PubMed

Stem Cell Res Ther. 2024 Dec 18;15(1):485. doi: 10.1186/s13287-024-04072-w.ABSTRACTBACKGROUND: Adipose-derived stem cells (ADSCs) are widely used in the field of regenerative medicine because of their various functions, including anti-inflammatory effects. ADSCs are considered to exert their anti-inflammatory effects by secreting anti-inflammatory cytokines and extracellular vesicles. Although recent studies have reported that metabolites have a variety of physiological activities, whether those secreted by ADSCs have anti-inflammatory properties remains unclear. Here, we performed multiomics analyses to examine the effect of ADSC-derived metabolites on M1-like macrophages, which play an important role in inflammatory responses.METHODS: The concentration of metabolites in the culture supernatant of ADSCs was quantified using capillary electrophoresis time-of-flight mass spectrometry. To evaluate their effects on inflammatory responses, M1-like macrophages were exposed to the conditioned ADSC medium or their metabolites, and RNA sequencing was used to detect gene expression changes. Immunoblotting was performed to examine how the metabolite suppresses inflammatory processes. To clarify the contribution of the metabolite in the conditioned medium to its anti-inflammatory effects, metabolite uptake was pharmacologically inhibited, and gene expression and the tumor necrosis factor-α concentration were measured by quantitative PCR and enzyme-linked immunosorbent assay, respectively.RESULTS: Metabolomic analysis showed large amounts of lactate in the culture supernatant. The conditioned medium and lactate significantly suppressed or increased the pro-inflammatory and anti-inflammatory gene expressions. However, sequencing and immunoblotting analysis revealed that lactate did not induce polarization from M1- to M2-like macrophages. Based on a recent report that the immunosuppressive effect of lactate depends on epigenetic reprogramming, histone acetylation was investigated, and H3K27ac expression was upregulated. In addition, 7ACC2, which specifically inhibits the monocarboxylate transporter 1, significantly inhibited the anti-inflammatory effect of the conditioned ADSC medium on M1-like macrophages.CONCLUSIONS: Our results showed that ADSCs suppress pro-inflammatory effects of M1-like macrophages by secreting lactate. This study adds to our understanding of the importance of metabolites and is also expected to elucidate new mechanisms of ADSC treatments.PMID:39696485 | DOI:10.1186/s13287-024-04072-w

Cancer Metab. 2024 Dec 18;12(1):37. doi: 10.1186/s40170-024-00366-y.ABSTRACTBACKGROUND: The efficacy of tyrosine kinase inhibitors (TKIs) targeting the EGFR is limited due to the persistence of drug-tolerant cell populations, leading to therapy resistance. Non-genetic mechanisms, such as metabolic rewiring, play a significant role in driving lung cancer cells into the drug-tolerant state, allowing them to persist under continuous drug treatment.METHODS: Our study employed a comprehensive approach to examine the impact of the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3) on the adaptivity of lung cancer cells to EGFR TKI therapies. We conducted metabolomics to trace glucose rerouting in response to PFKFB3 inhibition during TKI treatment. Live cell imaging and DCFDA oxidation were used to quantify levels of oxidation stress. Immunocytochemistry and Neutral Comet assay were employed to evaluate DNA integrity in response to therapy-driven oxidative stress.RESULTS: Our metabolic profiling revealed that PFKFB3 inhibition significantly alters the metabolic profile of TKI-treated cells. It limited glucose utilization in the polyol pathway, glycolysis, and TCA cycle, leading to a depletion of ATP levels. Furthermore, pharmacological inhibition of PFKFB3 overcome TKI-driven redox capacity by diminishing the expression of glutathione peroxidase 4 (GPX4), thereby exacerbating oxidative stress. Our study also unveiled a novel role of PFKFB3 in DNA oxidation and damage by controlling the expression of DNA-glycosylases involved in base excision repair. Consequently, PFKFB3 inhibition improved the cytotoxicity of EGFR-TKIs by facilitating ROS-dependent cell death.CONCLUSIONS: Our results suggest that PFKFB3 inhibition reduces glucose utilization and DNA damage repair, limiting the adaptivity of the cells to therapy-driven oxidative stress and DNA integrity insults. Inhibiting PFKFB3 can be an effective strategy to eradicate cancer cells surviving under EGFR TKI therapy before they enter the drug-resistant state. These findings may have potential implications in the development of new therapies for drug-resistant cancer treatment.PMID:39696407 | DOI:10.1186/s40170-024-00366-y

