA metagenomics sequencing and metabolomics shows that Muribaculaceae regulates ornithine level. The transcriptomic results of the testes indicate that the expressions of genes related to the low-density lipoprotein receptor (LDLR)-mediated testosterone synthesis pathway decrease after BBR administration. The transcriptional activity of the Ldlr gene in TM3 cells is increased with increased ornithine supplementation in the culture media, leading to increased testosterone synthesis. Overall, this study reveals an association between a BBR-induced decrease in Muribaculaceae abundance and defective spermatogenesis, providing a prospective therapeutic approach for addressing infertility-related decreases in serum testosterone triggered by changes in the gut microbiota composition.PMID:39420836 | DOI:10.3724/abbs.2024174

<em>Lacticaseibacillus plantarum</em> postbiotics prepared by the combined technique of pasteurization and ultrasound: effective measures to alleviate obesity based on the SCFAs-GPR41/GPR43 signaling pathway

Fri, 18/10/2024 - 12:00
Food Funct. 2024 Oct 18. doi: 10.1039/d4fo03591g. Online ahead of print.ABSTRACTPostbiotics have recently garnered substantial research attention, especially in obesity research. In this study, upon comparing the proliferative effects of three food-derived media-skim milk, soy milk, and almond milk-on Lactiplantibacillus plantarum J26 (L. plantarum J26), skim milk was found to be the most effective. The metabolomic analysis further unveiled that the metabolites produced by the strain cultured in skim milk influenced the greatest number of lipid metabolism-associated pathways. Additionally, to better preserve heat-sensitive substances, ultrasound and pasteurization were combined and used here for inactivation. L. plantarum J26 postbiotics, prepared through pasteurization combined with 400 W ultrasound treatment for 30 min, exhibited the most effectiveness at inhibiting cellular triglyceride accumulation, reducing its level to 0.99 mg per 104 CFU. The prepared postbiotics significantly reduced the increase in multiple indicators, including body weight, blood lipids, and adipokines in obese mice (p < 0.05). Following treatment, liver tissue damage as well as white and brown adipose tissue damage were also markedly improved in obese mice. According to gut microbiota sequencing, the postbiotic intervention increased Lactobacillus and Bifidobacterium abundances but reduced the abundances of obesity-associated Faecalibacterium and Erysipelotrichaceae. Additionally, the postbiotics elevated the acetate, propionate, and butyrate levels by 14.95%, 23.89%, and 8.31%, respectively. High postbiotic doses significantly upregulated the expression of GPR41/GPR43, short-chain fatty acid (SCFA) receptor genes, in the liver and adipose tissues (p < 0.05), thus correcting the obesity-induced anomalies in the SCFAs-GPR41/GPR43 signaling pathway. This research offers compelling evidence supporting the use of edible postbiotics in targeted obesity regulation.PMID:39420807 | DOI:10.1039/d4fo03591g

Integrated Metabolomic, Lipidomic and Proteomic Analysis Define the Metabolic Changes Occurring in Curled Areas in Leaves With Leaf Peach Curl Disease

Fri, 18/10/2024 - 12:00
Plant Cell Environ. 2024 Oct 17. doi: 10.1111/pce.15210. Online ahead of print.ABSTRACTPeach Leaf Curl Disease, caused by Taphrina deformans, is characterized by reddish hypertrophic and hyperplasic leaf areas. To comprehend the biochemical imbalances caused by the fungus, dissected symptomatic (C) and asymptomatic areas (N) from leaves with increasing disease extension were analyzed by an integrated approach including metabolomics, lipidomics, proteomics, and complementary biochemical techniques. Drastic metabolic differences were identified in C areas with respect to either N areas or healthy leaves, including altered chloroplastic functioning and composition, which differs from the typical senescence process. In C areas, alteration in redox-homoeostasis proteins and in triacylglycerols content, peroxidation and double bond index were observed. Proteomic data revealed induction of host enzymes involved in auxin and jasmonate biosynthesis and an upregulation of phenylpropanoid and mevalonate pathways and downregulation of the plastidic methylerythritol phosphate route. Amino acid pools were affected, with upregulation of proteins involved in asparagine synthesis. Curled areas exhibited a metabolic shift towards functioning as a sink tissue importing sugars, probably from N areas, and producing energy through fermentation and respiration and reductive power via the pentose phosphate route. Identifying the metabolic disturbances leading to disease symptoms is a key step in designing strategies to prevent or delay the progression of the disease.PMID:39420723 | DOI:10.1111/pce.15210

