Glycerophospholipid Metabolism Pathway Research Articles

Mechanical Study of Jian-Gan-Xiao-Zhi Decoction on Nonalcoholic Fatty Liver Disease Based on Integrated Network Pharmacology and Untargeted Metabolomics.

Jian-Gan-Xiao-Zhi decoction (JGXZ) has demonstrated beneficial effects on nonalcoholic fatty liver disease (NAFLD). However, the mechanisms by which JGXZ improve NAFLD are still unclear. Methods. In this study, we first used a high-fat diet (HFD) to establish a NAFLD rat model to clarify the therapeutic effect of JGXZ on NAFLD. Secondly, we used network pharmacology to predict the potential targets of JGXZ on NAFLD, and then the key targets obtained from network pharmacology were verified. Finally, we used untargeted metabolomics to study the metabolic regulatory mechanism of JGXZ. Results. JGXZ treatment could decrease body weight and ameliorate dyslipidemia in NAFLD model rats. H&E and oil red O staining indicated that JGXZ reduced steatosis and infiltration of inflammatory cells in the liver. In addition, network pharmacology research found that the potential targets of JGXZ on NAFLD pathway were mainly associated with improving oxidative stress, apoptosis, inflammation, lipid metabolism disorders, and insulin resistance. Further experimental verification confirmed that JGXZ could inhibit inflammation and improve oxidative stress, insulin resistance, and lipid metabolism disorders. Serum untargeted metabolomics analyses indicated that the JGXZ in the treatment of NAFLD may work through the linoleic acid metabolism, alpha-linolenic acid metabolism, tryptophan metabolism, and glycerophospholipid metabolism pathways. Conclusions. In conclusion, this study found that JGXZ has an ameliorative effect on NAFLD, and JGXZ alleviates the inflammatory response and oxidative stress and lipid metabolism disorders in NAFLD rats. The mechanism of action of JGXZ in the treatment of NAFLD may be related to the regulation of linoleic acid metabolism, tryptophan metabolism, alpha-linolenic acid metabolism, and glycerophospholipid metabolism.

Integrated ONT Full-Length Transcriptome and Metabolism Reveal the Mechanism Affecting Ovulation in Muscovy Duck (Cairina moschata).

Ovulation is a complicated physiological process that is regulated by a multitude of different pathways. In comparison to mammalian studies, there are few reports of ovulation in Muscovy ducks, and the molecular mechanism of ovarian development remained unclear. In order to identify candidate genes and metabolites related to Muscovy duck follicular ovulation, the study combined Oxford Nanopore Technologies (ONT) full-length transcriptome and metabolomics to analyze the differences in gene expression and metabolite accumulation in the ovaries between pre-ovulation (PO) and consecutive ovulation (CO) Muscovy ducks. 83 differentially accumulated metabolites (DAMs) were identified using metabolomics analysis, 33 of which are related to lipids. Combined with data from previous transcriptomic analyses found that DEGs and DAMs were particularly enriched in processes including the regulation of glycerophospholipid metabolism pathway, arachidonic acid metabolic pathway and the steroid biosynthetic pathway. In summary, the novel potential mechanisms that affect ovulation in Muscovy ducks may be related to lipid metabolism, and the findings provide new insights into the mechanisms of ovulation in waterfowl and will contribute to a better understanding of changes in the waterfowl ovarian development regulatory network.

Butter-Derived Ruminant Trans Fatty Acids Do Not Alleviate Atherosclerotic Lesions in High-Fat Diet-Fed ApoE-/- Mice.

Atherosclerosis (AS) is the most common cardiovascular disease (CVD). Currently, it is widely believed that R-TFA and I-TFA may cause different biological effects. In the present study, we aim to elucidate the effect of mixed R-TFA derived from butter on the development of AS in high-fat diet-fed ApoE-/- mice and find the possible mechanism. It was shown that butter-derived R-TFA promoted dyslipidemia, reduced thoracic and abdominal aorta diameters, and induced aortic lipid deposition and atherosclerotic lesions in high-fat diet-fed ApoE-/- mice. Meanwhile, butter-derived R-TFA affected the serum lipid profile of high-fat diet-fed ApoE-/- mice and the lipid metabolism of human umbilical vein endothelial cells (HUVECs). Through lipidomic techniques, we found that butter-derived R-TFA had a significant effect on the glycerophospholipid metabolic pathway. In conclusion, our results demonstrated that butter-derived R-TFA does not alleviate but promotes atherosclerotic lesions in high-fat diet-fed ApoE-/- mice and that the glycerophospholipid metabolic pathway plays a major role in this pro-atherosclerotic effect.

