Cell Membrane Metabolism Research Articles

Pre-fermentative supplementation of fatty acids alters the metabolic activity of wine yeasts

Fatty acids play important roles in the maintenance of cell membrane, viability and overall metabolism of wine yeasts (particularly Saccharomyces cerevisiae) during adverse winemaking conditions. We previously showed that linoleic acid supplementation markedly affect aroma compound production of S. cerevisiae wine strains. However, very little is known about how other commonly found fatty acids in grape juice modulate the growth and metabolism of S. cerevisiae. We aimed to determine the individual effect of five fatty acids on fermentation patterns and metabolism of two wine yeast strains (S. cerevisiae EC1118 and X5). Microvinification was performed at 15 °C by supplementing a grape juice (individually) with three different concentrations of saturated (palmitic acid), unsaturated (oleic, linoleic and γ-linolenic acids) and short-chain (hexanoic acid) fatty acids. Metabolite profiles of the resulting wines were determined using Gas-chromatography coupled to Mass-spectrometry (GC–MS). Our data show that the addition of γ-linolenic acid to the juice caused the production of higher amounts of amino and organic acids (except isoleucine and 2-oxoglutaric acid) in wines when fermented by EC1118, while palmitic acid supplementation showed similar trends when fermented by X5. The effect of linoleic acid was independent of yeast strains and we observed a global reduction of amino and organic acids (except pyruvic acid) while increased production of most of the fatty acids other than the supplemented ones. Our data clearly suggest that pre-fermentative supplementation of different fatty acids indeed influenced the growth and metabolism of wine yeasts in a different way. Thus, attention needs to be paid not only to the wine yeast strain used during the winemaking but also to the overall grape juice composition, including fatty acids, to obtain the desired wine characteristics.

Synthetic antimicrobial peptides delocalize membrane bound proteins thereby inducing a cell envelope stress response

BackgroundThree amphipathic cationic antimicrobial peptides (AMPs) were characterized by determining their effect on Gram-positive bacteria using Bacillus subtilis strain 168 as a model organism. These peptides were TC19 and TC84, derivatives of thrombocidin-1 (TC-1), the major AMPs of human blood platelets, and Bactericidal Peptide 2 (BP2), a synthetic designer peptide based on human bactericidal permeability increasing protein (BPI). MethodsTo elucidate the possible mode of action of the AMPs we performed a transcriptomic analysis using microarrays. Physiological analyses were performed using transmission electron microscopy (TEM), fluorescence microscopy and various B. subtilis mutants that produce essential membrane bound proteins fused to green fluorescent protein (GFP). ResultsThe transcriptome analysis showed that the AMPs induced a cell envelope stress response (cell membrane and cell wall). The cell membrane stress response was confirmed with the physiological observations that TC19, TC84 and BP2 perturb the membrane of B. subtilis. Using B. subtilis mutants, we established that the cell wall stress response is due to the delocalization of essential membrane bound proteins involved in cell wall synthesis. Other essential membrane proteins, involved in cell membrane synthesis and metabolism, were also delocalized due to alterations caused by the AMPs. ConclusionsWe showed that peptides TC19, TC84 and BP2 perturb the membrane causing essential proteins to delocalize, thus preventing the possible repair of the cell envelope after the initial interference with the membrane. General significanceThese AMPs show potential for eventual clinical application against Gram-positive bacterial cells and merit further application-oriented investigation.

PET-MRI Imaging of Cellular Trafficking of Lipid Metabolism and Its Association with Inflammatory and Genetic Markers in Breast Cancer

The tumour landscapes are varied, and depending on the orchestration of specific molecular pathways, signaling of its early manifestation could be understood. The conventional ways to signal the metabolic expression of cancers are notably via recognizing the altered glycolytic pathways in the cells whereby the transport of glucose is unchecked by the high demand of the ATP production by the cancer cells. It is notwithstanding that by relying on the glucose analogue (flurodeoxyglucose, FDG) signaling in cells, there are other cellular mechanism deemed to be explored, that is, the cell membrane or lipid metabolism. Molecular imaging–based nanoparticles are proving useful for cell trafficking studies, whereas radionuclide- and optical-based molecular–genetic reporters are yet to be determined. On the other hand, for receptor- or enzyme-based imaging or for studying the pharmacokinetic disposition of chemotherapeutic agents, the radionuclide-based techniques predominate. This review highlights the utility of the molecular imaging techniques in expressing the altered lipid metabolism, that is, choline transport in cells as an index of tumour aggressiveness in breast cancer.

