PubMed

Comparative analysis of the compatibility effects of Danggui-Sini Decoction on a blood stasis syndrome rat model using untargeted metabolomics. J Chromatogr B Analyt Technol Biomed Life Sci. 2018 Dec 22;1105:164-175 Authors: Wu JX, Zheng H, Yao X, Liu XW, Zhu HJ, Yin CL, Liu X, Mo YY, Huang HM, Cheng B, Wu F, Chen ZN, Song FM, Ruan JX, Zhang HY, Liu P, Liang YH, Song H, Guo HW, Su ZH Abstract Danggui-Sini Decoction (DSD) is one of the most widely used traditional Chinese medicine formulae (TCMF) for treating various diseases caused by cold coagulation and blood stasis due to its effect of nourishing blood to warm meridians in clinical use. However, studies of the mechanism of how it dispels blood stasis and its compatible regularity are challenging because of the complex pathophysiology of blood stasis syndrome (BSS) and the complexity of DSD, with multiple active ingredients acting on different targets. Observing variations of endogenous metabolites in rats with BSS after administering DSD may further our understanding of the mechanism of BSS and the compatible regularity of DSD. In this study, to understand the pathogenesis of BSS and assess the compatibility effects of DSD, an ultra-performance liquid chromatography quadrupole-time of flight mass spectrometry-based untargeted metabolomics approach was used. Serum metabolic profiles in rats with BSS that was induced by an ice water bath associated with subcutaneous injection of epinephrine hydrochloride were compared with the intervention groups which were administered with DSD or its compatibility. Using pattern recognition analysis, a clear separation between the BSS model and control group was observed; DSD and its compatibility intervention groups were clustered closer toward the control than the model group, which corroborates results of hemorheology studies. In addition, 20 metabolites were considered as potential biomarkers associated with the development of BSS. Nine metabolites were regulated by DSD in intervening blood stasis, they were considered to be correlated with the effect of nourishing blood to warm meridians. Additionally, the results suggested that the intervention effect of DSD on BSS may involve regulating four pathways, namely, arachidonic acid metabolism, glycerophospholipid metabolism, bile acid biosynthesis, and pyruvate metabolism. Moreover, each functional unit (monarch, minister, and assistant) in DSD regulates different metabolites and metabolic pathways to achieve different effects on dispelling blood stasis; however, their intervention efficacies are inferior to the holistic formula, which may be due to the synergism of the bioactive ingredients in seven herbs of DSD. This study demonstrated that metabolomics is a powerful tool for evaluating the efficacy and compatibility effects of traditional Chinese medicine (TCM). PMID: 30594827 [PubMed - as supplied by publisher]

Impact of Cr(VI) on the oxidation of polyunsaturated fatty acids in Helianthus annuus roots studied by metabolomic tools. Chemosphere. 2018 Dec 20;220:442-451 Authors: Gonzalez Ibarra AA, Wrobel K, Yanez Barrientos E, Corrales Escobosa AR, Gutierrez Corona JF, Enciso Donis I, Wrobel K Abstract The impact of Cr(VI) in sunflower roots has been studied, focusing on the oxidation of polyunsaturated fatty acids. Plants were grown hydroponically in the presence of 0, 1.0, 5.0 and 25 mgCr L-1. Methanolic root extracts were analyzed by capillary liquid chromatography coupled through negative electrospray ionization to a quadrupole-time of flight mass spectrometry (capHPLC-ESI-QTOF-MS). Using partial least squares algorithm, eighteen features strongly affected by Cr(VI) were detected and annotated as linoleic acid (LA), alpha-linolenic acid (ALA) and sixteen oxidation products containing hydroperoxy-, epoxy-, keto-, epoxyketo- or hydroxy-functionalities, all of them classified as oxylipins. Inspection of the MS/MS spectra acquired for features eluting at different retention times but assigned as a sole compound, confirmed isomers formation: three hydroperoxy-octadecadienoic acids (HpODE), two oxo-octadecadienoic acids (OxoODE) and four epoxyketo-octadecenoic acids (EKODE). Around 70% of metabolites in sunflower LA metabolic pathway were affected by Cr(VI) stress and additionally, four EKODE isomers not included in this pathway were found in the exposed roots. Among ALA-derived oxylipins, 13-epi-12-oxo-phytodienoic acid (OPDA) is of relevance, because of its participation in the activation of secondary metabolism. The abundances of all oxylipins were directly dependent on the Cr(VI) concentration in medium; furthermore, autooxidation of LA to HpODE isomers was observed after incubation with Cr(VI). These results point to the direct involvement of Cr(VI) in non-enzymatic oxidation of fatty acids; since oxylipins are signaling molecules important in plant defensive response, their synthesis under Cr(VI) exposure sustains the ability of sunflower to grow in Cr(VI)-contaminated environments. PMID: 30594795 [PubMed - as supplied by publisher]