Lipids Health Dis. 2024 Dec 18;23(1):402. doi: 10.1186/s12944-024-02380-x.ABSTRACTBACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely associated with many aspects of disturbed metabolic health. MASLD encompasses a wide spectrum of liver diseases, ranging from isolated steatosis to metabolic dysfunction-associated steatohepatitis (MASH), up to fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. Limited noninvasive diagnostic tools are currently available to distinguish the various stages of MASLD and as such liver biopsy remains the gold standard for MASLD diagnostics. We aimed to explore whether the plasma lipidome and its variations can serve as a biomarker for MASLD stages.METHODS: We investigated the plasma lipidome of 7 MASLD-free subjects and 32 individuals with MASLD, of whom 11 had MASH based on biopsy scoring.RESULTS: Compared with the MASLD-free subjects, individuals with MASLD had higher plasma concentrations of sphingolipids, glycerolipids, and glycerophospholipids. Only plasma concentrations of ceramide-1-phosphate C1P(d45:1) and phosphatidylcholine PC(O-36:3), PC(O-38:3), and PC(36:2) differed significantly between presence of MASH in individuals with MASLD. Of these lipids, the first three have a very low relative plasma abundance, thus only PC(36:2) might serve as a biomarker with higher plasma concentrations in MASLD individuals without MASH compared to those with MASH.CONCLUSIONS: Plasma lipids hold promise as biomarkers of MASLD stages, whereas plasma PC(36:2) concentrations would be able to distinguish individuals with MASH from those with MASLD without MASH.PMID:39696394 | DOI:10.1186/s12944-024-02380-x

J Nanobiotechnology. 2024 Dec 19;22(1):768. doi: 10.1186/s12951-024-03034-x.ABSTRACTBACKGROUND: Sleep disorder is widespread and involves a variety of intricate factors in its development. Sleep deprivation is a manifestation of sleep disorder, can lead to energy metabolism disturbances, weakened immune system, and compromised body functions. In extreme situations, sleep deprivation can cause organ failure, presenting significant risks to human health.PURPOSE: This study aimed to investigate the efficacy and mechanisms of Astragalus Radix vesicles-like nanoparticles (AR-VLNs) in counteracting the deleterious effects of sleep deprivation.METHODS: The ICR mice were divided into control, model, AR-VLNs high dose (equivalent to 20 g/kg crude drug), AR-VLNs low dose (equivalent to 10 g/kg crude drug), AR high dose (equivalent to 20 g/kg crude drug), and AR low dose (equivalent to 10 g/kg crude drug). The REM (rapid eye movement) sleep-deprivation model was established, and evaluations were conducted for motor function, antioxidant capacity, and energy metabolism indices. Moreover, CACO-2 cells damage was induced with lipopolysaccharide to evaluate the repairing ability of AR-VLNs on the intestinal cell mucosa by measuring permeability. Furthermore, metabolomics was employed to elucidate the mechanisms of AR-VLNs action.RESULTS: AR-VLNs were demonstrated to enhance the motor efficiency and antioxidant capacity in REM sleep-deprived mice, while also minimized pathological damage and restored the integrity of the intestinal mucosal barrier. In vitro experiments indicated the anti-inflammatory effect of AR-VLNs against LPS-induced cell damage. Additionally, metabolomic analysis linked these effects with regulation of the amino acid metabolic pathways. Further confirmation from molecular biology experiments revealed that the protective effects of AR-VLNs against the deleterious effects of REM sleep deprivation were associated with the restoration of the intestinal mucosal barrier and the enhancement of amino acid metabolism.CONCLUSION: AR-VLNs administration effectively improved energy metabolism disorders in REM sleep deprived mice, by facilitating the repair of the intestinal mucosal barrier and regulating the amino acid metabolism.PMID:39696385 | DOI:10.1186/s12951-024-03034-x

BMC Vet Res. 2024 Dec 19;20(1):569. doi: 10.1186/s12917-024-04402-3.ABSTRACTBACKGROUND: Infectious bursal disease virus (IBDV) is a highly contagious immunosuppressive virus of chickens. Chickens acquire infection by the oral route under natural conditions. Although the histological and pathological changes after IBDV infection are well described, the alterations in serum metabolome have not been reported. In this study, SPF chickens were infected with attenuated IBDV (atIBDV) strain LM and very virulent IBDV (vvIBDV) strain LX, respectively. On the seventh day after oral infection, serum samples of experimental chickens were identified using ultra-high performance liquid chromatography-MS/MS (UHPLC-MS/MS). The serum metabolic profiles were analyzed by multivariate statistical methods. KEGG enrichment analysis was performed to evaluate the dysregulated biological pathways.RESULTS: We identified 368 significantly altered metabolites in response to both atIBDV and vvIBDV infection. The metabolic disorder of amino acid and lipid was associated with IBDV infection, especially tryptophan, glycerophospholipid, lysine, and tyrosine metabolism. The differential metabolites enriched in the four metabolic pathways were PC(20:4(5Z,8Z,11Z,14Z)/18:0), PE(16:0/18:2(9Z,12Z)), PE(16:0/22:6(4Z,7Z,10Z,13Z,16Z,19Z)), PE(18:0/20:4(5Z,8Z,11Z,14Z)), PE(18:0/20:4(8Z,11Z,14Z,17Z)), PE(18:0/22:6(4Z,7Z,10Z,13Z,16Z,19Z)), PE(20:3(8Z,11Z,14Z)/16:0), PE(22:6(4Z,7Z,10Z,13Z,16Z,19Z)/16:0), PE-NMe(20:5(5Z,8Z,11Z,14Z,17Z)/18:0), PS(20:3(5Z,8Z,11Z)/18:2(9Z,12Z)), 2-aminobenzoic acid, 4-(2-aminophenyl)-2,4-dioxobutanoic acid, N-acetylserotonin, 5-hydroxyindoleacetate, indole-3-acetaldehyde, indole-3-acetate, p-coumaric acid, L-tyrosine, homovanillin, and S-glutaryldihydrolipoamide.CONCLUSION: The atIBDV and vvIBDV infection causes metabolic changes in chicken serum. The differential metabolites and dysregulated metabolic pathways reflect the host response to the IBDV infection.PMID:39696379 | DOI:10.1186/s12917-024-04402-3