A Mix of Probiotic Strains Prevents Hepatic Steatosis, and Improves Oxidative Stress Status and Gut Microbiota Composition in Obese Mice

Fri, 18/10/2024 - 12:00
Mol Nutr Food Res. 2024 Oct 17:e2300672. doi: 10.1002/mnfr.202300672. Online ahead of print.ABSTRACTSCOPE: The gut microbiota plays a role in fat accumulation and energy homeostasis. Therefore, probiotic supplementation may improve metabolic parameters and control body weight.METHODS AND RESULTS: In this study, mice are fed either a high-fat diet (HFD) or an HFD supplemented with oral gavage of a mixture of three probiotic strains, Bifidobacterium lactis Lafti B94, Lactobacillus plantarum HA-119, and Lactobacillus helveticus Lafti L10 for 7 weeks. It finds that probiotic supplementation modulates body weight gain, food energy efficiency, and fat accumulation caused by the HFD. This probiotic mix prevents liver damage and lipid metabolic disorders in HFD-fed obese mice. The probiotic supplementation significantly downregulates the expression of the proinflammatory cytokines interleukin-1β, tumor necrosis factor-α, and malondialdehyde (MDA) in the liver and upregulated catalase (CAT), superoxide dismutase (SOD), and nuclear respiratory factor 1 (Nrf1) expression. Mice supplemented with the probiotic mix also show different microbiota compositions, with an increase in Clostridia_UCG-014 and Lachnospiraceae_nk4a136_group and a decrease in the Dubosiella genus compared with those in mice fed only an HFD. Finally, the amounts of fecal pentanoic acid and the three bile acid species increase in mice with probiotic supplementation.CONCLUSION: Treatment with a combination of a mixture of three probiotic strains, B. lactis Lafti B94, L. plantarum HA-119, and L. helveticus Lafti L10 for 7 weeks, ameliorates the effects of HFD induced obesity in mice.PMID:39420712 | DOI:10.1002/mnfr.202300672

Metabolite profile and pharmacological relevance of <em>Solanum violaceum</em> Ortega leaf and fruit extracts

Fri, 18/10/2024 - 12:00
Nat Prod Res. 2024 Oct 17:1-5. doi: 10.1080/14786419.2024.2417371. Online ahead of print.ABSTRACTSolanum violaceum Ortega is a perennial tropical shrub traditionally used as conventional medicine for the treatment of various ailments. The present study aims to validate the use of S. violaceum Ortega leaf (SVLE) and fruit extracts (SVFE) in traditional medicine through untargeted metabolomics and assessment of its biological and phytochemical properties. GC-MS-based untargeted metabolomics identified derivatives of 59 and 50 metabolites in SVLE and SVFE, respectively. The study authenticated the presence of several bioactive compounds including Diosgenin, n-Hexadecanoic acid and Stigmasterol in SVLE and Ricinoleic acid, 9,12-Octadecadienoic acid and Oleic acid in SVFE, thus corroborating the use of the plant in traditional medicine as an anti-inflammatory and antioxidant agent. Both SVFE and SVLE demonstrated potent antioxidant, protease and anticoagulant properties with partial inhibitory effects on the physiological function of Factor Xa. This study provides insight into the phytochemical and pharmacological properties of S. violaceum and its potential ethnomedicinal relevance.PMID:39420624 | DOI:10.1080/14786419.2024.2417371

Metabolic Pathways Associated With Obesity and Hypertension in Black Caregivers of Persons Living With Dementia