Use of an integrated metabolomics platform for mechanistic investigations of three commonly used algaecides on cyanobacterium, Microcystis aeruginosa. J Hazard Mater. 2018 Dec 19;367:120-127 Authors: Zhang H, Meng G, Mao F, Li W, He Y, Gin KY, Ong CN Abstract Algal blooms are a global environmental and public health problem. Copper Sulfate (CuSO4), Hydrogen Peroxide (H2O2) and Sodium Carbonate Peroxide (SCP) are commonly used algaecides for algal bloom control. However, their efficacy and mechanisms of interaction with algae have not been well studied. This study aimed to compare their capability, and concurrently elucidate the metabolic responses of a common cyanobacterium, Microcystis aeruginosa. Algal responses were measured by cell density, chlorophyll a, toxin release and an integrated GC- and LC- Mass Spectrometry-Time of Flight metabolomics platform. CuSO4 was observed to kill the algae cells rapidly at relative low concentration, compared with the other two algaecides. However, it led to severe secondary contamination, with substantial release of various microcystins. Metabolomics data showed that a total of 32 metabolites were significantly changed compared with the controls. Most of the metabolites identified in CuSO4 treated algae were significantly reduced, whereas metabolites in algae treated with H2O2 and SCP were found to increase, and were of similar types. Although most of the metabolites identified for the three algaecides are associated to oxidative stress, the pathways affected appear to be different. PMID: 30594710 [PubMed - as supplied by publisher]

Integrative hepatic metabolomics and proteomics reveal insights into the mechanism of different feed efficiency with high or low dietary forage levels in Holstein heifers. J Proteomics. 2018 Dec 27;: Authors: Zhang J, Shi H, Li S, Cao Z, Yang H, Wang Y Abstract Feed efficiency (FE) can be affected by dietary composition, management, and metabolic conditions. The liver is the central metabolic organ in cattle; however, specific metabolic changes in the liver under different dietary forage levels have not been clarified. Therefore, this study aimed to investigate the hepatic physiology mechanisms of high or low dietary forage levels (80% or 20% forage, namely S80 and S20) on FE in dairy heifers using integrative metabolomic and proteomic methods. Feed efficiency was lower in the S80 group than the S20 group. A total of 29 metabolites and 60 proteins were significantly different between the liver samples of the two groups. Fourteen selected proteins were analyzed using parallel reaction monitoring to confirm the reliability of proteomic analysis. Integrative functional analysis of differentially expressed metabolites/proteins confirmed the enhanced hepatic ability of fatty acid oxidation, amino acid metabolism, pentose phosphate pathway, gluconeogenesis, ketone bodies synthesis, and oxidative stress defense in the S80 heifers. These metabolic pathways are associated with FE in ruminants. Thus, our results suggested that the aforementioned metabolic pathways may be responsible for the reduced FE in heifers fed high levels of forage. BIOLOGICAL SIGNIFICANCE: Improving the efficiency of animal production is a continuously urgent mission of all agricultural producers. Limit-feeding high concentrate diets to heifers is considered as an effective way to improve feed efficiency in heifers' raising, which can not only decrease the feeding and management cost but also relieve some environmental problems. However, the detailed metabolic and physiological changes and mechanisms associated with this strategy remain to be further characterized even some transcriptomics and microbiology work have been done. For extending the knowledge towards this strategy, an integrative metabolomic and proteomic method was used to investigate the hepatic physiology mechanisms of high or low dietary forage levels on feed efficiency in dairy heifers. Enhanced hepatic ability of fatty acid oxidation, amino acid metabolism, pentose phosphate pathway, gluconeogenesis, ketone bodies synthesis, and oxidative stress defense were found in high forage consumed in heifers, which were all related to energy utilization in ruminants and might be responsible for the reduced feed efficiency. Understanding the molecular mechanisms regulating the hepatic metabolism in high or low forage fed heifers may help to design alternative feeding or management strategies that improve feed efficiency. PMID: 30594576 [PubMed - as supplied by publisher]