Cardiovasc Diabetol. 2024 Dec 18;23(1):439. doi: 10.1186/s12933-024-02535-1.ABSTRACTBACKGROUND: Diabetic retinopathy (DR) is a major microvascular complication of diabetes mellitus and causes vision impairment and blindness. The presence of major risk factors for DR, such as high levels of HbA1c, does not predict all DR pathogenesis in the clinic, which suggests that uncovering the underlying mechanisms and identifying novel markers are needed. Previous evidence has shown that the serum metabolic signature of DR is unique and detectable compared with that of diabetes mellitus (DM). Here, we aimed to identify serum metabolites as reliable biomarkers for the presence of DR in type 2 DM (T2DM) patients.METHODS: We performed untargeted and targeted metabolomic studies using liquid chromatography‒mass spectrometry (LC‒MS) and multiple reaction monitoring (MRM) methods on the serum samples of T2DM patients. For the discovery dataset, 39 DR patients and 39 non-DR (NDR) patients were included. For the validation dataset, 95 DR patients and 95 non-DR (NDR) patients were included. Receiver operating characteristic curve analysis was performed to evaluate the discriminating power of the metabolites. Binary logistic regression models were fit to evaluate the associations of metabolite peak areas or neurotransmitter concentrations with the presence of DR and adjusted for known risk factors.RESULTS: A total of 7123 metabolites were tested. The 39 DR patients had a mean age of 56 years with an average diabetes duration of 12 years, and the 39 NDR patients had a mean age of 57 years with an average diabetes duration of 11 years. Nine serum candidate markers were further identified. Six out of nine markers were associated with DR after we adjusted for covariates, including blood pressure, HbA1c, diabetes duration, fasting blood glucose, triglyceride, eGFR etc. Among them, eicosapentaenoic acid (EPA) and L-tyrosine were validated in an independent, risk factor-matched sample set. The serum L-tyrosine concentration was decreased in DR group by 47% (-0.22 ± 0.87 vs. 0.48 ± 1.05, P < 0.001), of which the cutoff value was 0.10 mg/ml, with 86% sensitivity and 40% specificity (AUC = 0.62, 95% CI = 0.54-0.70, P = 0.005).CONCLUSIONS: Low levels of circulating L-Tyrosine indicate retinopathy occurrence in T2DM population.PMID:39696333 | DOI:10.1186/s12933-024-02535-1

Cell Commun Signal. 2024 Dec 18;22(1):597. doi: 10.1186/s12964-024-01951-w.ABSTRACTOne of the hallmarks of cancer is metabolic reprogramming which controls cellular homeostasis and therapy resistance. Here, we investigated the effect of momordicine-I (M-I), a key bioactive compound from Momordica charantia (bitter melon), on metabolic pathways in human head and neck cancer (HNC) cells and a mouse HNC tumorigenicity model. We found that M-I treatment on HNC cells significantly reduced the expression of key glycolytic molecules, SLC2A1 (GLUT-1), HK1, PFKP, PDK3, PKM, and LDHA at the mRNA and protein levels. We further observed reduced lactate accumulation, suggesting glycolysis was perturbed in M-I treated HNC cells. Metabolomic analyses confirmed a marked reduction in glycolytic and TCA cycle metabolites in M-I-treated cells. M-I treatment significantly downregulated mRNA and protein expression of essential enzymes involved in de novo lipogenesis, including ACLY, ACC1, FASN, SREBP1, and SCD1. Using shotgun lipidomics, we found a significant increase in lysophosphatidylcholine and phosphatidylcholine loss in M-I treated cells. Subsequently, we observed dysregulation of mitochondrial membrane potential and significant reduction of mitochondrial oxygen consumption after M-I treatment. We further observed M-I treatment induced autophagy, activated AMPK and inhibited mTOR and Akt signaling pathways and leading to apoptosis. However, blocking autophagy did not rescue the M-I-mediated alterations in lipogenesis, suggesting an independent mechanism of action. M-I treated mouse HNC MOC2 cell tumors displayed reduced Hk1, Pdk3, Fasn, and Acly expression. In conclusion, our study revealed that M-I inhibits glycolysis, lipid metabolism, induces autophagy in HNC cells and reduces tumor volume in mice. Therefore, M-I-mediated metabolic reprogramming of HNC has the potential for important therapeutic implications.PMID:39696286 | DOI:10.1186/s12964-024-01951-w