Transcriptome Analysis of Maize Immature Embryos Reveals the Roles of Cysteine in Improving Agrobacterium Infection Efficiency.

Maize Agrobacterium-mediated transformation efficiency has been greatly improved in recent years. Antioxidants, such as, cysteine, can significantly improve maize transformation frequency through improving the Agrobacterium infection efficiency. However, the mechanism underlying the transformation improvement after cysteine exposure has not been elucidated. In this study, we showed that the addition of cysteine to the co-cultivation medium significantly increased the Agrobacterium infection efficiency of hybrid HiII and inbred line Z31 maize embryos. Reactive oxygen species contents were higher in embryos treated with cysteine than that without cysteine. We further investigated the mechanism behind cysteine-related infection efficiency increase using transcriptome analysis. The results showed that the cysteine treatment up-regulated 939 genes and down-regulated 549 genes in both Z31 and HiII. Additionally, more differentially expressed genes were found in HiII embryos than those in Z31 embryos, suggesting that HiII was more sensitive to the cysteine treatment than Z31. GO analysis showed that the up-regulated genes were mainly involved in the oxidation reduction process. The up-regulation of these genes could help maize embryos to cope with the oxidative stress stimulated by Agrobacterium infection. The down-regulated genes were mainly involved in the cell wall and membrane metabolism, such as, aquaporin and expansin genes. Decreased expression of these cell wall integrity genes could loosen the cell wall, thereby improving the entry of Agrobacterium into plant cells. This study offers insight into the role of cysteine in improving Agrobacterium-mediated transformation of maize immature embryos.

Clinical PET Imaging in Prostate Cancer.

Prostate cancer is the second most common cancer in men worldwide, with a wide spectrum of biologic behavior ranging from indolent low-risk disease to highly aggressive castration-resistant prostate cancer. Conventional imaging with computed tomography, magnetic resonance imaging, and bone scintigraphy is limited for the detection of nodal disease and distant bone metastases. In addition, advances in the available therapeutic options, both localized and systemic, drive the requirement for precise diagnostic and prognostic tools to refine the individual therapeutic approach at various times in the management of patients with prostate cancer. Positron emission tomography (PET) has a rapidly evolving role in the assessment of prostate cancer, particularly in the scenario of biochemical relapse. Fluorine 18 (18F) fluorodeoxyglucose, the most widely available PET tracer, has limitations, particularly in indolent prostate cancer. In the past decade, several PET tracers with specific molecular targets have reached the clinical domain. These tracers include 18F-sodium fluoride, which is a bone-specific biomarker of osteoblastic activity; 18F-choline and carbon 11-choline, which are directed at cell membrane metabolism; gallium 68-prostate-specific membrane antigen ligands; and, more recently, an amino acid analog, 18F-fluciclovine (anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid; also known as FACBC), which is also directed at cell membrane turnover. The mechanisms of actions of the clinically available PET tracers are reviewed, as well as their role in the imaging of prostate cancer with reference to relevant guidelines and the technical and imaging pearls and pitfalls of these tracers. ©RSNA, 2017.

Ultra-high-field magnetic resonance spectroscopy in non-alcoholic fatty liver disease: Novel mechanistic and diagnostic insights of energy metabolism in non-alcoholic steatohepatitis and advanced fibrosis.

