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Sample records for ceramide pathway metagene

  1. Assessment of an RNA interference screen-derived mitotic and ceramide pathway metagene as a predictor of response to neoadjuvant paclitaxel for primary triple-negative breast cancer: a retrospective analysis of five clinical trials

    DEFF Research Database (Denmark)

    Juul, Nicolai Stefan; Szallasi, Zoltan Imre; Eklund, Aron Charles;

    2010-01-01

    )/progesterone-receptor (PR)/human epidermal growth factor receptor 2 (HER2; ERBB2)-negative (triple-negative) disease who do not achieve a pCR. Reliable identification of such patients is the first step in determining who might benefit from alternative treatment regimens in clinical trials. We previously identified genes......Addition of taxanes to preoperative chemotherapy in breast cancer increases the proportion of patients who have a pathological complete response (pCR). However, a substantial proportion of patients do not respond, and the prognosis is particularly poor for patients with oestrogen-receptor (ER...... involved in mitosis or ceramide metabolism that influenced sensitivity to paclitaxel, with an RNA interference (RNAi) screen in three cancer cell lines, including a triple-negative breast-cancer cell line. Here, we assess these genes as a predictor of pCR to paclitaxel combination chemotherapy in triple...

  2. A novel pathway of ceramide metabolism in Saccharomyces cerevisiae

    DEFF Research Database (Denmark)

    Voynova, Natalia S; Vionnet, Christine; Ejsing, Christer S.;

    2012-01-01

    be monitored using fluorescent NBD (7-nitrobenz-2-oxa-1,3-diazole) ceramides as an acceptor substrate for microsomal assays. The Lro1p-dependent transfer of oleic acid on to NBD ceramide was confirmed by high-resolution Fourier transform and tandem MS. Immunopurified Lro1p was equally able to acylate...... NBD ceramide. Lro1p acylates NBD ceramide by attaching a fatty acid to the hydroxy group on the first carbon atom of the long-chain base. Acylceramides are mobilized when cells are diluted into fresh medium in the presence of cerulenin, an inhibitor of fatty acid biosynthesis....

  3. Alterations of the Ceramide Metabolism in the Peri-Infarct Cortex Are Independent of the Sphingomyelinase Pathway and Not Influenced by the Acid Sphingomyelinase Inhibitor Fluoxetine

    OpenAIRE

    Brunkhorst, R.; Friedlaender, F.; Ferreirós, N.; Schwalm, S.; Koch, A.; Grammatikos, G.; Toennes, S.; Foerch, C; Pfeilschifter, J.; Pfeilschifter, W.

    2015-01-01

    Ceramides induce important intracellular signaling pathways, modulating proliferation, migration, apoptosis, and inflammation. However, the relevance of the ceramide metabolism in the reconvalescence phase after stroke is unclear. Besides its well-known property as a selective serotonin reuptake inhibitor, fluoxetine has been reported to inhibit the acid sphingomyelinase (ASM), a key regulator of ceramide levels which derives ceramide from sphingomyelin. Furthermore, fluoxetine has shown ther...

  4. Clathrin-dependent pathways and the cytoskeleton network are involved in ceramide endocytosis by a parasitic protozoan, Giardia lamblia.

    Science.gov (United States)

    Hernandez, Yunuen; Castillo, Cynthia; Roychowdhury, Sukla; Hehl, Adrian; Aley, Stephen B; Das, Siddhartha

    2007-01-01

    Although identified as an early-diverged protozoan, Giardia lamblia shares many similarities with higher eukaryotic cells, including an internal membrane system and cytoskeleton, as well as secretory pathways. However, unlike many other eukaryotes, Giardia does not synthesize lipids de novo, but rather depends on exogenous sources for both energy production and organelle or membrane biogenesis. It is not known how lipid molecules are taken up by this parasite and if endocytic pathways are involved in this process. In this investigation, we tested the hypothesis that highly regulated and selective lipid transport machinery is present in Giardia and necessary for the efficient internalization and intracellular targeting of ceramide molecules, the major sphingolipid precursor. Using metabolic and pathway inhibitors, we demonstrate that ceramide is internalized through endocytic pathways and is primarily targeted into perinuclear/endoplasmic reticulum membranes. Further investigations suggested that Giardia uses both clathrin-dependent pathways and the actin cytoskeleton for ceramide uptake, as well as microtubule filaments for intracellular localization and targeting. We speculate that this parasitic protozoan has evolved cytoskeletal and clathrin-dependent endocytic mechanisms for importing ceramide molecules from the cell exterior for the synthesis of membranes and vesicles during growth and differentiation. PMID:17087963

  5. Targeting ceramide metabolic pathway induces apoptosis in human breast cancer cell lines

    International Nuclear Information System (INIS)

    The sphingolipid ceramide is a pro apoptotic molecule of ceramide metabolic pathway and is hydrolyzed to proliferative metabolite, sphingosine 1 phosphate by the action of acid ceramidase. Being upregulated in the tumors of breast, acid ceramidase acts as a potential target for breast cancer therapy. We aimed at targeting this enzyme with a small molecule acid ceramidase inhibitor, Ceranib 2 in human breast cancer cell lines MCF 7 and MDA MB 231. Ceranib 2 effectively inhibited the growth of both the cell lines in dose and time dependant manner. Morphological apoptotic hallmarks such as chromatin condensation, fragmented chromatin were observed in AO/EtBr staining. Moreover, ladder pattern of fragmented DNA observed in DNA gel electrophoresis proved the apoptotic activity of Ceranib 2 in breast cancer cell lines. The apoptotic events were associated with significant increase in the expression of pro-apoptotic genes (Bad, Bax and Bid) and down regulation of anti-apoptotic gene (Bcl 2). Interestingly, increase in sub G1 population of cell cycle phase analysis and elevated Annexin V positive cells after Ceranib 2 treatment substantiated its apoptotic activity in MCF 7 and MDA MB 231 cell lines. Thus, we report Ceranib 2 as a potent therapeutic agent against both ER+ and ER− breast cancer cell lines. - Highlights: • Acid Ceramidase inhibitor, Ceranib 2 induced apoptosis in Breast cancer cell lines (MCF 7 and MDA MB 231 cell lines). • Apoptosis is mediated by DNA fragmentation and cell cycle arrest. • Ceranib 2 upregulated the expression of pro-apoptotic genes and down regulated anti-apoptotic gene expression. • More potent compared to the standard drug Tamoxifen

  6. Targeting ceramide metabolic pathway induces apoptosis in human breast cancer cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Vethakanraj, Helen Shiphrah; Babu, Thabraz Ahmed; Sudarsanan, Ganesh Babu; Duraisamy, Prabhu Kumar; Ashok Kumar, Sekar, E-mail: sekarashok@gmail.com

    2015-08-28

    The sphingolipid ceramide is a pro apoptotic molecule of ceramide metabolic pathway and is hydrolyzed to proliferative metabolite, sphingosine 1 phosphate by the action of acid ceramidase. Being upregulated in the tumors of breast, acid ceramidase acts as a potential target for breast cancer therapy. We aimed at targeting this enzyme with a small molecule acid ceramidase inhibitor, Ceranib 2 in human breast cancer cell lines MCF 7 and MDA MB 231. Ceranib 2 effectively inhibited the growth of both the cell lines in dose and time dependant manner. Morphological apoptotic hallmarks such as chromatin condensation, fragmented chromatin were observed in AO/EtBr staining. Moreover, ladder pattern of fragmented DNA observed in DNA gel electrophoresis proved the apoptotic activity of Ceranib 2 in breast cancer cell lines. The apoptotic events were associated with significant increase in the expression of pro-apoptotic genes (Bad, Bax and Bid) and down regulation of anti-apoptotic gene (Bcl 2). Interestingly, increase in sub G1 population of cell cycle phase analysis and elevated Annexin V positive cells after Ceranib 2 treatment substantiated its apoptotic activity in MCF 7 and MDA MB 231 cell lines. Thus, we report Ceranib 2 as a potent therapeutic agent against both ER{sup +} and ER{sup −} breast cancer cell lines. - Highlights: • Acid Ceramidase inhibitor, Ceranib 2 induced apoptosis in Breast cancer cell lines (MCF 7 and MDA MB 231 cell lines). • Apoptosis is mediated by DNA fragmentation and cell cycle arrest. • Ceranib 2 upregulated the expression of pro-apoptotic genes and down regulated anti-apoptotic gene expression. • More potent compared to the standard drug Tamoxifen.

  7. Ceramide Induces Human Hepcidin Gene Transcription through JAK/STAT3 Pathway.

    Directory of Open Access Journals (Sweden)

    Sizhao Lu

    Full Text Available Changes in lipid metabolism and iron content are observed in the livers of patients with fatty liver disease. The expression of hepcidin, an iron-regulatory and acute phase protein synthesized by the liver, is also modulated. The potential interaction of lipid and iron metabolism is largely unknown. We investigated the role of lipid intermediate, ceramide in the regulation of human hepcidin gene, HAMP. Human hepatoma HepG2 cells were treated with cell-permeable ceramide analogs. Ceramide induced significant up-regulation of HAMP mRNA expression in HepG2 cells. The effect of ceramide on HAMP expression was mediated through transcriptional mechanisms because it was completely blocked with actinomycin D treatment. Reporter assays also confirmed the activation of 0.6 kb HAMP promoter by ceramide. HepG2 cells treated with ceramide displayed increased phosphorylation of STAT3, JNK, and NF-κB proteins. However, ceramide induced the binding of STAT3, but not NF-κB or c-Jun, to HAMP promoter, as shown by the chromatin immunoprecipitation assays. The mutation of STAT3 response element within 0.6 kb HAMP promoter region significantly inhibited the stimulatory effect of ceramide on HAMP promoter activity. Similarly, the inhibition of STAT3 with a pan-JAK kinase inhibitor and STAT3 siRNA pool also diminished the induction of both HAMP promoter activity and mRNA expression by ceramide. In conclusion, we have shown a direct role for ceramide in the activation of hepatic HAMP transcription via STAT3. Our findings suggest a crosstalk between lipid and iron metabolism in the liver, which may contribute to the pathogenesis of obesity-related fatty liver disease.

  8. Ceramide Induces Human Hepcidin Gene Transcription through JAK/STAT3 Pathway.

    Science.gov (United States)

    Lu, Sizhao; Natarajan, Sathish Kumar; Mott, Justin L; Kharbanda, Kusum K; Harrison-Findik, Duygu Dee

    2016-01-01

    Changes in lipid metabolism and iron content are observed in the livers of patients with fatty liver disease. The expression of hepcidin, an iron-regulatory and acute phase protein synthesized by the liver, is also modulated. The potential interaction of lipid and iron metabolism is largely unknown. We investigated the role of lipid intermediate, ceramide in the regulation of human hepcidin gene, HAMP. Human hepatoma HepG2 cells were treated with cell-permeable ceramide analogs. Ceramide induced significant up-regulation of HAMP mRNA expression in HepG2 cells. The effect of ceramide on HAMP expression was mediated through transcriptional mechanisms because it was completely blocked with actinomycin D treatment. Reporter assays also confirmed the activation of 0.6 kb HAMP promoter by ceramide. HepG2 cells treated with ceramide displayed increased phosphorylation of STAT3, JNK, and NF-κB proteins. However, ceramide induced the binding of STAT3, but not NF-κB or c-Jun, to HAMP promoter, as shown by the chromatin immunoprecipitation assays. The mutation of STAT3 response element within 0.6 kb HAMP promoter region significantly inhibited the stimulatory effect of ceramide on HAMP promoter activity. Similarly, the inhibition of STAT3 with a pan-JAK kinase inhibitor and STAT3 siRNA pool also diminished the induction of both HAMP promoter activity and mRNA expression by ceramide. In conclusion, we have shown a direct role for ceramide in the activation of hepatic HAMP transcription via STAT3. Our findings suggest a crosstalk between lipid and iron metabolism in the liver, which may contribute to the pathogenesis of obesity-related fatty liver disease. PMID:26807955

  9. Glioma cell death induced by irradiation or alkylating agent chemotherapy is independent of the intrinsic ceramide pathway.