Orally Administered Brain Protein Combined With Probiotics Increases Treg Differentiation to Reduce Secondary Inflammatory Damage Following Craniocerebral Trauma.

Craniocerebral trauma is caused by external forces that can have detrimental effects on the vasculature and adjacent nerve cells at the site. After the mechanical and structural primary injury, a complex series of secondary cascades of injury exacerbates brain damage and cognitive dysfunction following mechanical and structural primary injury. Disruption of the blood-brain barrier and exposure of brain proteins following craniocerebral trauma, recognition by the immune system triggering autoimmune attack, and excessive secondary inflammatory responses causing malignant brain swelling, cerebral edema, and subsequent brain cell apoptosis provide a new direction for the suppression of brain inflammatory responses in the treatment of craniocerebral trauma. We observed that CD4+T/CD8+T in peripheral blood T cells of craniocerebral trauma rats were significantly higher than those of normal rats, and the ratio of CD4+CD25+Foxp3 (Foxp3)+Regulatory T cell (Treg) was significantly lower than that of normal rats and caused increased secondary inflammation. We constructed a rat model of post-surgical brain injury and orally administered brain protein combined with probiotics, which was observed to significantly reduce CD4+T/CD8+T and induce T-cell differentiation into CD4+CD25+Foxp3+Treg, thus, reducing secondary inflammatory responses following craniocerebral trauma. However, collecting intestinal stool and small intestinal tissues for broad target metabolomics, 16s rRNA bacteriomics, and the combined analysis of intestinal tissue proteomics revealed that oral administration of brain protein combined with probiotics activates glycerophospholipid and vitamin B6 metabolic pathways to promote the production of CD4+CD25+Foxp3+Treg. Therefore, we propose the novel idea that oral administration of brain protein combined with probiotics can induce immune tolerance by increasing Treg differentiation, thus, reducing secondary inflammatory injury following craniocerebral trauma.

Metabolomic Characterization of Acute Ischemic Stroke Facilitates Metabolomic Biomarker Discovery.

Acute ischemic stroke (AIS) is characterized by a sudden blockage of one of the main arteries supplying blood to the brain, leading to insufficient oxygen and nutrients for brain cells to function properly. Unfortunately, metabolic alterations in the biofluids with AIS are still not well understood. In this study, we performed high-throughput target metabolic analysis on 44 serum samples, including 22 from AIS patients and 22 from healthy controls. Multiple-reaction monitoring analysis of 180 common metabolites revealed a total of 29 metabolites that changed significantly (VIP > 1, p < 0.05). Multivariate statistical analysis unraveled a striking separation between AIS patients and healthy controls. Comparing the AIS group with the control group, the contents of argininosuccinic acid, beta-D-glucosamine, glycerophosphocholine, L-abrine, and L-pipecolic acid were remarkably downregulated in AIS patients. Twenty-nine out of 112 detected metabolites enriched in disturbed metabolic pathways, including aminoacyl-tRNA biosynthesis, glycerophospholipid metabolism, lysine degradation, phenylalanine, tyrosine, and tryptophan biosynthesis metabolic pathways. Collectively, these results will provide a sensitive, feasible diagnostic prospect for AIS patients.

Liuwei Dihuang Decoction Alleviates Cognitive Dysfunction in Mice With D-Galactose-Induced Aging by Regulating Lipid Metabolism and Oxidative Stress via the Microbiota-Gut-Brain Axis.

BackgroundAging is an important cause of cognitive dysfunction. Liuwei Dihuang decoction (LW), a commonly applied Chinese medicine formula, is widely used for the treatment of aging-related diseases in China. Previously, LW was confirmed to be effective in prolonging life span and reducing oxidative stress in aged mice. Unfortunately, the underlying mechanism of LW remains unclear. The aim of this study was to interpret the mechanism by which LW alleviates cognitive dysfunction related to aging from the perspective of the microbiota-gut-brain axis.MethodAll C57BL/6 mice (n = 60) were randomly divided into five groups: the control, model, vitamin E (positive control group), low-dose LW and high-dose LW groups (n = 12 in each group). Except for those in the control group, D-galactose was subcutaneously injected into mice in the other groups to induce the aging model. The antiaging effect of LW was evaluated by the water maze test, electron microscopy, 16S rRNA sequencing, combined LC–MS and GC–MS metabolomics, and ELISA.ResultsLiuwei Dihuang decoction ameliorated cognitive dysfunction and hippocampal synaptic ultrastructure damage in aging mice. Moreover, LW decreased Proteobacteria abundance and increased gut microbiota diversity in aging mice. Metabolomic analysis showed that LW treatment was associated with the significantly differential abundance of 14 metabolites, which were mainly enriched in apelin signaling, sphingolipid metabolism, glycerophospholipid and other metabolic pathways. Additionally, LW affected lipid metabolism and oxidative stress in aging mice. Finally, we also found that LW-regulated microbial species such as Proteobacteria and Fibrobacterota had potential relationships with lipid metabolism, oxidative stress and hippocampal metabolites.ConclusionIn brief, LW improved cognitive function in aging mice by regulating lipid metabolism and oxidative stress through restoration of the homeostasis of the microbiota-gut-brain axis.

