Metabolomic Profiling of Blood-Derived Microvesicles in Breast Cancer Patients

Malignant cells differ from benign ones in their metabolome and it is largely unknown whether this difference is reflected in the metabolic profile of their microvesicles (MV), which are secreted into the blood of cancer patients. Here, they are present together with MV from the various blood and endothelial cells. Harvesting MV from 78 breast cancer patients (BC) and 30 controls, we characterized the whole blood MV metabolome using targeted and untargeted mass spectrometry. Especially (lyso)-phosphatidylcholines and sphingomyelins were detected in a relevant abundance. Eight metabolites showed a significant discriminatory power between BC and controls. High concentrations of lysoPCaC26:0 and PCaaC38:5 were associated with shorter overall survival. Comparing BC subtype-specific metabolome profiles, 24 metabolites were differentially expressed between luminal A and luminal B. Pathway analysis revealed alterations in the glycerophospholipid metabolism for the whole cancer cohort and in the ether lipid metabolism for the molecular subtype luminal B. Although this mixture of blood-derived MV contains only a minor number of tumor MV, a combination of metabolites was identified that distinguished between BC and controls as well as between molecular subtypes, and was predictive for overall survival. This suggests that these metabolites represent promising biomarkers and, moreover, that they may be functionally relevant for tumor progression.

Key Proteins and Metabolic Pathways Involved in 24-Epibrasionlide Improving Drought Tolerance of Rhododendron delavayi Franch

Rhododendron delavayi Franch. is a famous ornamental plant. However, seasonal drought caused by a monsoon climate seriously limits its growth and flowering performance in urban gardens. Our previous study has found that brassinosteroids (BRs) can improve the tolerance of R. delavayi to drought stress. Here, we employed a data-independent acquisition (DIA) approach to compare the protein expression profiles under drought treatment (D) and pre-treatment with BR before drought treatment (BR). With an increase in drought stress, the net photosynthetic rate, stomatal conductance, and transpiration rate in the BR treatment showed more stable changes that were significantly higher than those in the D treatment. However, the contents of malondialdehyde, soluble sugar, soluble protein, and the activity of superoxide dismutase (SOD), peroxidase, and catalase showed opposite trends. The pre-treatment with BR alleviated the negative effect of drought stress on the photosynthetic performance of R. delavayi. A total of 3453 differentially expressed proteins (DEPs) were identified, and 683 DEPs were significantly expressed in the D and BR treatments. The DEPs uniquely expressed in the BR treatment participated in the pathways of “ribosome”, “ether lipid metabolism”, “photosynthesis”, and “oxidative phosphorylation”. The improvement effect of the BR treatment on the drought tolerance of R. delavayi was mainly attributed to improved photosynthesis by alleviating stomatal closure and oxidative stress, maintaining the integrity and stability of the ribosomal complex to mediate protein synthesis and the balance between energy metabolism and carbon metabolism. Our study presents a comprehensive understanding of the key proteins and metabolic pathways related to the response of R. delavayi to drought and will contribute to the breeding of drought-tolerant rhododendrons.

Gut Microbiota Interplay With COVID-19 Reveals Links to Host Lipid Metabolism Among Middle Eastern Populations

The interplay between the compositional changes in the gastrointestinal microbiome, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) susceptibility and severity, and host functions is complex and yet to be fully understood. This study performed 16S rRNA gene-based microbial profiling of 143 subjects. We observed structural and compositional alterations in the gut microbiota of the SARS-CoV-2-infected group in comparison to non-infected controls. The gut microbiota composition of the SARS-CoV-2-infected individuals showed an increase in anti-inflammatory bacteria such as Faecalibacterium (p-value = 1.72 × 10–6) and Bacteroides (p-value = 5.67 × 10–8). We also revealed a higher relative abundance of the highly beneficial butyrate producers such as Anaerostipes (p-value = 1.75 × 10–230), Lachnospiraceae (p-value = 7.14 × 10–65), and Blautia (p-value = 9.22 × 10–18) in the SARS-CoV-2-infected group in comparison to the control group. Moreover, phylogenetic investigation of communities by reconstructing unobserved state (PICRUSt) functional prediction analysis of the 16S rRNA gene abundance data showed substantial differences in the enrichment of metabolic pathways such as lipid, amino acid, carbohydrate, and xenobiotic metabolism, in comparison between both groups. We discovered an enrichment of linoleic acid, ether lipid, glycerolipid, and glycerophospholipid metabolism in the SARS-CoV-2-infected group, suggesting a link to SARS-CoV-2 entry and replication in host cells. We estimate the major contributing genera to the four pathways to be Parabacteroides, Streptococcus, Dorea, and Blautia, respectively. The identified differences provide a new insight to enrich our understanding of SARS-CoV-2-related changes in gut microbiota, their metabolic capabilities, and potential screening biomarkers linked to COVID-19 disease severity.