    Directory of Open Access Journals (Sweden)

    Dorothee Gramatzki

    Full Text Available BACKGROUND/AIMS: Resistance to genotoxic therapy is a characteristic feature of glioma cells. Acid sphingomyelinase (ASM hydrolyzes sphingomyelin to ceramide and glucosylceramide synthase (GCS catalyzes ceramide metabolism. Increased ceramide levels have been suggested to enhance chemotherapy-induced death of cancer cells. METHODS: Microarray and clinical data for ASM and GCS in astrocytomas WHO grade II-IV were acquired from the Rembrandt database. Moreover, the glioblastoma database of the Cancer Genome Atlas network (TCGA was used for survival data of glioblastoma patients. For in vitro studies, increases in ceramide levels were achieved either by ASM overexpression or by the GCS inhibitor DL-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP in human glioma cell lines. Combinations of alkylating chemotherapy or irradiation and ASM overexpression, PPMP or exogenous ceramide were applied in parental cells. The anti-glioma effects were investigated by assessing proliferation, metabolic activity, viability and clonogenicity. Finally, viability and clonogenicity were assessed in temozolomide (TMZ-resistant cells upon treatment with PPMP, exogenous ceramide, alkylating chemotherapy, irradiation or their combinations. RESULTS: Interrogations from the Rembrandt and TCGA database showed a better survival of glioblastoma patients with low expression of ASM or GCS. ASM overexpression or PPMP treatment alone led to ceramide accumulation but did not enhance the anti-glioma activity of alkylating chemotherapy or irradiation. PPMP or exogenous ceramide induced acute cytotoxicity in glioblastoma cells. Combined treatments with chemotherapy or irradiation led to additive, but not synergistic effects. Finally, no synergy was found when TMZ-resistant cells were treated with exogenous ceramide or PPMP alone or in combination with TMZ or irradiation. CONCLUSION: Modulation of intrinsic glioma cell ceramide levels by ASM overexpression or GCS

  10. Mechanisms involved in cellular ceramide homeostasis

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    Hussain M

    2012-07-01

    Full Text Available Abstract Sphingolipids are ubiquitous and critical components of biological membranes. Their biosynthesis starts with soluble precursors in the endoplasmic reticulum and culminates in the Golgi complex and plasma membrane. Ceramides are important intermediates in the biosynthesis of sphingolipids, such as sphingomyelin, and their overload in the membranes is injurious to cells. The major product of ceramide metabolism is sphingomyelin. We observed that sphingomyelin synthase (SMS 1 or SMS2 deficiencies significantly decreased plasma and liver sphingomyelin levels. However, SMS2 but not SMS1 deficiency increased plasma ceramides. Surprisingly, SMS1 deficiency significantly increased glucosylceramide and ganglioside GM3, but SMS2 deficiency did not. To explain these unexpected findings about modest to no significant changes in ceramides and increases in other sphingolipids after the ablation of SMS1, we hypothesize that cells have evolved several organelle specific mechanisms to maintain ceramide homeostasis. First, ceramides in the endoplasmic reticulum membranes are controlled by its export to Golgi by protein mediated transfer. Second, in the Golgi, ceramide levels are modulated by their enzymatic conversion to different sphingolipids such as sphingomyelin, and glucosylceramides. Additionally, these sphingolipids can become part of triglyceride-rich apolipoprotein B-containing lipoproteins and be secreted. Third, in the plasma membrane ceramide levels are maintained by ceramide/sphingomyelin cycle, delivery to lysosomes, and efflux to extracellular plasma acceptors. All these pathways might have evolved to ensure steady cellular ceramide levels.

  11. Consistent metagenes from cancer expression profiles yield agent specific predictors of chemotherapy response

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    Pusztai Lajos

    2011-07-01

    Full Text Available Abstract Background Genome scale expression profiling of human tumor samples is likely to yield improved cancer treatment decisions. However, identification of clinically predictive or prognostic classifiers can be challenging when a large number of genes are measured in a small number of tumors. Results We describe an unsupervised method to extract robust, consistent metagenes from multiple analogous data sets. We applied this method to expression profiles from five "double negative breast cancer" (DNBC (not expressing ESR1 or HER2 cohorts and derived four metagenes. We assessed these metagenes in four similar but independent cohorts and found strong associations between three of the metagenes and agent-specific response to neoadjuvant therapy. Furthermore, we applied the method to ovarian and early stage lung cancer, two tumor types that lack reliable predictors of outcome, and found that the metagenes yield predictors of survival for both. Conclusions These results suggest that the use of multiple data sets to derive potential biomarkers can filter out data set-specific noise and can increase the efficiency in identifying clinically accurate biomarkers.

  12. ORMDL proteins regulate ceramide levels during sterile inflammation.

    Science.gov (United States)

    Cai, Lin; Oyeniran, Clement; Biswas, Debolina D; Allegood, Jeremy; Milstien, Sheldon; Kordula, Tomasz; Maceyka, Michael; Spiegel, Sarah

    2016-08-01

    The bioactive sphingolipid metabolite, ceramide, regulates physiological processes important for inflammation and elevated levels of ceramide have been implicated in IL-1-mediated events. Although much has been learned about ceramide generation by activation of sphingomyelinases in response to IL-1, the contribution of the de novo pathway is not completely understood. Because yeast ORM1 and ORM2 proteins negatively regulate ceramide levels through inhibition of serine palmitoyltransferase, the first committed step in ceramide biosynthesis, we examined the functions of individual mammalian ORM orthologs, ORM (yeast)-like (ORMDL)1-3, in regulation of ceramide levels. In HepG2 liver cells, downregulation of ORMDL3 markedly increased the ceramide precursors, dihydrosphingosine and dihydroceramide, primarily from de novo biosynthesis based on [U-(13)C]palmitate incorporation into base-labeled and dual-labeled dihydroceramides, whereas downregulation of each isoform increased dihydroceramides [(13)C]labeled in only the amide-linked fatty acid. IL-1 and the IL-6 family cytokine, oncostatin M, increased dihydroceramide and ceramide levels in HepG2 cells and concomitantly decreased ORMDL proteins. Moreover, during irritant-induced sterile inflammation in mice leading to induction of the acute-phase response, which is dependent on IL-1, expression of ORMDL proteins in the liver was strongly downregulated and accompanied by increased ceramide levels in the liver and accumulation in the blood. Together, our results suggest that ORMDLs may be involved in regulation of ceramides during IL-1-mediated sterile inflammation. PMID:27313060

  13. A Novel Sit4 Phosphatase Complex Is Involved in the Response to Ceramide Stress in Yeast

    OpenAIRE

    Alexandra Woodacre; Lone, Museer A.; Daniel Jablonowski; Roger Schneiter; Flaviano Giorgini; Raffael Schaffrath

    2013-01-01

    Ceramide is a building block for complex sphingolipids in the plasma membrane, but it also plays a significant role in secondary signalling pathways regulating cell proliferation and apoptosis in response to stress. Ceramide activated protein phosphatase activity has been previously observed in association with the Sit4 protein phosphatase. Here we find that sit4Δ mutants have decreased ceramide levels and display resistance to exogenous ceramides and phytosphingosine. Mutants lacking SIT4 or...

  14. Exogenous C2 Ceramide Suppresses Matrix Metalloproteinase Gene Expression by Inhibiting ROS Production and MAPK Signaling Pathways in PMA-Stimulated Human Astroglioma Cells

    OpenAIRE

    Ji-Sun Jung; Young-Ho Ahn; Byung-In Moon; Hee-Sun Kim

    2016-01-01

    Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases, which play a pivotal role in invasion, migration, and angiogenesis of glioma. Therefore, controlling MMPs is potentially an important therapeutic strategy for glioma. In the present study, we found that exogenous cell-permeable short-chain C2 ceramide inhibits phorbol myristate acetate (PMA)-induced MMP-1, -3, and -9 gene expressions in U87MG and U373MG human astroglioma cells. In addition, C2 ceramide inhibited t...

  15. Enzymatic Production of Ceramide

    DEFF Research Database (Denmark)

    Zhang, Long

    Ceramid og ceramidderivat har skabt stort interesse som aktive komponenter både indenfor lægemiddels og kosmetikindustrien. Dette projekt er et studie af enzymatisk produktion af ceramid. Hoveddelen af afhandingen fokuserer på enzymatisk hydrolyse af sphingomyelin (SM). Naturlig SM fra forskellig...

  16. Clathrin-dependent pathways and the cytoskeleton network are involved in ceramide endocytosis by a parasitic protozoan, Giardia lamblia

    OpenAIRE

    Hernandez, Yunuen; Castillo, Cynthia; Roychowdhury, Sukla; Hehl, Adrian; Aley, Stephen B.; Das, Siddhartha

    2006-01-01

    Although identified as an early-diverged protozoan, Giardia lamblia shares many similarities with higher eukaryotic cells, including an internal membrane system and cytoskeleton, as well as secretory pathways. However, unlike many other eukaryotes, Giardia does not synthesize lipids de novo, but rather depends on exogenous sources for both energy production and organelle or membrane biogenesis. It is not known how lipid molecules are taken up by this parasite and if endocytic pathways are inv...

  17. Oxidized phospholipids induce ceramide accumulation in RAW 264.7 macrophages: role of ceramide synthases.

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    Lingaraju M Halasiddappa

    Full Text Available Oxidized phospholipids (OxPLs, including 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC and 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphocholine (POVPC are among several biologically active derivatives that are generated during oxidation of low-density lipoproteins (LDLs. These OxPLs are factors contributing to pro-atherogenic effects of oxidized LDLs (OxLDLs, including inflammation, proliferation and death of vascular cells. OxLDL also elicits formation of the lipid messenger ceramide (Cer which plays a pivotal role in apoptotic signaling pathways. Here we report that both PGPC and POVPC are cytotoxic to cultured macrophages and induce apoptosis in these cells which is associated with increased cellular ceramide levels after several hours. In addition, exposure of RAW 264.7 cells to POVPC and PGPC under the same conditions resulted in a significant increase in ceramide synthase activity, whereas, acid or neutral sphingomyelinase activities were not affected. PGPC is not only more toxic than POVPC, but also a more potent inducer of ceramide formation by activating a limited subset of CerS isoforms. The stimulated CerS activities are in line with the C16-, C22-, and C24:0-Cer species that are generated under the influence of the OxPL. Fumonisin B1, a specific inhibitor of CerS, suppressed OxPL-induced ceramide generation, demonstrating that OxPL-induced CerS activity in macrophages is responsible for the accumulation of ceramide. OxLDL elicits the same cellular ceramide and CerS effects. Thus, it is concluded that PGPC and POVPC are active components that contribute to the capacity of this lipoprotein to elevate ceramide levels in macrophages.

  18. Short-term Mg deficiency upregulates protein kinase C isoforms in cardiovascular tissues and cells; relation to NF-kB, cytokines, ceramide salvage sphingolipid pathway and PKC-zeta: hypothesis and review

    Science.gov (United States)

    Altura, Burton M; Shah, Nilank C; Shah, Gatha J; Zhang, Aimin; Li, Wenyan; Zheng, Tao; Perez-Albela, Jose Luis; Altura, Bella T

    2014-01-01

    Numerous recent,epidemiological studies reveal that Western populations are growing more and more deficient in daily Mg intake which have been linked to etiology of cardiovascular (CV) diseases. A growing body of evidence suggests that a major missing link to this dilemma may reside within the sphingolipid-ceramide pathways. For the past 25 years , our labs have been focusing on these pathways in Mg-deficient mammals. The objective of this paper is two-fold: 1) to test various hypotheses and 2) to review the current status of the field and how protein kinase C isoforms may be pivotal to solving some of the CV attributes of Mg deficiency. Below, we test the hypotheses that: 1) short-term dietary deficiency of magnesium (MgD) would result in the upregulation of protein kinase C (PKC) isoforms in left ventricular (LV) and aortic smooth muscle (ASM) and serum; 2) MgD would result in a release of select cytokines and an upregulation of NF-kB in LV and ASM, and in primary cultured aortic smooth muscle cells (PCASMC); 3) MgD would result in an activation of the sphingolipid salvage pathway in LV and ASM, and in PCASMC; 4) MgD would result in a synthesis of sphingosine, but not sphinganine, in PCASMC which could be inhibited by fumonisin B1 (FB) an inhibitor of ceramide synthase (CS), but not scyphostatin an inhibitor of neutral sphingomyelinase (N-SMase); 5) incubation of PCASMC (in low Mg2+) with the PKC-mimic PMA would result in release and synthesis of NF-kB, cytokines, and ceramide but not sphingosine. The new data indicate that short-term MgD (10% normal dietary intake) result in an upregulation of all three classes of PKC isoforms in LV, aortic muscle and in serum coupled to the upregulation of ceramide, NF-kB activation, and cytokines. High degrees of linear correlation were found to exist between upregulation of PKC isoforms, p65 and cytokine release, suggesting cross-talk between these molecules and molecular pathways. Our experiments with PCASMCs demonstrated

  19. The role of ceramide in receptor- and stress-induced apoptosis studied in acidic ceramidase-deficient Farber disease cells

    OpenAIRE

    Burek, C. J.; Roth, J.; Koch, H. G.; Harzer, K.; Los, Marek Jan; Schulze-Osthoff, Klaus

    2001-01-01

    The activation of sphingomyelinases leading to the generation of ceramide has been implicated in various apoptotic pathways. However, the role of ceramide as an essential death mediator remains highly controversial. In the present study, we investigated the functional relevance of ceramide in a genetic model by using primary cells from a Farber disease patient. These cells accumulate ceramide as the result of an inherited deficiency of acidic ceramidase. We demonstrate that Farber disease lym...