TAT&RGD Peptide-Modified Naringin-Loaded Lipid Nanoparticles Promote the Osteogenic Differentiation of Human Dental Pulp Stem Cells.

BackgroundNaringin is a naturally occurring flavanone that promotes osteogenesis. Owing to the high lipophilicity, poor in vivo bioavailability, and extensive metabolic alteration upon administration, the clinical efficacy of naringin is understudied. Additionally, information on the molecular mechanism by which it promotes osteogenesis is limited.MethodsIn this study, we prepared TAT & RGD peptide-modified naringin-loaded nanoparticles (TAT-RGD-NAR-NPs), evaluated their potency on the osteogenic differentiation of human dental pulp stem cells (hDPSCs), and studied its mechanism of action through metabolomic analysis.ResultsThe particle size and zeta potential of TAT-RGD-NAR-NPs were 160.70±2.05 mm and –20.77±0.47mV, respectively. The result of cell uptake assay showed that TAT-RGD-NAR-NPs could effectively enter hDPSCs. TAT-RGD-NAR-NPs had a more significant effect on cell proliferation and osteogenic differentiation promotion. Furthermore, in metabolomic analysis, naringin particles showed a strong influence on the glycerophospholipid metabolism pathway of hDPSCs. Specifically, it upregulated the expression of PLA2G3 and PLA2G1B (two isozymes of phospholipase A2, PLA2), increased the biosynthesis of lysophosphatidic acid (LPA).ConclusionThese results suggested that TAT-RGD-NPs might be used for transporting naringin to hDPSCs for modulating stem cell osteogenic differentiation. The metabolomic analysis was used for the first time to elucidate the mechanism by which naringin promotes hDPSCs osteogenesis by upregulating PLA2G3 and PLA2G1B.

Metabolomics of bronchoalveolar lavage in children with persistent wheezing

BackgroundRecent studies have demonstrated the important role of metabolomics in the pathogenesis of asthma. However, the role of lung metabolomics in childhood persistent wheezing (PW) or wheezing recurrence remains poorly understood.MethodsIn this prospective observational study, we performed a liquid chromatography/mass spectrometry-based metabolomic survey on bronchoalveolar lavage samples collected from 30 children with PW and 30 age-matched infants (control group). A 2-year follow-up study on these PW children was conducted.ResultsChildren with PW showed a distinct characterization of respiratory metabolome compared with control group. Children with PW had higher abundances of choline, oleamide, nepetalactam, butyrylcarnitine, l-palmitoylcarnitine, palmitoylethanolamide, and various phosphatidylcholines. The glycerophospholipid metabolism pathway was the most relevant pathway involving in PW pathophysiologic process. Additionally, different gender, prematurity, and systemic corticoids use demonstrated a greater impact in airway metabolite compositions. Furthermore, for PW children with recurrence during the follow-up period, children who were born prematurely had an increased abundance of butyrylcarnitine relative to those who were carried to term.ConclusionsThis study suggests that the alterations of lung metabolites could be associated with the development of wheezing, and this early alteration could also be correlated with wheezing recurrence later in life.

Averrhoa carambola extractive inhibits breast cancer via regulating CEPT1 and LYPLA1

Liposomes have been widely exploited as a drug delivery system in treating tumors because of their advantage to enhance anti-tumor efficacy and reduce side effects. In this study, the tumor-targeted 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4‑dione (DMDD, i.e., Averrhoa carambola extractive) liposomes (HA/TN-DLP) were conducted and assessed. HA/TN-DLP showed controllable drug loading (up to 83%) with high stability. In vitro and in vivo studies showed good cell uptake behavior and high inhibition rate of breast cancer compared to free DMDD. HA/TN-DLP might be the suitable for DMDD due to its better advantages in delivery, penetrability, and targeting-tumor capability. For in vivo mouse model tests, HA/TN-DLP effectively inhibited tumor growth compared to free DMDD. Further analyses indicated that HA/TN-DLP inhibited the glycerophospholipid metabolism pathway by reducing the biosynthesis of phosphatidylcholine and 1-acyl-sn‑glycero-3-phosphocholine through regulating the expressions of CEPT1 and LYPLA1, and inhibited tumor cell growth by regulating the PI3K/Akt and NF-κB signaling pathways. In conclusion, the obviously enhanced antitumor effect further demonstrated that HA/TN-DLP may be a promising tumor-targeting agent.

