C16 Sphinganine Research Articles

A discovery in traditional Chinese medicine compatibility: Cinnabaris suppresses the Strychni Semen-induced neurotoxicity in Shang-Ke-Jie-Gu tablet

BackgroundCinnabaris, as a commonly used mineral drugs, is a classic sedative medicine. Shang-Ke-Jie-Gu tablet is a famous Chinese patent medicine with Cinnabaris, However, the function of Cin in the prescription hasn't been clarified. PurposeOur study evaluated the toxicity of Shang-Ke-Jie-Gu tablet (SK) with or without Cinnabaris, and illuminate the related mechanisms that why cinnabaris is necessary. MethodsThe toxicity of SK and Cin free Shang-Ke-Jie-Gu tablet (CFSK) was evaluated by physical and behavioral tests and histological examinations. The detoxificaion mechanism of Cin on Strychni Semen (SS)-induced neurotoxicity in SK was performed based on the analysis of intestinal absorption, liver metabolism, serum metabolomics, and gut microbiota. The mercury accumulation of SK was assayed using human hair by ICP-MS. ResultsCin was found to inhibit the neurotoxicity of SS in SK. Our study shows that Cin could inhibit SS's absorption in small intestine and promote its metabolism in the liver. A serum metabolomics study showed that taurine and hypotaurine metabolism and retrograde endocannabinoid signaling pathway were associated with Cin attenuation. Association analysis with gut microbiota suggested that Cin could downregulate four key metabolites, including 12‑hydroxy arachidonic acid, GM4(d18:1/18:0), C16 sphinganine, and LysoPC(18:1(11Z)/0:0), by downregulating Lachnospiraceae_NK4A136 and upregulating Prevotella to inhibit the toxic effects of SS. In addition, the danger of mercury poisoning in a longer time administration of SK was evaluated using human hair, and no visible increase in mercury was observed. ConclusionAs a new discovery in compatibility, Cin was proved to be capable of inhibiting the neurotoxicity not only in SK but also in Cin-SS combination, displaying vital roles in Traditional Chinese Medicines.

Secretion of Sphinganine by Drug-Induced Cancer Cells and Modified Mimetic Sphinganine (MMS) as c-Src Kinase Inhibitor.

Cancer cells exhibit selective metabolic reprogramming to promote proliferation, invasiveness, and metastasis. Sphingolipids such as sphingosine and sphinganine have been reported to modulate cell death processes in cancer cells. However, the potential of extracellular sphinganine and its mimetic compounds as inducers of cancer cell death has not been thoroughly investigated. We obtained extracellular conditioned medium from HCT-116 cells treated with the previously reported anticancer composition, goat urine DMSO fraction (GUDF). The extracellular metabolites were purified using a novel and in-house developed vertical tube gel electrophoresis (VTGE) technique and identified through LC-HRMS. Extracellular metabolites such as sphinganine, sphingosine, C16 sphinganine, and phytosphingosine were screened for their inhibitory role against intracellular kinases using molecular docking. Molecular dynamics (MD) simulations were performed to study the inhibitory potential of a novel designed modified mimetic sphinganine (MMS) (Pubchem CID: 162625115) upon c-Src kinase. Furthermore, inhibitory potential and ADME profile of MMS was compared with luteolin, a known c-Src kinase inhibitor. Data showed accumulation of sphinganine and other sphingolipids such as C16 sphinganine, phytosphingosine, and ceramide (d18:1/14:0) in the extracellular compartment of GUDF-treated HCT-116 cells. Molecular docking projected c-Src kinase as an inhibitory target of sphinganine. MD simulations projected MMS with strong (-7.1 kcal/mol) and specific (MET341, ASP404) binding to the inhibitory pocket of c-Src kinase. The projected MMS showed comparable inhibitory role and acceptable ADME profile over known inhibitors. In summary, our findings highlight the significance of extracellular sphinganine and other sphingolipids, including C16 sphinganine, phytosphingosine, and ceramide (d18:1/14:0), in the context of drug-induced cell death in HCT-116 cancer cells. Furthermore, we demonstrated the importance of extracellular sphinganine and its modified mimetic sphinganine (MMS) as a potential inhibitor of c-Src kinase. These findings suggest that MMS holds promise for future applications in targeted and combinatorial anticancer therapy.

Integration of soil microbiology and metabolomics to elucidate the mechanism of the accelerated infestation of tobacco by the root-knot nematode.