  20. Ceramides and cell signaling molecules in psoriatic epidermis: reduced levels of ceramides, PKC-alpha, and JNK.

    Science.gov (United States)

    Lew, Bark-Lynn; Cho, Yunhi; Kim, Jungmin; Sim, Woo-Young; Kim, Nack-In

    2006-02-01

    Ceramides are the main lipids in the stratum corneum and are generated during cellular stress and apoptosis by de novo synthesis or by the action of sphingomyelinase. In addition, they are lipid second messengers produced by sphingolipid metabolism and trigger important cell responses, including protein kinase C-alpha (PKC-alpha) activation and the stimulation of signal transduction pathways with apoptosis and stress-activated protein kinases (SAPK), such as c-jun N-terminal kinase (JNK). Thus, ceramides have anti-proliferative and apoptotic effects. This study measured the changes in the levels of epidermal ceramides and ceramide-related apoptotic signaling molecules in psoriasis patients. Samples from lesional and non-lesional epidermis were obtained from psoriasis patients. Total ceramides were fractionated using thin-layer chromatography, and the levels of PKC-alpha and JNK expression were measured using Western blot analysis with specific antibodies. The ceramide level was reduced significantly, and this was associated with the downregulation of apoptotic signaling molecules, such as PKC-alpha and JNK, in the lesional epidermis of psoriasis patients. These results suggest that the decreased level of ceramides downregulates the apoptotic pathway, leading to epidermal proliferation in psoriasis. PMID:16479073

  1. Targeting acid sphingomyelinase reduces cardiac ceramide accumulation in the post-ischemic heart.

    Science.gov (United States)

    Klevstig, Martina; Ståhlman, Marcus; Lundqvist, Annika; Scharin Täng, Margareta; Fogelstrand, Per; Adiels, Martin; Andersson, Linda; Kolesnick, Richard; Jeppsson, Anders; Borén, Jan; Levin, Malin C

    2016-04-01

    Ceramide accumulation is known to accompany acute myocardial ischemia, but its role in the pathogenesis of ischemic heart disease is unclear. In this study, we aimed to determine how ceramides accumulate in the ischemic heart and to determine if cardiac function following ischemia can be improved by reducing ceramide accumulation. To investigate the association between ceramide accumulation and heart function, we analyzed myocardial left ventricle biopsies from subjects with chronic ischemia and found that ceramide levels were higher in biopsies from subjects with reduced heart function. Ceramides are produced by either de novo synthesis or hydrolysis of sphingomyelin catalyzed by acid and/or neutral sphingomyelinase. We used cultured HL-1 cardiomyocytes to investigate these pathways and showed that acid sphingomyelinase activity rather than neutral sphingomyelinase activity or de novo sphingolipid synthesis was important for hypoxia-induced ceramide accumulation. We also used mice with a partial deficiency in acid sphingomyelinase (Smpd1(+/-) mice) to investigate if limiting ceramide accumulation under ischemic conditions would have a beneficial effect on heart function and survival. Although we showed that cardiac ceramide accumulation was reduced in Smpd1(+/-) mice 24h after an induced myocardial infarction, this reduction was not accompanied by an improvement in heart function or survival. Our findings show that accumulation of cardiac ceramides in the post-ischemic heart is mediated by acid sphingomyelinase. However, targeting ceramide accumulation in the ischemic heart may not be a beneficial treatment strategy. PMID:26930027

  2. Metagenes Associated with Survival in Non-Small Cell Lung Cancer

    Science.gov (United States)

    Urgard, Egon; Vooder, Tõnu; Võsa, Urmo; Välk, Kristjan; Liu, Mingming; Luo, Cheng; Hoti, Fabian; Roosipuu, Retlav; Annilo, Tarmo; Laine, Jukka; Frenz, Christopher M.; Zhang, Liqing; Metspalu, Andres

    2011-01-01

    NSCLC (non-small cell lung cancer) comprises about 80% of all lung cancer cases worldwide. Surgery is most effective treatment for patients with early-stage disease. However, 30%–55% of these patients develop recurrence within 5 years. Therefore, markers that can be used to accurately classify early-stage NSCLC patients into different prognostic groups may be helpful in selecting patients who should receive specific therapies. A previously published dataset was used to evaluate gene expression profiles of different NSCLC subtypes. A moderated two-sample t-test was used to identify differentially expressed genes between all tumor samples and cancer-free control tissue, between SCC samples and AC/BC samples and between stage I tumor samples and all other tumor samples. Gene expression microarray measurements were validated using qRT-PCR. Bayesian regression analysis and Kaplan-Meier survival analysis were performed to determine metagenes associated with survival. We identified 599 genes which were down-regulated and 402 genes which were up-regulated in NSCLC compared to the normal lung tissue and 112 genes which were up-regulated and 101 genes which were down-regulated in AC/BC compared to the SCC. Further, for stage Ib patients the metagenes potentially associated with survival were identified. Genes that expressed differently between normal lung tissue and cancer showed enrichment in gene ontology terms which were associated with mitosis and proliferation. Bayesian regression and Kaplan-Meier analysis showed that gene-expression patterns and metagene profiles can be applied to predict the probability of different survival outcomes in NSCLC patients. PMID:21695068

  3. Hyperthyroidism Evokes Myocardial Ceramide Accumulation

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    Agnieszka Mikłosz

    2015-01-01

    Full Text Available Background: Thyroid hormones (THs are key regulators of cardiac physiology as well as modulators of different cellular signals including the sphingomyelin/ceramide pathway. The objective of this study was to examine the effect of hyperthyroidism on the metabolism of sphingolipids in the muscle heart. Methods: Male Wistar rats were treated for 10 days with triiodothyronine (T3 at a dose of 50µg/100g of body weight. Animals were then anaesthetized and samples of the left ventricle were excised. Results: We have demonstrated that prolonged, in vivo, T3 treatment increased the content of sphinganine (SFA, sphingosine (SFO, ceramide (CER and sphingomyelin (SM, but decreased the level of sphingosine-1-phosphate (S1P in cardiac muscle. Accordingly, the changes in sphingolipids content were accompanied by a lesser activity of neutral sphingomyelinase and without significant changes in ceramidases activity. Hyperthyroidism also induced activation of AMP-activated protein kinase (AMPK with subsequently increased expression of mitochondrial proteins: cytochrome c oxidase IV (COX IV, β-hydroxyacyl-CoA dehydrogenase (β-HAD, carnityne palmitoyltransferase I (CPT I and nuclear peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α. Conclusions: We conclude that prolonged T3 treatment increases sphingolipids metabolism which is reflected by higher concentration of SFA and CER in heart muscle. Furthermore, hyperthyroidism-induced increase in heart sphingomyelin (SM concentration might be one of the mechanisms underlying maintenance of CER at relatively low level by its conversion to SM together with decreased S1P content.

  4. Eczema and ceramides: an update

    DEFF Research Database (Denmark)

    Jungersted, Jakob Mutanu; Agner, Tove

    2013-01-01

    mutations in almost 50% of patients with moderate/severe atopic dermatitis, and lipid disturbances, mainly expressed as insufficient ceramides. In this review, with an emphasis on human studies, we consider the latest research on ceramides, on ceramides in different types of eczema and following various...... types of treatment. We also consider the genetic influence on stratum corneum lipids. The review is an update on research indexed in PubMed following the discovery of the filaggrin mutations in atopic dermatitis in 2006, but when newer publications cannot stand alone, we include publications from before...

  5. Ceramide inhibits PKCθ by regulating its phosphorylation and translocation to lipid rafts in Jurkat cells.

    Science.gov (United States)

    Hage-Sleiman, Rouba; Hamze, Asmaa B; El-Hed, Aimée F; Attieh, Randa; Kozhaya, Lina; Kabbani, Sarah; Dbaibo, Ghassan

    2016-08-01

    Protein kinase C theta (PKCθ) is a novel, calcium-independent member of the PKC family of kinases that was identified as a central player in T cell signaling and proliferation. Upon T cell activation by antigen-presenting cells, PKCθ gets phosphorylated and activated prior to its translocation to the immunological synapse where it couples with downstream effectors. PKCθ may be regulated by ceramide, a crucial sphingolipid that is known to promote differentiation, growth arrest, and apoptosis. To further investigate the mechanism, we stimulated human Jurkat T cells with either PMA or anti-CD3/anti-CD28 antibodies following induction of ceramide accumulation by adding exogenous ceramide, bacterial sphingomyelinase, or Fas ligation. Our results suggest that ceramide regulates the PKCθ pathway through preventing its critical threonine 538 (Thr538) phosphorylation and subsequent activation, thereby inhibiting the kinase's translocation to lipid rafts. Moreover, this inhibition is not likely to be a generic effect of ceramide on membrane reorganization. Other lipids, namely dihydroceramide, palmitate, and sphingosine, did not produce similar effects on PKCθ. Addition of the phosphatase inhibitors okadaic acid and calyculin A reversed the inhibition exerted by ceramide, and this suggests involvement of a ceramide-activated protein phosphatase. Such previously undescribed mechanism of regulation of PKCθ raises the possibility that ceramide, or one of its derivatives, and may prove valuable in novel therapeutic approaches for disorders involving autoimmunity or excessive inflammation-where PKCθ plays a critical role. PMID:26798039

  6. Ceramide in Stem Cell Differentiation and Embryo Development: Novel Functions of a Topological Cell-Signaling Lipid and the Concept of Ceramide Compartments

    Directory of Open Access Journals (Sweden)

    Erhard Bieberich

    2011-01-01

    Full Text Available In the last two decades, the view on the function of ceramide as a sole metabolic precursor for other sphingolipids has completely changed. A plethora of studies has shown that ceramide is an important lipid cell-signaling factor regulating apoptosis in a variety of cell types. With the advent of new stem cell technologies and knockout mice for specific steps in ceramide biosynthesis, this view is about to change again. Recent studies suggest that ceramide is a critical cell-signaling factor for stem cell differentiation and cell polarity, two processes at the core of embryo development. This paper discusses studies on ceramide using in vitro differentiated stem cells, embryo cultures, and knockout mice with the goal of linking specific developmental stages to exciting and novel functions of this lipid. Particular attention is devoted to the concept of ceramide as a topological cell-signaling lipid: a lipid that forms distinct structures (membrane domains and vesicles termed “sphingosome”, which confines ceramide-induced cell signaling pathways to localized and even polarized compartments.

  7. Ceramide and ceramide 1-phosphate in health and disease

    Directory of Open Access Journals (Sweden)

    Gómez-Muñoz Antonio

    2010-02-01

    Full Text Available Abstract Sphingolipids are essential components of cell membranes, and many of them regulate vital cell functions. In particular, ceramide plays crucial roles in cell signaling processes. Two major actions of ceramides are the promotion of cell cycle arrest and the induction of apoptosis. Phosphorylation of ceramide produces ceramide 1-phosphate (C1P, which has opposite effects to ceramide. C1P is mitogenic and has prosurvival properties. In addition, C1P is an important mediator of inflammatory responses, an action that takes place through stimulation of cytosolic phospholipase A2, and the subsequent release of arachidonic acid and prostaglandin formation. All of the former actions are thought to be mediated by intracellularly generated C1P. However, the recent observation that C1P stimulates macrophage chemotaxis implicates specific plasma membrane receptors that are coupled to Gi proteins. Hence, it can be concluded that C1P has dual actions in cells, as it can act as an intracellular second messenger to promote cell survival, or as an extracellular receptor agonist to stimulate cell migration.

  8. Ceramide signaling in cancer and stem cells

    OpenAIRE

    Bieberich, Erhard

    2008-01-01

    Most of the previous work on the sphingolipid ceramide has been devoted to its function as an apoptosis inducer. Recent studies, however, have shown that in stem cells, ceramide has additional nonapoptotic functions. In this article, ceramide signaling will be reviewed in light of ‘systems interface biology’: as an interconnection of sphingolipid metabolism, membrane biophysics and cell signaling. The focus will be on the metabolic interconversion of ceramide and sphingomyelin or sphingosine-...

  9. Ceramide stimulates ABCA12 expression via peroxisome proliferator-activated receptor {delta} in human keratinocytes.

    Science.gov (United States)

    Jiang, Yan J; Uchida, Yoshikazu; Lu, Biao; Kim, Peggy; Mao, Cungui; Akiyama, Masashi; Elias, Peter M; Holleran, Walter M; Grunfeld, Carl; Feingold, Kenneth R

    2009-07-10

    ABCA12 (ATP binding cassette transporter, family 12) is a cellular membrane transporter that facilitates the delivery of glucosylceramides to epidermal lamellar bodies in keratinocytes, a process that is critical for permeability barrier formation. Following secretion of lamellar bodies into the stratum corneum, glucosylceramides are metabolized to ceramides, which comprise approximately 50% of the lipid in stratum corneum. Gene mutations of ABCA12 underlie harlequin ichthyosis, a devastating skin disorder characterized by abnormal lamellar bodies and a severe barrier abnormality. Recently we reported that peroxisome proliferator-activated receptor (PPAR) and liver X receptor activators increase ABCA12 expression in human keratinocytes. Here we demonstrate that ceramide (C(2)-Cer and C(6)-Cer), but not C(8)-glucosylceramides, sphingosine, or ceramide 1-phosphate, increases ABCA12 mRNA expression in a dose- and time-dependent manner. Inhibitors of glucosylceramide synthase, sphingomyelin synthase, and ceramidase and small interfering RNA knockdown of human alkaline ceramidase, which all increase endogenous ceramide levels, also increased ABCA12 mRNA levels. Moreover, simultaneous treatment with C(6)-Cer and each of these same inhibitors additively increased ABCA12 expression, indicating that ceramide is an important inducer of ABCA12 expression and that the conversion of ceramide to other sphingolipids or metabolites is not required. Finally, both exogenous and endogenous ceramides preferentially stimulate PPARdelta expression (but not other PPARs or liver X receptors), whereas PPARdelta knockdown by siRNA transfection specifically diminished the ceramide-induced increase in ABCA12 mRNA levels, indicating that PPARdelta is a mediator of the ceramide effect. Together, these results show that ceramide, an important lipid component of epidermis, up-regulates ABCA12 expression via the PPARdelta-mediated signaling pathway, providing a substrate-driven, feed

  10. Network Analysis of a Comprehensive Knowledge Repository Reveals a Dual Role for Ceramide in Alzheimer's Disease.

    Science.gov (United States)

    Mizuno, Satoshi; Ogishima, Soichi; Kitatani, Kazuyuki; Kikuchi, Masataka; Tanaka, Hiroshi; Yaegashi, Nobuo; Nakaya, Jun