Abstract 2009: Elucidating the mechanistic effect of targeting Ref-1 redox function on MPNST survival signaling using patient-derived xenolines

Abstract Malignant Peripheral Nerve Sheath Tumor (MPNST) is a rare soft tissue sarcoma common in patients with NF1 (neurofibromatosis type 1). MPNSTs respond poorly to most chemotherapeutics due to molecular heterogeneity and altered signal transduction pathways. Ref-1 and STAT3 are highly expressed in MPNST patient samples offering druggable pathways. Inhibition of one singular protein, like Ref-1 to block the activity of many important transcription factors (TFs), STAT3, HIF1a, and NFkB is key to improving success in MPNST therapy. Inhibition of both Ref-1 and STAT3 in MPNST lines resulted in decreased proliferation, wound healing, tumor signaling, and deactivation of MPNST survival genes. Further, knockdown of Ref-1 or STAT3 resulted in a concordant decrease in NFkB activity. Ref-1 redox inhibitor, APX3330 that completed Phase I clinical trial (NCT03375086), potently inhibited in vitro growth of a panel of MPNST cells. We have also been developing new more potent analogs of APX3330 for inhibition of Ref-1 redox function and potent cell killing in our panel of MPNST cells. Several of these analogs significantly and potently reduced NFkB and HIF1a activity at concentrations where cell killing was minimal, pointing toward an on-target effect. Based on the role of Ref-1 in transcriptional regulation of MPNST, RNA sequencing after knockdown of Ref-1 was used to determine mechanistic effects on MPNST gene expression. We have identified 443 genes up-regulated and 758 genes down-regulated in two MPNST cell lines with siRef-1. The pathways enriched by the commonly up-regulated genes included RNA polymerase, P53 downstream, glycerophospholipid, and other lipid metabolism pathways; the pathways enriched by the commonly down-regulated genes included cell cycle, adaptive immune response, and VEGF signaling pathways. From this data, we also found that OXPHOS (Oxidative Phosphorylation) pathway genes (like NDUFS2, SURF1, COX15) were down with siRef-1 along with others like AURKA, RNASEH2A, CDC20, GINS4, TIMELESS that were identified in our previous publication to be MPNST survival genes. Based on our published observations that Ref-1 inhibition dramatically affects metabolic pathways, we used OXPHOS deficient and proficient osteosarcoma cells and confirmed the impact of Ref-1 redox activity on metabolism. Furthermore, if we combine Ref-1 inhibition with a-ketoglutarate (aKG) and target the tumor cells’ dependence on aspartate biosynthesis, the tumor cell death was dramatic (p &amp;lt; 0.0001). Two new xenolines were established from patient PDXs and are being validated for growth inhibition and downregulation of MPNST survival genes with Ref-1 knockdown and redox inhibition using APX analogs both in vitro and in vivo. Successful derailing of MPNST survival pathways by targeting Ref-1 redox function is our aim to treat this rare but deadly cancer. Citation Format: Silpa Gampala, Olivia Babb, Nikkitha Umesh Ganesh, Steven D. Rhodes, Reza M. Saadatzadeh, Kai Pollard, Christine Pratilas, Jing-Ruey Joanna Yeh, Karen E. Pollok, Wade D. Clapp, Mark R. Kelley, Chi Zhang, Melissa L. Fishel. Elucidating the mechanistic effect of targeting Ref-1 redox function on MPNST survival signaling using patient-derived xenolines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2009.

Blood-based untargeted metabolomics in relapsing-remitting multiple sclerosis revealed the testable therapeutic target.

Metabolic aberrations impact the pathogenesis of multiple sclerosis (MS) and possibly can provide clues for new treatment strategies. Using untargeted metabolomics, we measured serum metabolites from 35 patients with relapsing-remitting multiple sclerosis (RRMS) and 14 healthy age-matched controls. Of 632 known metabolites detected, 60 were significantly altered in RRMS. Bioinformatics analysis identified an altered metabotype in patients with RRMS, represented by four changed metabolic pathways of glycerophospholipid, citrate cycle, sphingolipid, and pyruvate metabolism. Interestingly, the common upstream metabolic pathway feeding these four pathways is the glycolysis pathway. Real-time bioenergetic analysis of the patient-derived peripheral blood mononuclear cells showed enhanced glycolysis, supporting the altered metabolic state of immune cells. Experimental autoimmune encephalomyelitis mice treated with the glycolytic inhibitor 2-deoxy-D-glucose ameliorated the disease progression and inhibited the disease pathology significantly by promoting the antiinflammatory phenotype of monocytes/macrophage in the central nervous system. Our study provided a proof of principle for how a blood-based metabolomic approach using patient samples could lead to the identification of a therapeutic target for developing potential therapy.