Plasma mitochondrial DNA and metabolomic alterations in severe critical illness. Crit Care. 2018 Dec 29;22(1):360 Authors: Johansson PI, Nakahira K, Rogers AJ, McGeachie MJ, Baron RM, Fredenburgh LE, Harrington J, Choi AMK, Christopher KB Abstract BACKGROUND: Cell-free plasma mitochondrial DNA (mtDNA) levels are associated with endothelial dysfunction and differential outcomes in critical illness. A substantial alteration in metabolic homeostasis is commonly observed in severe critical illness. We hypothesized that metabolic profiles significantly differ between critically ill patients relative to their level of plasma mtDNA. METHODS: We performed a metabolomic study with biorepository plasma samples collected from 73 adults with systemic inflammatory response syndrome or sepsis at a single academic medical center. Patients were treated in a 20-bed medical ICU between 2008 and 2010. To identify key metabolites and metabolic pathways related to plasma NADH dehydrogenase 1 (ND1) mtDNA levels in critical illness, we first generated metabolomic data using gas and liquid chromatography-mass spectroscopy. We performed fold change analysis and volcano plot visualization based on false discovery rate-adjusted p values to evaluate the distribution of individual metabolite concentrations relative to ND1 mtDNA levels. We followed this by performing orthogonal partial least squares discriminant analysis to identify individual metabolites that discriminated ND1 mtDNA groups. We then interrogated the entire metabolomic profile using pathway overrepresentation analysis to identify groups of metabolite pathways that were different relative to ND1 mtDNA levels. RESULTS: Metabolomic profiles significantly differed in critically ill patients with ND1 mtDNA levels ≥ 3200 copies/μl plasma relative to those with an ND1 mtDNA level < 3200 copies/μl plasma. Several analytical strategies showed that patients with ND1 mtDNA levels ≥ 3200 copies/μl plasma had significant decreases in glycerophosphocholines and increases in short-chain acylcarnitines. CONCLUSIONS: Differential metabolic profiles during critical illness are associated with cell-free plasma ND1 mtDNA levels that are indicative of cell damage. Elevated plasma ND1 mtDNA levels are associated with decreases in glycerophosphocholines and increases in short-chain acylcarnitines that reflect phospholipid metabolism dysregulation and decreased mitochondrial function, respectively. PMID: 30594224 [PubMed - in process]

Related Articles TAp73 modifies metabolism and positively regulates growth of cancer stem-like cells in a redox-sensitive manner. Clin Cancer Res. 2018 Dec 28;: Authors: Sharif T, Dai C, Martell E, Saleh M, Hanes M, Murphy P, Kennedy B, Venugopal C, Subapanditha MK, Giacomantonio CA, Marcato P, Singh SK, Gujar S Abstract PURPOSE: Stem-like cancer cells, with characteristic self-renewal abilities, remain highly refractory to various clinical interventions. As such, stemness-inhibiting entities, such as tumor suppressor p53, are therapeutically pursued for their anti-cancer activities. Interestingly, similar implications for tumor suppressor TAp73 in regulating stemness features within stem-like cancer cells have remained unknown. EXPERIMENTAL DESIGN: This study utilizes various in vitro molecular biology techniques including; immunoblotting, qRT-PCR, and mass spectrometry-based proteomics and metabolomics approaches to study the role of TAp73 in human and murine embryonal carcinoma stem-like cells (ECSLCs) as well as human breast cancer stem-like cells (BCSLCs). These findings were confirmed using patient-derived brain tumor-initiating cells (BTICs) and in vivo xenograft models. RESULTS: TAp73 inhibition decreases the expression of stem cell transcription factors Oct4, Nanog and Sox-2, as well as tumorsphere formation capacity in ECSLCs. In vivo, TAp73-deficient ECSLCs and BCSLCs demonstrate decreased tumorigenic potential when xenografted in mice. Mechanistically, TAp73 modifies the proline regulatory axis through regulation of enzymes GLS, OAT and PYCR1 involved in the interconversion of proline-glutamine-ornithine. Further, TAp73 deficiency exacerbates glutamine-dependency, enhances accumulation of ROS through reduced SOD1 expression, and promotes differentiation by arresting cell cycle and elevating autophagy. Most importantly, the knockdown of TAp73 in CD133HI BTICs, separated from three different glioblastoma patients, strongly decreases the expression of pro-survival factors Sox-2, BMI-1 and SOD1, and profoundly decreases their self-renewal capacity as evidenced through their reduced tumorsphere formation ability. CONCLUSION: Collectively, we reveal a clinically relevant aspect of cancer cell growth and stemness regulation through TAp73-mediated redox-sensitive metabolic reprogramming. PMID: 30593514 [PubMed - as supplied by publisher]