    2016-01-01

    Alzheimer's disease (AD) is the most common cause of senile dementia. Many inflammatory factors such as amyloid-β and pro-inflammatory cytokines are known to contribute to the inflammatory response in the AD brain. Sphingolipids are widely known to have roles in the pathogenesis of inflammatory diseases, where the precise roles for sphingolipids in inflammation-associated pathogenesis of AD are not well understood. Here we performed a network analysis to clarify the importance of sphingolipids and to model relationships among inflammatory factors and sphingolipids in AD. In this study, we have updated sphingolipid signaling and metabolic cascades in a map of AD signaling networks that we named "AlzPathway," a comprehensive knowledge repository of signaling pathways in AD. Our network analysis of the updated AlzPathway indicates that the pathways related to ceramide are one of the primary pathways and that ceramide is one of the important players in the pathogenesis of AD. The results of our analysis suggest the following two prospects about inflammation in AD: (1) ceramide could play important roles in both inflammatory and anti-inflammatory pathways of AD, and (2) several factors such as Sphingomyelinase and Siglec-11 may be associated with ceramide related inflammation and anti-inflammation pathways in AD. In this study, network analysis of comprehensive knowledge repository reveals a dual role for ceramide in AD. This result provides a clue to clarify sphingolipids related inflammatory and anti-inflammatory pathways in AD. PMID:26849355

  11. Network Analysis of a Comprehensive Knowledge Repository Reveals a Dual Role for Ceramide in Alzheimer's Disease.

    Directory of Open Access Journals (Sweden)

    Satoshi Mizuno

    Full Text Available Alzheimer's disease (AD is the most common cause of senile dementia. Many inflammatory factors such as amyloid-β and pro-inflammatory cytokines are known to contribute to the inflammatory response in the AD brain. Sphingolipids are widely known to have roles in the pathogenesis of inflammatory diseases, where the precise roles for sphingolipids in inflammation-associated pathogenesis of AD are not well understood. Here we performed a network analysis to clarify the importance of sphingolipids and to model relationships among inflammatory factors and sphingolipids in AD. In this study, we have updated sphingolipid signaling and metabolic cascades in a map of AD signaling networks that we named "AlzPathway," a comprehensive knowledge repository of signaling pathways in AD. Our network analysis of the updated AlzPathway indicates that the pathways related to ceramide are one of the primary pathways and that ceramide is one of the important players in the pathogenesis of AD. The results of our analysis suggest the following two prospects about inflammation in AD: (1 ceramide could play important roles in both inflammatory and anti-inflammatory pathways of AD, and (2 several factors such as Sphingomyelinase and Siglec-11 may be associated with ceramide related inflammation and anti-inflammation pathways in AD. In this study, network analysis of comprehensive knowledge repository reveals a dual role for ceramide in AD. This result provides a clue to clarify sphingolipids related inflammatory and anti-inflammatory pathways in AD.

  12. Ceramide-induced TCR up-regulation

    DEFF Research Database (Denmark)

    Menné, C; Lauritsen, Jens Peter Holst; Dietrich, J;

    2000-01-01

    kinase C activity. Thus, an increase in protein kinase C activity affects TCR recycling kinetics leading to a new TCR equilibrium with a reduced level of TCR expressed at the T cell surface. Down-regulation of TCR expression compromises T cell activation. Conversely, TCR up-regulation is expected to...... pathway. Finally, we showed that TCR up-regulation probably plays a physiological role by increasing T cell responsiveness. Thus, by affecting the TCR recycling kinetics, T cells have the potential both to up- and down-regulate TCR expression and thereby adjust T cell responsiveness....... increase T cell responsiveness. The purpose of this study was to identify and characterize potential pathways for TCR up-regulation. We found that ceramide affected TCR recycling dynamics and induced TCR up-regulation in a concentration- and time-dependent manner. Experiments applying phosphatase...

  13. Ethnicity and stratum corneum ceramides

    DEFF Research Database (Denmark)

    Jungersted, J.M.; Høgh, Julie Kaae; Hellgren, Lars; Jemec, G.; Agner, T.

    2010-01-01

    cyanoacrylate method and analysed using high-performance thin layer chromatography. RESULTS: For the ceramide/cholesterol ratio we found statistically significant differences between groups, with Asians having the highest ratio (P <0·001 as compared with both white-skinned individuals and Africans), white...

  14. Ceramides and Cell Signaling Molecules in Psoriatic Epidermis: Reduced Levels of Ceramides, PKC-α, and JNK

    OpenAIRE

    Lew, Bark-Lynn; Cho, Yunhi; Kim, Jungmin; Sim, Woo-Young; Kim, Nack-In

    2006-01-01

    Ceramides are the main lipids in the stratum corneum and are generated during cellular stress and apoptosis by de novo synthesis or by the action of sphingomyelinase. In addition, they are lipid second messengers produced by sphingolipid metabolism and trigger important cell responses, including protein kinase C-alpha (PKC-α) activation and the stimulation of signal transduction pathways with apoptosis and stress-activated protein kinases (SAPK), such as c-jun N-terminal kinase (JNK). Thus, c...

  15. Ceramides and barrier function in healthy skin

    DEFF Research Database (Denmark)

    Mutanu Jungersted, Jakob; Hellgren, Lars; Høgh, Julie Kaae; Drachmann, Tue; Jemec, Gregor; Agner, Tove

    2010-01-01

    Lipids in the stratum corneum are key components in the barrier function of the skin. Changes in lipid composition related to eczematous diseases are well known, but limited data are available on variations within healthy skin. The objective of the present study was to compare ceramide subgroups...... and ceramide/cholesterol ratios in young, old, male and female healthy skin. A total of 55 participants with healthy skin was included in the study. Lipid profiles were correlated with transepidermal water loss and with information on dry skin from a questionnaire including 16 people. No statistically...... significant differences were found between young and old skin for ceramide subgroups or ceramide/cholesterol ratios, and there was no statistically significant correlation between answers about dry skin and ceramide levels. Interestingly, a statistically significant higher ceramide/cholesterol ratio was found...

  16. New ceramides from Acnistus arborescens

    Energy Technology Data Exchange (ETDEWEB)

    Maia, Ana Isabel V.; Veras, Maria Leopoldina; Braz-Filho, Raimundo; Silveira, Edilberto R.; Pessoa, Otilia Deusdenia L., E-mail: opessoa@ufc.b [Universidade Federal do Ceara (UFC), Fortaleza, CE (Brazil). Dept. de Quimica Organica e Inorganica; Lopes, Norberto P. [Universidade de Sao Paulo (USP), Ribeirao Preto, SP (Brazil). Faculdade de Ciencias Farmaceuticas. Dept. de Fisica e Quimica

    2010-07-01

    Two new ceramides, N-(4-hydroxyphenethyl)octacosamide (1) and rel-(2S,3S,4R,16E)-2- [(2'R)-2'-hydroxynonadecanoylamino]-heneicosadec-16-ene-1,3,4-triol (2) were isolated from the EtOH extract of Acnistus arborescens. The structures were elucidated by spectroscopic (1D and 2D NMR experiments, HR-ESI-MS, LR-MS and IR) methods. (author)

  17. Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate.

    Science.gov (United States)

    Cuvillier, O; Pirianov, G; Kleuser, B; Vanek, P G; Coso, O A; Gutkind, S; Spiegel, S

    1996-06-27

    Ceramide is an important regulatory participant of programmed cell death (apoptosis) induced by tumour-necrosis factor (TNF)-alpha and Fas ligand, members of the TNF superfamily. Conversely, sphingosine and sphingosine-1-phosphate, which are metabolites of ceramide, induce mitogenesis and have been implicated as second messengers in cellular proliferation induced by platelet-derived growth factor and serum. Here we report that sphingosine-1-phosphate prevents the appearance of the key features of apoptosis, namely intranucleosomal DNA fragmentation and morphological changes, which result from increased concentrations of ceramide. Furthermore, inhibition of ceramide-mediated apoptosis by activation of protein kinase C results from stimulation of sphingosine kinase and the concomitant increase in intracellular sphingosine-1-phosphate. Finally sphingosine-1-phosphate not only stimulates the extracellular signal-regulated kinase (ERK) pathway, it counteracts the ceramide-induced activation of stress-activated protein kinase (SAPK/JNK). Thus, the balance between the intracellular levels of ceramide and sphingosine-1-phosphate and their regulatory effects on different family members of mitogen-activated protein kinases determines the fate of the cell. PMID:8657285

  18. Enzymatic production of ceramide from sphingomyelin

    DEFF Research Database (Denmark)

    Zhang, Long; Hellgren, Lars; Xu, Xuebing

    2006-01-01

    Due to its major role in maintaining the water-retaining properties of the epidermis, ceramide is of great commercial potentials in cosmetic and pharmaceutical industries such as in hair and skin care products. Chemical synthesis of ceramide is a costly process, and developments of alternative cost...

  19. Ceramide in apoptosis: a revisited role.

    Science.gov (United States)

    Levade, Thierry; Malagarie-Cazenave, Sophie; Gouazé, Valérie; Ségui, Bruno; Tardy, Claudine; Betito, Susan; Andrieu-Abadie, Nathalie; Cuvillier, Olivier

    2002-08-01

    The sphingolipid ceramide has recently emerged as a new transducer or modulator of apoptotic cell death. This function, however, has recently been challenged. Here, in the light of recent observations, the role of ceramide in apoptosis signaling is discussed. PMID:12374195

  20. Structure of cholesterol/ceramide monolayer mixtures

    DEFF Research Database (Denmark)

    Scheffer, L.; Solomonov, I.; Weygand, M.J.;

    2005-01-01

    The structure of monolayers of cholesterol/ ceramide mixtures was investigated using grazing incidence x-ray diffraction, immunofluorescence, and atomic force microscopy techniques. Grazing incidence x-ray diffraction measurements showed the existence of a crystalline mixed phase of the two...... components within a range of compositions of cholesterol/ ceramide between 100: 0 and 67: 33. The mixed phase coexists with the ceramide crystalline phase in the range of compositions between 50: 50 and 30: 70; between 30: 70 and 0: 100 only the highly crystalline phase of ceramide was detected. The latter...... was determined and modeled. Immunolabeling was performed with an antibody specific to the cholesterol monohydrate crystalline arrangement. The antibody recognizes crystalline cholesterol monolayers, but does not interact with crystalline ceramide. Immunofluorescence and atomic force microscopy data...

  1. Short Term Palmitate Supply Impairs Intestinal Insulin Signaling via Ceramide Production.

    Science.gov (United States)

    Tran, Thi Thu Trang; Postal, Bárbara Graziela; Demignot, Sylvie; Ribeiro, Agnès; Osinski, Céline; Pais de Barros, Jean-Paul; Blachnio-Zabielska, Agnieszka; Leturque, Armelle; Rousset, Monique; Ferré, Pascal; Hajduch, Eric; Carrière, Véronique

    2016-07-29

    The worldwide prevalence of metabolic diseases is increasing, and there are global recommendations to limit consumption of certain nutrients, especially saturated lipids. Insulin resistance, a common trait occurring in obesity and type 2 diabetes, is associated with intestinal lipoprotein overproduction. However, the mechanisms by which the intestine develops insulin resistance in response to lipid overload remain unknown. Here, we show that insulin inhibits triglyceride secretion and intestinal microsomal triglyceride transfer protein expression in vivo in healthy mice force-fed monounsaturated fatty acid-rich olive oil but not in mice force-fed saturated fatty acid-rich palm oil. Moreover, when mouse intestine and human Caco-2/TC7 enterocytes were treated with the saturated fatty acid, palmitic acid, the insulin-signaling pathway was impaired. We show that palmitic acid or palm oil increases ceramide production in intestinal cells and that treatment with a ceramide analogue partially reproduces the effects of palmitic acid on insulin signaling. In Caco-2/TC7 enterocytes, ceramide effects on insulin-dependent AKT phosphorylation are mediated by protein kinase C but not by protein phosphatase 2A. Finally, inhibiting de novo ceramide synthesis improves the response of palmitic acid-treated Caco-2/TC7 enterocytes to insulin. These results demonstrate that a palmitic acid-ceramide pathway accounts for impaired intestinal insulin sensitivity, which occurs within several hours following initial lipid exposure. PMID:27255710

  2. Enzymatic Production of Ceramide from Sphingomyelin

    DEFF Research Database (Denmark)

    Zhang, Long; Hellgren, Lars; Xu, Xuebing

    Ceramide is the key intermediate in the biosynthesis of all complex sphingolipids. Due to its major role in maintaining the water-retaining properties of the epidermis, ceramide is of great commercial potential in cosmetic and pharmaceuticals such as hair and skin care products. Currently, chemical...... contains a ceramide moiety, is a ubiquitous component of animal cell membranes, and dairy products or by-products is a rich source of sphingomyelin. It has been verified that enzymatic modification of sphingomyelin is a feasible approach for production of ceramide. The reaction system has been optimized...... through system evaluation and the optimization of several important factors. Sphingomyelin hydrolysis proved to be more efficient in two-phase (water: organic solvent) system than in one-phase (water-saturated organic solvent) system. Phospholipase C from Clostridium perfringens is the tested enzyme which...

  3. Structure of cholesterol/ceramide monolayer mixtures

    DEFF Research Database (Denmark)

    Scheffer, L.; Solomonov, I.; Weygand, M.J.; Kjær, K.; Leiserowitz, L.; Addadi, L.