BMC Psychiatry. 2024 Dec 18;24(1):907. doi: 10.1186/s12888-024-06369-9.ABSTRACTBACKGROUND: The psychosocial factors play an important role in the development of depression in adolescents. we used metabolomics techniques to explore the links among childhood trauma, rumination, resilience, and adolescent depression.METHODS: We selected 57 adolescent depression patients and 53 healthy adolescents. The Childhood Trauma Questionnaire (CTQ), Hamilton Depression Scale (HAMD), Resilience Scale (CD-RISC), and Redundant Thinking Response Scale (RRS) were employed for the purpose of psychological assessment. The patients were regrouped according to their scores using the 27% high-low grouping method. Blood specimens were collected from all adolescents and metabolic data were obtained using LC-MS.RESULTS: We found no statistically significant difference between the groups in terms of age, gender, and body mass index (BMI). HAMD, CTQ, and RRS scores were significantly higher in the adolescent depression group (MDD) than in the adolescent healthy control group (HC), and CD-RISP scores were significantly lower than in the HC group (P < 0.001). There were significant differences between the low childhood trauma group (LCT) and high childhood trauma group (HCT), the low rumination group (LRR) and high rumination group (HRR), and the low resilience group (LPR) and high resilience group (HPR) (P < 0.001). RRS, CTQ and HAMD scores were positively correlated, RRS and CTQ scores were positively correlated, CD-RIS was negatively correlated with HAMD, RRS and CTQ scores (P < 0.01). More importantly, we found that DHEAS and LPA (22:6) were identified as significant differential metabolites in both the depressed and normal groups, as well as in the high and low childhood trauma groups. N-Acetyl-L-aspartic acid and DHEAS were identified as significant differential metabolites in both the depressed and normal groups, as well as in the high and low childhood rumination groups. Pseudouridine and LPA(22:6) were identified as significant differential metabolites in both the depressed and normal groups, as well as in the high and low childhood resilience groups.CONCLUSION: Psychological factors (childhood trauma, rumination, resilience) are biologically linked to the development of depression in adolescents. The impact of rumination on adolescent depression may be associated with DHEA. The impact of childhood trauma and resilience on adolescent depression may be associated with LPA (22:6).PMID:39696147 | DOI:10.1186/s12888-024-06369-9

BMC Genomics. 2024 Dec 18;25(1):1194. doi: 10.1186/s12864-024-11093-5.ABSTRACTBACKGROUND: Meat quality in yak is influenced by the fluctuation of nutritional composition in different grazing seasons on the Qinghai-Tibetan Plateau. However, the molecular mechanism underlying in yak meat remains unknown. Therefore, this study aimed to investigate the seasonal dynamics of meat quality in yak by transcriptomics and metabolomics techniques. Twelve healthy female yaks with a similar weight were divided into two groups, including the warm season group (WS) and cold season group (CS). After slaughter, samples of longissimus lumborum were collected and subjected to transcriptomics and metabolomics to explore the effects of different seasons on meat quality.RESULTS: Yak in the WS group had higher contents of n-3 Polyunsaturated fatty acid (PUFA), n-6 PUFA, threonine, and valine compared to the CS group, but the pH45min and b* values were lower. A total of 75 differentially expressed metabolites in the longissimus lumborum muscle were identified, with 23 metabolites upregulated and 52 metabolites downregulated in the WS group. These metabolites were mainly enriched in the pathway of glycine, serine and threonine metabolism, tryptophan metabolism, and carbohydrate digestion and absorption. In comparison, the WS group exhibited 262 upregulated genes in the longissimus lumborum muscle and 81 downregulated genes relatives to the CS group, which were enriched in the fat deposition of TGF-beta, ECM-receptor interaction, MAPK, and PPAR signaling pathway.CONCLUSIONS: Among these, downregulated genes NPNT, GADL1, SESN3, and CPXM1 were associated with lipid metabolism and fat deposition in grazing yaks. It was found that DDC, DHTKD1, CCBL1, GCDH, and AOC1 involved in the tryptophan metabolism played an important role in the regulation of energy metabolism in yak.PMID:39695977 | DOI:10.1186/s12864-024-11093-5