Tobacco root-knot nematode (TRKN) disease is a soil-borne disease that presents a major hazard to the cultivation of tobacco, causing significant reduction in crop quality and yield, and affecting soil microbial diversity and metabolites. However, differences in rhizosphere soil microbial communities and metabolites between healthy tobacco soils and tobacco soils with varying degrees of TRKN infection remain unclear. In this study, diseased rhizosphere soils of tobacco infected with different degrees of TRKN [severally diseased (DH) soils, moderately diseased (DM) soils, and mildly diseased (DL) soils] and healthy (H) rhizosphere soils were collected. Here, we combined microbiology with metabolomics to investigate changes in rhizosphere microbial communities and metabolism in healthy and TRKN-infected tobacco using high-throughput sequencing and LC-MS/MS platforms. The results showed that the Chao1 and Shannon indices of bacterial communities in moderately and mildly diseased soils were significantly higher than healthy soils. The Proteobacteria, Actinobacteria, Ascomycota, Burkholderia, Bradyrhizobium and Dyella were enriched in the rhizosphere soil of healthy tobacco. Basidiomycota, Agaricales, Pseudeurotiaceae and Ralstonia were enriched in severally diseased soils. Besides, healthy soils exhibited a relatively complex and interconnected network of bacterial molecular ecologies, while in severally and moderately diseased soils the fungal molecular networks are relatively complex. Redundancy analysis showed that total nitrogen, nitrate nitrogen, available phosphorus, significantly affected the changes in microbial communities. In addition, metabolomics results indicated that rhizosphere soil metabolites were significantly altered after tobacco plants were infected with TRKNs. The relative abundance of organic acids was higher in severally diseased soils. Spearman's analyses showed that oleic acid, C16 sphinganine, 16-hydroxyhexadecanoic acid, D-erythro-3-methylmalate were positively correlated with Basidiomycota, Agaricales, Ralstonia. In conclusion, this study revealed the relationship between different levels of TRKN invasion of tobacco root systems with bacteria, fungi, metabolites and soil environmental factors, and provides a theoretical basis for the biological control of TRKN disease.

Mice ovarian microbiome investigation divulges prospective fount of anticancer and antimicrobial metabolites

The impact of bacterial microbiome metabolites on human health, most particularly on the prevention and treatment of cancer, has gained significant interest in recent times. The study focused on the isolation of bacterial flora associated with the ovaries of 8-week-old mice and examined its ability to produce metabolites with potential antibacterial, antioxidant, and anticancer properties. The isolates were identified based on biochemical and 16S rRNA sequencing. The ethyl acetate extract from isolates was screened for antimicrobial and antioxidant capacity. The 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate the cytotoxicity of the selected isolate against the ovarian carcinoma cell lines SKOV-3 and PA-1. The ethyl acetate extract from Bacillus velezensis OM03 exhibited significant antibacterial activity against all the tested bacteria, with a MIC value ranging from 50 to 100 µg/mL. Furthermore, the extracts demonstrated hydrogen peroxide and 2, 2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activities at rates of 88.50% and 87.78%, respectively. The extracts displayed substantial concentration-dependent antiproliferative/cytotoxic activities against SKOV-3 and PA-1 cell lines after 24 and 48 h of treatments, respectively. Further chemical analysis of the extract using HR-LCMS revealed the presence of bioactive compounds such as myriocin, 2,3-diethylpyrazine, dihydrodeoxystreptomycin, cyclo (L-Phe-L-Pro), C16 sphinganine, and other twenty-nine compounds that have been formerly reported and are accountable for the targeted activities. Bacillus velezensis OM03 may be further investigated for the creation of novel therapeutics, particularly for the treatment of ovarian cancer.

Multi-omics reveals Bifidobacterium longum CECT7894 alleviate food allergy by regulating the Sphingolipid metabolism pathway