    2005-01-01

    The structure of monolayers of cholesterol/ ceramide mixtures was investigated using grazing incidence x-ray diffraction, immunofluorescence, and atomic force microscopy techniques. Grazing incidence x-ray diffraction measurements showed the existence of a crystalline mixed phase of the two...... was determined and modeled. Immunolabeling was performed with an antibody specific to the cholesterol monohydrate crystalline arrangement. The antibody recognizes crystalline cholesterol monolayers, but does not interact with crystalline ceramide. Immunofluorescence and atomic force microscopy data...

  4. Ceramide mediates lung fibrosis in cystic fibrosis

    OpenAIRE

    Ziobro, Regan; Henry, Brian; Edwards, Michael J.; Lentsch, Alex B.; Gulbins, Erich

    2013-01-01

    Fibrosis of the lung is one of the major clinical problems of cystic fibrosis and chronic obstructive pulmonary disease. However, the molecular mechanisms leading to pulmonary fibrosis are poorly characterized and require definition. Here, we demonstrate that chronic accumulation of ceramide in the lung contributes to the development of fibrosis in aged cystic fibrosis mice. Genetic or pharmacological normalization of ceramide in cystic fibrosis mice, which was achieved by heterozygosity of a...

  5. Ceramide signalling: regulatory role in cell proliferation, differentiation and apoptosis in human epidermis.

    Science.gov (United States)

    Geilen, C C; Wieder, T; Orfanos, C E

    1997-09-01

    The stratum corneum of vertebrates is a major structural compartment that provides mechanical protection and prevents skin desiccation. The water barrier function of the stratum corneum was first reported in 1944, and this was shown later to be associated with multilayered lipid lamellae localized in the extracellular spaces. The major lipid components isolated from the cornified epidermal layers are ceramides, which belong to the class of sphingolipids, cholesterol and free fatty acids; their biosynthesis is in tight relationship with the cutaneous barrier function. In studies in which the barrier is artificially disturbed, lipid biosynthesis is found to be directly regulated by barrier permeability. As mentioned above, the ceramides involved in this process are located in the extracellular spaces of the upper epidermal layers, whereas sphingomyelin, the most common sphingolipid, is an integral part of the bilayer plasma membrane of the keratinocytes. During the last few years, however, increasing evidence has shown that sphingolipids may also take part in cell signalling, and the term 'sphingomyelin cycle' has been coined to describe this novel path-way of signal transduction. Intracellular messengers of the sphingomyelin cycle are ceramides as the products of an agonist-stimulated sphingomyelin hydrolysis. Increased levels of intracellular ceramides induce cell differentiation and/or apoptosis and reduce cell proliferation. In contrast to the extracellular barrier-forming ceramides which are complex partly O-acylated species containing long-chain fatty acids, intracellular signal-transducing ceramides are not O-acylated and have acyl chain lengths of 16 and 18 carbon atoms. We present here a review of our present knowledge on the sphingomyelin cycle as a possible signal transduction pathway in the human epidermis. We discuss the common origin of extracellular ceramides constituting the lipid barrier and of intracellular ceramides generated by agonist

  6. Anti-immunoglobulin-induced apoptosis in WEHI 231 cells involves the slow formation of ceramide from sphingomyelin and is blocked by bcl-XL.

    Science.gov (United States)

    Wiesner, D A; Kilkus, J P; Gottschalk, A R; Quintáns, J; Dawson, G

    1997-04-11

    Prolonged (>24 h) exposure to anti-IgM (an antigen surrogate that induces membrane cross-linking and apoptosis) induced a 3-fold increase in the mass of endogenous ceramide measured by 32P labeling by diacylglycerol kinase and a 4-fold increase in ceramide as measured by metabolic labeling with [3H]palmitate in a B-lymphocyte cell line, WEHI 231. This correlated with the induction of apoptosis. Shorter exposure times to anti-IgM (up to 8 h) failed to elicit apoptosis and did not elicit increased ceramide formation. After 8 h, apoptosis occurs concomitantly with ceramide formation over the next 40 h. Further, we showed that exogenous ceramide mimicked anti-IgM-induced apoptosis and that apoptosis was potentiated in serum-free media. Treatment of cells with an inhibitor of ceramide catabolism, N-oleoylethanolamine, increased both ceramide formation and apoptosis and accelerated apoptosis induced by anti-IgM. To examine further how ceramide metabolism is involved in apoptosis, we derived cell lines from a small population of cells resistant to N-oleoylethanolamine. These cell lines were selected based on an altered ceramide metabolic pathway, were resistant to apoptosis induced by anti-IgM, and showed no significant increase in ceramide when challenged with anti-IgM. The basis of this resistance was shown to be the failure to activate neutral sphingomyelinase activity following 24-h treatment with anti-IgM, in contrast to the 2-fold increase in neutral sphingomyelinase activity observed in wild type cells. We have shown previously that transfection of WEHI cells with bcl-xL conferred resistance to anti-IgM-induced apoptosis, whereas transfection with bcl-2 did not (Gottschalk, A., Boise, L., Thompson, C., and Quintans, J. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 7350-7354). In this study, these bcl-xL transfectants also displayed increased resistance to exogenous N-acetylsphingosine (C2-ceramide) or N-hexanoylsphingosine (C6-ceramide). However, when challenged with

  7. Stress-induced cell death is mediated by ceramide synthesis in Neurospora crassa.

    Science.gov (United States)

    Plesofsky, Nora S; Levery, Steven B; Castle, Sherry A; Brambl, Robert

    2008-12-01

    The combined stresses of moderate heat shock (45 degrees C) and analog-induced glucose deprivation constitute a lethal stress for Neurospora crassa. We found that this cell death requires fatty acid synthesis and the cofactor biotin. In the absence of the cofactor, the stressed cells are particularly sensitive to exogenous ceramide, which is lethal at low concentrations. When we extracted endogenous sphingolipids, we found that unique ceramides were induced (i) by the inhibitory glucose analog 2-deoxyglucose and (ii) by combined heat shock and 2-deoxyglucose. We determined that the former is a 2-deoxyglucose-modified ceramide. By structural analysis, we identified the latter, induced by dual stress, as C(18)(OH)-phytoceramide. We also identified C(24)(OH)-phytoceramide as a constitutive ceramide that continues to be produced during the combined stresses. The unusual C(18)(OH)-phytoceramide is not made by germinating asexual spores subjected to the same heat and carbon stress. Since these spores, unlike growing cells, do not die from the stresses, this suggests a possible connection between synthesis of the dual-stress-induced ceramide and cell death. This connection is supported by the finding that a (dihydro)ceramide synthase inhibitor, australifungin, renders cells resistant to death from these stresses. The OS-2 mitogen-activated protein kinase, homologous to mammalian p38, may be involved in the cell death signaling pathway. Strains lacking OS-2 survived the combined stresses better than the wild type, and phosphorylated OS-2 increased in wild-type cells in response to heat shock and combined heat and carbon stress. PMID:18952903

  8. T-cell receptor downregulation by ceramide-induced caspase activation and cleavage of the zeta chain

    DEFF Research Database (Denmark)

    Menné, C; Lauritsen, Jens Peter Holst; Dietrich, J;

    2001-01-01

    gamma L-based motif-dependent and the tyrosine kinase-dependent pathways. This pathway is dependent on ceramide-induced activation of caspases and correlate with caspase-mediated cleavage of the zeta chain. Thus, a 10--15% downregulation of the TCR was induced following the treatment of the T cells with...... ceramide for 4 h. A close correlation between TCR downregulation, caspase activation, and cleavage of the zeta chain was found. Furthermore, the caspase inhibitors abolished the cleavage of the zeta chain and TCR downregulation in parallel with the inhibition of the caspase activity....

  9. p53-independent early and late apoptosis is mediated by ceramide after exposure of tumor cells to photon or carbon ion irradiation

    International Nuclear Information System (INIS)

    To determine whether ceramide is responsible for the induction of p53-independent early or late apoptosis in response to high- and low-Linear-Energy-Transfer (LET) irradiation. Four cell lines displaying different radiosensitivities and p53-protein status were irradiated with photons or 33.4 or 184 keV/μm carbon ions. The kinetics of ceramide production was quantified by fluorescent microscopy or High-Performance-Liquid-Chromatogaphy and the sequence of events leading to apoptosis by flow cytometry. Regardless of the p53-status, both low and high-LET irradiation induced an early ceramide production in radiosensitive cells and late in the radioresistant. This production strongly correlated with the level of early apoptosis in radiosensitive cells and delayed apoptosis in the radioresistant ones, regardless of radiation quality, tumor type, radiosensitivity, or p53-status. Inhibition of caspase activity or ceramide production showed that, for both types of radiation, ceramide is essential for the initiation of early apoptosis in radiosensitive cells and late apoptosis following mitotic catastrophe in radioresistant cells. Ceramide is a determining factor in the onset of early and late apoptosis after low and high-LET irradiation and is the mediator of the p53-independent-apoptotic pathway. We propose that ceramide is the molecular bridge between mitotic catastrophe and the commitment phase of delayed apoptosis in response to irradiation

  10. Mechanisms involved in ceramide-induced cell cycle arrest in human hepatocarcinoma cells

    Institute of Scientific and Technical Information of China (English)

    Jing Wang; Xiao-Wen Lv; Jie-Ping Shi; Xiao-Song Hu

    2007-01-01

    AIM:To investigate the effect of ceramide on the cell cycle in human hepatocarcinoma Bel7402 cells.Possible molecular mechanisms were explored.METHODS:[3-(4,5)-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide(MTT)assay,plasmid transfection,reporter assay,FACS and Western blotting analyses were employed to investigate the effect and the related molecular mechanisms of C2-ceramide on the cell cycle of Bel7402 cells.RESULTS:C2-ceramide was found to inhibit the growth of Bel7402 cells by inducing cell cycle arrest.During the process,the expression of p21 protein increased,while that of cyclinD1,phospho-ERK1/2 and c-myc decreased.Furthermore,the level of CDK7 was downregulated,while the transcriptional activity of PPARγ was upregulated.Addition of GW9662,which is a PPARγ specific antagonist,could reserve the modulation action on CDK7.CONCLUSION:Our results support the hypothesis that cell cycle arrest induced by C2-ceramide may be mediated via accumulation of p21 and reduction of cyclinD1 and CDK7,at least partly,through PPARγ activation.The ERK signaling pathway was involved in this process.

  11. PKCzeta protects against UV-C-induced apoptosis by inhibiting acid sphingomyelinase-dependent ceramide production

    OpenAIRE

    Charruyer, Alexandra; Jean, Christine; Colomba, Audrey; Jaffrézou, Jean-Pierre; Quillet-Mary, Anne; Laurent, Guy; Bezombes, Christine

    2007-01-01

    Abstract In a recent study, we described that UV-C irradiation resulted in redox-dependent activation and relocalization of acid sphingomyelinase (A-SMase) to the external surface of raft membrane microdomains, hydrolysis of sphingomyelin (SM) associated to the plasma membrane outer leaflet, ceramide (CER) generation and apoptosis. In the present study, we have investigated the influence of PKC? , an atypical form of PKC on this pathway. This study shows that PKC? overexpression r...

  12. Mechanisms of ceramide-induced COX-2-dependent apoptosis in human ovarian cancer OVCAR-3 cells partially overlapped with resveratrol

    DEFF Research Database (Denmark)

    Lin, Hung-Yun; Delmas, Dominique; Vang, Ole;

    2013-01-01

    kinase-dependent apoptosis in human ovarian cancer OVCAR-3 cells, concomitant with an increase in the expression of COX-2 and p53 phosphorylation. Blockade of cyclooxygenase-2 (COX-2) activity by siRNA or NS398 correspondingly inhibited ceramide-induced p53 Ser-15 phosphorylation and apoptosis; thus COX......, resveratrol and ceramide converge on an endocytosis-requiring, ERK1/2-dependent signal transduction pathway and induction of COX-expression as an essential molecular antecedent for subsequent p53-dependent apoptosis. In addition, expressions of caspase-3 and -7 are observed. However, a p38 kinase...

  13. Lipid alterations in experimental murine colitis: role of ceramide and imipramine for matrix metalloproteinase-1 expression.

    Directory of Open Access Journals (Sweden)

    Jessica Bauer

    Full Text Available BACKGROUND: Dietary lipids or pharmacologic modulation of lipid metabolism are potential therapeutic strategies in inflammatory bowel disease (IBD. Therefore, we analysed alterations of bioactive lipids in experimental models of colitis and examined the functional consequence of the second messenger ceramide in inflammatory pathways leading to tissue destruction. METHODOLOGY/PRINCIPAL FINDINGS: Chronic colitis was induced by dextran-sulphate-sodium (DSS or transfer of CD4(+CD62L(+ cells into RAG1(-/--mice. Lipid content of isolated murine intestinal epithelial cells (IEC was analysed by tandem mass spectrometry. Concentrations of MMP-1 in supernatants of Caco-2-IEC and human intestinal fibroblasts from patients with ulcerative colitis were determined by ELISA. Imipramine was used for pharmacologic inhibition of acid sphingomyelinase (ASM. Ceramide increased by 71% in chronic DSS-induced colitis and by 159% in the transfer model of colitis. Lysophosphatidylcholine (LPC decreased by 22% in both models. No changes were detected for phosphatidylcholine. Generation of ceramide by exogenous SMase increased MMP-1-protein production of Caco-2-IEC up to 7-fold. Inhibition of ASM completely abolished the induction of MMP-1 by TNF or IL-1beta in Caco-2-IEC and human intestinal fibroblasts. CONCLUSIONS/SIGNIFICANCE: Mucosal inflammation leads to accumulation of ceramide and decrease of LPC in the intestinal epithelium. One aspect of ceramide generation is an increase of MMP-1. Induction of MMP-1 by TNF or IL-1beta is completely blocked by inhibition of ASM with imipramine. Therefore, inhibition of ASM may offer a treatment strategy to reduce MMP-1 expression and tissue destruction in inflammatory conditions.