BMC Plant Biol. 2024 Dec 18;24(1):1186. doi: 10.1186/s12870-024-05923-7.ABSTRACTBACKGROUND: Lotus (Nelumbo nucifera) is a significant aquatic ornamental genus widely utilized in horticulture for its decorative, culinary, medicinal, and other practical uses. It presents a variety of flower shapes, including few-petalled, semi-double-petalled, double-petalled and thousand-petalled flowers, making it an ideal candidate for studying the flower development of aquatic plants. However, the molecular mechanism of floral development in lotus remains elusive.RESULTS: In this study, two APETALA2 (AP2) homologues, NnAP2a and NnAP2b, were identified in lotus. Interestingly, both NnAP2a and NnAP2b proteins contained two conserved AP2 domains and were verified to be located primarily in the nucleus. Both NnAP2a and NnAP2b showed high expression levels in the floral buds and petals. Ectopic expression of NnAP2a and NnAP2b in Arabidopsis led to an increase in the number of petals and sepals compared to the wild type (WT). Meanwhile, each of the two NnAP2 genes was able to rescue the sepal and petal defective phenotype of the ap2-6 mutant in Arabidopsis. Furthermore, protein-protein interaction assays indicated that NnAP2s could form a protein complex with other proteins involved in floral organ development, such as AP3, PISTILLATA (PI), and SEPALLATA3 (SEP3).CONCLUSIONS: These results suggest that NnAP2s could influence sepal and petal development in N. nucifera. Our findings not only provide some insights into molecular mechanism underlying sepal and petal development and formation of lotus, but also might help its breeding in improving flower morphology.PMID:39695956 | DOI:10.1186/s12870-024-05923-7

BMC Plant Biol. 2024 Dec 18;24(1):1182. doi: 10.1186/s12870-024-05924-6.ABSTRACTAs a significant fruit and timber tree species among conifers, Pinus koraiensis remains it evergreen status throughout the harsh winters of the north, a testament to its intricate and prolonged evolutionary adaptation. This study delves into the annual trends of physiological indicators, gene expression levels, and metabolite accumulation to dissect the seasonal adaptability of P. koraiensis needles. Chlorophyll content reaches its zenith primarily between July and September, whereas carotenoids persist until spring. Additionally, notable seasonal variations are observed in the levels of soluble sugar and protein. Transcriptome data is categorized into four distinct stages: spring (S2), summer (S3-S4), autumn (S5), and winter (S6-S1). The differential expression of transcription factor genes, including bHLH, MYB-related, AP2/ERF, C3H, and NAC, provides insights into the needles' seasonal adaptations. Analysis of chlorophyll and carotenoid metabolism, sugar metabolism, and the MAPK signaling pathway identifies PSY5 (Cluster-50735.3), AMY13 (Cluster-37114.0), pgm1 (Cluster-46022.0), and MEKK1-1 (Cluster-33069.0) may as potential key genes involved in sustaining the needle's evergreen nature and cold resistance. Ultimately, a comprehensive annual adaptability map for P. koraiensis is proposed, enhancing understanding of its responses to seasonal variations.PMID:39695949 | DOI:10.1186/s12870-024-05924-6

BMC Bioinformatics. 2024 Dec 18;25(1):383. doi: 10.1186/s12859-024-05994-1.ABSTRACTBACKGROUND: Metabolomics is a high-throughput technology that measures small molecule metabolites in cells, tissues or biofluids. Analysis of metabolomics data is a multi-step process that involves data processing, quality control and normalization, followed by statistical and bioinformatics analysis. The latter step often involves pathway analysis to aid biological interpretation of the data. This approach is limited to endogenous metabolites that can be readily mapped to metabolic pathways. An alternative to pathway analysis that can be used for any classes of metabolites, including unknown compounds that are ubiquitous in untargeted metabolomics data, involves defining metabolite-metabolite interactions using experimental data. Our group has developed several network-based methods that use partial correlations of experimentally determined metabolite measurements. These were implemented in CorrelationCalculator and Filigree, two software tools for the analysis of metabolomics data we developed previously. The latter tool implements the Differential Network Enrichment Analysis (DNEA) algorithm. This analysis is useful for building differential networks from metabolomics data containing two experimental groups and identifying differentially enriched metabolic modules. While Filigree is a user-friendly tool, it has certain limitations when used for the analysis of large-scale metabolomics datasets.RESULTS: We developed the DNEA R package for the data-driven network analysis of metabolomics data. We present the DNEA workflow and functionality, algorithm enhancements implemented with respect to the package's predecessor, Filigree, and discuss best practices for analyses. We tested the performance of the DNEA R package and illustrated its features using publicly available metabolomics data from the environmental determinants of diabetes in the young. To our knowledge, this package is the only publicly available tool designed for the construction of biological networks and subsequent enrichment testing for datasets containing exogenous, secondary, and unknown compounds. This greatly expands the scope of traditional enrichment analysis tools that can be used to analyze a relatively small set of well-annotated metabolites.CONCLUSIONS: The DNEA R package is a more flexible and powerful implementation of our previously published software tool, Filigree. The modular structure of the package, along with the parallel processing framework built into the most computationally extensive steps of the algorithm, make it a powerful tool for the analysis of large and complex metabolomics datasets.PMID:39695921 | DOI:10.1186/s12859-024-05994-1

