PubMed

Related Articles Photosystem-II D1 protein mutants of Chlamydomonas reinhardtii in relation to metabolic rewiring and remodelling of H-bond network at QB site. Sci Rep. 2018 Oct 03;8(1):14745 Authors: Antonacci A, Lambreva MD, Margonelli A, Sobolev AP, Pastorelli S, Bertalan I, Johanningmeier U, Sobolev V, Samish I, Edelman M, Havurinne V, Tyystjärvi E, Giardi MT, Mattoo AK, Rea G Abstract Photosystem II (PSII) reaction centre D1 protein of oxygenic phototrophs is pivotal for sustaining photosynthesis. Also, it is targeted by herbicides and herbicide-resistant weeds harbour single amino acid substitutions in D1. Conservation of D1 primary structure is seminal in the photosynthetic performance in many diverse species. In this study, we analysed built-in and environmentally-induced (high temperature and high photon fluency - HT/HL) phenotypes of two D1 mutants of Chlamydomonas reinhardtii with Ala250Arg (A250R) and Ser264Lys (S264K) substitutions. Both mutations differentially affected efficiency of electron transport and oxygen production. In addition, targeted metabolomics revealed that the mutants undergo specific differences in primary and secondary metabolism, namely, amino acids, organic acids, pigments, NAD, xanthophylls and carotenes. Levels of lutein, β-carotene and zeaxanthin were in sync with their corresponding gene transcripts in response to HT/HL stress treatment in the parental (IL) and A250R strains. D1 structure analysis indicated that, among other effects, remodelling of H-bond network at the QB site might underpin the observed phenotypes. Thus, the D1 protein, in addition to being pivotal for efficient photosynthesis, may have a moonlighting role in rewiring of specific metabolic pathways, possibly involving retrograde signalling. PMID: 30283151 [PubMed - in process]

Related Articles Glycerophosphatidylcholine PC(36:1) absence and 3'-phosphoadenylate (pAp) accumulation are hallmarks of the human glioma metabolome. Sci Rep. 2018 Oct 03;8(1):14783 Authors: Li W, Jia H, Li Q, Cui J, Li R, Zou Z, Hong X Abstract Glioma is the most prevalent malignant brain tumor. A comprehensive analysis of the glioma metabolome is still lacking. This study aims to explore new special metabolites in glioma tissues. A non-targeted human glioma metabolomics was performed by UPLC-Q-TOF/MS. The gene expressions of 18 enzymes associated with 3'-phosphoadenylate (pAp) metabolism was examined by qRT-PCR. Those enzymes cover the primary metabolic pathway of pAp. We identified 15 new metabolites (13 lipids and 2 nucleotides) that were significantly different between the glioma and control tissues. Glycerophosphatidylcholine [PC(36:1)] content was high and pAp content was significantly low in the control brain (p  < 0.01). In glioma tissues, PC(36:1) was not detected and pAp content was significantly increased. The gene expressions of 3'-nucleotidases (Inositol monophosphatase (IMPAD-1) and 3'(2'),5'-bisphosphate nucleotidase 1(BPNT-1)) were dramatically down-regulated. Meanwhile, the gene expression of 8 sulfotransferases (SULT), 2 phosphoadenosine phosphosulfate synthases (PAPSS-1 and PAPSS-2) and L-aminoadipate-semialdehyde dehydrogenase-phosphopante-theinyl transferase (AASDHPPT) were up-regulated. PC(36:1) absence and pAp accumulation are the most noticeable metabolic aberration in glioma. The dramatic down-regulation of IMPAD-1 and BPNT-1 are the primary cause for pAp dramatic accumulation. Our findings suggest that differential metabolites discovered in glioma could be used as potentially novel therapeutic targets or diagnostic biomarkers and that abnormal metabolism of lipids and nucleotides play roles in the pathogenesis of glioma. PMID: 30283018 [PubMed - in process]