Epigenetic events involved in OCT1-dependent impaired response of hepatocellular carcinoma to sorafenib. Br J Pharmacol. 2018 Dec 28;: Authors: Al-Abdulla R, Lozano E, Macias RIR, Monte MJ, Briz O, O'Rourke CJ, Serrano MA, Banales JM, Avila MA, Martinez-Chantar ML, Geier A, Andersen JB, Marin JJG Abstract BACKGROUND AND PURPOSE: In hepatocellular carcinoma (HCC), the expression of the human organic cation transporter-1 (hOCT1, gene SLC22A1) is reduced. The molecular bases of this phenotypic characteristic and the relationship with the poor response of HCC to sorafenib were investigated. EXPERIMENTAL APPROACH AND KEY RESULTS: hOCT1 over-expression in human hepatoma cells (HuH7 and HepG2) enhanced sorafenib, but not regorafenib, uptake in a quinine sensitive manner. The analysis of HCC transcriptomes (TCGA, n=366) showed reduced hOCT1 mRNA, which was inversely correlated with SLC22A1 promoter methylation. The demethylating agent decitabine enhanced hOCT1 expression in hepatoma cells. In clinical samples of HCC, determination of total and alternatively spliced hOCT1 mRNA transcripts revealed enhanced proportion of aberrant short variants. Six miRNAs highly expressed in HCC (TCGA) were identified by in silico analysis as candidates to target hOCT1 mRNA. When overexpressed in HepG2 cells a significant hOCT1 mRNA decay was induced only by hsa-mir-330 and hsa-mir-1468. Analysis of 39 paired samples from TCGA revealed that only hsa-mir-330 was consistently up-regulated in HCC. The expression of the orthologues mOct1 and rOct1 was reduced in spontaneously generated HCC in Fxr-/- mice and chemically induced HCC in rats, respectively. This resulted in impaired uptake of sorafenib (HPLC-MS/MS). In mice, sorafenib treatment efficiently inhibited the growth of subcutaneously implanted tumours only if these were generated by cells over-expressing hOCT1. CONCLUSION AND IMPLICATIONS: Impaired hOCT1 expression/function in HCC, which is due in part to epigenetic modifications, plays an important role in the poor pharmacological response of this cancer to sorafenib. PMID: 30592786 [PubMed - as supplied by publisher]

Discriminating high-risk cervical Human Papilloma Virus infections with urinary biomarkers via non-targeted GC-MS-based metabolomics. PLoS One. 2018;13(12):e0209936 Authors: Godoy-Vitorino F, Ortiz-Morales G, Romaguera J, Sanchez MM, Martinez-Ferrer M, Chorna N Abstract Genital human papillomavirus (HPV) is the world's most commonly diagnosed sexually transmitted infection, and high-risk HPV types are strongly linked to cervical dysplasia and carcinoma. Puerto Ricans are among the US citizens with higher HPV prevalence and lower screening rates and access to treatment. This bleak statistic was as a motivation to detect biomarkers for early diagnosis of HPV in this population. We collected both urine and cervical swabs from 43 patients attending San Juan Clinics. Cervical swabs were used for genomic DNA extractions and HPV genotyping with the HPV SPF10-LiPA25 kit, and gas chromatography-mass spectrometry (GC-MS) was employed on the urine-derived products for metabolomics analyses. We aimed at discriminating between patients with different HPV categories: HPV negative (HPV-), HPV positive with simultaneous low and high-risk infections (HPV+B) and HPV positive exclusively high-risk (HPV+H). We found that the metabolome of HPV+B is closer to HPV- than to HPV+H supporting evidence that suggests HPV co-infections may be antagonistic due to viral interference leading to a lower propensity for cervical cancer development. In contrast, metabolites of patients with HPV+H were significantly different from those that were HPV-. We identified three urinary metabolites 5-Oxoprolinate, Erythronic acid and N-Acetylaspartic acid that discriminate HPV+H cases from negative controls. These metabolites are known to be involved in a variety of biochemical processes related to energy and metabolism and may likely be biomarkers for HPV high-risk cervical infection. However, further validation should follow using a larger patient cohort and diverse populations to confirm our finding. PMID: 30592768 [PubMed - in process]

Tissue-specific metabolomics analysis identifies the liver as a major organ of metabolic disorders in amyloid precursor protein/presenilin 1 (APP/PS1) mice of Alzheimer's disease. J Proteome Res. 2018 Dec 28;: Authors: Zheng H, Cai A, Shu Q, Niu Y, Xu P, Li C, Lin L, Gao H Abstract Alzheimer's disease (AD) is regarded as a metabolic disorder and more attention has been paid to brain metabolism. However, AD may also affect metabolism in the peripheral organs beyond the brain. In this study, therefore, we investigated metabolic changes in the liver, kidney and heart of amyloid precursor protein/presenilin 1 (APP/PS1) mice at 1, 5 and 10 months of age by using 1H NMR-based metabolomics and chemometrics. Metabolomic results reveal that the liver was the earliest affected organ in APP/PS1 mice during amyloid pathology progression, followed by the kidney and heart. Moreover, a hypometabolic state was found in the liver of APP/PS1 mice at 5 months of age, and the disturbed metabolites were mainly involved in energy metabolism, amino acid metabolism, nucleic acid metabolism as well as ketone and fatty acid metabolism. In conclusion, our results suggest that AD is a systemic metabolic dysfunction and hepatic metabolic abnormality may reflect amyloid pathology progression. PMID: 30592618 [PubMed - as supplied by publisher]