Integrated Lipidomic and Transcriptomic Analysis Reveals Phospholipid Changes in Somatic Embryos of Picea asperata in Response to Partial Desiccation.

Partial desiccation treatment (PDT) is an effective technology for promoting the germination and conversion of conifer somatic embryos (SEs). PDT, as a drought stress, induces intensive physiological responses in phospholipid metabolism, which are not well understood in the conifer SEs. Here, we integrated lipidomics, transcriptomics and proteomics analyses to reveal the molecular basis of lipid remodeling under PDT in Picea asperata SEs. Among the 82 lipid molecular species determined by mass spectrometry, phosphatidic acid (PA) had a significant effect after PDT and was the most critical lipid in the response to PDT. The transcriptomics results showed that multiple transcripts in the glycerolipid and glycerophospholipid metabolism pathways were differentially expressed, and these included five PLDα1 transcripts that catalyze the conversion of phosphatidylcholine (PC) to PA. Furthermore, the enzyme activity of this phospholipase D (PLD) was significantly enhanced in response to PDT, and PDT also significantly increased the protein level of PLDα1 (MA_10436582g0020). In addition, PA is a key factor in gibberellin, abscisic acid and ethylene signal transduction. One GDI1, one DELLA, three ABI1s, two SnRK2s, one CTR and 12 ERFs showed significantly differential expression between SEs before and after PDT in this study. Our data suggest that the observed increases in the PA contents might result from the activation of PLDα by PDT. PA not only affects the physical and chemical properties of the cell membrane but also participates in plant hormone signal transduction. Our work provides novel insight into the molecular mechanism through which PDT promotes the germination of SEs of coniferous tree species and fills the gap in the understanding of the mechanism of somatic embryo lipid remodeling in response to PDT.

Serum liquid metabolites reveals the heterogeneity in advanced lung adenocarcinoma patients with EGFR sensitizing mutations.

e21065 Background: There is a differential therapeutic efficacy of advanced lung adenocarcinoma (LUAD) patients with EGFR sensitizing mutations (mEGFR). This study aimed to explore the differences in serum liquid metabolites of EGFR mutation types and to provide further evidence for revealing the mechanism of the difference in efficacy. Methods: In total, 42 LUAD patients with mEGFR (19 deletions or 21 L858R mutations) who received EGFR-TKIs therapy were included. Prospectively collected serum samples before initial treatment were utilized to perform nontargeted liquid metabolomics profiling analyses under the application of Ultrahigh Performance Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (UPLC-MS/MS). Multi-dimensional statistical methods such as partial least squares discrimination analysis (PLS-DA) were used to further screen and identify differential metabolites associated with EGFR mutation type. Results: The metabolic signature molecules in the metabolic profile were extracted, and a total of 1995 positive ion mode (ESI+) and 365 negative ion mode (ESI-) signature molecules were obtained. 29 metabolites displayed significant differences between the two groups, which belong to lipids including phosphatidylcholines (PCs), phosphatidylglycerol (PGs), phosphatidylethanolamine (PEs), ceramides (Cers) and sphingomyelins (SMs). Gene mutation subtypes change the proportion of saturated phospholipids and unsaturated phospholipids, with significantly higher saturated phospholipids in patients with the EGFR 21 L858R mutation. Then, pathway enrichment analysis was performed on the differential metabolites, mainly enriched in glycerophospholipid and sphingolipids metabolism pathway. Conclusions: This study not only demonstrates the heterogeneity of lipid metabolism among gene mutation subtypes, but also provides the possibility to reveal the mechanism of survival differences.

Didymin Ameliorates Liver Fibrosis by Alleviating Endoplasmic Reticulum Stress and Glycerophospholipid Metabolism: Based on Transcriptomics and Metabolomics.