Background & AimsWith the rising prevalence of non‐alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) non‐invasive tools obtaining pathomechanistic insights to improve risk stratification are urgently needed. We therefore explored high‐ and ultra‐high‐field magnetic resonance spectroscopy (MRS) to obtain novel mechanistic and diagnostic insights into alterations of hepatic lipid, cell membrane and energy metabolism across the spectrum of NAFLD.Methods MRS and liver biopsy were performed in 30 NAFLD patients with NAFL (n=8) or NASH (n=22). Hepatic lipid content and composition were measured using 3‐Tesla proton (1H)‐MRS. 7‐Tesla phosphorus (31P)‐MRS was applied to determine phosphomonoester (PME) including phosphoethanolamine (PE), phosphodiester (PDE) including glycerophosphocholine (GPC), phosphocreatine (PCr), nicotinamide adenine dinucleotide phosphate (NADPH), inorganic phosphate (Pi), γ‐ATP and total phosphorus (TP). Saturation transfer technique was used to quantify hepatic ATP flux.ResultsHepatic steatosis in 1H‐MRS highly correlated with histology (P<.001) showing higher values in NASH than NAFL (P<.001) without differences in saturated or unsaturated fatty acid indices. PE/TP ratio increased with advanced fibrosis (F3/4) (P=.002) whereas GPC/PME+PDE decreased (P=.05) compared to no/mild fibrosis (F0‐2). γ‐ATP/TP was lower in advanced fibrosis (P=.049), while PCr/TP increased (P=.01). NADPH/TP increased with higher grades of ballooning (P=.02). Pi‐to‐ATP exchange rate constant (P=.003) and ATP flux (P=.001) were lower in NASH than NAFL.ConclusionsUltra‐high‐field MRS, especially saturation transfer technique uncovers changes in energy metabolism including dynamic ATP flux in inflammation and fibrosis in NASH. Non‐invasive profiling by MRS appears feasible and may assist further mechanistic and therapeutic studies in NAFLD/NASH.

Technique of proton and phosphorous MR spectroscopy

Magnetic resonance spectroscopy (MRS) is an important non-invasive method that can reveal the concentration and spatial distribution of particular biochemically relevant tissue metabolites. Proton MRS is routinely applicable in the clinical setting providing good quality results even with a moderate magnetic field strength of 1.5 T. Relative values of metabolite concentrations are mostly used for the assessment of metabolic disorders. Absolute quantification of metabolites can be achieved by means of internal or external reference scans. Phosphorous MRS extends the range of detectable molecules to energy and cell membrane metabolism. The lower detection limit of metabolite concentrations is in the range of some mmol/kg. Depending on the magnetic field strength, MRS enables aspatial resolution of afew milliliters. The use of phosphorous MRS is considerably limited because higher field strengths of at least 3.0 T and additional expensive hardware for signal processing are required.

Natural Selection in Virulence Genes of Francisella tularensis.

A fundamental tenet of evolution is that alleles that are under negative selection are often deleterious and confer no evolutionary advantage. Negatively selected alleles are removed from the gene pool and are eventually extinguished from the population. Conversely, alleles under positive selection do confer an evolutionary advantage and lead to an increase in the overall fitness of the organism. These alleles increase in frequency until they eventually become fixed in the population. Francisella tularensis is a zoonotic pathogen and a potential biothreat agent. The most virulent type of F. tularensis, Type A, is distributed across North America with Type A.I occurring mainly in the east and Type A.II appearing mainly in the west. F. tularensis is thought to be a genome in decay (losing genes) because of the relatively large number of pseudogenes present in its genome. We hypothesized that the observed frequency of gene loss/pseudogenes may be an artifact of evolution in response to a changing environment, and that genes involved in virulence should be under strong positive selection. To test this hypothesis, we sequenced and compared whole genomes of Type A.I and A.II isolates. We analyzed a subset of virulence and housekeeping genes from several F. tularensis subspecies genomes to ascertain the presence and extent of positive selection. Eleven previously identified virulence genes were screened for positive selection along with 10 housekeeping genes. Analyses of selection yielded one housekeeping gene and 7 virulence genes which showed significant evidence of positive selection at loci implicated in cell surface structures and membrane proteins, metabolism and biosynthesis, transcription, translation and cell separation, and substrate binding and transport. Our results suggest that while the loss of functional genes through disuse could be accelerated by negative selection, the genome decay in Francisella could also be the byproduct of adaptive evolutiondriven by complex interactions between host, pathogen, and thier environment, as evidenced by several of its virulence genes which are undergoing strong, positive selection.