Food allergy (FA) is one of the global human health problems, affecting about 1 in 12 children and 1 in 10 adults worldwide. Probiotics have alleviating effects on FA, but the mechanisms have not been fully understood. We sought to explore the therapeutic potential of probiotics Bifidobacterium longum CECT7894 (B. longum CECT7894) on anaphylaxis in the ovalbumin (OVA)-induced FA model using an integrated multiomics approaches. The results revealed treatment with B. longum CECT7894 relieved OVA-induced allergic symptoms such as pathological changes in small intestine to some extent. Furthermore, probiotics utilization also reduced IgE levels. The transcriptomic data demonstrated that the expressions of genes associated with sphingolipid metabolism were altered in the group received B. longum CECT7894 compared to the sensitized group, including Sgpl1, Trpc1 and Prss8. In addition, the abundances of Sphingobacterium at the genus level, Sphingobacterium sp. 21 and B. longum at the species level, which might related with sphingolipid metabolism, were significantly altered by B. longum CECT7894 when compared to the OVA group. Employed the metabolomics analysis, phytosphingosine, C16 sphinganine, sphinganine and sphingosine were identified as significantly changed metabolites and sphingolipid metabolism pathway was significantly enriched by pathway enrichment analysis. The Spearman's correlation analysis further demonstrated that there were strong correlations between serum biochemical indicators, transcripts, gut microbiota and metabolites. Based on the findings described above, from the perspective of genes, gut flora and metabolites changes, it can be concluded that B. longum CECT7894 might suppress OVA-induced FA by regulating the sphingolipid metabolism pathway.

Potential plasma biomarker panels identification for the diagnosis of first-episode schizophrenia and monitoring antipsychotic monotherapy with the use of metabolomics analyses

Schizophrenia (SCZ) is a severe mental disorder. Using liquid chromatography mass spectrometry, we performed comprehensive metabolomics analyses of plasma samples from healthy controls (HC) and first episode SCZ patients before and after an acute period of medication. Ten lipid metabolites and 27 soluble small molecules were identified as potential biomarkers associated with the diagnosis and treatment of SCZ. These metabolites were significantly reduced in SCZ, and lipids and sulfate were significantly increased after treatment. Of the metabolites identified, four showed significant correlations with the Positive and Negative Syndrome Scale total scores. A biomarker panel composed of alpha-dimorphecolic, Phosphatidylcholine (PC) (16:0/18:1(11Z)), 1-methylnicotinamide, Phosphatidylethanolamine (PE) (20:2(11Z,14Z)/18:2(9Z,12Z)), sulfate, and L-tryptophan was selected to distinguish SCZ from HC; this provided the maximum classification performance with an AUC of 0.972. A biomarker panel including C16 sphinganine, gamma-linolenic acid, linoleic acid, PC(16:0/18:1(11Z)), PE(20:2(11Z,14Z)/18:2(9Z,12Z)), and sulfate, was selected for discrimination between SCZ before and after medication, and produced the optimal classification performance with an AUC of 0.905. Disturbances in lipid metabolism, sulfation modification, tryptophan metabolism, anti-inflammatory and antioxidant systems, and unsaturated fatty acids metabolism, were identified in SCZ. Our findings could facilitate the development of objective diagnostic or drug treatment monitoring tools for schizophrenia.

Effect of Sorghum Mulches on Emergence and Seedling Growth of Beggarticks, Goose Grass, and Sesame

Rotation of sorghum (Sorghum bicolor L. Moench) with sesame (Sesamum indicum L.) in drought prone areas of Zimbabwe has raised concerns on whether these two crops are compatible in the rotational system. This is because sorghum is known to exhibit strong allelopathic effects on both crop and weed species. A greenhouse experiment was conducted to assess the effect of soil incorporated sorghum residues on the emergence and seedling growth of sesame and weeds. The emergence and early seedling growth of sesame and the weed significantlyp<0.05increased with increases in the amount of soil incorporated sorghum residues. Incorporating 27.7 g of the ground sorghum herbage caused a stimulatory effect on the emergence and early seedling growth of the test species. Liquid chromatography-mass spectrometry revealed the presence of 6 probable allelochemicals in sorghum residues, namely, 4-methylaminobutyrate, C16 sphinganine, oleamide, tauroursdeoxycholic acid, pisatin, and anhalonidine. From this study, it can be concluded that dry sorghum residues do not have an inhibitory effect on sesame emergence and growth at mulch rates that retard emergence and growth of weeds.

Metabolomic and antioxidant enzyme activity changes in response to cadmium stress under boron application of wheat (Triticum aestivum).