IntroductionOriganum vulgare L. is a traditional Chinese herb, having a strong hepatoprotective effect. In our previous experiments, we have isolated an ingredient from this herb and identified it as didymin. This study aimed to investigate the effects and underlying mechanisms of didymin on liver injury and fibrosis, elucidating whether it was the pharmacodynamic material basis of Origanum vulgare L.MethodsMice were injected with CCl4 for 10 weeks to induce liver fibrosis, followed by didymin treatment for 6 weeks. Then, biochemical analysis and histopathological examinations were conducted to evaluate the therapeutic effects of didymin in alleviating fibrosis. Next, the possible mechanisms of didymin were predicted by transcriptomics and then verified by the multiple relevant examinations.ResultsThe pharmacodynamic experiments indicated that didymin significantly attenuated CCl4-induced hepatic injury and fibrogenesis, as evidenced by the ameliorative pathological tissue, low transaminase activity, and decreased collagen accumulation. Interestingly, the transcriptome analysis predicted that the potential targets were likely to be endoplasmic reticulum stress (ERS), inflammation, apoptosis, and metabolic pathways. And the predictions were then verified by the following examinations: (1) didymin significantly inhibited ERS by regulating the ATF6, IRE1α, and PERK pathways; (2) didymin markedly alleviated hepatocyte apoptosis by restoring the expression of Bcl-2 and caspase families, as well as the mitochondrial dysfunction; (3) didymin significantly decreased the production of the pro-inflammatory cytokines (IL-1β and IL-6); (4) didymin inhibited the glycerophospholipid metabolism pathway by decreasing the synthesis of phosphatidylethanolamines and phosphatidylcholines.ConclusionOur findings demonstrate that didymin can ameliorate liver fibrosis, which is mainly attributed to the inhibition of ERS, inflammation, and glycerophospholipid metabolism.

Dissecting the Regulation of Arachidonic Acid Metabolites by Uncaria rhynchophylla (Miq). Miq. in Spontaneously Hypertensive Rats and the Predictive Target sEH in the Anti-Hypertensive Effect Based on Metabolomics and Molecular Docking.

Uncaria rhynchophylla (Miq). Miq. (UR), as a traditional Chinese medicine, was employed in treating hypertension as a safe and effective therapy. The pharmacological properties of UR have characteristics of multiple biological targets and multiple functional pathways. Hypertension is related to impaired metabolic homeostasis and is especially associated with the abnormal regulation of arachidonic acid metabolites, the classical cardiovascular active compounds. This study aimed to examine the anti-hypertensive effect of UR extract (URE) and its regulating role in differential metabolic pathways. The results showed that daily administration of URE at a dose of 4 g crude drug/kg orally could exert hypotensive effects on spontaneously hypertensive rats (SHRs) for 8 weeks. Non-targeted metabolomics analysis of the plasma samples suggested that the anti-hypertension effect of URE in SHRs was associated with the reorganization of the perturbed metabolic network, such as the pathways of glycerophospholipid metabolism, linoleic acid metabolism, and arachidonic acid metabolism. For the targeted metabolomics, twenty-eight arachidonic acid metabolites in SHRs were quantitatively analyzed for the first time based on ultra-high performance liquid chromatography-tandem mass spectrometry method after URE administration. URE restored the functions of these cardiovascular active compounds and rebalanced the dynamics of arachidonic acid metabolic flux. Among them, the inhibition of soluble epoxide hydrolase (sEH) enzyme activity and up-regulation of vasodilators epoxyeicosatrienoic acids (EETs) were identified as contributors to the anti-hypertension effect of URE on SHRs, and sEH represented an attractive and promising drug-binding target of URE. With the molecular docking approach, 13 potential anti-hypertension ingredients as well as sEH inhibitors were discovered, which were worthy of further investigation and verification in future studies.

Detection of immune‐related enzyme activity, gene expression and metabolomic profiling in Chinese mitten crab Eriocheir sinensis parasitized by Polyascus gregaria

Polyascus gregaria is a specialized crustacean parasite of Chinese mitten crab; however, only limited information on interactions between parasite and its host is available. This study examined interactions between P. gregaria and Chinese mitten crab with regard to immune-related enzyme activities and expression of respective genes in the hepatopancreas. To further elucidate the pathogen–host interactions, untargeted gas chromatography–mass spectrometry (GC–MS) metabolomics was used to analyse changes in metabolites in response to P. gregaria infection. Superoxide dismutase, acid phosphatase and alkaline phosphatase activities were significantly increased in parasitized crabs, whereas phenoloxidase activity was significantly decreased. Moreover, the expression of three immune-related genes, that is proPO, Toll1 and Toll2, was markedly downregulated in parasitized crabs. In the metabolomic assay, 73 differential metabolites were identified, and they were significantly enriched in 71 pathways. Among these metabolites, 58 were significantly upregulated and 15 were downregulated. Lysolipids lysoPE, lysoPC, lysoPG, LysoPI and lysoPS were the most strongly upregulated metabolites, and 9-cis-retinol, glycerophosphocholine and 5-thymidylic acid were the top three downregulated metabolites. Most of these metabolites were enriched in the glycerophospholipid metabolism pathway, which was one of the most significantly activated pathway responses to P. gregaria infection. This increase in lysoglycerophospholipids caused major structural and functional abnormalities in the membranes of host tissues, especially in the hepatopancreas. We propose that long-term infection with P. gregaria induces silence of the innate immune system, disturbs intracellular homeostasis and causes cell membrane immune-related dysfunction in Chinese mitten crab. These results may help us better understand P. gregaria infection in Chinese mitten crab.