Related Articles Targeted metabolomics of sulfated bile acids in urine for the diagnosis and grading of intrahepatic cholestasis of pregnancy. Genes Dis. 2018 Dec;5(4):358-366 Authors: Li Y, Zhang X, Chen J, Feng C, He Y, Shao Y, Ding M Abstract Intrahepatic cholestasis of pregnancy (ICP) is related to cholestatic disorder in pregnancy. Total urinary sulfated bile acids (SBAs) were found increased in ICP. We distinguished the metabolic profiling of urinary SBAs in ICP to find potential biomarkers for the diagnosis and grading of ICP. The targeted metabolomics based on high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was used to analyze urinary SBAs profiling in mild and severe ICP cases, as well as healthy controls. 16 kinds of urinary SBAs were determined by HPLC-MS/MS. Sulfated dihydroxy glycine bile acid (di-GBA-S), glycine cholic acid 3-sulfate (GCA-3S), sulfated dihydroxy taurine bile acid (di-TBA-S) and taurine cholic acid 3-sulfate (TCA-3S) increased significantly in ICP group compared with the control group. Seven kinds of SBAs were significantly different (p < 0.05) between the ICP group and the control group, with the variable importance in the projection (VIP) value more than one by the orthogonal partial least squares discriminant analysis (OPLS-DA). GCA-3S was well-suited to be used as the biomarker for the diagnosis of ICP with the sensitivity of 100% and specificity of 95.5%. A multi-variable logistic regression containing GCA-3S and di-GBA-S-1 was constructed to distinguish severe ICP from mild ICP, with the sensitivity of 94.4% and specificity of 100%. The developed HPLC-MS/MS method is suitable for the measurement of urinary SBAs profiling. Moreover, the urinary SBAs in the metabolomic profiling have the potential to be used as non-intrusive biomarkers for the diagnosis and grading of ICP. PMID: 30591938 [PubMed]

Related Articles Low-Field, Benchtop NMR Spectroscopy as a Potential Tool for Point-of-Care Diagnostics of Metabolic Conditions: Validation, Protocols and Computational Models. High Throughput. 2018 Dec 27;8(1): Authors: Percival BC, Grootveld M, Gibson M, Osman Y, Molinari M, Jafari F, Sahota T, Martin M, Casanova F, Mather ML, Edgar M, Masania J, Wilson PB Abstract Novel sensing technologies for liquid biopsies offer promising prospects for the early detection of metabolic conditions through omics techniques. Indeed, high-field nuclear magnetic resonance (NMR) facilities are routinely used for metabolomics investigations on a range of biofluids in order to rapidly recognise unusual metabolic patterns in patients suffering from a range of diseases. However, these techniques are restricted by the prohibitively large size and cost of such facilities, suggesting a possible role for smaller, low-field NMR instruments in biofluid analysis. Herein we describe selected biomolecule validation on a low-field benchtop NMR spectrometer (60 MHz), and present an associated protocol for the analysis of biofluids on compact NMR instruments. We successfully detect common markers of diabetic control at low-to-medium concentrations through optimised experiments, including α-glucose (≤2.8 mmol/L) and acetone (25 µmol/L), and additionally in readily accessible biofluids, particularly human urine. We present a combined protocol for the analysis of these biofluids with low-field NMR spectrometers for metabolomics applications, and offer a perspective on the future of this technique appealing to 'point-of-care' applications. PMID: 30591692 [PubMed]

Related Articles Metabolomics and Age-Related Macular Degeneration. Metabolites. 2018 Dec 27;9(1): Authors: Brown CN, Green BD, Thompson RB, den Hollander AI, Lengyel I, EYE-RISK consortium Abstract Age-related macular degeneration (AMD) leads to irreversible visual loss, therefore, early intervention is desirable, but due to its multifactorial nature, diagnosis of early disease might be challenging. Identification of early markers for disease development and progression is key for disease diagnosis. Suitable biomarkers can potentially provide opportunities for clinical intervention at a stage of the disease when irreversible changes are yet to take place. One of the most metabolically active tissues in the human body is the retina, making the use of hypothesis-free techniques, like metabolomics, to measure molecular changes in AMD appealing. Indeed, there is increasing evidence that metabolic dysfunction has an important role in the development and progression of AMD. Therefore, metabolomics appears to be an appropriate platform to investigate disease-associated biomarkers. In this review, we explored what is known about metabolic changes in the retina, in conjunction with the emerging literature in AMD metabolomics research. Methods for metabolic biomarker identification in the eye have also been discussed, including the use of tears, vitreous, and aqueous humor, as well as imaging methods, like fluorescence lifetime imaging, that could be translated into a clinical diagnostic tool with molecular level resolution. PMID: 30591665 [PubMed]