Boron (B) has previously been shown to inhibit cadmium (Cd) uptake in wheat. Here, we investigated the physiological response of external B application (C for no B added, B for B added, B+Cd for B and Cd added, B/Cd for B 24 h pretreatment before Cd added, B and Cd were 46.2 μM and 5 μM, respectively) on wheat growth under Cd stress. The results showed that the wheat growth was significantly weaker under Cd treatment, while B application did not significantly improve the wheat growth under Cd stress. However, B application decreased Cd concentrations and malondialdehyde (MDA) concentrations of shoot and root. The key enzyme activities including superoxide dismutase (SOD) and peroxidase (POD) significantly increased under Cd treatments while decreased under B treatments. Further, a total of 198, 680 and 204 of the differential metabolites were isolated between B and C treatment, Cd and C treatment and B+Cd and Cd treatment, respectively. The metabolites with up-accumulation in B application (B+Cd) roots were mainly galactaric acid, citric acid, N6-galacturonyl-L-lysine, D-glucose, while the metabolites with down-accumulation were mainly threoninyl-tryptophan and C16 sphinganine. The differential metabolic pathways were mainly concentrated in linoleic acid metabolism, galactose metabolism, sphingolipid metabolism, glycolysis/gluconeogenesis, propanoate metabolism in diabetic complications between B+Cd treatment and B treatment. The results indicate that B alleviates Cd toxicity in winter wheat by inhibiting Cd uptake, increasing antioxidant enzyme activity and changing metabolites.

CONJUGATION WITH SILVER NANOPARTICLES ENHANCES ANTI-ACANTHAMOEBIC ACTIVITY OF KAPPAPHYCUS ALVAREZII.

Nanomedicine has the potential in enhancing the efficacy and bioavailability of anti-infective agents. Here we determined whether conjugation of the Malaysian cultivated seaweed Kappaphycus alvarezii with silver-conjugated nanoparticles enhanced anti-acanthamoebic properties. Silver-conjugated K. alvarezii were successfully synthesized, followed by characterization with Fourier transform infrared spectroscopy, ultraviolet-visible spectrophotometry, and transmission electron microscopy. Amoebicidal effects were evaluated against Acanthamoeba castellanii, and cytotoxicity assays were performed using HaCaT cells. Viability assays revealed that silver nanoparticles conjugated with K. alvarezii extract exhibited significant antiamoebic properties (P < 0.05). Nano-conjugates induced the production of reactive oxygen species. Importantly, silver-conjugated extract inhibited amoeba-mediated host cell damage as established by lactate dehydrogenase release. Neither the nano-conjugates nor the extract showed cytotoxicity against human cells in vitro. Liquid chromatography and mass spectroscopy revealed several molecules, including 2,6-nonadien-1-ol, N-desmethyl trifluoperazine, dulciol B, lucidumol A, acetoxolone, 2-[4,6-bis(2,4-dimethylphenyl)-1,3,5-triazin-2-yl]-5-(octyloxy)phenol, C16 sphinganine, 22-tricosenoic acid, and β-dihydrorotenone, of which dulciol B and C16 sphinganine are known to possess antimicrobial activities. In summary, marine organisms are an important source of bioactive molecules with anti-acanthamoebic properties that can be enhanced by conjugating with silver nanoparticles. Natural products combined with nanotechnology using multifunctional nanoparticle complexes can deliver therapeutic agents effectively and hold promise in the development of new formulations of anti-acanthamoebic agents.

Effects of a Sudden Drop in Salinity on Scapharca subcrenata Antioxidant Defenses and Metabolism Determined Using LC-MS Non-targeted Metabolomics

In this experiment, the effects of a sudden drop in salinity on the antioxidant defense system and related gene expression of the ark shell Scapharca subcrenata were examined. The sudden drop in seawater salinity after a rainstorm was simulated, and subsequently differentially expressed metabolic markers were identified by LC-MS non-targeted metabolomics. When the salinity dropped to 14‰ (S14), the total anti-oxidant content, activity of Na+/K+-ATPase, superoxide dismutase (SOD), and catalase (CAT), content of malondialdehyde, and expression levels of Mn-SOD, CAT, and C-type lectin of S. subcrenata were significantly higher than in groups with salinity of 22‰ (S22) or 30‰ (S30) (P < 0.05). The activity of glutathione peroxidase (GPx), the content of reduced glutathione, and the expression levels of GPx were not significantly different between S14 and S22, but the values in each group were significantly higher than those in S30 (P < 0.05). Using the metabolomics technique, 361, 271, and 264 metabolites with significant differences were identified from S22 vs. S14, S30 vs. S14, and S30 vs. S22, respectively. The drop in salinity was accompanied by up-regulation of phosphatidylcholine (PC) (20:4 (5Z, 8Z, 11Z, 14Z)/P-18: 1 (11Z)), PC (16:0/22: 6 (4Z, 7Z, 10Z, 13Z, 16Z, 19Z)), phosphatidylethanolamine (PE) (18:4 (6Z, 9Z, 12Z, 15Z)/24:1 (15Z)), phosphatidylinositol (PI) (20:1 (11Z)/0:0), phalluside-1, C16 sphinganine, and LacCer (d18:0/14:0) and by significant down-regulation of PI-Cer (d18:1/14:0) and PE (14:0/16:1(9Z). The results of this study illustrate how these nine metabolites can be used as metabolic markers for the response of S. subcrenata to a sudden drop in salinity. They also provide the theoretical groundwork for selection of bottom areas with salinity that is optimal for release and proliferation of S. subcrenata, which is needed to restore the declining populations of this species.