Related Articles Metabolomic Analyses Reveal Extensive Progenitor Cell Deficiencies in a Mouse Model of Duchenne Muscular Dystrophy. Metabolites. 2018 Oct 03;8(4): Authors: Joseph J, Cho DS, Doles JD Abstract Duchenne muscular dystrophy (DMD) is a musculoskeletal disorder that causes severe morbidity and reduced lifespan. Individuals with DMD have an X-linked mutation that impairs their ability to produce functional dystrophin protein in muscle. No cure exists for this disease and the few therapies that are available do not dramatically delay disease progression. Thus, there is a need to better understand the mechanisms underlying DMD which may ultimately lead to improved treatment options. The muscular dystrophy (MDX) mouse model is frequently used to explore DMD disease traits. Though some studies of metabolism in dystrophic mice exist, few have characterized metabolic profiles of supporting cells in the diseased environment. Using nontargeted metabolomics we characterized metabolic alterations in muscle satellite cells (SCs) and serum of MDX mice. Additionally, live-cell imaging revealed MDX-derived adipose progenitor cell (APC) defects. Finally, metabolomic studies revealed a striking elevation of acylcarnitines in MDX APCs, which we show can inhibit APC proliferation. Together, these studies highlight widespread metabolic alterations in multiple progenitor cell types and serum from MDX mice and implicate dystrophy-associated metabolite imbalances in APCs as a potential contributor to adipose tissue disequilibrium in DMD. PMID: 30282911 [PubMed]

Related Articles Exploring a Novel Screening Method for Patients with Oral Squamous Cell Carcinoma: A plasma Metabolomics Analysis. Kobe J Med Sci. 2018 Sep 11;64(1):E26-E35 Authors: Enomoto Y, Kimoto A, Suzuki H, Nishiumi S, Yoshida M, Komori T Abstract AIM: This study aimed to explore novel metabolite biomarker candidates for screening oral squamous cell carcinoma (OSCC). PATIENTS & METHODS: We collected plasma samples from 48 patients with OSCC and 29 with an oral disease and conducted a plasma metabolomics analysis of patients with OSCC using gas chromatography mass spectrometry. Then, we used the cross-validation procedure to ensure the accuracy of biomarker candidates. RESULTS: We selected four biomarker candidates against OSCC. Their sensitivity was more than 90%, and the AUC was over 0.9 according to the receiver operating characteristic curve analysis. CONCLUSIONS: The findings of this study suggest four potential metabolites as biomarkers for OSCC screening. PMID: 30282895 [PubMed - in process]

Related Articles Metabolic Profiling of the hippocampus of rats experiencing nicotine-withdrawal symptoms. Biol Pharm Bull. 2018 Oct 02;: Authors: Akimoto H, Oshima S, Michiyama Y, Negishi A, Nemoto T, Kobayashi D Abstract Nicotine-withdrawal symptoms have been indicated as a possible risk factor for neuropsychiatric events, such as depression and suicide, during use of smoking-cessation drugs. We aimed to investigate whether the results of the metabolomic analysis of the rat brain reflect nicotine-withdrawal symptoms. We also aimed to investigate the relative changes in each metabolite in the brains of rats with nicotine-withdrawal symptoms. We created rats experiencing nicotine-withdrawal symptoms through repeat administration of nicotine followed by a 12-h withdrawal period, and rats recovered from nicotine-withdrawal symptoms followed by an 18-h withdrawal period. We then implemented brain metabolic profiling by combining high-resolution magic-angle spinning 1H nuclear magnetic resonance (NMR) spectroscopy with partial least square discriminant analysis (PLS-DA). We found that metabolic profiling of the brain reflects the state during nicotine-withdrawal symptoms and the state after recovery from nicotine-withdrawal symptoms. Additionally, N-acetylaspartate and glutamate increased and aspartate, GABA, and creatine decreased in the hippocampus of rats experiencing nicotine-withdrawal symptoms. Therefore, it is suggested that neurogenesis and neuronal differentiation could be changed and abnormal energy metabolism could occur in the hippocampus during nicotine-withdrawal symptoms. PMID: 30282850 [PubMed - as supplied by publisher]