Stem Cell Res Ther. 2024 Dec 18;15(1):479. doi: 10.1186/s13287-024-04092-6.ABSTRACTBACKGROUND: Multi-lineage differentiation of mesenchymal adult stem cells (m-ASCs) is crucial for tissue regeneration and accompanied with metabolism reprogramming, among which dental-pulp-derived m-ASCs has obvious advantage of easy accessibility. Stem cell fate determination and differentiation are closely related to metabolism status in cell microenvironment, which could actively interact with epigenetic modification. In recent years, glutamine-α-ketoglutarate (αKG) axis was proved to be related to aging, tumorigenesis, osteogenesis etc., while its role in m-ASCs still lack adequate research evidence.METHODS: We employed metabolomic analysis to explore the change pattern of metabolites during dental-pulp-derived m-ASCs differentiation. A murine incisor clipping model was established to investigate the influence of αKG on dental tissue repairment. shRNA technique was used to knockdown the expression of related key enzyme-dehydrogenase 1(GLUD1). RNA-seq, m6A evaluation and MeRIP-qPCR were used to dig into the underlying epigenetic mechanism.RESULTS: Here we found that the glutamine-αKG axis displayed an increased tendency along with the osteo/odontogenic differentiation of dental-pulp-derived m-ASCs, same as expression pattern of GLUD1. Further, the key metabolite αKG was found able to accelerate the repairment of clipped mice incisor and promote dentin formation. Exogenous DM-αKG was proved able to promote osteo/odontogenic differentiation of dental-pulp-derived m-ASCs, while the inhibition of glutamine-derived αKG level via GLUD1 knockdown had the opposite effect. Under the circumstance of GLUD1 knockdown, extracellular matrix (ECM) function and PI3k-Akt signaling pathway was screened out to be widely involved in the process with insulin-like growth factor 2 (IGF2) participation via RNA-seq. Inhibition of glutamine-αKG axis may affect IGF2 translation efficiency via m6A methylation and can be significantly rescued by αKG supplementation.CONCLUSION: Our findings indicate that glutamine-αKG axis may epigenetically promote osteo/odontogenic differentiation of dental-pulp-derived m-ASCs and dentin regeneration, which provide a new research vision of potential dental tissue repairment therapy method or metabolite-based drug research.PMID:39695862 | DOI:10.1186/s13287-024-04092-6

Environ Microbiome. 2024 Dec 18;19(1):109. doi: 10.1186/s40793-024-00647-5.ABSTRACTWhile waves, swells and currents are important drivers of the ocean, their specific influence on the biocolonization of marine surfaces has been little studied. The aim of this study was to determine how hydrodynamics influence the dynamics of microbial communities, metabolic production, macrofoulers and the associated vagile fauna. Using a field device simulating a shear stress gradient, a multi-scale characterization of attached communities (metabarcoding, LC-MS, biochemical tests, microscopy) was carried out for one month each season in Toulon Bay (northwestern Mediterranean). Shear stress appeared to be the primary factor influencing biomass, EPS production and community structure and composition. Especially, the transition from static to dynamic conditions, characterized by varying shear stress intensities, had a more pronounced effect on prokaryotic and eukaryotic beta-diversity than changes in shear stress intensity or seasonal physico-chemical parameters. In static samples, mobile microbe feeders such as arthropods and nematodes were predominant, whereas shear stress favored the colonization of sessile organisms and heterotrophic protists using the protective structure of biofilms for growth. The increase in shear stress resulted in a decrease in biomass but an overproduction of EPS, specifically exopolysaccharides, suggesting an adaptive response to withstand shear forces. Metabolite analysis highlighted the influence of shear stress on community dynamics. Specific metabolites associated with static conditions correlated positively with certain bacterial and algal groups, indirectly indicating reduced grazer control with increasing shear stress.PMID:39695832 | DOI:10.1186/s40793-024-00647-5