Abstract DL-1: Molecular Evolution Under Neoadjuvant Chemotherapy

Abstract In the NeoAva study, a randomized phaseII trial of Her2- breast cancer patients (n=132) neoadjuvantly treated with chemotherapy (FEC and taxane) with or without bevacizumab, serial biopsies were obtained; at time of diagnosis, at 12 weeks into treatment and at 25 weeks at surgical removal. High-throughput molecular analyses of DNA, mRNA, miRNA, metabolites using MR spectroscopy (HR-MAS) as well as proteins using RPPA of the serial samples were conducted. Pathological complete response (pCR) in breast and axilla was the primary clinical endpoint. The overall pCR rates were higher in the ER- tumors vs. ER+ tumors, (9 of 23) vs (12 of 109). Addition of bevacizumab seemed to improve pCR in the ER+ patient group (9 vs 3) and not in ER- patient group (5 vs 4). We studied the different molecular levels separately and combined in order to capture the changes during treatment of the two regimes and correlate the findings to response. Breast tumors are constituted of a number of subclonal populations. Some of these subclones will have stronger resistance to the applied treatment regime than others and will therefore constitute an increasing proportion of the tumor mass as treatment progresses, while sensitive populations will decline. Using the data from the different molecular levels, the subclonal architecture during treatment was evaluated. Clear subtype specific response to treatment was observed. Luminal A tumors showed a substantial change in gene expression during both treatment periods. In Luminal B and Basal-like tumors, changes were mainly evident during the first treatment period. Bevacizumab enhanced and accelerated the efficacy of chemotherapy in patients with ER+ tumors, and the effect was most evident in patients with Luminal B type. Tumors that achieved pCR showed a significant higher expression of genes enriched for immune response related pathways, compared to the tumors that did not achieve pCR in the ER- group, particularly in tumors from patients treated with chemotherapy combined with bevacizumab. Analyses of selected proteins showed bevacizumab induced changes in expression for several proteins during the treatment period. MR spectroscopy metabolic profiles at surgery successfully discriminated nonresponders from responders. Additionally, metabolic profiles reflected changes in all patient groups as an effect of chemotherapy. Changes during treatment in responders included reduced levels of choline containing metabolites (involved in cell membrane metabolism) and higher levels of glucose (indicating lower glucose consumption). A reduction of the antioxidant glutathione was associated with the administration of bevacizumab. Patients displayed substantial differences in observed tumor DNA alterations and tumor percentage over time. In most cases, tumors that retained aberrations at all time points did not increase in size. Signs of subclonal reduction were observed, with some aberrations disappearing and others being retained during treatment. These results highlight the importance of dissecting the tumor heterogeneity and molecular profile at all levels during tumor evolution under treatment. Even though sequential biopsies are invasive procedures, it could have major impact on patient prediction and prognosis. Citation Format: Børresen-Dale A-L. Molecular Evolution Under Neoadjuvant Chemotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr DL-1.

"Omics" of High Altitude Biology: A Urinary Metabolomics Biomarker Study of Rats Under Hypobaric Hypoxia.

High altitude medicine is an emerging subspecialty that has crosscutting relevance for 21(st) century science and society: from sports medicine and aerospace industry to urban and rural communities living in high altitude. Recreational travel to high altitude has also become increasingly popular. Rarely has the biology of high altitude biology been studied using systems sciences and omics high-throughput technologies. In the present study, 1H-NMR-based metabolomics, along with multivariate analyses, were employed in a preclinical rat model to characterize the urinary metabolome under hypobaric hypoxia stress. Rats were exposed to simulated altitude of 6700 m above the sea level. The urine samples were collected from pre- and post-exposure (1, 3, 7, and 14 days) of hypobaric hypoxia. Metabolomics urinalysis showed alterations in TCA cycle metabolites (citrate, α-ketoglutarate), cell membrane metabolism (choline), gut micro-flora metabolism (hippurate, phenylacetylglycine), and others (N-acetyl glutamate, creatine, taurine) in response to hypobaric hypoxia. Taurine, a potential biomarker of hepatic function, was elevated after 3 days of hypobaric hypoxia, which indicates altered liver functioning. Liver histopathology confirmed the damage to tissue architecture due to hypobaric hypoxia. The metabolic pathway analysis identified taurine metabolism and TCA as important pathways that might have contributed to hypobaric hypoxia-induced pathophysiology. This study demonstrates the use of metabolomics as a promising tool for discovery and understanding of novel biochemical responses to hypobaric hypoxia exposure, providing new insight in the field of high altitude medicine and the attendant health problems that occur in response to high altitude. The findings reported here also have potential relevance for sports medicine and aviation sciences.