Fri, 18/10/2024 - 12:00
Nurs Res. 2024 Oct 10. doi: 10.1097/NNR.0000000000000783. Online ahead of print.ABSTRACTBACKGROUND: In the U.S., Black adults have the highest prevalence of obesity and hypertension, increasing their risk of morbidity and mortality. Caregivers of persons with dementia are also at increased risk of morbidity and mortality due to the demands of providing care. Thus, Black caregivers-who are the second largest group of caregivers of persons with dementia in the U.S.-have the highest risks for poor health outcomes among all caregivers. However, the physiologic changes associated with multiple chronic conditions in Black caregivers are poorly understood.OBJECTIVES: In this study, metabolomics were compared to the metabolic profiles of Black caregivers with obesity, with or without hypertension. Our goal was to identify metabolites and metabolic pathways that could be targeted to reduce obesity and hypertension rates in this group.METHODS: High-resolution, untargeted metabolomic assays were performed on plasma samples from 26 self-identified Black caregivers with obesity, 18 of whom had hypertension. Logistic regression and pathway analyses were employed to identify metabolites and metabolic pathways differentiating caregivers with obesity only and caregivers with both obesity and hypertension.RESULTS: Key metabolic pathways discriminating caregivers with obesity only and caregivers with obesity and hypertension were butanoate and glutamate metabolism, fatty acid activation/biosynthesis, and the carnitine shuttle pathway. Metabolites related to glutamate metabolism in the butanoate metabolism pathway were more abundant in caregivers with hypertension, while metabolites identified as butyric acid/butanoate and R-(3)-hydroxybutanoate were less abundant. Caregivers with hypertension also had lower levels of several unsaturated fatty acids.DISCUSSION: In Black caregivers with obesity, multiple metabolic features and pathways differentiated among caregivers with and without hypertension. If confirmed in future studies, these findings would support ongoing clinical monitoring and culturally tailored interventions focused on nutrition (particularly polyunsaturated fats and animal protein), exercise, and stress management to reduce the risk of hypertension in Black caregivers with obesity.PMID:39420455 | DOI:10.1097/NNR.0000000000000783

Sex-specific phenotypical, functional and metabolic profiles of human term placenta macrophages

Thu, 17/10/2024 - 12:00
Biol Sex Differ. 2024 Oct 17;15(1):80. doi: 10.1186/s13293-024-00652-w.ABSTRACTBACKGROUND: Placental macrophages, Hofbauer cells (HBC) are the only fetal immune cell population within the stroma of healthy placenta along pregnancy. They are central players in maintaining immune tolerance during pregnancy. Immunometabolism emerged a few years ago as a new field that integrates cellular metabolism with immune responses, however, the immunometabolism of HBC has not been explored yet. Here we studied the sex-specific differences in the phenotypic, functional and immunometabolic profile of HBC.METHODS: HBC were isolated from human term placentas (N = 31, 16 from male and 15 female neonates). Ex vivo assays were carried out to assess active metabolic and endoplasmic reticulum stress pathways by flow cytometry, confocal microscopy, gene expression and in silico approaches.RESULTS: HBC from female placentas displayed a stronger M2 phenotype accompanied by high rates of efferocytosis majorly sustained on lipid metabolism. On the other hand, male HBC expressed a weaker M2 phenotype with higher glycolytic metabolism. LPS stimulation reinforced the glycolytic metabolism in male but not in female HBC. Physiological endoplasmic reticulum stress activates IRE-1 differently, since its pharmacological inhibition increased lipid mobilization, accumulation and efferocytosis only in female HBC. Moreover, differential sex-associated pathways accompanying the phenotypic and functional profiles of HBC appeared related to the placental villi environment.CONCLUSIONS: These results support sex-associated effects on the immunometabolism of the HBC and adds another layer of complexity to the intricate maternal-fetal immune interaction.PMID:39420346 | DOI:10.1186/s13293-024-00652-w

Correction: Acyl-coenzyme a binding protein (ACBP) - a risk factor for cancer diagnosis and an inhibitor of immunosurveillance

Thu, 17/10/2024 - 12:00
Mol Cancer. 2024 Oct 17;23(1):231. doi: 10.1186/s12943-024-02152-2.NO ABSTRACTPMID:39420364 | DOI:10.1186/s12943-024-02152-2

MASLD in persons with HIV is associated with high cardiometabolic risk as evidenced by altered advanced lipoprotein profiles and targeted metabolomics