Microbiome-metabolome responses of Fuzhuan brick tea crude polysaccharides with immune-protective benefit in cyclophosphamide-induced immunosuppressive mice

The present study investigated the immune-protective effect of polysaccharides from Fuzhuan brick tea (FBTPs) in cyclophosphamide (Cy)-induced immunosuppressive mice. The results showed that high-dose of FBTPs administration remarkably alleviated Cy-evoked immune damage through improving the body features, organ indices, immune responses and oxidative stress in the mice. Further microbiota analysis revealed that FBTPs obviously restored Cy-evoked microbial dysbiosis by increasing several beneficial bacteria Lactobacillus, Allobaculum, Unclassified_f_Lachnospiraceae and norank_f_Lachnospiraceae, while reducing Bacteroides, norank_f_Ruminococcaceae, Colidextribacter, Alloprevotella, norank_f_Desulfovibrionaceae and Helicobacter. Meanwhile, metabolomics analysis found that FBTPs significantly altered a range of microbial metabolites, including inosine, deoxyinosine, taurine, sinapic acid, maltotriose, butyric acid, lysophosphatidyl cholines (LysoPCs), lysophosphatidic acids (LysoPAs) and choline. These altered metabolites were involved in purine metabolism, ABC transporters, sulfur metabolism, neuroactive ligand-receptor interaction, biosynthesis of phenylpropanoids, carbohydrate digestion and absorption, protein digestion and absorption, choline metabolism in cancer and glycerophospholipid metabolism pathways, which were mainly related to immune responses, antioxidant capacity and energy supply of the immunosuppressive mice. Additionally, some significant correlations were observed between the specific microbiota and effective metabolites. These results provide a novel insight into the immune-protective effect of FBTPs on regulating the intestinal microbiota and metabolism, which are helpful for thoroughly understanding the nutrition of FBTPs and providing a solid basis for the deeper utilization of Fuzhuan brick tea (FBT).

Lactobacillus plantarum FRT4 alleviated obesity by modulating gut microbiota and liver metabolome in high-fat diet-induced obese mice.

BackgroundObesity has become a global epidemic recognized by the World Health Organization. Probiotics supplementation has been shown to contribute to improve lipid metabolism. However, mechanisms of action of probiotics against obesity are still not clear. Lactobacillus plantarum FRT4, a probiotic previously isolated from a kind of local yogurt, had good acid and bile salt tolerance and lowered cholesterol in vitro.ObjectiveThis study aimed to evaluate the effect of L. plantarum FRT4 on serum and liver lipid profile, liver metabolomics, and gut microbiota in mice fed with a high-fat diet (HFD).DesignMice were fed with either normal diet or HFD for 16 weeks and administered 0.2 mL of 1 × 109 or 1 × 1010 CFU/mL dosage of L. plantarum FRT4 during the last 8 weeks of the diet. Cecal contents were analyzed by 16S rRNA sequencing. Hepatic gene expression and metabolites were detected by real-time quantitative polymerase chain reaction (PCR) and metabolomics, respectively.ResultsL. plantarum FRT4 intervention significantly reduced the HFD-induced body weight gain, liver weight, fat weight, serum cholesterol, triglyceride, and alanine aminotransferase (ALT) levels in the liver (P < 0.05). Liver metabolomics demonstrated that the HFD increased choline, glycerophosphocholine, and phosphorylcholine involved in the glycerophospholipid metabolism pathway. All these changes were reversed by FRT4 treatment, bringing the levels close to those in the control group. Further mechanisms showed that FRT4 favorably regulated gut barrier function and pro-inflammatory biomediators. Furthermore, FRT4 intervention altered the gut microbiota profiles and increased microbial diversity. The relative abundances of Bacteroides, Parabateroides, Anaerotruncus, Alistipes, Intestinimonas, Butyicicoccus, and Butyricimonas were significantly upregulated. Finally, Spearman’s correlation analysis revealed that several specific genera were strongly correlated with glycerophospholipid metabolites (P < 0.05).ConclusionsThese findings suggested that L. plantarum FRT4 had beneficial effects against obesity in HFD-induced obese mice and can be used as a potential functional food for the prevention of obesity.