Related Articles The airway epithelium undergoes metabolic reprogramming in individuals at high risk for lung cancer. JCI Insight. 2016 11 17;1(19):e88814 Authors: Rahman SM, Ji X, Zimmerman LJ, Li M, Harris BK, Hoeksema MD, Trenary IA, Zou Y, Qian J, Slebos RJ, Beane J, Spira A, Shyr Y, Eisenberg R, Liebler DC, Young JD, Massion PP Abstract The molecular determinants of lung cancer risk remain largely unknown. Airway epithelial cells are prone to assault by risk factors and are considered to be the primary cell type involved in the field of cancerization. To investigate risk-associated changes in the bronchial epithelium proteome that may offer new insights into the molecular pathogenesis of lung cancer, proteins were identified in the airway epithelial cells of bronchial brushing specimens from risk-stratified individuals by shotgun proteomics. Differential expression of selected proteins was validated by parallel reaction monitoring mass spectrometry in an independent set of individual bronchial brushings. We identified 2,869 proteins, of which 312 proteins demonstrated a trend in expression. Pathway analysis revealed enrichment of carbohydrate metabolic enzymes in high-risk individuals. Glucose consumption and lactate production were increased in human bronchial epithelial BEAS2B cells treated with cigarette smoke condensate for 7 months. Increased lipid biosynthetic capacity and net reductive carboxylation were revealed by metabolic flux analyses of [U-13C5] glutamine in this in vitro model, suggesting profound metabolic reprogramming in the airway epithelium of high-risk individuals. These results provide a rationale for the development of potentially new chemopreventive strategies and selection of patients for surveillance programs. PMID: 27882349 [PubMed - indexed for MEDLINE]

Related Articles Temporal clustering analysis of endothelial cell gene expression following exposure to a conventional radiotherapy dose fraction using Gaussian process clustering. PLoS One. 2018;13(10):e0204960 Authors: Heinonen M, Milliat F, Benadjaoud MA, François A, Buard V, Tarlet G, d'Alché-Buc F, Guipaud O Abstract The vascular endothelium is considered as a key cell compartment for the response to ionizing radiation of normal tissues and tumors, and as a promising target to improve the differential effect of radiotherapy in the future. Following radiation exposure, the global endothelial cell response covers a wide range of gene, miRNA, protein and metabolite expression modifications. Changes occur at the transcriptional, translational and post-translational levels and impact cell phenotype as well as the microenvironment by the production and secretion of soluble factors such as reactive oxygen species, chemokines, cytokines and growth factors. These radiation-induced dynamic modifications of molecular networks may control the endothelial cell phenotype and govern recruitment of immune cells, stressing the importance of clearly understanding the mechanisms which underlie these temporal processes. A wide variety of time series data is commonly used in bioinformatics studies, including gene expression, protein concentrations and metabolomics data. The use of clustering of these data is still an unclear problem. Here, we introduce kernels between Gaussian processes modeling time series, and subsequently introduce a spectral clustering algorithm. We apply the methods to the study of human primary endothelial cells (HUVECs) exposed to a radiotherapy dose fraction (2 Gy). Time windows of differential expressions of 301 genes involved in key cellular processes such as angiogenesis, inflammation, apoptosis, immune response and protein kinase were determined from 12 hours to 3 weeks post-irradiation. Then, 43 temporal clusters corresponding to profiles of similar expressions, including 49 genes out of 301 initially measured, were generated according to the proposed method. Forty-seven transcription factors (TFs) responsible for the expression of clusters of genes were predicted from sequence regulatory elements using the MotifMap system. Their temporal profiles of occurrences were established and clustered. Dynamic network interactions and molecular pathways of TFs and differential genes were finally explored, revealing key node genes and putative important cellular processes involved in tissue infiltration by immune cells following exposure to a radiotherapy dose fraction. PMID: 30281653 [PubMed - in process]