Thu, 17/10/2024 - 12:00
Lipids Health Dis. 2024 Oct 17;23(1):339. doi: 10.1186/s12944-024-02317-4.ABSTRACTBACKGROUND: Metabolic dysfunction associated steatotic liver disease (MASLD) is associated with increased cardiovascular disease (CVD) risk in persons with HIV (PWH). The lipidomic and metabolomic alterations contributing to this risk are poorly understood. We aimed to characterize the advanced lipoprotein and targeted metabolomic profiles in PWH and assess if the presence and severity of MASLD influence these profiles.METHODS: This is a cross-sectional analysis of a prospectively enrolled multicenter cohort. PWH without alcohol abuse or known liver disease underwent vibration-controlled transient elastography for controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). Lipidomic and metabolomic profiling was undertaken with nuclear magnetic resonance (NMR) spectroscopy. Hepatic steatosis was defined as CAP ≥ 263 dB/m and clinically significant fibrosis (CSF) as LSM ≥ 8 kPa. Logistic regression models assessed associations between MASLD, CSF and lipidomic and metabolic parameters.RESULTS: Of 190 participants (71% cisgender male, 96% on antiretroviral therapy), 58% had MASLD and 12% CSF. Mean (SD) age was 48.9 (12.1) years and body mass index (BMI) 29.9 (6.4) kg/m2. Compared to PWH without MASLD (controls), PWH with MASLD had lower HDL-C but higher total triglyceride, VLDL-C, branched-chain amino acids, GlycA, trimethylamine N-oxide levels, Lipoprotein-Insulin Resistance and Diabetes Risk Indices. There were no significant differences in these parameters between participants with MASLD with or without CSF. In a multivariable regression analysis, MASLD was independently associated with changes in most of these parameters after adjustment for age, gender, race/ethnicity, type 2 diabetes mellitus, BMI, and lipid lowering medications use.CONCLUSIONS: MASLD in PWH is independently associated with altered advanced lipoprotein and targeted metabolic profiles, indicating a higher CVD risk in this population.PMID:39420356 | DOI:10.1186/s12944-024-02317-4

Multi-omics insights into the microbiota-gut-brain axis and cognitive improvement post-bariatric surgery

Thu, 17/10/2024 - 12:00
J Transl Med. 2024 Oct 17;22(1):945. doi: 10.1186/s12967-024-05757-9.ABSTRACTBACKGROUND: Although numerous studies have shown that bariatric surgery results in sustained weight loss and modifications in gut microbiota composition and cognitive function, the exact underlying mechanisms are unclear. This study aimed to investigate the effects of bariatric surgery on cognitive function through the microbiota-gut-brain axis (MGBA).METHODS: Demographic data, serum samples, fecal samples, cognitive assessment scales, and resting-state functional connectivity magnetic resonance imaging (rs-fMRI) scans were obtained from 39 obese patients before and after (6 months) laparoscopic sleeve gastrectomy (LSG). PCA analysis, OPLS-DA analysis, and permutation tests were used to conduct fecal 16 S microbiota profiling, serum metabolomics, and neuroimaging analyses, and a bariatric surgery-specific rs-fMRI brain functional connectivity network was constructed. Spearman correlation analysis and Co-inertia analysis were employed to correlate significant alterations in cognitive assessment scales and resting-state functional connectivity difference networks with differential serum metabolites and 16 S microbiota data to identify key gut microbiota and serum metabolic factors.RESULTS: LSG significantly reduced the weight of obese patients, with reductions of up to 28%. Furthermore, cognitive assessment scale measurements revealed that LSG enhanced cognitive functions, including memory (HVLT, p = 0.000) and executive function (SCWT, p = 0.008). Also, LSG significantly altered gut microbiota composition (p = 0.001), with increased microbial abundance and diversity (p < 0.05). Moreover, serum metabolite levels were significantly altered, revealing intergroup differences in 229 metabolites mapped to 72 metabolic pathways (p < 0.05, VIP > 1). Spearman correlation analysis among cognitive assessment scales, gut microbiota species, and serum metabolites revealed correlations with 68 gut microbiota species and 138 serum metabolites (p < 0.05). Furthermore, pairwise correlations were detected between gut microbiota and serum metabolites (p < 0.05). Functional neuroimaging analysis revealed that LSG increased functional connectivity in cognitive-related frontotemporal networks (FPN, p < 0.01). Additionally, normalization of the default mode network (DMN) and salience network (SN) connectivity was observed after LSG (p < 0.001). Further canonical correlation and correlation analysis suggested that the cognitive-related brain network changes induced by LSG were associated with key gut microbiota species (Akkermansia, Blautia, Collinsella, Phascolarctobacterium, and Ruminococcus, p < 0.05) and neuroactive metabolites (Glycine, L-Serine, DL-Dopa, SM (d18:1/24:1(15Z), p < 0.05).CONCLUSION: These findings indicate the pathophysiological role of the microbiota-gut-brain axis in enhancing cognitive function after bariatric surgery, and the study provides a basis for clinical dietary adjustments, probiotic supplementation, and guidance for bariatric surgery, but further research is still needed.TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2100049403. Registered 02 August 2021, https://www.chictr.org.cn/ .PMID:39420319 | DOI:10.1186/s12967-024-05757-9

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