Systematic Survey of the Alteration of the Faecal Microbiota in Rats With Gastrointestinal Disorder and Modulation by Multicomponent Drugs

Gastrointestinal disorder (GID) is a global health disease which leads to heavy public medical burden. Disorders in the intestinal flora have been found in gastrointestinal disorder patients. However, the interaction between GID and the intestinal flora in faecal has not been studied comprehensively. In addition, multicomponent drugs represented by traditional Chinese medicine (TCM) are widely used for treating GID, but their modulation of the intestinal flora has not been investigated. Therefore, in this study, a high-throughput sequencing strategy was used to investigate alterations in the intestinal flora in a rat GID model, followed by an investigation of the modulation by a representative TCM, Xiaoerfupi (XEFP) granule. The results showed that in rats with GID, the relative abundances of Erysipelotrichaceae, Lachnospiraceae, Streptococcaceae increased and that of Ruminococcaceae decreased. At the macro level, the levels of LysoPC(16:0), LysoPC(20:2), LysoPC(15:0), LysoPC(20:2 (11Z, 14Z)), LysoPC(20:1), LysoPC(15:0), LysoPC(20:0) and LysoPE (0:0/20:0) in serum increased and levels of PC(36:4), PC(38:4), PC(o-36;4), PE (MonoMe(13,5)/MonoMe(11,5)) decreased. The imbalance of metabolites was restored by XEFP through ether lipid metabolism pathway. Increase in the phyla Firmicutes/Bacteroidetes (F/B) ratio of the GID rats was restored by XEFP as well. Moreover, XEFP can relief the symptoms of GID rats by increasing bacteria Ruminococcaceae and decreasing Streptococcaceae, Erysipelotrichaceae and Lachnospiraceae in faecal microbiota level. This study represents a comprehensive survey of the interaction between GID and the intestinal flora and a systematic evaluation of modulation by a multicomponent drug.

Mass Spectrometry and Computer Simulation Predict the Interactions of AGPS and HNRNPK in Glioma

Ether lipids are overexpressed in malignant tumor and play an important role in tumor process. Glioma is the most common malignant central nervous system tumor, and the content of ether lipids is higher than that of normal tissues. Alkylglycerone phosphate synthase (AGPS) is a key enzyme in the synthesis of ether esters and plays a vital role in maintaining the morphology and pathogenic properties of tumor cells. The cell proliferation and the content of tumor-related lipid such as monoalkylglycerol ether (MAGe), lysophosphatidic acid ether (LPAe), lysophosphatidylcholine ether (LPCe), lysophosphatidylethanolamine ether (LPEe), phosphatidyl inositol (PI), phosphatidylcholine (PC), and phosphatidylserine (PS) were suppressed after AGPS silencing in U251, H4, and TJ905 cells; however, heterogeneous nuclear ribonucleoprotein K (HNRNPK) could reverse the above phenomenon such as cellar proliferation and ether lipid secretion. We found that HNRNPK was the target protein of AGPS by coimmunoprecipitation and mass spectrometry assay and verified by western blot assay in U251 cells. It confirmed that AGPS and HNRNPK are coexpressed in the cellular nucleus by a confocal laser microscope. The main protein-protein interaction mechanism between AGPS and HNRNPK is hydrogen bond, conjugation bond, hydrophobic bond, and electrostatic force by computer simulation prediction.

Planktonic Archaeal Ether Lipid Origins in Surface Waters of the North Pacific Subtropical Gyre

Thaumarchaeota and Thermoplasmatota are the most abundant planktonic archaea in the sea. Thaumarchaeota contain tetraether lipids as their major membrane lipids, but the lipid composition of uncultured planktonic Thermoplasmatota representatives remains unknown. To address this knowledge gap, we quantified archaeal cells and ether lipids in open ocean depth profiles (0–200 m) of the North Pacific Subtropical Gyre. Planktonic archaeal community structure and ether lipid composition in the water column partitioned into two separate clusters: one above the deep chlorophyll maximum, the other within and below it. In surface waters, Thermoplasmatota densities ranged from 2.11 × 106 to 6.02 × 106 cells/L, while Thaumarchaeota were undetectable. As previously reported for Thaumarchaeota, potential homologs of archaeal tetraether ring synthases were present in planktonic Thermoplasmatota metagenomes. Despite the absence of Thaumarchaeota in surface waters, measurable amounts of intact polar ether lipids were found there. Based on cell abundance estimates, these surface water archaeal ether lipids contributed only 1.21 × 10–9 ng lipid/Thermoplasmatota cell, about three orders of magnitude less than that reported for Thaumarchaeota cells. While these data indicate that even if some tetraether and diether lipids may be derived from Thermoplasmatota, they would only comprise a small fraction of Thermoplasmatota total biomass. Therefore, while both MGI Thaumarchaeota and MGII/III Thermoplasmatota are potential biological sources of archaeal GDGTs, the Thaumarchaeota appear to be the major contributors of archaeal tetraether lipids in planktonic marine habitats. These results extend and confirm previous reports of planktonic archaeal lipid sources, and further emphasize the need for Thermoplasmatota cultivation, to better characterize the membrane lipid constituents of marine planktonic Thermoplasmatota, and more precisely define the sources and patterns of archaeal tetraether lipid distributions in marine plankton.