Related Articles From Food for Survival to Food for Personalized Optimal Health: A Historical Perspective of How Food and Nutrition Gave Rise to Nutrigenomics. J Am Coll Nutr. 2018 Oct 03;:1-12 Authors: Sikalidis AK Abstract Human nutrition has progressed impressively from the hunter-gatherer mode to that of promising personalized nutrition for health optimization through advanced and sophisticated omics technologies. The contemporary major diseases, while having strong genetic components, do not conform to Mendelian genetics; hence, their expression/manifestation is not controlled by a single gene. Noncommunicable diseases such as obesity, cancer, type 2 diabetes mellitus, and cardiovascular disease are attributed to a series of chronic anomalies closely related to dietary, among other, environmental factors, and consistent deregulation of one or more groups of genes (polygenic). Collectively, these diseases constitute the main cause of death globally and pose tremendous financial burden on healthcare systems. Dietary interventions offer significant possibilities for cost-effective strategies to reduce risk of a series of metabolic diseases and/or improve the outcome of prognosis. In recent decades, the ability of particular nutrients to influence certain cellular functions as well as the regulation of several metabolic pathways via genomic interplay has been demonstrated. Nutrients can influence cellular responses and hence exert an effect on health parameters and outcomes. Several nutrients have been documented to extend their regulatory capacity at various levels including gene expression profile signatures' modulation. In addition, specific nutrients can modulate expression/activation of genes that encode regulatory hormones, which in turn are signaling agents strongly affecting metabolism and subsequently risk levels for certain metabolic diseases. The field of nutrigenomics attempts to revolutionize modern thinking on diet, food, and health; whether it will deliver is still an open matter of debate Key teaching points: A brief, yet comprehensive account on how food and nutrition evolved to give rise to nutrigenomics. Discusses potential of nutrigenomics for public health contribution in noncommunicable diseases. Debates credibility of nutrigenomics' commercial products versus the bio-hype in the field. Presents experts' and stakeholders' opinions for future directions of nutrigenomics. PMID: 30280996 [PubMed - as supplied by publisher]

Related Articles Arginine reprogramming in ADPKD results in arginine-dependent cystogenesis. Am J Physiol Renal Physiol. 2018 Oct 03;: Authors: Trott JF, Hwang VJ, Ishimaru T, Chmiel K, Zhou X, Shim K, Stewart B, Mahjoub MR, Jen KY, Barupal D, Li X, Weiss RH Abstract Research into metabolic reprogramming in cancer has become commonplace, yet this area of research has only recently come of age in nephrology. In light of the parallels between cancer and ADPKD, the latter is currently being studied as a metabolic disease. In clear cell renal cell carcinoma (RCC), which is now considered a metabolic disease, we and others have shown derangements in the enzyme arginosuccinate synthase (ASS1) resulting in RCC cells becoming auxotrophic for arginine and leading to a new therapeutic paradigm involving reducing extracellular arginine. Based on our earlier finding that glutamine pathways are reprogrammed in ARPKD, and given the connection between arginine and glutamine synthetic pathways via citrulline, we investigated the possibility of arginine reprogramming in ADPKD. We now show that, in a remarkable parallel to RCC, ASS1 expression is reduced in murine and human ADPKD, and arginine depletion results in a dose dependent compensatory increase in ASS1 levels as well as decreased cystogenesis in vitro and ex vivo with minimal toxicity to normal cells. Non-targeted metabolomics analysis of mouse kidney cell lines grown in arginine-deficient vs. arginine-replete media suggests arginine-dependent alterations in the glutamine and proline pathways. Thus, depletion of this conditionally-essential amino acid by dietary or pharmacological means, such as with arginine-degrading enzymes, may be a novel treatment for this disease. PMID: 30280600 [PubMed - as supplied by publisher]