Related Articles Mechanism of Curcuma wenyujin Rhizoma on Acute Blood Stasis in Rats Based on a UPLC-Q/TOF-MS Metabolomics and Network Approach. Molecules. 2018 Dec 27;24(1): Authors: Hao M, Ji, Li L, Su L, Gu W, Gu L, Wang Q, Lu T, Mao C Abstract Rhizome of Curcuma wenyujin, which is called EZhu in China, is a traditional Chinese medicine used to treat blood stasis for many years. However, the underlying mechanism of EZhu is not clear at present. In this study, plasma metabolomics combined with network pharmacology were used to elucidate the therapeutic mechanism of EZhu in blood stasis from a metabolic perspective. The results showed that 26 potential metabolite markers of acute blood stasis were screened, and the levels were all reversed to different degrees by EZhu preadministration. Metabolic pathway analysis showed that the improvement of blood stasis by Curcuma wenyujin rhizome was mainly related to lipid metabolism (linoleic acid metabolism, ether lipid metabolism, sphingolipid metabolism, glycerophospholipid metabolism, and arachidonic acid metabolism) and amino acid metabolisms (tryptophan metabolism, lysine degradation). The component-target-pathway network showed that 68 target proteins were associated with 21 chemical components in EZhu. Five metabolic pathways of the network, including linoleic acid metabolism, sphingolipid metabolism, glycerolipid metabolism, arachidonic acid metabolism, and steroid hormone biosynthesis, were consistent with plasma metabolomics results. In conclusion, plasma metabolomics combined with network pharmacology can be helpful to clarify the mechanism of EZhu in improving blood stasis and to provide a literature basis for further research on the therapeutic mechanism of EZhu in clinical practice. PMID: 30591632 [PubMed - in process]

Related Articles Metabolomics-based Discovery of Serum Biomarkers to Predict the Side-effects of Neoadjuvant Chemoradiotherapy for Esophageal Squamous Cell Carcinoma. Anticancer Res. 2019 Jan;39(1):519-526 Authors: Nishiumi S, Fujigaki S, Kobayashi T, Kojima T, Ito Y, Daiko H, Kato K, Shoji H, Kodama Y, Honda K, Yoshida M Abstract BACKGROUND/AIM: Neoadjuvant chemoradiotherapy has side-effects that adversely affect patients' quality of life. The aim of this study was to identify serum metabolite biomarkers that might be used to predict the side-effects of neoadjuvant chemoradiotherapy for esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: Metabolomic analysis of serum samples from 26 patients with ESCC that were collected before neoadjuvant chemoradiotherapy was performed. The metabolites associated with hematological toxicity or nephrotoxicity were evaluated. RESULTS: Serum levels of glutaric acid, glucuronic acid, and cystine were significantly higher in hematological toxicity, and phosphatidylcholines and phosphatidylethanolamines exhibited a tendency to be higher in those with hematological toxicity. The serum level of pyruvic acid was significantly lower in nephrotoxicity, and lysophosphatidylcholines and lysophosphatidylethanolamines tended to be lower in those with nephrotoxicity. CONCLUSION: Our study found that serum levels of some metabolites differed significantly between patients with and without hematological or renal side-effects. These metabolites may be useful biomarkers for predicting hematological toxicity or nephrotoxicity after neoadjuvant chemoradiotherapy for ESCC. PMID: 30591504 [PubMed - in process]

Related Articles Identification of a natural inhibitor of methionine adenosyltransferase 2A regulating one-carbon metabolism in keratinocytes. EBioMedicine. 2018 Dec 24;: Authors: Bai J, Gao Y, Chen L, Yin Q, Lou F, Wang Z, Xu Z, Zhou H, Li Q, Cai W, Sun Y, Niu L, Wang H, Wei Z, Lu S, Zhou A, Zhang J, Wang H Abstract BACKGROUND: Psoriasis is a common chronic inflammatory skin disease which lacks effective strategies for the treatment. Natural compounds with biological activities are good tools to identify new targets with therapeutic potentials. Acetyl-11-keto-β-boswellic acid (AKBA) is the most bioactive ingredient of boswellic acids, a group of compounds with anti-inflammatory and anti-cancer properties. Target identification of AKBA and metabolomics analysis of psoriasis helped to elucidate the molecular mechanism underlying its effect, and provide new target(s) to treat the disease. METHODS: To explore the targets and molecular mechanism of AKBA, we performed affinity purification, metabolomics analysis of HaCaT cells treated with AKBA, and epidermis of imiquimod (IMQ) induced mouse model of psoriasis and psoriasis patients. FINDINGS: AKBA directly interacts with methionine adenosyltransferase 2A (MAT2A), inhibited its enzyme activity, decreased level of S-adenosylmethionine (SAM) and SAM/SAH ratio, and reprogrammed one‑carbon metabolism in HaCaT cells. Untargeted metabolomics of epidermis showed one‑carbon metabolism was activated in psoriasis patients. Topical use of AKBA improved inflammatory phenotype of IMQ induced psoriasis-like mouse model. Molecular docking and site-directed mutagenesis revealed AKBA bound to an allosteric site at the interface of MAT2A dimer. INTERPRETATION: Our study extends the molecular mechanism of AKBA by revealing a new interacting protein MAT2A. And this leads us to find out the dysregulated one‑carbon metabolism in psoriasis, which indicates the therapeutic potential of AKBA in psoriasis. FUND: The National Natural Science Foundation, the National Program on Key Basic Research Project, the Shanghai Municipal Commission, the Leading Academic Discipline Project of the Shanghai Municipal Education Commission. PMID: 30591370 [PubMed - as supplied by publisher]