  14. Ceramide synthases expression and role of ceramide synthase-2 in the lung: insight from human lung cells and mouse models.

    Directory of Open Access Journals (Sweden)

    Irina Petrache

    Full Text Available Increases in ceramide levels have been implicated in the pathogenesis of both acute or chronic lung injury models. However, the role of individual ceramide species, or of the enzymes that are responsible for their synthesis, in lung health and disease has not been clarified. We now show that C24- and C16-ceramides are the most abundant lung ceramide species, paralleled by high expression of their synthetic enzymes, ceramide synthase 2 (CerS2 and CerS5, respectively. Furthermore, the ceramide species synthesis in the lung is homeostatically regulated, since mice lacking very long acyl chain C24-ceramides due to genetic deficiency of CerS2 displayed a ten-fold increase in C16-ceramides and C16-dihydroceramides along with elevation of acid sphingomyelinase and CerS5 activities. Despite relatively preserved total lung ceramide levels, inhibition of de novo sphingolipid synthesis at the level of CerS2 was associated with significant airflow obstruction, airway inflammation, and increased lung volumes. Our results suggest that ceramide species homeostasis is crucial for lung health and that CerS2 dysfunction may predispose to inflammatory airway and airspace diseases.

  15. Systemic ceramide accumulation leads to severe and varied pathological consequences

    OpenAIRE

    Alayoubi, Abdulfatah M; Wang, James C M; Au, Bryan C.Y.; Carpentier, Stéphane; Garcia, Virginie; Dworski, Shaalee; El-Ghamrasni, Samah; Kirouac, Kevin N.; Exertier, Mathilde J; Xiong, Zi Jian; Privé, Gilbert G.; Calogera M Simonaro; Casas, Josefina; Fabrias, Gemma; Schuchman, Edward H.

    2013-01-01

    Farber disease (FD) is a severe inherited disorder of lipid metabolism characterized by deficient lysosomal acid ceramidase (ACDase) activity, resulting in ceramide accumulation. Ceramide and metabolites have roles in cell apoptosis and proliferation. We introduced a single-nucleotide mutation identified in human FD patients into the murine Asah1 gene to generate the first model of systemic ACDase deficiency. Homozygous Asah1 P361R/P361R animals showed ACDase defects, accumulated ceramide, de...

  16. Mechanisms and impact of ceramide phosphoethanolamine biosynthesis

    OpenAIRE

    Hentes Vacaru, A.M.

    2009-01-01

    Sphingolipids represent an essential class of membrane molecules in eukaryotic cells. They are primarily found in the outer leaflet of the plasma membrane where they help create a rigid and impermeable barrier to the extracellular environment. While sphingomyelin (SM) is the most abundant sphingolipid in mammals and nematodes, insects produce the SM analogue ceramide phosphoethanolamine (CPE) as a major plasma membrane constituent. Little is known about the biological role of CPE or about the...

  17. Topically applied ceramide accumulates in skin glyphs

    OpenAIRE

    Zhang Q; Flach CR; Mendelsohn R; Mao G; Pappas A; Mack MC; Walters RM; Southall MD

    2015-01-01

    Qihong Zhang,1 Carol R Flach,1 Richard Mendelsohn,1 Guangru Mao,2 Apostolos Pappas,2 M Catherine Mack,2 Russel M Walters,2 Michael D Southall2 1Department of Chemistry, Rutgers University, Newark, 2Johnson & Johnson Consumer Companies, Inc., Skillman, NJ, USAAbstract: Ceramides (CERs), structural components of the stratum corneum (SC), impart essential barrier properties to this thin outer layer of the epidermis. Variations in CER species within this layer have been linked to several ...

  18. Ceramide induces release of mitochondrial proapop-totic proteins in caspase-dependent and -independent manner in HT-29 cells

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    In this study, the release of mitochondrial proapoptotic intermembrane space proteins induced by ex-ogenous C2-ceramide in human colon carcinoma (HT-29) cell line was investigated. HT-29 cells were treated with 12.5, 25 and 50 μmol/L C2-ceramide in vitro. Flow cytometer was used to detect the mito-chondrial membrane potential (ΔΨm). Subcellular fractions were extracted by Mitochondrial/Cytosol Fractionation Kit after C2-ceramide treatment for 24 h. SDS-PAGE was used to determine the level of cytochrome c (Cyt c), high temperature requirement A2 (HtrA2) and second mitochondrial-derived ac-tivator of caspases (Smac) released from mitochondria, the expression of X-linked inhibitor of apop-tosis protein (XIAP) and caspase-3 for 24 h. The results showed that ΔΨm began to decrease from 6 h after 25 and 50 μmol/L C2-ceramide treatment (P<0.05) and cyclosporin A (CsA) could inhibit the col-lapse of ΔΨm through regulating mitochondrial membrane permeability transition pore. There was no effect of C2-ceramide on the expression of Cyt c, HtrA2 and Smac in the total levels. 12.5, 25 and 50 μmol/L C2-ceramide could induce Cyt c, HtrA2 and Smac to release from mitochondria to cytosol and down-regulate the expression of XIAP (P<0.05). Also there was expression of cleaved caspase-3 with C2-ceramide treatment. After the treatment with caspase inhibitor, C2-ceramide still induced the release of Cyt c and HtrA2, but Smac did not. Therefore, C2-ceramide could induce apoptosis of HT-29 cells through the mitochondria pathway. The release of Cyt c, HtrA2 and Smac from mitochondria did not occur via the same mechanism, the release of Cyt c and HtrA2 was caspase-independent and the re-lease of Smac was caspase-dependent.

  19. Ceramide induces release of mitochondrial proapoptotic proteins in caspase-dependent and -independent manner in HT-29 cells

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    In this study, the release of mitochondrial proapoptotic intermembrane space proteins induced by exogenous C2-ceramide in human colon carcinoma (HT-29) cell line was investigated. HT-29 cells were treated with 12.5, 25 and 50 μmol/L C2-ceramide in vitro. Flow cytometer was used to detect the mitochondrial membrane potential (△Ψm). Subcellular fractions were extracted by Mitochondrial/Cytosol Fractionation Kit after C2-ceramide treatment for 24 h. SDS-PAGE was used to determine the level of cytochrome c (Cyt c), high temperature requirement A2 (HtrA2) and second mitochondrial-derived activator of caspases (Smac) released from mitochondria, the expression of X-linked inhibitor of apoptosis protein (XIAP) and caspase-3 for 24 h. The results showed that △Ψm began to decrease from 6 h after 25 and 50 μmol/L C2-ceramide treatment (P<0.05) and cyclosporin A (CsA) could inhibit the collapse of △Ψm through regulating mitochondrial membrane permeability transition pore. There was no effect of C2-ceramide on the expression of Cyt c, HtrA2 and Smac in the total levels. 12.5, 25 and 50 μmol/L C2-ceramide could induce Cyt c, HtrA2 and Smac to release from mitochondria to cytosol and down-regulate the expression of XIAP (P<0.05). Also there was expression of cleaved caspase-3 with C2-ceramide treatment. After the treatment with caspase inhibitor, C2-ceramide still induced the release of Cyt c and HtrA2, but Smac did not. Therefore, C2-ceramide could induce apoptosis of HT-29 cells through the mitochondria pathway. The release of Cyt c, HtrA2 and Smac from mitochondria did not occur via the same mechanism, the release of Cyt c and HtrA2 was caspase-independent and the release of Smac was caspase-dependent.

  20. Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy

    OpenAIRE

    Sentelle, R. David; Senkal, Can E.; Jiang, Wenhui; Ponnusamy, Suriyan; Gencer, Salih; Selvam, Shanmugam Panneer; Ramshesh, Venkat K.; Peterson, Yuri K.; Lemasters, John J.; Szulc, Zdzislaw M.; Bielawski, Jacek; Ogretmen, Besim

    2012-01-01

    Mechanisms by which autophagy promotes cell survival or death are unclear. We provide evidence that C18-pyridinium ceramide (C18-Pyr-Cer) treatment, or endogenous C18-ceramide generation by ceramide synthase 1 (CerS1) expression mediates autophagic cell death, independent of apoptosis in human cancer cells. C18-ceramide-induced lethal autophagy was regulated via microtubule-associated protein 1 light chain 3 beta lipidation (LC3B-II) and selective targeting of mitochondria by LC3B-II-containi...

  1. Lipid domain morphologies in phosphatidylcholine-ceramide monolayers

    DEFF Research Database (Denmark)

    Karttunen, Mikko; Haataja, Mikko P; Säily, Matti;

    2009-01-01

    In cells, one of the main roles of ceramide-enriched membrane domains is to recruit or exclude intracellular signaling molecules and receptors, thereby facilitating signal transduction cascades. Accordingly, in model membranes, even low contents of ceramide segregate into lateral domains. The...... of fluorescent NBD-phosphatidylcholine into DMPC/Cer mixtures was found to be very sensitive to the N-acyl chain length. Shorter ceramides (Cer10-Cer14) formed flower-like (seaweed) domains, whereas longer ceramides (N-acyl chain length>14 carbon atoms) formed round and regular domains. We attribute...

  2. Sphingosine 1-phosphate inhibits activation of caspases that cleave poly(ADP-ribose) polymerase and lamins during Fas- and ceramide-mediated apoptosis in Jurkat T lymphocytes.

    Science.gov (United States)

    Cuvillier, O; Rosenthal, D S; Smulson, M E; Spiegel, S

    1998-01-30

    Ceramide, a sphingolipid generated by the hydrolysis of membrane-associated sphingomyelin, appears to play a role as a gauge of apoptosis. A further metabolite of ceramide, sphingosine 1-phosphate (SPP), prevents ceramide-mediated apoptosis, and it has been suggested that the balance between intracellular ceramide and SPP levels may determine the cell fate (Cuvillier, O., Pirianov, G, Kleuser, B., Vanek, P. G., Coso, O. A., Gutkind, J. S., and Spiegel, S. (1996) Nature 381, 800-803). Here, we investigated the role of SPP and the protein kinase C activator, phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), in the caspase cascade leading to the proteolysis of poly(ADP-ribose) polymerase (PARP) and lamins. In Jurkat T cells, Fas ligation or addition of exogenous C2-ceramide induced activations of caspase-3/CPP32 and caspase-7/Mch3 followed by PARP cleavage, effects that can be blocked either by SPP or TPA. Furthermore, both SPP and TPA inhibit the activation of caspase-6/Mch2 and subsequent lamin B cleavage. Ceramide, in contrast to Fas ligation, did not induce activation of caspase-8/FLICE and neither SPP nor TPA were able to prevent this activation. Thus, SPP, likely generated via protein kinase C-mediated activation of sphingosine kinase, suppresses the apoptotic pathway downstream of FLICE but upstream of the executioner caspases, caspase-3, -6, and -7. PMID:9446602

  3. Ceramides: A potential therapeutic target in pulmonary emphysema

    NARCIS (Netherlands)

    J. Tibboel (Jeroen); I.K.M. Reiss (Irwin); J.C. de Jongste (Johan); M.R. Post (Martin)

    2013-01-01

    textabstractBackground: The aim of this manuscript was to characterize airway ceramide profiles in a rodent model of elastase-induced emphysema and to examine the effect of pharmacological intervention directed towards ceramide metabolism.Methods: Adult mice were anesthetized and treated with an int

  4. Ceramide mediates Ox-LDL-induced human vascular smooth muscle cell calcification via p38 mitogen-activated protein kinase signaling.

    Directory of Open Access Journals (Sweden)

    Lizhen Liao

    Full Text Available Vascular calcification is associated with significant cardiovascular morbidity and mortality, and has been demonstrated as an actively regulated process resembling bone formation. Oxidized low density lipoprotein (Ox-LDL has been identified as a regulatory factor involved in calcification of vascular smooth muscle cells (VSMCs. Additionally, over-expression of recombinant human neutral sphingomyelinase (N-SMase has been shown to stimulate VSMC apoptosis, which plays an important role in the progression of vascular calcification. The aim of this study is to investigate whether ceramide regulates Ox-LDL-induced calcification of VSMCs via activation of p38 mitogen-activated protein kinase (MAPK pathway. Ox-LDL increased the activity of N-SMase and the level of ceramide in cultured VSMCs. Calcification and the osteogenic transcription factor, Msx2 mRNA expression were reduced by N-SMase inhibitor, GW4869 in the presence of Ox-LDL. Usage of GW4869 inhibited Ox-LDL-induced apoptosis in VSMCs, an effect which was reversed by C2-ceramide. Additionally, C2-ceramide treatment accelerated VSMC calcification, with a concomitant increase in ALP activity. Furthermore, C2-ceramide treatment enhanced Ox-LDL-induced VSMC calcification. Addition of caspase inhibitor, ZVAD-fmk attenuated Ox-LDL-induced calcification. Both Ox-LDL and C2-ceramide treatment increased the phosphorylation of p38 MAPK. Inhibition of p38 MAPK by SB203580 attenuated Ox-LDL-induced calcification of VSMCs. These data suggest that Ox-LDL activates N-SMase-ceramide signaling pathway, and stimulates phosphorylation of p38 MAPK, leading to apoptosis in VSMCs, which initiates VSMC calcification.