Related Articles Combination Metabolomics Approach for Identifying Endogenous Substrates of Carnitine/Organic Cation Transporter OCTN1. Pharm Res. 2018 Oct 02;35(11):224 Authors: Masuo Y, Ohba Y, Yamada K, Al-Shammari AH, Seba N, Nakamichi N, Ogihara T, Kunishima M, Kato Y Abstract PURPOSE: Solute carrier SLC22A4 encodes the carnitine/organic cation transporter OCTN1 and is associated with inflammatory bowel disease, although little is known about how this gene is linked to pathogenesis. The aim of the present study was to identify endogenous substrates that are associated with gastrointestinal inflammation. METHODS: HEK293/OCTN1 and mock cells were incubated with colon extracts isolated from dextran sodium sulfate-induced colitis mice; the subsequent cell lysates were mixed with the amino group selective reagent 3-aminopyridyl-N-hydroxysuccinimidyl carbamate (APDS), to selectively label OCTN1 substrates. Precursor ion scanning against the fragment ion of APDS was then used to identify candidate OCTN1 substrates. RESULTS: Over 10,000 peaks were detected by precursor ion scanning; m/z 342 had a higher signal in HEK293/OCTN1 compared to mock cells. This peak was detected as a divalent ion that contained four APDS-derived fragments and was identified as spermine. Spermine concentration in peripheral blood mononuclear cells from octn1 gene knockout mice (octn1-/-) was significantly lower than in wild-type mice. Lipopolysaccharide-induced gene expression of inflammatory cytokines in peritoneal macrophages from octn1-/- mice was lower than in wild-type mice. CONCLUSIONS: The combination metabolomics approach can provide a novel tool to identify endogenous substrates of OCTN1. PMID: 30280275 [PubMed - in process]

Related Articles Metabolite quantification of faecal extracts from colorectal cancer patients and healthy controls. Oncotarget. 2018 Sep 07;9(70):33278-33289 Authors: Le Gall G, Guttula K, Kellingray L, Tett AJ, Ten Hoopen R, Kemsley KE, Savva GM, Ibrahim A, Narbad A Abstract Colorectal cancer (CRC), a primary cause of morbidity and mortality worldwide is expected to rise in the coming years. A better understanding of the metabolic changes taking place during the disease progression is needed for effective improvements of screening strategies and treatments. In the present study, Nuclear Magnetic Resonance (NMR) metabolomics was used to quantify the absolute concentrations of metabolites in faecal extracts from two cohorts of CRC patients and healthy controls. The quantification of over 80 compounds revealed that patients with CRC had increased faecal concentrations of branched chain fatty acids (BCFA), isovalerate and isobutyrate plus valerate and phenylacetate but diminished concentrations of amino acids, sugars, methanol and bile acids (deoxycholate, lithodeoxycholate and cholate). These results suggest that alterations in microbial activity and composition could have triggered an increase in utilisation of host intestinal slough cells and mucins and led to an increase in BCFA, valerate and phenylacetate. Concurrently, a general reduction in the microbial metabolic function may have led to reduced levels of other components (amino acids, sugars and bile acids) normally produced under healthy conditions. This study provides a thorough listing of the most abundant compounds found in human faecal waters and presents a template for absolute quantification of metabolites. The production of BCFA and phenylacetate in colonic carcinogenesis warrants further investigations. PMID: 30279959 [PubMed]

Related Articles A Non-Targeted LC-MS Profiling Reveals Elevated Levels of Carnitine Precursors and Trimethylated Compounds in the Cord Plasma of Pre-Eclamptic Infants. Sci Rep. 2018 Oct 02;8(1):14616 Authors: Jääskeläinen T, Kärkkäinen O, Jokkala J, Litonius K, Heinonen S, Auriola S, Lehtonen M, Hanhineva K, Laivuori H, FINNPEC Abstract Preeclampsia (PE) is a complex pregnancy disorder. It is not extensively known how the metabolic alterations of PE women contribute to the metabolism of newborn. We applied liquid chromatography-mass spectrometry (LC-MS) based non-targeted metabolomics to determine whether the metabolic profile of plasma from umbilical cord differs between infants born to PE and non-PE pregnancies in the FINNPEC study. Cord plasma was available from 42 newborns born from PE and 53 from non-PE pregnancies. 133 molecular features differed between PE and non-PE newborns after correction for multiple testing. Decreased levels of 4-pyridoxic acid were observed in the cord plasma samples of PE newborns when compared to non-PE newborns. Compounds representing following areas of metabolism were increased in the cord plasma of PE newborns: urea and creatine metabolism; carnitine biosynthesis and acylcarnitines; putrescine metabolites; tryptophan metabolism and phosphatidylcholines. To our knowledge, this study is the first one to apply LC-MS based metabolomics in cord plasma of PE newborns. We demonstrate that this strategy provides a global picture of the widespread metabolic alterations associated with PE and particularly the elevated levels of carnitine precursors and trimethylated compounds appear to be associated with PE at birth. PMID: 30279541 [PubMed - in process]