A Data Science-Based Analysis Points at Distinct Patterns of Lipid Mediator Plasma Concentrations in Patients With Dementia.

Based on accumulating evidence of a role of lipid signaling in many physiological and pathophysiological processes including psychiatric diseases, the present data driven analysis was designed to gather information needed to develop a prospective biomarker, using a targeted lipidomics approach covering different lipid mediators. Using unsupervised methods of data structure detection, implemented as hierarchal clustering, emergent self-organizing maps of neuronal networks, and principal component analysis, a cluster structure was found in the input data space comprising plasma concentrations of d = 35 different lipid-markers of various classes acquired in n = 94 subjects with the clinical diagnoses depression, bipolar disorder, ADHD, dementia, or in healthy controls. The structure separated patients with dementia from the other clinical groups, indicating that dementia is associated with a distinct lipid mediator plasma concentrations pattern possibly providing a basis for a future biomarker. This hypothesis was subsequently assessed using supervised machine-learning methods, implemented as random forests or principal component analysis followed by computed ABC analysis used for feature selection, and as random forests, k-nearest neighbors, support vector machines, multilayer perceptron, and naïve Bayesian classifiers to estimate whether the selected lipid mediators provide sufficient information that the diagnosis of dementia can be established at a higher accuracy than by guessing. This succeeded using a set of d = 7 markers comprising GluCerC16:0, Cer24:0, Cer20:0, Cer16:0, Cer24:1, C16 sphinganine, and LacCerC16:0, at an accuracy of 77%. By contrast, using random lipid markers reduced the diagnostic accuracy to values of 65% or less, whereas training the algorithms with randomly permuted data was followed by complete failure to diagnose dementia, emphasizing that the selected lipid mediators were display a particular pattern in this disease possibly qualifying as biomarkers.

Characterization of Anti-Salmonella typhi Compounds from Medicinal Mushroom Extracts from Zimbabwe.

Antibiotic resistance has become a global concern and threatens the clinical efficacy of many drugs, leading to increased screening of several sources of potential antimicrobial substances. Mushrooms have long been recognized as a valuable source of nutritive and pharmacologically active compounds. Our previous studies showed that the acetone, ethanol, methanol, and cold water crude extracts of various mushrooms-Amanita and Cantharellus species, Ganoderma lucidum, and Lactarius kabansus-exhibited high antibacterial activity against Salmonella typhi. The objective of this study was to isolate, characterize, and identify antibacterial compounds from these crude mushroom extracts. The crude extracts were separated by preparative thin-layer chromatography. Fractions (n = 99) were obtained and screened for antimicrobial activity against S. typhi by using the MTT assay. Of the isolated components, 13 exhibited high inhibitory activity against the growth of S. typhi, with half-maximal inhibitory concentrations ranging from 206 to 619 µg/mL. Some of the highly potent antibacterial compounds were identified by using liquid chromatography-mass spectrometry. Terpenoids (lucidenic acid M and cavipetin D), a phospholipid (C16 sphinganine), and fatty acid amines (stearamide and palmitic amide) were some of the compounds found to be responsible for the antibacterial activity observed. The importance of local mushrooms as sources of antibacterial compounds was revealed. The high inhibitory activity of some mushroom extracts strongly suggests that the mushrooms contain compounds that have great potential for use in developing therapeutic agents against infections caused by S. typhi.

Ethanolic extract of Brucea javanica inhibit proliferation of HCT-116 colon cancer cells via caspase activation.