Anatomical and Gene Expression Analyses of Two Blueberry Genotypes Displaying Differential Fruit Detachment

Fruit detachment in blueberry (Vaccinium sp.) may occur through the physiological process of abscission or through physical separation by breakage. Natural and induced fruit detachment through abscission occurs at the peduncle–pedicel junction (PPJ), while detachment through breakage typically occurs at the fruit–pedicel junction (FPJ). The ease of fruit detachment varies across blueberry genotypes, and a better understanding of such variation may allow for the development of genotypes better suited for hand and mechanical harvesting. TH-729 and ‘Suziblue’ are sibling southern highbush blueberry (hybrids composed largely of Vaccinium corymbosum and Vaccinium darrowi) genotypes derived from the same cross (‘Star’ × TH-474) and differ in their fruit detachment characteristics. Anatomical and molecular basis of the difference in fruit detachment between these genotypes was investigated in this study. Greater than 85% of the mature fruit of TH-729 detached at the PPJ in response to mechanical shaking in contrast to that observed in ‘Suziblue’, where greater than 90% of the fruit detached at the FPJ. The anatomy of the abscission zones (AZs) at the PPJ was similar between the two genotypes indicating that they did not differ in the establishment of the AZ. The fracture plane at the PPJ of manually detached fruit was more even in TH-729 compared with that in ‘Suziblue’, where many ruptured cells were evident. These data suggest advanced progression of abscission at the PPJ in TH-729 compared with that in ‘Suziblue’. The expression of 28 genes related to cell wall and membrane metabolism, phytohormone metabolism and signaling, and transcriptional regulation was compared between the two genotypes. Of these, two genes, ILL1 (iaa-leu resistant 1 like 3) and BIM1 (bes-interacting myc like1), associated with auxin metabolism and brassinosteroid signaling displayed over 3-fold and 1.5-fold higher transcript accumulation, respectively, in TH-729. Also, OPR1 (12-oxophytodienoate reductase), a gene associated with jasmonate (JA) biosynthesis, displayed 33% lower transcript levels in TH-729. As phytohormone signaling regulates the acquisition of competence for abscission, these data suggest that this phase of abscission progression at the PPJ differed between the two genotypes. Together, data from this study suggest inherent differences in the progression of abscission at the PPJ in blueberry. Such variation can be exploited to develop genotypes with desired harvesting characteristics.

The impact of phosphorus on the immune system and the intestinal microbiota with special focus on the pig.

There is increasing interest in dietary ingredients that are appropriate to support digestive and immune functions, but also maintain a stable microbial ecosystem in the gastrointestinal tract (GIT), particularly in weaned pigs. P is an essential nutrient for both microbes and their host, as it is involved, for example, in bone formation, energy metabolism, cellular signalling and stabilisation of cell membranes. Non-ruminant animals have limited access to phytate, the main storage form of P in plant seeds. The release of P bound to phytate requires phytase activity of plant or microbial origin, resulting in the formation of variable phosphorylated inositol phosphates (InsPs). The present review focuses on interactions between variations in dietary P supply, the immune system of the host, and the intestinal microbial ecosystem. Although results on the interaction between P and the immune system are inconsistent, several studies in different species have shown a positive impact of dietary P and phytase addition on the adaptive immune response. Recent studies with pigs suggest that P supply may influence intestinal microbial composition and activity. Individual InsPs or phosphate may also affect properties of pathogenic micro-organisms, such as metabolism or virulence. In conclusion, P may be considered as part of an integrated approach to support immune functions and maintain a stable microbial ecosystem in the GIT, thereby providing a barrier against potential pathogens. Within this regard, differences in phytate-P content and intrinsic phytase activity of plant feedstuffs, as well as the formation of individual InsPs, have to be taken into account.

Developmental Changes for the Hemolymph Metabolome of Silkworm (Bombyx mori L.).