Related Articles Pyrophosphate inhibits gluconeogenesis by restricting UDP-glucose formation in vivo. Sci Rep. 2018 Oct 02;8(1):14696 Authors: Ferjani A, Kawade K, Asaoka M, Oikawa A, Okada T, Mochizuki A, Maeshima M, Hirai MY, Saito K, Tsukaya H Abstract Pyrophosphate (PPi) is produced by anabolic reactions and serves as an energy donor in the cytosol of plant cells; however, its accumulation to toxic levels disrupts several common biosynthetic pathways and is lethal. Before acquiring photosynthetic capacity, young seedlings must endure a short but critical heterotrophic period, during which they are nourished solely by sugar produced from seed reserves by the anabolic process of gluconeogenesis. Previously, we reported that excess PPi in H+-PPase-knockout fugu5 mutants of Arabidopsis thaliana severely compromised gluconeogenesis. However, the precise metabolic target of PPi inhibition in vivo remained elusive. Here, CE-TOF MS analyses of major metabolites characteristic of gluconeogenesis from seed lipids showed that the Glc6P;Fru6P level significantly increased and that Glc1P level was consistently somewhat higher in fugu5 compared to wild type. In contrast, the UDP-Glc level decreased significantly in the mutants. Importantly, specific removal of PPi in fugu5, and thus in AVP1pro:IPP1 transgenic lines, restored the Glc1P and the Glc6P;Fru6P levels, increased the UDP-Glc level ~2.0-fold, and subsequently increased sucrose synthesis. Given the reversible nature of the Glc1P/UDP-Glc reaction, our results indicate that UGP-Glc pyrophosphorylase is the major target when excess PPi exerts inhibitory effects in vivo. To validate our findings, we analyzed metabolite responses using a mathematical theory called structural sensitivity analysis (SSA), in which the responses of concentrations in reaction systems to perturbations in enzyme activity are determined from the structure of the network alone. A comparison of our experimental data with the results of pure structural theory predicted the existence of unknown reactions as the necessary condition for the above metabolic profiles, and confirmed the above results. Our data support the notion that H+-PPase plays a pivotal role in cytosolic PPi homeostasis in plant cells. We propose that the combination of metabolomics and SSA is powerful when seeking to identify and predict metabolic targets in living cells. PMID: 30279540 [PubMed - in process]

Related Articles Diagnostic value of plasma tryptophan and symmetric dimethylarginine levels for acute kidney injury among tacrolimus-treated kidney transplant patients by targeted metabolomics analysis. Sci Rep. 2018 Oct 02;8(1):14688 Authors: Zhang F, Wang Q, Xia T, Fu S, Tao X, Wen Y, Chan S, Gao S, Xiong X, Chen W Abstract Few literatures have evaluated the exact role of metabolomics in the identification process of potential biomarkers for acute kidney injury among the patients receiving renal transplantation. On top of this, the success of metabolomics in biomarker translation seems to lie in the robust quantitative method. As such, a single-center retrospective observational study was conducted enrolling 42 patients underwent renal transplantation with/without acute kidney injury, as well as 24 healthy volunteers, in Shanghai Changzheng Hospital. Plasma amino acid metabolic patterns for the participants were investigated by targeted UHPLC-MS/MS metabolic profiling. The most significant changes of the explored metabolites were related to the disturbance of tryptophan metabolism and arginine metabolism. Abnormal circulating tryptophan and symmetric dimethylarginine were identified to be potential biomarkers of acute kidney injury, combination of which showed a higher area under receiver-operator curve value (AUC = 0.901), improved sensitivity (0.889) and specificity (0.831) compared with creatinine only. Overall, these results revealed that targeted metabolomics analysis would be a potent and promising strategy for identification and pre-validation of biomarkers of acute kidney injury in renal transplantation patients. PMID: 30279519 [PubMed - in process]