Brucea javanica (L.) Merr. is a well-known plant in Chinese System of Medicine. Its fruits and seeds have been reported to possess curative properties against various ailments. The chemical constituents and biological activity of this plant have been an interesting area in plant and chemistry medicine. The aim of this study is to evaluate the antiproliferative effects of the B. javanica extract against a colon cancer cell line and identification of the chemical components derived from the extract. An ethanolic extract from B. javanica fruits was prepared by cold maceration method, subjected to LC-MS profiling to elucidate the composition abbreviated as BJEE. The extract was screened for the cytotoxicity effects on HCT-116 colon cancer cells via MTT and LDH methods. Additionally, AO/PI staining verified apoptosis features in HCT-116 cells through microscopic analysis. ROS, caspase activity, and gene expression has been performed to identify its possible mechanism of actions which contribute to apoptosis. Output data from this study showed BJEE inhibited the cell proliferation of HCT-116 colon cancer cells at IC50 value of 8.9 ± 1.32 (μg mL−1) and significantly increased the levels of caspase-8, 9, and 3/7 in treated cells in comparison to untreated. The changes in expression of caspase genes and some apoptosis genes like Bax and Bcl-2 were confirmed using RT-PCR. Phytochemical analysis by LC-MS identified six major active compounds (bruceine D, isobrucein A, quassimarin, C16 sphinganine, phytosphingosine, and enigmol) in BJEE that may play a key role in cell apoptosis. The current study showed BJEE could be a promising agent for colorectal cancer therapy by significant increase in caspase activity level, and up-regulation of the specific apoptotic genes.

Discrimination and clinical value of plasma metabolomic profiles in multidrug resistant epithelial ovarian cancer

Objective: To explore the alteration of plasma metabolomic profiles, screen the new serum markers of multidrug resistant epithelial ovarian cancer (EOC), and investigate the mechanism. Methods: The serum of 132 cases with cisplatin-resistant EOC, cisplatin-sensitive EOC, benign ovarian cyst and healthy donors were collected. Differentially plasma metabolic profiles were identified by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). The significantly different metabolites of each group were screened by using principal component analysis. Then compounds that played a key role in cisplatin resistance were identified by using nuclear magnetic resonance (NMR). The relationships between these compounds and clinical characteristics and prognosis were analyzed. Results: LC-MS/MS identified 25 800 metabolic compounds. According to the descending dimension algorithm by principal component analysis, six compounds which were the biggest contributor to grouping were identified. The identified results of NMR showed that the serum level of C16 Sphinganine was lower while Dodemorph was higher in the EOC than those of the normal control. Compared to the cisplatin sensitive group, cisplatin resistant group exhibited a specific metabolic trait characterized by upregulation of 1-Monopalmitin, Ricinoleic acid methyl ester, Polyoxyethylene (600) mono-ricinoleate/Glycidyl stearate and downregulation of Calycanthidine. The four components were all associated with fatty acid metabolism, and the combinational diagnostic sensitivity of these biomarkers for cisplatin-resistance was 86.50% and the specificity was 81.80%, the area of receiver operating characteristic (ROC) curve was 0.93. Conclusions: The metabolic signatures of normal control, benign ovarian cyst, cisplatin sensitivity and cisplatin resistance can be clearly separated from each other by LC-MS/MS technology.The combinational four biomarkers including Calycanthidine, 1-Monopalmitin, Ricinoleic acid methl ester and Polyoxyethylene (600) mono-ricinoleate/Glycidyl stearate are more sensitive and specific for the diagnosis of cisplatin resistant EOC, and may provide the potentially predict markers of chemotherapeutic response in metabolic level. The fatty acid metabolism may participate in the cisplatin resistant progression of EOC.

Metabolomics identifies metabolite biomarkers associated with acute rejection after heart transplantation in rats

The aim of this study was to identify metabolite biomarkers associated with acute rejection after heart transplantation in rats using a LC-MS-based metabolomics approach. A model of heterotopic cardiac xenotransplantation was established in rats, with Wistar rats as donors and SD rats as recipients. Blood and cardiac samples were collected from blank control rats (Group A), rats 5 (Group B) and 7 days (Group C) after heart transplantation, and pretreated rats 5 (Group D) and 7 days (Group E) post-transplantation for pathological and metabolomics analyses. We assessed International Society for Heart and Lung Transplantation (ISHLT) grades 0, 3B, 4, 1 and 1 rejection in groups A to E. There were 15 differential metabolites between groups A and B, 14 differential metabolites between groups A and C, and 10 differential metabolites between groups B and C. In addition, four common differential metabolites, including D-tagatose, choline, C16 sphinganine and D-glutamine, were identified between on days 5 and 7 post-transplantation. Our findings demonstrate that the panel of D-tagatose, choline, C16 sphinganine and D-glutamine exhibits a high sensitivity and specificity for the early diagnosis of acute rejection after heart transplantation, and LC-MS-based metabolomics approach has a potential value for screening post-transplantation biomarkers.