Dietary ε-Polylysine Affects on Gut Microbiota and Plasma Metabolites Profiling in Mice.

Given the antibacterial effects of ε-polylysine acting on cell membranes, and that glycerol phospholipids are important components of the cell membrane, we hypothesized that ε-polylysine may regulate glycerophospholipid metabolism by modifying the gut microbiota. To test this hypothesis, we treated post-weaning C57 mice with different levels of ε-polylysine (0, 300, 600, and 1,200 ppm) in their basic diet. The growth performance and morphology of intestine were then determined. Modification of the gut microbiota and their function were analyzed using 16S rDNA sequencing. Metabolite identification was performed using the LC-MS method. The results showed that body weight decreased with an increasing supplemental level of ε-polylysine from 5 to 7 weeks (P < 0.05), but no significant difference was observed after 8 weeks (P > 0.05). Supplementation with 1,200 ppm ε-polylysine changed the morphology of the jejunum and ileum, increased the villus length, decreased the crypt depth of the jejunum, and decreased the villus length and crypt depth of the ileum (P < 0.05). ε-Polylysine shifted the intestine microbiota by changing alpha diversity (Chao 1, observed species, Shannon, and Simpson indices) and varied at different times. ε-polylysine decreased Firmicutes and increased Bacteroidetes at 4 week, but increased Firmicutes and decreased Bacteroidetes at 10 week. ε-Polylysine regulated genera associated with lipid metabolism such as Parabacteroides, Odoribacter, Akkermansia, Alistipes, Lachnospiraceae UCG-001, Collinsella, Ruminococcaceae, and Intestinimonas. During the adult period, the genera Alistipes, Lachnospiraceae UCG-001, and Streptomyces were positively associated with PC, PE, LysoPC, LysoPE, 1-Arachidonoylglycerophosphoinositol and OHOHA-PS (R > 0.6, P < 0.001), but changes in Blautia, Christensenellaceae R-7 group, Odoribacter, Allobaculum, Ruminococcaceae UCG-004, Ruminococcaceae UCG-005, and Lachnospiraceae UCG-010 were negatively correlated with glycerophospholipid metabolites (R < −0.6, P < 0.001). The abundance of glycerophospholipid metabolites, including PC, PE, lysoPC, and lysoPE, were decreased by ε-polylysine. Furthermore, ε-polylysine reduced the incidence of the genera including Ruminococcus, Prevotella, Prevotellaceae, Butyricimonas, and Escherichia-Shigella and reduced the abundance of Faecalibaculum, Christensenellaceae R-7 group, Coriobacteriaceae UCG-002. In conclusion, ε-polylysine modified gut microbiota composition and function while also restraining pathogenic bacteria. The glycerophospholipid metabolism pathway and associated metabolites may be regulated by intestinal bacteria.

Metabolomic Profiling of Plasma Reveals Differential Disease Severity Markers in COVID-19 Patients.

The severity, disabilities, and lethality caused by the coronavirus 2019 (COVID-19) disease have dumbfounded the entire world on an unprecedented scale. The multifactorial aspect of the infection has generated interest in understanding the clinical history of COVID-19, particularly the classification of severity and early prediction on prognosis. Metabolomics is a powerful tool for identifying metabolite signatures when profiling parasitic, metabolic, and microbial diseases. This study undertook a metabolomic approach to identify potential metabolic signatures to discriminate severe COVID-19 from non-severe COVID-19. The secondary aim was to determine whether the clinical and laboratory data from the severe and non-severe COVID-19 patients were compatible with the metabolomic findings. Metabolomic analysis of samples revealed that 43 metabolites from 9 classes indicated COVID-19 severity: 29 metabolites for non-severe and 14 metabolites for severe disease. The metabolites from porphyrin and purine pathways were significantly elevated in the severe disease group, suggesting that they could be potential prognostic biomarkers. Elevated levels of the cholesteryl ester CE (18:3) in non-severe patients matched the significantly different blood cholesterol components (total cholesterol and HDL, both p < 0.001) that were detected. Pathway analysis identified 8 metabolomic pathways associated with the 43 discriminating metabolites. Metabolomic pathway analysis revealed that COVID-19 affected glycerophospholipid and porphyrin metabolism but significantly affected the glycerophospholipid and linoleic acid metabolism pathways (p = 0.025 and p = 0.035, respectively). Our results indicate that these metabolomics-based markers could have prognostic and diagnostic potential when managing and understanding the evolution of COVID-19.