Parasit Vectors. 2024 Dec 18;17(1):522. doi: 10.1186/s13071-024-06610-0.ABSTRACTBACKGROUND: Toxoplasma gondii is an obligate protozoan parasite capable of infecting a wide range of warm-blooded animals and humans. Current treatment options, primarily pyrimethamine and sulfadiazine, have limitations, such as high recurrence rates, long treatment durations, and limited effectiveness against T. gondii. There is an unmet need for novel, safe, low-toxicity, and highly effective treatments. This study aimed to evaluate the anti-T. gondii effects of glabridin, a natural compound derived from the roots of a widely used medicinal plant.METHODS: The cytotoxicity of glabridin in Vero cells was assessed using a CCK-8 cell viability assay. Quantitative polymerase chain reaction (qPCR) targeting the Tg-529 gene was developed to quantify T. gondii and assess the inhibitory effects of glabridin on parasite proliferation. Ultrastructural changes in T. gondii after treatment were examined using electron microscopy. The levels of reactive oxygen species (ROS) and mitochondrial membrane potential (ΔΨm) were examined to assess the effects of glabridin on ROS levels and ΔΨm in T. gondii tachyzoites. Additionally, metabolomics and transcriptomics analyses were conducted to investigate the mechanisms underlying glabridin's anti-T. gondii effects.RESULTS: Glabridin exhibited low toxicity to host cells and effectively inhibited T. gondii invasion and proliferation in vitro in a time-dependent manner. Glabridin-treated tachyzoites exhibited significant structural alterations, along with increased ROS production and a reduction in ΔΨm. Metabolomic analysis indicated that glabridin significantly affected amino acid metabolism pathways in T. gondii. In vivo, glabridin treatment significantly improved survival rates in T. gondii-infected BALB/c mice at a dosage of 100 mg/kg.CONCLUSIONS: This study demonstrates that glabridin has potent anti-T. gondii effects in vitro and in vivo, likely through disruption of amino acid metabolism in the parasite. These findings highlight glabridin's potential as a promising therapeutic agent for toxoplasmosis.PMID:39695816 | DOI:10.1186/s13071-024-06610-0

Cell Commun Signal. 2024 Dec 18;22(1):599. doi: 10.1186/s12964-024-01983-2.ABSTRACTBACKGROUND: The innate immune system serves as the host's first line of defense against invading pathogens. Stimulator of interferon genes (STING) is a key component of this system, yet its relationship with glucose metabolism, particularly in antiviral immunity, remains underexplored.METHODS: Metabolomics analysis was used for detecting metabolic alterations in spleens from STING knockout (KO) and wild-type (WT) mice. Co-immunoprecipitation was employed for determining ubiquitination of TKT. Mass spectrometry was used for detecting interaction proteins of STING. Enzyme activity kits were used for detecting the activities of TKT and G6PD.RESULTS: In this study, we demonstrate that herpes simplex virus (HSV) infection activates the pentose phosphate pathway (PPP) in host cells, thereby initiating an antiviral immune response. Using STING-manipulated cells and systemic knockout mice, we show that STING positively regulates PPP, which, in turn, limits HSV infection. Inhibition of the PPP significantly reduced the production of antiviral immune factors and dampened STING-induced innate immune responses. Mechanistically, we discovered that STING interacts with transketolase (TKT), a key enzyme in the non-oxidative branch of the PPP, and reduces its ubiquitination via the E3 ubiquitin ligase UBE3A, stabilizing TKT. Silencing TKT or inhibiting its activity with oxythiamine diminished antiviral immune factor production.CONCLUSION: Our findings reveal that the PPP plays a synergistic role in generating antiviral immune factors during viral infection and suggest that PPP activation could serve as an adjunct strategy for antiviral therapy.PMID:39695767 | DOI:10.1186/s12964-024-01983-2

Cardiovasc Diabetol. 2024 Dec 18;23(1):446. doi: 10.1186/s12933-024-02505-7.ABSTRACTBACKGROUND: Type 2 diabetes (T2D) has become a worldwide pandemic. While ceramides may serve as intermediary between obesity-related lipotoxicity and T2D, the relationship with simple glycosphingolipids remains uncertain. The aim of this study was to characterize the associations between blood glycosphingolipid and ceramide species with T2D and to identify a circulating sphingolipid profile that could serve as novel biomarker for T2D risk.METHODS: Cross-sectional relationship between sphingolipid levels, insulin resistance, and T2D prevalence were evaluated in 2,072 American adults from MIDUS cohort. Prospectively, the association between sphingolipid species and the incidence of T2D was analyzed using a case-cohort design nested within the PREDIMED trial (250 cases and a random sample of 692 participants, with 3.8 years of median follow-up). Circulating levels of sphingolipid species in both populations were measured using LC/MS. Hazard ratios were estimated with weighted Cox regression models using Barlow weights.RESULTS: In American adults, only CER18:0 and CER22:0 were linked to insulin resistance and a higher prevalence of T2D. Conversely, three lactosylceramides (LCER 14:0, 16:0, and 24:1) showed a strong inverse relationship with both insulin resistance and T2D. These findings led to development of two sphingolipid scores. In the prospective analysis, these scores consistently predicted a reduced risk of T2D incidence in PREDIMED (HR: 0.64, 95% CI 0.44 to 0.94 and 0.58, 0.40 to 0.85 respectively) between extreme quartiles, with 5-year absolute risk differences of 9.6% (95% CI: 0.3-20.5%) and 11.4% (1.0-21.6%). They were validated in the same trial with samples obtained after 1 year of follow-up.CONCLUSIONS: Our findings support the potential usefulness of circulating sphingolipid profiles as novel biomarkers for T2D risk. Moreover, this study opens the door for future research on the predictive value and possible protective roles of lactosylceramides in T2D.PMID:39695759 | DOI:10.1186/s12933-024-02505-7