Silkworm (Bombyx mori) is a lepidopteran-holometabolic model organism. To understand its developmental biochemistry, we characterized the larval hemolymph metabonome from the third instar to prepupa stage using (1)H NMR spectroscopy whilst hemolymph fatty acid composition using GC-FID/MS. We unambiguously assigned more than 60 metabolites, among which tyrosine-o-β-glucuronide, mesaconate, homocarnosine, and picolinate were reported for the first time from the silkworm hemolymph. Phosphorylcholine was the most abundant metabolite in all developmental stages with exception for the periods before the third and fourth molting. We also found obvious developmental dependence for the hemolymph metabonome involving multiple pathways including protein biosyntheses, glycolysis, TCA cycle, the metabolisms of choline amino acids, fatty acids, purines, and pyrimidines. Most hemolymph amino acids had two elevations during the feeding period of the fourth instar and prepupa stage. Trehalose was the major blood sugar before day 8 of the fifth instar, whereas glucose became the major blood sugar after spinning. C16:0, C18:0 and its unsaturated forms were dominant fatty acids in hemolymph. The developmental changes of hemolymph metabonome were associated with dietary nutrient intakes, biosyntheses of cell membrane, pigments, proteins, and energy metabolism. These findings offered essential biochemistry information in terms of the dynamic metabolic changes during silkworm development.

Rapamycin ameliorates brain metabolites alterations after transient focal ischemia in rats

Rapamycin has been shown to protect against middle cerebral artery occlusion (MCAo) induced ischemic injury. In this study, the neuroprotective effect of rapamycin on the metabolic changes induced by MCAo was evaluated using nuclear magnetic resonance (NMR) spectroscopy of brain tissues. MCAo in rats was induced by insertion of nylon filament. One hour after ischemia, rapamycin (250µg/kg, i.p.) in dimethyl sulfoxide was administered. Reperfusion was done 2h after ischemia. Twenty-four hours after ischemia phospholipase A2 (PLA2) levels and metabolic changes were assessed. Perchloric acid extraction was performed on the brain of all animals (n=7; sham, vehicle; DMSO and rapamycin 250µg/kg) and the various brain metabolites were assessed by NMR spectroscopy. In all 44 metabolites were assigned in the proton NMR spectrum of rat brain tissues. In the vehicle group, we observed increased lactate levels and decreased levels of glutamate/glutamine, choline containing compounds, creatine/phosphocreatine (Cr/PCr), taurine, myo-inositol, γ-amino butryic acid (GABA), N-aspartyl aspartate (NAA), purine and pyrimidine metabolites. In rapamycin treated rats, there was increase in the levels of choline containing compounds, NAA, myo-inositol, glutamate/glutamine, GABA, Cr/PCr and taurine as compared to those of vehicle control (P<0.05). Rapamycin treatment reduced PLA2 levels as compared to vehicle group (P<0.05). Our findings indicated that rapamycin reduced the increased PLA2 levels and altered brain metabolites after MCAo. These protective effects might be attributed to its effect on cell membrane metabolism; glutamate induced toxicity and calcium homeostasis in stroke.

PET/CT imaging in prostate cancer

Prostate cancer is the second most common male malignancy worldwide with a wide spectrum of biological behaviour ranging from fairly indolent disease to highly aggressive metastatic castrate resistant tumours. In the past decade there have been advances in therapies for treating advanced and recurrent prostate cancer and improved diagnostic/prognostic tools are required to refine the therapeutic approach at various stages in the management of prostate cancer patients. For tumour staging/lesion localisation multiparametric prostate MRI is the modality of choice. Several PET tracers are proving more sensitive than conventional imaging techniques for early detection of lymph node and bone metastases. However a general limitation of PET is the spatial resolution which limits the reliability for detection of small lesions. The use of F-18 fluoro-deoxyglucose (FDG) PET/CT in prostate cancer has been disappointing largely due to the fact that many prostate cancers have only low level glucose metabolism. C-11/F-18 choline, markers of cell membrane metabolism, are now widely used in Europe and in certain UK centres particularly in the scenario of biochemical relapse and high risk staging with equivocal findings on conventional work-up [1-3]. However, in cases of biochemical relapse with low PSA rise and low PSA velocity, choline PET has low detection rates [4]. Prostate specific membrane antigen (PSMA), a cell surface membrane glycoprotein, is a promising target for the diagnosis and treatment of prostate cancer. Recently Ga-68 radiolabelled ligand targeted to PSMA has been introduced to a few European centres. Early data suggests this may be more sensitive than choline PET/CT in patients with biochemical failure and low PSA [5-7]. In addition it offers the opportunity for Lu-177 or Y-90 targeted radionuclide therapy. F-18 sodium fluoride (NaF) is highly sensitive compared to bone scintigraphy with Tc99m labelled phosphates but only assess skeletal disease [8]. Other PET tracers being explored include C-11 acetate targeting lipogenesis, tracers radiolabelling bombesin and targeting gastrin-releasing peptide receptor (GRPR), amino acid transport with anti-1-amino-3-F18-fluorocyclobutane-1-carboxylic acid (FACBC ) and F-18-fluoro-5α-dihydrotestosterone (FDHT) targeting the androgen receptor [9,10]. This talk reviews the diagnostic utility of PET in prostate cancer.