Related Articles Renoprotective effect of Zhenwu decoction against renal fibrosis by regulation of oxidative damage and energy metabolism disorder. Sci Rep. 2018 Oct 02;8(1):14627 Authors: Li S, Xiao X, Han L, Wang Y, Luo G Abstract Zhenwu decoction (ZWD) is a promising traditional Chinese prescription against renal fibrosis, while its underlying mechanism remains unclear. Rat model of renal fibrosis were established and divided into control group, model group, ZWD treatment group and enalapril maleate treatment group. Metabolic profiles on serum samples from each group were acquired by using ultra performance liquid chromatography coupled with quadrupole time-of-flight high-resolution mass spectrometry. Metabolomics combined with molecular biology were comparatively conducted on samples of various groups. Fifteen potential biomarkers were identified and these biomarkers are mainly phospholipids and fatty acids. The results showed renal fibrosis was associated with oxidative damage and energy metabolism disorder. The results of histopathology, biochemistry and metabolomics demonstrated that ZWD exhibited an efficient renoprotective effect by alleviating oxidative stress, increasing energy metabolism and regulating fibrotic cytokines. This study provided scientific support for the research and development of new drugs from traditional Chinese medicine. PMID: 30279506 [PubMed - in process]

Related Articles Metabolic Alterations Associated with Atorvastatin/Fenofibric Acid Combination in Patients with Atherogenic Dyslipidaemia: A Randomized Trial for Comparison with Escalated-Dose Atorvastatin. Sci Rep. 2018 Oct 02;8(1):14642 Authors: Han JS, Kim K, Jung Y, Lee JH, Namgung J, Lee HY, Suh J, Hwang GS, Lee SH Abstract In the current study, the metabolic effects of atorvastatin dose escalation versus atorvastatin/fenofibric acid combination were compared using metabolomics analyses. Men and women with combined hyperlipidaemia were initially prescribed atorvastatin (10 mg, ≥4 weeks). Patients who reached low-density lipoprotein-cholesterol targets, but had triglyceride and high-density lipoprotein-cholesterol levels ≥150 mg/dL and <50 mg/dL, respectively, were randomized to receive atorvastatin 20 mg or atorvastatin 10 mg/fenofibric acid 135 mg for 12 weeks. Metabolite profiling of serum was performed and changes in metabolites after drug treatment in the two groups were compared. Analysis was performed using patients' samples obtained before and after treatment. Of 89 screened patients, 37 who met the inclusion criteria were randomized, and 34 completed the study. Unlike that in the dose-escalation group, distinct clustering of both lipid and aqueous metabolites was observed in the combination group after treatment. Most lipid metabolites of acylglycerols and many of ceramides decreased, while many of sphingomyelins increased in the combination group. Atorvastatin dose escalation modestly decreased lysophosphatidylcholines; however, the effect of combination therapy was variable. Most aqueous metabolites decreased, while L-carnitine remarkably increased in the combination group. In conclusion, the atorvastatin/fenofibric acid combination induced distinct metabolite clustering. Our results provide comprehensive information regarding metabolic changes beyond conventional lipid profiles for this combination therapy. PMID: 30279504 [PubMed - in process]