  5. Important roles of brain-specific carnitine palmitoyltransferase and ceramide metabolism in leptin hypothalamic control of feeding.

    Science.gov (United States)

    Gao, Su; Zhu, Guangjing; Gao, Xuefei; Wu, Donghai; Carrasco, Patricia; Casals, Núria; Hegardt, Fausto G; Moran, Timothy H; Lopaschuk, Gary D

    2011-06-01

    Brain-specific carnitine palmitoyltransferase-1 (CPT-1c) is implicated in CNS control of food intake. In this article, we explore the role of hypothalamic CPT-1c in leptin's anorexigenic actions. We first show that adenoviral overexpression of CPT-1c in hypothalamic arcuate nucleus of rats increases food intake and concomitantly up-regulates orexigenic neuropeptide Y (NPY) and Bsx (a transcription factor of NPY). Then, we demonstrate that this overexpression antagonizes the anorectic actions induced by central leptin or compound cerulenin (an inhibitor of fatty acid synthase). The overexpression of CPT-1c also blocks leptin-induced down-regulations of NPY and Bsx. Furthermore, the anorectic actions of central leptin or cerulenin are impaired in mice with brain CPT-1c deleted. Both anorectic effects require elevated levels of hypothalamic arcuate nucleus (Arc) malonyl-CoA, a fatty acid-metabolism intermediate that has emerged as a mediator in hypothalamic control of food intake. Thus, these data suggest that CPT-1c is implicated in malonyl-CoA action in leptin's hypothalamic anorectic signaling pathways. Moreover, ceramide metabolism appears to play a role in leptin's central control of feeding. Leptin treatment decreases Arc ceramide levels, with the decrease being important in leptin-induced anorectic actions and down-regulations of NPY and Bsx. Of interest, our data indicate that leptin impacts ceramide metabolism through malonyl-CoA and CPT-1c, and ceramide de novo biosynthesis acts downstream of both malonyl-CoA and CPT-1c in mediating their effects on feeding and expressions of NPY and Bsx. In summary, we provide insights into the important roles of malonyl-CoA, CPT-1c, and ceramide metabolism in leptin's hypothalamic signaling pathways. PMID:21593415

  6. Endurance and Resistance Training Affect High Fat Diet-Induced Increase of Ceramides, Inflammasome Expression, and Systemic Inflammation in Mice

    Directory of Open Access Journals (Sweden)

    Cornelia Mardare

    2016-01-01

    Full Text Available The study aimed to investigate the effects of differentiated exercise regimes on high fat-induced metabolic and inflammatory pathways. Mice were fed a standard diet (ST or a high fat diet (HFD and subjected to regular endurance training (ET or resistance training (RT. After 10 weeks body weight, glucose tolerance, fatty acids (FAs, circulating ceramides, cytokines, and immunological mediators were determined. The HFD induced a significant increase in body weight and a disturbed glucose tolerance (p<0.05. An increase of plasma FA, ceramides, and inflammatory mediators in adipose tissue and serum was found (p<0.05. Both endurance and resistance training decreased body weight (p<0.05 and reduced serum ceramides (p<0.005. While RT attenuated the increase of NLRP-3 (RT expression in adipose tissue, ET was effective in reducing TNF-α and IL-18 expression. Furthermore, ET reduced levels of MIP-1γ, while RT decreased levels of IL-18, MIP-1γ, Timp-1, and CD40 in serum (p<0.001, respectively. Although both exercise regimes improved glucose tolerance (p<0.001, ET was more effective than RT. These results suggest that exercise improves HFD-induced complications possibly through a reduction of ceramides, the reduction of inflammasome activation in adipose tissues, and a systemic downregulation of inflammatory cytokines.

  7. LCL124, a Cationic Analog of Ceramide, Selectively Induces Pancreatic Cancer Cell Death by Accumulating in Mitochondria

    OpenAIRE

    Beckham, Thomas H; Lu, Ping; Jones, Elizabeth E.; Marrison, Tucker; Lewis, Clayton S.; Cheng, Joseph C.; Ramshesh, Venkat K.; Beeson, Gyda; Beeson, Craig C.; Richard R. Drake; Bielawska, Alicja; Bielawski, Jacek; Szulc, Zdzislaw M; Ogretmen, Besim; Norris, James S.

    2013-01-01

    Treatment of pancreatic cancer that cannot be surgically resected currently relies on minimally beneficial cytotoxic chemotherapy with gemcitabine. As the fourth leading cause of cancer-related death in the United States with dismal survival statistics, pancreatic cancer demands new and more effective treatment approaches. Resistance to gemcitabine is nearly universal and appears to involve defects in the intrinsic/mitochondrial apoptotic pathway. The bioactive sphingolipid ceramide is a crit...

  8. Cholesterol interactions with ceramide and sphingomyelin.

    Science.gov (United States)

    García-Arribas, Aritz B; Alonso, Alicia; Goñi, Felix M

    2016-09-01

    Sphingolipids contain in their polar heads chemical groups allowing them to establish a complex network of H-bonds (through different OH and NHgroups) with other lipids in the bilayer. In the recent years the specific interaction of sphingomyelin (SM) with cholesterol (Chol) has been examined, largely in the context of the "lipid raft" hypothesis. Formation of SM-Ceramide (Cer) complexes, proposed to exist in cell membranes in response to stress, has also been described. More recently, a delicate balance of phase formation and transformation in ternary mixtures of SM, Chol and Cer, with mutual displacement of Chol and Cer from their interaction with SM is considered to exist. In addition, data demonstrating direct Chol-Cer interaction are becoming available. PMID:27132117

  9. Molecular dynamics modelling of EGCG clusters on ceramide bilayers

    Energy Technology Data Exchange (ETDEWEB)

    Yeo, Jingjie; Cheng, Yuan; Li, Weifeng; Zhang, Yong-Wei [Institute of High Performance Computing, A*STAR, 138632 (Singapore)

    2015-12-31

    A novel method of atomistic modelling and characterization of both pure ceramide and mixed lipid bilayers is being developed, using only the General Amber ForceField. Lipid bilayers modelled as pure ceramides adopt hexagonal packing after equilibration, and the area per lipid and bilayer thickness are consistent with previously reported theoretical results. Mixed lipid bilayers are modelled as a combination of ceramides, cholesterol, and free fatty acids. This model is shown to be stable after equilibration. Green tea extract, also known as epigallocatechin-3-gallate, is introduced as a spherical cluster on the surface of the mixed lipid bilayer. It is demonstrated that the cluster is able to bind to the bilayers as a cluster without diffusing into the surrounding water.

  10. Topically applied ceramide accumulates in skin glyphs

    Directory of Open Access Journals (Sweden)

    Zhang Q

    2015-07-01

    Full Text Available Qihong Zhang,1 Carol R Flach,1 Richard Mendelsohn,1 Guangru Mao,2 Apostolos Pappas,2 M Catherine Mack,2 Russel M Walters,2 Michael D Southall2 1Department of Chemistry, Rutgers University, Newark, 2Johnson & Johnson Consumer Companies, Inc., Skillman, NJ, USAAbstract: Ceramides (CERs, structural components of the stratum corneum (SC, impart essential barrier properties to this thin outer layer of the epidermis. Variations in CER species within this layer have been linked to several skin diseases. A recent proliferation of CER-containing topical skin-care products warrants the elucidation of CER penetration profiles in both healthy and diseased skin. In the current study, the spatial distributions of CER concentration profiles, following topical application of two species of CER, were tracked using infrared imaging. Suspensions of single-chain perdeuterated sphingosine and phytosphingosine CER in oleic acid were applied, in separate experiments, to the surface of healthy intact ex vivo human skin using Franz diffusion cells. Following either a 24- or 48-hour incubation period at 34°C, infrared images were acquired from microtomed skin sections. Both CER species accumulated in glyph regions of the skin and penetrated into the SC, to a limited extent, only in these regions. The concentration profiles observed herein were independent of the CER species and incubation time utilized in the study. As a result, a very heterogeneous, sparse, spatial distribution of CERs in the SC was revealed. In contrast, oleic acid was found to be fairly homogeneously distributed throughout the SC and viable epidermis, albeit at lower concentrations in the latter. A more uniform, lateral distribution of CERs in the SC would likely be important for barrier efficacy or enhancement.Keywords: stratum corneum, infrared imaging, topical delivery, oleic acid

  11. Intrinsic, pro-apoptotic effects of IGFBP-3 on breast cancer cells are reversible: Involvement of PKA, Rho and ceramide.

    Directory of Open Access Journals (Sweden)

    Claire M Perks

    2011-05-01

    Full Text Available We established previously that IGFBP-3 could exert positive or negative effects on cell function depending upon the extracellular matrix composition and by interacting with integrin signalling. To elicit its pro-apoptotic effects IGFBP-3 bound to caveolin-1 and the beta 1 integrin receptor and increased their association culminating in MAPK activation. Disruption of these complexes or blocking the beta 1 integrin receptor reversed these intrinsic actions of IGFBP-3. In this study we have examined the signalling pathway between integrin receptor binding and MAPK activation that mediates the intrinsic, pro-apoptotic actions of IGFBP-3. We found on inhibiting protein kinase A(PKA, Rho associated kinase (ROCK and ceramide, the accentuating effects of IGFBP-3 on apoptotic triggers were reversed, such that IGFBP-3 then conferred cell survival. We established that IGFBP-3 activated Rho, the upstream regulator of ROCK and that beta1 integrin and PKA were upstream of Rho activation, whereas the involvement of ceramide was downstream. The beta 1 integrin, PKA, Rho and ceramide were all upstream of MAPK activation. These data highlight key components involved in the pro-apoptotic effects of IGFBP-3 and that inhibiting them leads to a reversal in the action of IGFBP-3.

  12. Lamellar granule biogenesis: a role for ceramide glucosyltransferase, lysosomal enzyme transport, and the Golgi.

    Science.gov (United States)

    Madison, K C; Sando, G N; Howard, E J; True, C A; Gilbert, D; Swartzendruber, D C; Wertz, P W

    1998-08-01

    Although lamellar granules are critical to the formation of the epidermal permeability barrier and are a known marker of late keratinocyte differentiation, very little is known about the physiologic regulators of lamellar granule assembly and extrusion. Ceramide glucosyltransferase (CGT), the enzyme responsible for the synthesis of lamellar granule glucosylceramides (GlcCer; the precursors of the stratum corneum ceramides), is localized to the Golgi apparatus in other cell types. We have found that CGT is induced during keratinocyte culture differentiation coincident with increased GlcCer content and the appearance of lamellar granules. In this study we show that the differentiation-related CGT induction is likely mediated at the transcriptional level. In addition, all-trans retinoic acid, a well-known inhibitor of keratinocyte differentiation, prevents the appearance of lamellar granules and decreases culture CGT activity and GlcCer content without affecting sphingomyelin or total lipid content, indicating a specific inhibition of this enzymatic pathway. These data show a direct relationship between CGT activity and epidermal differentiation, suggesting that regulation of CGT expression is a critical part of epidermal barrier generation. The differentiation dependence of CGT activity, the key role of this Golgi-localized enzyme in epidermal GlcCer synthesis, and our previous finding that ceramides are converted to GlcCer in the Golgi apparatus in keratinocyte cultures, strongly suggest a Golgi origin for lamellar granules. In contrast to CGT, the activity of the lysosomal enzymes acid lipase and glucocerebrosidase is less clearly related to epidermal differentiation and the appearance of lamellar granules, although both enzymes show striking colocalization and enrichment in a subcellular lamellar granule fraction derived from pig epidermis. Acid lipase activity in the lamellar granule fraction was found to contain primarily a small lysosomal form of the enzyme

  13. The role of MAPK signalling pathways in acetic acid-induced cell death of Saccharomyces cerevisiae

    OpenAIRE

    Azevedo, Flávio Humberto Torres Dias Feio de

    2011-01-01

    Dissertação de mestrado em Genética Molecular Mitogenic Activated Protein Kinase (MAPK) cascades are important signalling pathways that allow yeast cells to swiftly adapt to changing environmental conditions. Previous studies suggested that the High Osmolarity Glycerol (HOG) MAPK pathway and ceramide production are involved in acetic-acid induced apoptosis in yeast. Evidence that changes in the levels of endogenous ceramides can affect yeast cell fate has also been put forth...

  14. Differential protection by wildtype vs. organelle-specific Bcl-2 suggests a combined requirement of both the ER and mitochondria in ceramide-mediated caspase-independent programmed cell death

    Directory of Open Access Journals (Sweden)

    Belka Claus

    2009-10-01

    Full Text Available Abstract Background Programmed cell death (PCD is essential for development and homeostasis of multicellular organisms and can occur by caspase-dependent apoptosis or alternatively, by caspase-independent PCD (ciPCD. Bcl-2, a central regulator of apoptosis, localizes to both mitochondria and the endoplasmic reticulum (ER. Whereas a function of mitochondrial and ER-specific Bcl-2 in apoptosis has been established in multiple studies, corresponding data for ciPCD do not exist. Methods We utilized Bcl-2 constructs specifically localizing to mitochondria (Bcl-2 ActA, the ER (Bcl-2 cb5, both (Bcl-2 WT or the cytosol/nucleus (Bcl-2 ΔTM and determined their protective effect on ceramide-mediated ciPCD in transiently and stably transfected Jurkat cells. Expression of the constructs was verified by immunoblots. Ceramide-mediated ciPCD was induced by treatment with human recombinant tumor necrosis factor and determined by flow cytometric measurement of propidium iodide uptake as well as by optical analysis of cell morphology. Results Only wildtype Bcl-2 had the ability to efficiently protect from ceramide-mediated ciPCD, whereas expression of Bcl-2 solely at mitochondria, the ER, or the cytosol/nucleus did not prevent ceramide-mediated ciPCD. Conclusion Our data suggest a combined requirement for both mitochondria and the ER in the induction and the signaling pathways of ciPCD mediated by ceramide.