Exploration of Lipid Metabolism in Gastric Cancer: A Novel Prognostic Genes Expression Profile

BackgroundAlterations in lipid metabolism are increasingly being recognized. However, the application of lipid metabolism in the prognosis of gastric cancer (GC) has not yet been explored.MethodsA total of 204 lipid metabolism relative genes were analyzed in the GC cohort from The Cancer Genome Atlas (TCGA), and four independent cohorts from Gene Expression Omnibus (GEO) and one cohort from Wuhan Union Hospital were applied for external validation. Differential expression and enrichment analyses were performed between GC and normal tissue. The LASSO-Cox proportional hazard regression model was applied to select prognostic genes and to construct a gene expression profile.ResultsOur research indicated that higher expression level of AKR1B1, PLD1, and UGT8 were correlated with worse prognosis of GC patients, while AGPAT3 was correlated with better prognosis. Furthermore, we developed a gene profile composed of AGPAT3, AKR1B1, PLD1, and UGT8 suggested three groups with a significant difference in overall survival (OS). The profile was successfully validated in an independent cohort and performed well in the immunohistochemical cohort. Furthermore, we found that ether lipid metabolism, glycerophospholipid metabolism, and glycerolipid metabolism were upregulated, and fatty acid β-oxidation and other lipid peroxidation processes were reduced in GC.ConclusionCollectively, we found lipid metabolism is reliable and clinically applicable in predicting the prognosis of GC based on a novel gene profile.

Ether Lipid Biosynthesis Promotes Lifespan Extension and Enables Diverse Prolongevity Paradigms

Biguanides, including the world's most commonly prescribed drug for type 2 diabetes, metformin, not only lower blood sugar, but also promote longevity in preclinical models. Epidemiologic studies in humans parallel these findings, indicating favorable effects of metformin on longevity and on reducing the incidence and morbidity associated with aging-related diseases, such as cancer. In spite of these promising observations, the full spectrum of the molecular effectors responsible for these health benefits remains elusive. Through unbiased genetic screening in C. elegans, we uncovered a novel role for genes necessary for ether lipid biosynthesis in the favorable effects of biguanides. We demonstrate that biguanides govern lifespan extension via a complex effect on the ether lipid landscape requires enzymes responsible for both ether lipid biogenesis and polyunsaturated fatty acid synthesis. Remarkably, loss of the ether lipid biosynthetic machinery also mitigates lifespan extension attributable to dietary restriction, target of rapamycin (TOR) inhibition, and mitochondrial electron transport chain inhibition. Furthermore, overexpression of a single, key ether lipid biosynthetic enzyme, fard-1/FAR1, is sufficient to promote lifespan extension. These findings illuminate the ether lipid biosynthetic machinery as a novel therapeutic target to promote healthy aging.

Untargeted metabolomic approach to study the serum metabolites in women with polycystic ovary syndrome

Background Polycystic ovary syndrome (PCOS) is not only a kind of common endocrine syndrome but also a metabolic disorder, which harms the reproductive system and the whole body metabolism of the PCOS patients worldwide. In this study, we aimed to investigate the differences in serum metabolic profiles of the patients with PCOS compared to the healthy controls. Material and methods 31 PCOS patients and 31 matched healthy female controls were recruited in this study, the clinical characteristics data were recorded, the laboratory biochemical data were detected. Then, we utilized the metabolomics approach by UPLC-HRMS technology to study the serum metabolic changes between PCOS and controls. Results The metabolomics analysis showed that there were 68 downregulated and 78 upregulated metabolites in PCOS patients serum compared to those in the controls. These metabolites mainly belong to triacylglycerols, glycerophosphocholines, acylcarnitines, diacylglycerols, peptides, amino acids, glycerophosphoethanolamines and fatty acid. Pathway analysis showed that these metabolites were enriched in pathways including glycerophospholipid metabolism, fatty acid degradation, fatty acid biosynthesis, ether lipid metabolism, etc. Diagnosis value assessed by ROC analysis showed that the changed metabolites, including Leu–Ala/Ile–Ala, 3-(4-Hydroxyphenyl) propionic acid, Ile–Val/Leu–Val, Gly–Val/Val–Gly, aspartic acid, DG(34:2)_DG(16:0/18:2), DG(34:1)_DG(16:0/18:1), Phe–Trp, DG(36:1)_DG(18:0/18:1), Leu–Leu/Leu–Ile, had higher AUC values, indicated a significant role in PCOS. Conclusion The present study characterized the difference of serum metabolites and related pathway profiles in PCOS patients, this finding hopes to provide potential metabolic markers for the prognosis and diagnosis of this disease.