Metabolic aberrations in fronto-parietal brain regions in recently detoxified alcohol dependent individuals: contribution to impaired abstract reasoning abilities

Event Abstract Back to Event Metabolic aberrations in fronto-parietal brain regions in recently detoxified alcohol dependent individuals: contribution to impaired abstract reasoning abilities Deepika Bagga1, Namita Singh1*, Subash Khushu1, Prabhjot Kaur2, Mohan Garg3 and Debajyoti Bhattacharya4 1 INMAS, NMR Research Centre, India 2 INMAS, India 3 Panjab University, India 4 Base Hospital, India Excessive alcohol consumption leads to a variety of neuropsychological deficits, most evident in higher order cognitive functions, such as abstract reasoning and problem solving. A recent fMRI study at our centre has shown the role of fronto-parietal network in abstract reasoning abilities.1 Considering this, we performed a 1H MRS study on frontal gyrus and superior parietal lobule in alcoholics to explore the yet largely unknown relationship between metabolic alterations and impaired abstract reasoning abilities. The study included 25 alcohol dependent subjects and 20 healthy subjects. MRS data was obtained with a single voxel (SVS) point resolved spectroscopy sequence (PRESS) (TR=3300ms, TE= 30ms, voxel size=10*10*10 mm, averages=256) with water suppression.Relative concentrations of N-acetylaspartate (NAA), choline (Cho), myo-inositol (mI) and glutamate-glutamine (Glx) were reported as ratios relative to creatine. A correlation analysis was performed between metabolic ratios and the response accuracy (obtained from our abstract reasoning based fMRI task).1 Results showed significant reductions in NAA/Cr and Glx/Cr whereas there was a significant increase in Cho/Cr and mI/Cr in both the brain regions. Reductions in NAA levels attributes to neuronal loss while reduced Glx levels may reflect perturbation of Glu-Gln system. Raised mI may reflect astrocyte proliferation whereas increased Cho ratios indicate altered cell membrane metabolism. A significant correlation was observed between the response accuracy and NAA/Cr and Cho/Cr ratios suggesting metabolic alterations underlie the poor performance.The neuronal compromise that these metabolic changes reflect may contribute to the abstract reasoning deficits in alcohol dependent subjects. Our study thus shows a possible relationship between altered metabolism and function in the fronto-parietal circuit in chronic alcoholism.

Selection and characterization of Cheonggukjang (fast fermented soybean paste)-originated bacterial strains with a high level of S-adenosyl-L-methionine production and probiotics efficacy.

This study was executed to develop probiotics producing S-adenosyl-L-methionine (SAMe), a methyl group donor in the 5-methyltetrahydrofolate methylation reaction in animal cells. SAMe is an essential substance in the synthesis, activation, and metabolism of hormones, neurotransmitters, nucleic acids, phospholipids, and cell membranes of animals. SAMe is also known as a nutritional supplement for improving human brain function. In this study, SAMe-producing strains were identified in six kinds of Cheonggukjang, and strains with excellent SAMe production were identified, with one strain in the Enterococcus genus and six strains in the Bacillus genus. Strains with a large amount of SAMe production included lactic acid bacteria, such as Enterococcus faecium, Enterococcus durans, and Enterococcus sanguinicola, as well as various strains in the Bacillus genus. The SAMe-overproducing strains showed antibacterial activity against some harmful microbes, in addition to weak acid resistance and strong bile resistance, indicating characteristics of probiotics. Cheonggukjang-originated beneficial bacterial strains overproducing SAMe may be commercially useful for manufacturing SAMe-rich foods.