Related Articles Remodeling of the collagen matrix in aging skin promotes melanoma metastasis and affects immune cell motility. Cancer Discov. 2018 Oct 02;: Authors: Kaur A, Ecker BL, Douglass SM, Kugel CH, Webster MR, Almeida FV, Somasundaram R, Hayden J, Ban E, Ahmadzadeh H, Franco-Barraza J, Shah N, Mellis IA, Keeney F, Kossenkov A, Tang HY, Yin X, Liu Q, Xu X, Fane M, Brafford P, Herlyn M, Speicher DW, Wargo JA, Tetzlaff MT, Haydu LE, Raj A, Shenoy V, Cukierman E, Weeraratna AT Abstract Physical changes in skin are among the most visible signs of aging. We found that young dermal fibroblasts secrete high levels of extracellular matrix (ECM) constituents, including proteoglycans, glycoproteins and cartilage-linking proteins. The most abundantly secreted was HAPLN1, a hyaluronic and proteoglycan link protein. HAPLN1 was lost in aged fibroblasts, resulting in a more aligned ECM that promoted metastasis of melanoma cells. Reconstituting HAPLN1 inhibited metastasis in an aged microenvironment, in 3D skin reconstruction models, and in vivo. Intriguingly, aged fibroblast-derived matrices had the opposite effects on the migration of T-cells, inhibiting their motility. HAPLN1 treatment of aged fibroblasts restored motility of mononuclear immune cells, while impeding that of polymorphonuclear immune cells, which in turn affected Treg recruitment. These data suggest while age-related physical changes in the ECM can promote tumor cell motility, they may adversely impact the motility of some immune cells, resulting in an overall change in the immune microenvironment. Understanding the physical changes in aging skin may provide avenues for more effective therapy for older melanoma patients. PMID: 30279173 [PubMed - as supplied by publisher]

Related Articles Red blood cells as an organ? How deep omics characterization of the most abundant cell in the human body highlights other systemic metabolic functions beyond oxygen transport. Expert Rev Proteomics. 2018 Oct 02;: Authors: Nemkov T, Reisz JA, Xia Y, Zimring JC, D'Alessandro A Abstract INTRODUCTION: Recently, the classification of two "novel" organs, the mesentere and interstitium, was saluted as a scientific breakthrough and disseminated into mainstream media. The novelty of these findings did not pertain to the characterization of some previously unexplored phenomena, rather to the appreciation that well-established tissues may play some hitherto unexplored functions critical to system homeostasis. Areas covered: Here we provocatively comment on the potential classification of red blood cells - by far the most abundant host cell in the human body (~83% of the total cells) - as an organ involved in many functions beyond gas transport. In this perspective article, we describe some of these functions with a special emphasis on the role erythrocytes play with respect to systemic metabolic homeostasis. We thus focus on how these functions modulate the cross-talk of red blood cells among each other and with other cell types including immune cells. Expert commentary: The appreciation of RBCs as an organ impacting systemic metabolic homeostasis and other cell functions while engaging in complex metabolic activity beyond oxygen transport can foster the development of novel therapeutic interventions in pathologic hypoxemia, inflammation, neurodgenerative diseases, aging and cancer. PMID: 30278801 [PubMed - as supplied by publisher]

Related Articles Use of 5-azacytidine in a proof-of-concept study to evaluate the impact of pre-natal and post-natal exposures, as well as within generation persistent DNA methylation changes in Daphnia. Ecotoxicology. 2018 Jul;27(5):556-568 Authors: Athanasio CG, Sommer U, Viant MR, Chipman JK, Mirbahai L Abstract Short-term exposures at critical stages of development can lead to delayed adverse effects long after the initial stressor has been removed, a concept referred to as developmental origin of adult disease. This indicates that organisms' phenotypes may epigenetically reflect their past exposure history as well as reflecting chemicals currently present in their environment. This concept has significant implications for environmental monitoring. However, there is as yet little or no implementation of epigenetics in environmental risk assessment. In a proof-of-principle study we exposed Daphnia magna to 5-azacytidine, a known DNA de-methylating agent. Exposures covered combinations of prenatal and postnatal exposures as well as different exposure durations and recovery stages. Growth, the transcription of genes and levels of metabolites involved in regulating DNA methylation, and methylation levels of several genes were measured. Our data shows that prenatal exposures caused significant changes in the methylome of target genes, indicating that prenatal stages of Daphnia are also susceptible to same level of change as post-natal stages of Daphnia. While the combination of pre- and postnatal exposures caused the most extreme reduction in DNA methylation compared to the control group. Furthermore, some of the changes in the methylation patterns were persistent even after the initial stressor was removed. Our results suggest that epigenetic biomarkers have the potential to be used as indicators of past chemical exposure history of organisms and provide strong support for implementing changes to the current regimes for chemical risk assessment to mimic realistic environmental scenarios. PMID: 29623456 [PubMed - indexed for MEDLINE]

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