Related Articles Transcriptomics and metabonomics analyses of maternal DEHP exposure on male offspring. Environ Sci Pollut Res Int. 2018 Sep;25(26):26322-26329 Authors: Zhang Y, Zhang W, Fu X, Zhou F, Yu H, Na X Abstract The objectives of this study were to evaluate the effect of maternal Di-2-ethylhexyl phthalate (DEHP) exposure on male offspring and to explore the mechanism of changes with the metabolic alterations and differential genes. Pregnant female Sprague-Dawley (SD) rats were intragastrically administered with 600 mg/kg body weight of DEHP or corn oil (CON) throughout pregnancy and lactation. The growth of male offspring was investigated until 14 weeks old, the indices of blood were detected, and mechanism was studied using metabonomics and transcriptomics. Compared with the CON group, body weight, body length, food intake, body fat weight, Lee's index, organ coefficient, blood lipids, and oral glucose tolerance test (OGTT) of male offspring were not significantly changed in maternal DEHP group. However, serum biochemical indexes such as alanine transaminase (ALT), total protein (TP), albumin (ALB), blood urea nitrogen (BUN), and creatinine (CREA) were markedly reduced in maternal DEHP group (p < 0.05). In addition, insulin level was elevated and catalase (CAT) level was decreased notably in maternal DEHP group compared with the CON group (p < 0.05). Furthermore, thyroxine (T4) level was lower and thyroid stimulating hormone (TSH) level was higher in maternal DEHP group (p < 0.05). Metabonomics revealed seven principal metabolites were identified, including increased L-allothreonine, creatine, uric acid, retinyl ester, L-palmitoylcarnitine, and decreased glycocholic acid and LysoPC (18:3). Transcriptomics displayed 35 differential genes were involved in the mechanism of maternal DEHP exposure. Therefore, this research confirms the effect of a certain dose of maternal DEHP exposure on male offspring and understands exactly the mechanism of these changes with metabonomics and transcriptomics. PMID: 29978319 [PubMed - indexed for MEDLINE]

Bayesian inference of networks across multiple sample groups and data types. Biostatistics. 2018 Dec 26;: Authors: Shaddox E, Peterson CB, Stingo FC, Hanania NA, Cruickshank-Quinn C, Kechris K, Bowler R, Vannucci M Abstract In this article, we develop a graphical modeling framework for the inference of networks across multiple sample groups and data types. In medical studies, this setting arises whenever a set of subjects, which may be heterogeneous due to differing disease stage or subtype, is profiled across multiple platforms, such as metabolomics, proteomics, or transcriptomics data. Our proposed Bayesian hierarchical model first links the network structures within each platform using a Markov random field prior to relate edge selection across sample groups, and then links the network similarity parameters across platforms. This enables joint estimation in a flexible manner, as we make no assumptions on the directionality of influence across the data types or the extent of network similarity across the sample groups and platforms. In addition, our model formulation allows the number of variables and number of subjects to differ across the data types, and only requires that we have data for the same set of groups. We illustrate the proposed approach through both simulation studies and an application to gene expression levels and metabolite abundances on subjects with varying severity levels of chronic obstructive pulmonary disease. Bayesian inference; Chronic obstructive pulmonary disease (COPD); Data integration; Gaussian graphical model; Markov random field prior; Spike and slab prior. PMID: 30590505 [PubMed - as supplied by publisher]

An alternative to mineral phosphorus fertilizers: The combined effects of Trichoderma harzianum and compost on Zea mays, as revealed by 1H NMR and GC-MS metabolomics. PLoS One. 2018;13(12):e0209664 Authors: Vinci G, Cozzolino V, Mazzei P, Monda H, Spaccini R, Piccolo A Abstract The ability of Trichoderma harzianum (strain OMG-08) as plant growth promoting fungus (PGPF), was tested on Zea mays plants grown in soil pots added with different inorganic (triple superphosphate and rock phosphate) and organic (cow and horse manure composts) P fertilizers. The effect of treatments was evaluated by following the variations of plants dry biomass and nutrient content, as well as the metabolic changes in plant leaves by both GC-MS and NMR spectroscopy. A synergic effect was observed in treatments with both composts and fungus inoculation, in which not only plant growth and P uptake were enhanced, but also the expression of different metabolites related to an improved photosynthetic activity. Conversely, the combination of Trichoderma with inorganic fertilizers was less effective and even showed a reduction of plants shoot biomass and N content. The corresponding plant metabolome revealed metabolic compounds typical of biotic or abiotic stresses, which may be attributed to a reduced capacity of inorganic fertilizers to provide a sufficient P availability during plant growth. Our findings also indicate that the molecular composition of compost differentiated the Trichoderma activity in sustaining plant growth. The positive effects of the combined Trichoderma and compost treatment suggest that it may become an alternative to the phosphorus mineral fertilization. PMID: 30589863 [PubMed - in process]