Effects of breviscapine on amyloid beta 1-42 induced Alzheimer's disease mice: A HPLC-QTOF-MS based plasma metabonomics study.

Herba Erigerontis has long been used to cure apoplexy hemiplegia and precordial pain in China. In addition, the bioactivities of its total flavonoids-breviscapine included inhibiting amyloid beta (Aβ) fibril formation, antioxidation and metal chelating, which are beneficial to treat Alzheimer's disease (AD). Hence, A HPLC-QTOF-MS based plasma metabonomics approach was applied to investigate the neuroprotective effects of breviscapine on intracerebroventricular injection of aggregated Aβ 1-42 induced AD mice for the first time in the study. Ten potential biomarkers were screened out by multivariate statistical analysis, eight of which were further identified as indoleacrylic acid, C16 sphinganine, LPE (22:6), sulfolithocholic acid, LPC (16:0), PA (22:1/0:0), taurodeoxycholic acid, and PC (0:0/18:0). According to their metabolic pathways, it was supposed that breviscapine ameliorated the learning and memory deficits of AD mice predominantly by regulating phospholipids metabolism, elevating serotonin level and lowering cholesterols content in vivo.

Co-option of the sphingolipid metabolism for the production of nitroalkene defensive chemicals in termite soldiers

The aliphatic nitroalkene (E)-1-nitropentadec-1-ene (NPD), reported in early seventies in soldiers of the termite genus Prorhinotermes, was the first documented nitro compound produced by insects. Yet, its biosynthetic origin has long remained unknown. Here, we investigated in detail the biosynthesis of NPD in P. simplex soldiers. First, we track the dynamics in major metabolic pathways during soldier ontogeny, with emphasis on likely NPD precursors and intermediates. Second, we propose a hypothesis of NPD formation and verify its individual steps using in vivo incubations of putative precursors and intermediates. Third, we use a de novo assembled RNA-Seq profiles of workers and soldiers to identify putative enzymes underlying NPD formation. And fourth, we describe the caste- and age-specific expression dynamics of candidate initial genes of the proposed biosynthetic pathway.Our observations provide a strong support to the following biosynthetic scenario of NPD formation, representing an analogy of the sphingolipid pathway starting with the condensation of tetradecanoic acid with l-serine and leading to the formation of a C16 sphinganine. The C16 sphinganine is then oxidized at the terminal carbon to give rise to 2-amino-3-hydroxyhexadecanoic acid, further oxidized to 2-amino-3-oxohexadecanoic acid. Subsequent decarboxylation yields 1-aminopentadecan-2-one, which then proceeds through six-electron oxidation of the amino moiety to give rise to 1-nitropentadecan-2-one. Keto group reduction and hydroxyl moiety elimination lead to NPD. The proposed biosynthetic sequence has been constructed from age-related quantitative dynamics of individual intermediates and confirmed by the detection of labeled products downstream of the administered labeled intermediates. Comparative RNA-Seq analyses followed by qRT-PCR validation identified orthologs of serine palmitoyltransferase and 3-ketodihydrosphingosine reductase genes as highly expressed in the NPD production site, i.e. the frontal gland of soldiers. A dramatic onset of expression of the two genes in the first days of soldier's life coincides with the start of NPD biosynthesis, giving further support to the proposed biosynthetic hypothesis.

Metabolomic Responses of Human Hepatocytes to Emodin, Aristolochic Acid, and Triptolide: Chemicals Purified from Traditional Chinese Medicines.

The present study was undertaken to investigate the metabolic responses of human liver cells HL-7702 on chemicals purified from traditional Chinese medicine: emodin, triptolide, and aristolochic acid. Cytotoxicity tests demonstrated a dose-dependent toxic effect of emodin, triptolide, and aristolochic acid on HL7702 cells for 48 h. Emodin (14 μM), aristolochic acid (12 μg/mL), or triptolide (18 nM) was individually administrated to HL7702 and cell samples were collected after 48 h for metabolites extraction and analysis. Pattern recognition analysis reflected the significant difference in metabolic profiles between chemical-treated groups and the control group. Finally, eight metabolites including N1 -acetylspermidine, Glu Gly, N-undecanoylglycine, C16 sphinganine, sphinganine, glutathione, l-palmitoylcarnitine, and elaidic carnitine were detected as potential common biomarkers. Three pathways including sphinganine metabolism, fatty acid oxidation, and oxidative stress were identified. Our findings indicated that metabolomics would be an efficient approach to understand the molecular mechanism of hepatotoxicity induced by chemicals.