Nutr Metab (Lond). 2024 Dec 18;21(1):106. doi: 10.1186/s12986-024-00876-y.ABSTRACTIntermittent fasting is currently a highly sought-after dietary pattern. To explore the potential biomarkers of intermittent fasting, untargeted metabolomics analysis of fecal metabolites in two groups of mice, intermittent fasting and normal feeding, was conducted using UPLC-HRMS. The data was further analyzed through interpretable machine learning (ML) to data mine the biomarkers for two dietary patterns. We developed five machine learning models and results showed that under three-fold cross-validation, Random Forest model was the most suitable for distinguishing the two dietary patterns. Finally, Shapely Additive exPlanations (SHAP) were explored to perform a weighted explanatory analysis on the Random Forest model, and the contribution of each metabolite to the model was calculated. Results indicated that Ganoderenic Acid C is the potential biomarkers to distinguish the two dietary patterns. Our work provides new insights for metabolic biomarker analysis and lays a theoretical foundation for the selection of a healthieir dietary lifestyle.PMID:39695671 | DOI:10.1186/s12986-024-00876-y

BMC Biol. 2024 Dec 18;22(1):292. doi: 10.1186/s12915-024-02087-6.ABSTRACTBACKGROUND: Many members of the oxysterol-binding protein-related protein (ORP) family have been characterized in detail over the past decades, but the lipid transport and other functions of ORP7 still remain elusive. What is known about ORP7 points toward an endoplasmic reticulum and plasma membrane-localized protein, which also interacts with GABA type A receptor-associated protein like 2 (GABARAPL2) and unlipidated Microtubule-associated proteins 1A/1B light chain 3B (LC3B), suggesting a further autophagosomal/lysosomal association. Functional roles of ORP7 have been suggested in cholesterol efflux, hypercholesterolemia, and macroautophagy. We performed a hypothesis-free multi-omics analysis of chemical ORP7 inhibition utilizing transcriptomics and lipidomics as well as proximity biotinylation interactomics to characterize ORP7 functions in a primary cell type, human umbilical vein endothelial cells (HUVECs). Moreover, assays on angiogenesis, cholesterol efflux, and lipid droplet quantification were conducted.RESULTS: Pharmacological inhibition of ORP7 leads to an increase in gene expression related to lipid metabolism and inflammation, while genes associated with cell cycle and cell division were downregulated. Lipidomic analysis revealed increases in ceramides and lysophosphatidylcholines as well as saturated and monounsaturated triacylglycerols. Significant decreases were seen in all cholesteryl ester and in some unsaturated triacylglycerol species, compatible with the detected decrease of mean lipid droplet area. Along with the reduced lipid stores, ATP-binding cassette subfamily G member 1 (ABCG1)-mediated cholesterol efflux and angiogenesis decreased. Interactomics revealed an interaction of ORP7 with AKT1, a central metabolic regulator.CONCLUSIONS: The transcriptomics results suggest an increase in prostanoid as well as oxysterol synthesis, which could be related to the observed upregulation of proinflammatory genes. We envision that the defective angiogenesis in HUVECs subjected to ORP7 inhibition could be the result of an unfavorable plasma membrane lipid composition and/or reduced potential for cell division. To conclude, the present study suggests multifaceted functions of ORP7 in lipid homeostasis, angiogenic tube formation, and gene expression of lipid metabolism, inflammation, and cell cycle in primary endothelial cells.PMID:39695567 | DOI:10.1186/s12915-024-02087-6

BMC Cancer. 2024 Dec 18;24(1):1545. doi: 10.1186/s12885-024-13286-3.ABSTRACTOBJECT: Aim to investigate the multi-omic characteristics of the bone marrow supernatant of relapsed acute myeloid leukemia (AML) and search for proteins and metabolites associated with relapse.METHODS: A total of 40 bone marrow supernatant from 7 patients with relapsed AML and 33 patients with non-relapsed AML were collected for proteomics and metabonomics analysis. Unsupervised clustering was used to discover the characteristics of proteins and metabolites. The prognostic significances of proteins were assessed concerning the relapse status(including death) and relapse-free survival.RESULT: Totally 996 proteins and 4,831 metabolites were identified in bone marrow supernatant, and two of 7 clusters were revealed through unsupervised clustering and were associated with ASXL1, TP53, and RUNX1 mutations, which were listed as high-risk factors in the 2022 edition of the WHO classification of tumors of the hematopoietic and lymphoid tissues. Among the identified proteins and metabolites, 57 proteins and 190 metabolites were found to be closely related to relapse.CONCLUSION: This study has revealed a significant correlation between protein expression in the bone marrow microenvironment of AML and three high-risk mutations: ASXL1, TP53, and RUNX1. Based on this finding, we further identified 227 differential proteins closely associated with these three mutations, as well as 57 proteins directly related to disease recurrence. Additionally, lipid metabolism plays a crucial role in the occurrence and development of AML within its bone marrow microenvironment.PMID:39695514 | DOI:10.1186/s12885-024-13286-3