Related Articles Revealing Different Lung Metastatic Potentials Induced Metabolic Alterations of Hepatocellular Carcinoma Cells via Proton Nuclear Magnetic Resonance Spectroscopy. J Cancer. 2018;9(24):4696-4705 Authors: Chen Y, Lin D, Chen Z, Feng J, Liao N Abstract Background: Hepatocellular carcinoma (HCC) causes death mainly by disseminated metastasis progression and major challenge of clinical management is to distinguish lethal metastatic stage from indolent stage. It is shown that metastatic progression is closely related to cellular metabolism. But detailed metabolic alterations and molecular mechanisms still kept unclear between subtypes of different lung metastatic potentials. Methods: The current work used NMR-based metabolomics in the study of HCC cells with high malignancy but differed in lung metastatic potentials. Cell extracts and cultured media from MHCC97L and MHCC97H were utilized to reveal metabolic alterations related to metastatic potentials. Multivariate analyses were performed to identify characteristic metabolites which were used subsequently to draw the map of relative biochemical pathways by combining KEGG database. Results: The NMR spectra of both MHCC97L and MHCC97H include various signals from necessary nutritional components and metabolic intermediates. A series of characteristic metabolites were determined from both cell extracts and media. The ability on nutrient uptake varied from cell lines. Most of amino acids decreased in high metastatic cell line, so altered amino acid metabolisms and energy metabolism were revealed in high metastatic MHCC97H cell line. The majority pathways involved six essential amino acids in which the observed branched-chain amino acids together with lysine contributed to biosynthesis or degradation. Basically MHCC97H cell line could induce more active events than that of MHCC97L to progress to high metastasis with certain molecular events. Characteristic metabolites-derived classifiers performed robustly during prediction and confirmed their critical role in supporting metastasis progression. Conclusions: Our results provide evidence that NMR-metabolomics analyses of cells are able to understand metastatic characteristics accountable for biological properties. The proposed characteristic metabolites will help to understand HCC metastatic characterizations and may be filtered as potential biomarkers. PMID: 30588254 [PubMed]

Related Articles Analysis of repeated leukocyte DNA methylation assessments reveals persistent epigenetic alterations after an incident myocardial infarction. Clin Epigenetics. 2018 Dec 27;10(1):161 Authors: Ward-Caviness CK, Agha G, Chen BH, Pfeiffer L, Wilson R, Wolf P, Gieger C, Schwartz J, Vokonas PS, Hou L, Just AC, Bandinelli S, Hernandez DG, Singleton AB, Prokisch H, Meitinger T, Kastenmüller G, Ferrucci L, Baccarelli AA, Waldenberger M, Peters A Abstract BACKGROUND: Most research into myocardial infarctions (MIs) have focused on preventative efforts. For survivors, the occurrence of an MI represents a major clinical event that can have long-lasting consequences. There has been little to no research into the molecular changes that can occur as a result of an incident MI. Here, we use three cohorts to identify epigenetic changes that are indicative of an incident MI and their association with gene expression and metabolomics. RESULTS: Using paired samples from the KORA cohort, we screened for DNA methylation loci (CpGs) whose change in methylation is potentially indicative of the occurrence of an incident MI between the baseline and follow-up exams. We used paired samples from the NAS cohort to identify 11 CpGs which were predictive in an independent cohort. After removing two CpGs associated with medication usage, we were left with an "epigenetic fingerprint" of MI composed of nine CpGs. We tested this fingerprint in the InCHIANTI cohort where it moderately discriminated incident MI occurrence (AUC = 0.61, P = 6.5 × 10-3). Returning to KORA, we associated the epigenetic fingerprint loci with cis-gene expression and integrated it into a gene expression-metabolomic network, which revealed links between the epigenetic fingerprint CpGs and branched chain amino acid (BCAA) metabolism. CONCLUSIONS: There are significant changes in DNA methylation after an incident MI. Nine of these CpGs show consistent changes in multiple cohorts, significantly discriminate MI in independent cohorts, and were independent of medication usage. Integration with gene expression and metabolomics data indicates a link between MI-associated epigenetic changes and BCAA metabolism. PMID: 30587240 [PubMed - in process]