Identification of diagnostic biomarkers and metabolic pathway shifts of heat-stressed lactating dairy cows

Controlling heat stress (HS) is a global challenge for the dairy industry. However, simple and reliable biomarkers that aid the diagnoses of HS-induced metabolic disorders have not yet been identified. In this work, an integrated metabolomic and lipidomic approach using 1H nuclear magnetic resonance and ultra-fast LC–MS was employed to investigate the discrimination of plasma metabolic profiles between HS-free and HS lactating dairy cows. Targeted detection using LC–MS in multiple reaction monitoring mode was used to verify the reliability of the metabolites as biomarker candidates. Overall, 41 metabolites were identified as candidates for lactating dairy cows exposed to HS, among which 13 metabolites, including trimethylamine, glucose, lactate, betaine, creatine, pyruvate, acetoacetate, acetone, β-hydroxybutyrate, C16 sphinganine, lysophosphatidylcholine (18:0), phosphatidylcholine (16:0/14:0), and arachidonic acid, had high sensitivity and specificity in diagnosing HS status, and are likely to be the potential biomarkers of HS dairy cows. All of these potentially diagnostic biomarkers were involved in carbohydrate, amino acid, lipid, or gut microbiome-derived metabolism, indicating that HS affected the metabolic pathways in lactating dairy cows. Further research is warranted to evaluate these biomarkers in practical applications and to elucidate the physiological mechanisms of HS-induced metabolic disorders. Biological significanceHeat stress (HS) annually causes huge losses to global dairy industry, including animal performance decrease, metabolic disorder and health problem. So far, physiological mechanisms underlying HS of dairy cows still remain elusive. To our best knowledge, this is the first attempt to elucidate the HS-induced metabolic disorders of dairy cows using integrated 1H NMR and LC–MS-based metabolic study. The results not only provided potential diagnostic biomarkers for HS lactating dairy cows, but also significantly explored the related physiological mechanisms of metabolic pathway shifts induced by HS environment. This work offers comprehensive insights into the global metabolic alterations of dairy cows exposed to HS and provides a new perspective for further study.

A metabonomic analysis of the effect of quercetin on toxicity induced by chronic exposure to low-level dichlorvos in rat plasma.

A previous study of ours has reported that chronic exposure to low-level dichlorvos (DDVP, 7.2 mg per kg bw) damages the liver, interferes with fatty acid metabolism, and disturbs the antioxidant defense system in rats. This study aims to investigate whether or not quercetin can protect against DDVP-induced toxicity through metabonomics and to elucidate the mechanism underlying this protective effect. Rats were randomly assigned into the control group, DDVP-treated group, quercetin-treated group, and quercetin plus DDVP-treated group. DDVP and quercetin were administered to the rats daily via drinking water and gavage, respectively, continuously for 90 d. The metabonomic profiles of rat plasma were analyzed using ultra-performance liquid chromatography-mass spectrometry. Finally, 11 metabolites were identified, including those of quercetin, isorhamnetin, and quercetin-3-glucuronide. The 11 metabolites showed significant changes in some treatment groups compared with the control group. Arachidonic acid, phytosphingosine, and C16 sphinganine significantly decreased while p-cresol, lysoPE (16:0/0:0), lysoPC (15:0/0:0), lysoPC (16:0/0:0), lysoPC (0:0/18:0), and tryptophan significantly increased in the DDVP-treated group compared with the control group. The tendency of the aforementioned metabolites to change was significantly ameliorated in the high-dose quercetin (50 mg per kg bw per day) plus DDVP-treated group compared with the DDVP-treated group. However, the levels of these metabolites in the high-dose quercetin plus DDVP-treated group were still significantly different from those in the control group. The results indicate that high-dose quercetin (50 mg per kg bw per day) elicits a partial protective effect on DDVP-induced toxicity. The histopathology of the liver tissues was consistent with the above results. Quercetin demonstrated regulatory effects on the metabolism of lipids and amino acids, the antioxidant defense system, etc. Therefore, increasing the daily intake of quercetin can ameliorate the toxicity induced by chronic exposure to low-level DDVP residue in food and/or water.