Metabolomic strategy for the detection of metabolic effects of spermine supplementation in weaned rats.

The purpose of this study is to examine the effects of spermine supplementation on weaned rat metabolism. A metabolomic strategy employing high-resolution (1)H NMR spectroscopy and multivariate data analysis was used to investigate rat biological responses to spermine ingestion. Rats received intragastric administration of either 0.2 or 0.4 μmol/g body weight of spermine or saline for 3 days. Plasma samples taken 48 h after the last spermine ingestion were analyzed. Spermine supplementation significantly increased the plasma levels of 1-methylhistidine, 3-hydroxybutyrate, alanine, glutamate, glycerolphosphocholine, phosphorylcholine, myo-inositol, phenylalanine, lysine, glutamine, trimethylanine, tyrosine, valine, formate, glucose, and lipids. These results suggest that spermine ingestion can alter common systemic metabolic processes, including cell membrane metabolism, lipid metabolism, glucose-alanine cycle metabolism, amino acid metabolism, and gut microbiota metabolism. This study also shows the important role of spermine administration in modulating the metabolism of weaned rats.

Impaired visual information processing in alcohol-dependent subjects: a proton magnetic resonance spectroscopy study of the primary visual cortex.

Chronic alcoholism is associated with impaired cognitive abilities, with a more severe deficit in visual than in verbal functions. The visual processing deficits have classically been associated with impaired function of the visual cortex, located in the occipital lobe. The present study sought to increase current understanding of the impaired visual processing abilities in alcohol-dependent subjects and their correlation with metabolic aberrations in the occipital lobe using in vivo proton magnetic resonance spectroscopy (¹H MRS). To that end, ¹H MRS was carried out in the primary visual cortex on 35 alcohol-dependent subjects and 35 healthy controls. Neuropsychological tests for visual processing skills were performed on all the subjects, and the deficits were reported as raw dysfunction rating scores. The alcohol-dependent subjects showed a significant increase in choline/creatine (Cho/Cr) and myo-Inositol/creatine (mI/Cr) ratios, whereas N-acetyl-aspartate/creatine (NAA/Cr) and glutamate-glutamine/creatine (Glu-Gln)/Cr ratios were significantly decreased. Reductions in NAA levels might be attributed to neuronal loss, whereas reductions in Glu-Gln levels might reflect perturbation of the Glu-Gln system in alcohol-dependent individuals, which could represent a neuroprotective adaptation. Elevations in mI levels may reflect astrocyte proliferation as well as an osmotic response to cell shrinkage, whereas a significant increase in Cho levels indicates altered cell membrane metabolism. Also, a significant inverse correlation between NAA/Cr and raw dysfunction scores (rDyS) on the Nahor-Benson (NB) test and Glu-Gln/Cr with rDyS of the NB and the Bender-Gestalt (BG) test was observed, whereas a positive correlation between rDyS of the BG and the NB test and Cho/Cr was observed. The results suggest that metabolic alterations in the primary visual cortex may contribute to the neuropsychological impairment in visual information processing observed in alcohol-dependent subjects.

PET/CT imaging in cancer: current applications and future directions.

Positron emission tomography (PET) is a radiotracer imaging method that yields quantitative images of regional in vivo biology and biochemistry. PET, now used in conjunction with computed tomography (CT) in PET/CT devices, has had its greatest impact to date on cancer and is now an important part of oncologic clinical practice and translational cancer research. In this review of current applications and future directions for PET/CT in cancer, the authors first highlight the basic principles of PET followed by a discussion of the biochemistry and current clinical applications of the most commonly used PET imaging agent, (18) F-fluorodeoxyglucose (FDG). Then, emerging methods for PET imaging of other biologic processes relevant to cancer are reviewed, including cellular proliferation, tumor hypoxia, apoptosis, amino acid and cell membrane metabolism, and imaging of tumor receptors and other tumor-specific gene products. The focus of the review is on methods in current clinical practice as well as those that have been translated to patients and are currently in clinical trials.