  15. Differential protection by wildtype vs. organelle-specific Bcl-2 suggests a combined requirement of both the ER and mitochondria in ceramide-mediated caspase-independent programmed cell death

    International Nuclear Information System (INIS)

    Programmed cell death (PCD) is essential for development and homeostasis of multicellular organisms and can occur by caspase-dependent apoptosis or alternatively, by caspase-independent PCD (ciPCD). Bcl-2, a central regulator of apoptosis, localizes to both mitochondria and the endoplasmic reticulum (ER). Whereas a function of mitochondrial and ER-specific Bcl-2 in apoptosis has been established in multiple studies, corresponding data for ciPCD do not exist. We utilized Bcl-2 constructs specifically localizing to mitochondria (Bcl-2 ActA), the ER (Bcl-2 cb5), both (Bcl-2 WT) or the cytosol/nucleus (Bcl-2 ΔTM) and determined their protective effect on ceramide-mediated ciPCD in transiently and stably transfected Jurkat cells. Expression of the constructs was verified by immunoblots. Ceramide-mediated ciPCD was induced by treatment with human recombinant tumor necrosis factor and determined by flow cytometric measurement of propidium iodide uptake as well as by optical analysis of cell morphology. Only wildtype Bcl-2 had the ability to efficiently protect from ceramide-mediated ciPCD, whereas expression of Bcl-2 solely at mitochondria, the ER, or the cytosol/nucleus did not prevent ceramide-mediated ciPCD. Our data suggest a combined requirement for both mitochondria and the ER in the induction and the signaling pathways of ciPCD mediated by ceramide

  16. Moisturizers and Ceramide-containing Moisturizers May Offer Concomitant Therapy with Benefits

    OpenAIRE

    Lynde, Chuck W.; Andriessen, Anneke; Barankin, Benjamin; de Gannes, Gillian; Gulliver, Wayne; Haber, Richard; Mccuaig, Catherine; Rajan, Poonam; Skotnicki, Sandra P.; Thomas, Richard; Toole, Jack; Vender, Ron

    2014-01-01

    Introduction: Ceramide-containing moisturizers may offer benefits as an adjunct to acne treatment. Methods: An expert panel of 11 Canadian dermatologists, including an international clinical scientist, used the following modified Delphi process: 1) A systematic literature review for acne treatment, dry skin, irritation, depletion of ceramides in acne, and benefits of moisturizers and ceramide-containing moisturizers was conducted; 2) panel members gave their opinion on the resulting statement...

  17. All members in the sphingomyelin synthase gene family have ceramide phosphoethanolamine synthase activity[S

    OpenAIRE

    Ding, Tingbo; Kabir, Inamul; Li, Yue; Lou, Caixia; Yazdanyar, Amirfarbod; Xu, Jiachen; Dong, Jibin; Zhou, Hongwen; Park, Taesik; Boutjdir, Mohamed; Li, Zhiqiang; Jiang, Xian-Cheng

    2015-01-01

    Sphingomyelin synthase-related protein (SMSr) synthesizes the sphingomyelin analog ceramide phosphoethanolamine (CPE) in cells. Previous cell studies indicated that SMSr is involved in ceramide homeostasis and is crucial for cell function. To further examine SMSr function in vivo, we generated Smsr KO mice that were fertile and had no obvious phenotypic alterations. Quantitative MS analyses of plasma, liver, and macrophages from the KO mice revealed only marginal changes in CPE and ceramide a...

  18. Regulation of secretory transport by protein kinase D–mediated phosphorylation of the ceramide transfer protein

    OpenAIRE

    Fugmann, Tim; Hausser, Angelika; Schöffler, Patrik; Schmid, Simone; Pfizenmaier, Klaus; Olayioye, Monilola A.

    2007-01-01

    Protein kinase D (PKD) has been identified as a crucial regulator of secretory transport at the trans-Golgi network (TGN). Recruitment and activation of PKD at the TGN is mediated by the lipid diacylglycerol, a pool of which is generated by sphingomyelin synthase from ceramide and phosphatidylcholine. The nonvesicular transfer of ceramide from the endoplasmic reticulum to the Golgi complex is mediated by the lipid transfer protein CERT (ceramide transport). In this study, we identify CERT as ...

  19. An Inverse Relationship Between Ceramide Synthesis and Clinical Severity in Patients with Psoriasis

    OpenAIRE

    Cho, Yunhi; Lew, Bark-Lynn; Seong, Kyunghwa; Kim, Nack-In

    2004-01-01

    Ceramides play major roles in maintaining the epidermal barrier. It has been sus-pected that the depletion of ceramides, associated with disrupted barrier function in the epidermis, leads to the clinical manifestation of dryness and inflammation seen in patients with psoriasis. The aim of the present study was to determine the relation-ship between the level of ceramide synthesis in the epidermis and the clinical severity in patients with psoriasis. Samples from lesional and unlesional epider...

  20. Short-chain ceramides depress integrin cell surface expression and function in colorectal cancer cells.

    Science.gov (United States)

    Morad, Samy A F; Bridges, Lance C; Almeida Larrea, Alex D; Mayen, Anthony L; MacDougall, Matthew R; Davis, Traci S; Kester, Mark; Cabot, Myles C

    2016-07-01

    Colorectal cancer (CRC) is highly metastatic, significantly so to liver, a characteristic that embodies one of the most challenging aspects of treatment. The integrin family of cell-cell and cell-matrix adhesion receptors plays a central role in migration and invasion, functions that underlie metastatic potential. In the present work we sought to determine the impact of ceramide, which plays a key modulatory role in cancer suppression, on integrin cell surface expression and function in CRC cells in order to reveal possible ceramide-centric effects on tumor cell motility. Human CRC cells LoVo, HT-29, and HCT-116 were employed, which represent lines established from primary and metastatic sites. A cell-permeable, short-chain analog, C6-ceramide, was used as ceramide mimic. Exposure of cells to C6-ceramide (24 h) promoted a dose-dependent (2.5-10 µM) decrease in the expression of cell surface β1 and β4 integrin subunits in all cell lines; at 10 µM C6-ceramide, the decreases ranged from 30 to 50% of the control. Expression of cell surface αVβ6 integrin, which is associated with advanced invasion in CRC, was also suppressed by C6-ceramide. Decreases in integrin expression translated to diminished cellular adhesion, 50% of the control at 5 µM C6-ceramide, and markedly reduced cellular migration, approximately 30-40% of the control in all cell lines. Physicochemical examination revealed potent efficacy of nano-formulated C6-ceramide, but inferior activity of dihydro-C6-ceramide and L-C6-ceramide, compared to the unsaturated counterpart and the natural d-enantiomer, respectively. These studies demonstrate novel actions of ceramides that may have application in suppression of tumor metastasis, in addition to their known tumor suppressor effects. PMID:27045476

  1. Effect of monoglycerides and fatty acids on a ceramide bilayer

    OpenAIRE

    Akinshina, Anna; Das, Chinmay; Noro, Massimo G.

    2016-01-01

    Monoglycerides and unsaturated fatty acids, naturally present in trace amounts in the stratum corneum (top layer of skin) lipid matrix, are commonly used in pharmaceutical, cosmetic and health care formulations. However, a detailed molecular understanding of how the oil additives get incorporated into the skin lipids from topical application and, once incorporated, how they affect the properties and integrity of the lipid matrix remains unexplored. Using ceramide 2 bilayers as skin lipid surr...

  2. Solenopsin A and analogs exhibit ceramide-like biological activity

    OpenAIRE

    Karlsson, Isabella; Zhou, Xin; Thomas, Raquela; Smith, Allorie T; Bonner, Michael Y.; Bakshi, Pooja; Banga, Ajay K.; Bowen, J. Phillip; Qabaja, Ghassan; Ford, Shavon L; Ballard, Matthew D; Petersen, Kimberly S.; Li, Xuechen; Chen, Guangping; Ogretmen, Besim

    2015-01-01

    Background (−)-Solenopsin A is a piperidine alkaloid that is a component of the venom of the fire ant Solenopsis invicta. Previously, we have demonstrated that solenopsin exhibit anti-angiogenic activity and downregulate phosphoinositol-3 kinase (PI3K) in the p53 deficient renal cell carcinoma cell line 786-O. Solenopsin has structural similarities to ceramide, a major endogenous regulator of cell signaling and cancer therapy induced apoptosis. Methods Different analogs of solenopsin were syn...

  3. Treating atopic dermatitis: safety, efficacy, and patient acceptability of a ceramide hyaluronic acid emollient foam

    Directory of Open Access Journals (Sweden)

    Pacha O

    2012-05-01

    Full Text Available Omar Pacha, Adelaide A HebertDepartment of Dermatology, University of Texas Health Science Center, Houston, TX, USAAbstract: Advances in current understanding of the pathophysiology of atopic dermatitis have led to improved targeting of the structural deficiencies in atopic skin. Ceramide deficiency appears to be one of the major alterations in atopic dermatitis and the replenishment of this epidermal component through topically applied ceramide based emollients appears to be safe, well tolerated, and effective. Recently a ceramide hyaluronic acid foam has become commercially available and increasing evidence supports its safety and efficacy in patients who suffer from atopic dermatitis.Keywords: atopic dermatitis, ceramide, Hylatopic, eczema, non-steroidal, dermatology

  4. Sphingomyelinase D/Ceramide 1-Phosphate in Cell Survival and Inflammation

    Directory of Open Access Journals (Sweden)

    Io-Guané Rivera

    2015-04-01

    Full Text Available Sphingolipids are major constituents of biological membranes of eukaryotic cells. Many studies have shown that sphingomyelin (SM is a major phospholipid in cell bilayers and is mainly localized to the plasma membrane of cells, where it serves both as a building block for cell architecture and as a precursor of bioactive sphingolipids. In particular, upregulation of (C-type sphingomyelinases will produce ceramide, which regulates many physiological functions including apoptosis, senescence, or cell differentiation. Interestingly, the venom of some arthropodes including spiders of the genus Loxosceles, or the toxins of some bacteria such as Corynebacterium tuberculosis, or Vibrio damsela possess high levels of D-type sphingomyelinase (SMase D. This enzyme catalyzes the hydrolysis of SM to yield ceramide 1-phosphate (C1P, which promotes cell growth and survival and is a potent pro-inflammatory agent in different cell types. In particular, C1P stimulates cytosolic phospholipase A2 leading to arachidonic acid release and the subsequent formation of eicosanoids, actions that are all associated to the promotion of inflammation. In addition, C1P potently stimulates macrophage migration, which has also been associated to inflammatory responses. Interestingly, this action required the interaction of C1P with a specific plasma membrane receptor, whereas accumulation of intracellular C1P failed to stimulate chemotaxis. The C1P receptor is coupled to Gi proteins and activates of the PI3K/Akt and MEK/ERK1-2 pathways upon ligation with C1P. The proposed review will address novel aspects on the control of inflammatory responses by C1P and will highlight the molecular mechanisms whereby C1P exerts these actions.

  5. Sphingolipid and Ceramide Homeostasis: Potential Therapeutic Targets

    Directory of Open Access Journals (Sweden)

    Simon A. Young

    2012-01-01

    Full Text Available Sphingolipids are ubiquitous in eukaryotic cells where they have been attributed a plethora of functions from the formation of structural domains to polarized cellular trafficking and signal transduction. Recent research has identified and characterised many of the key enzymes involved in sphingolipid metabolism and this has led to a heightened interest in the possibility of targeting these processes for therapies against cancers, Alzheimer's disease, and numerous important human pathogens. In this paper we outline the major pathways in eukaryotic sphingolipid metabolism and discuss these in relation to disease and therapy for both chronic and infectious conditions.

  6. [Sphingolipid-mediated apoptotic signaling pathways].

    Science.gov (United States)

    Cuvillier, Olivier; Andrieu-Abadie, Nathalie; Ségui, Bruno; Malagarie-Cazenave, Sophie; Tardy, Claudine; Bonhoure, Elisabeth; Levade, Thierry

    2003-01-01

    Various sphingolipids are being viewed as bioactive molecules and/or second messengers. Among them, ceramide (or N-acylsphingosine) and sphingosine generally behave as pro-apoptotic mediators. Indeed, ceramide mediates the death signal initiated by numerous stress agents which either stimulate its de novo synthesis or activate sphingomyelinases that release ceramide from sphingomyelin. For instance, the early generation of ceramide promoted by TNF is mediated by a neutral sphingomyelinase the activity of which is regulated by the FAN adaptor protein, thereby controlling caspase activation and the cell death programme. In addition, the activity of this neutral sphingomyelinase is negatively modulated by caveolin, a major constituent of some membrane microdomains. The enzyme sphingosine kinase also plays a crucial role in apoptosis signalling by regulating the intracellular levels of two sphingolipids having opposite effects, namely the pro-apoptotic sphingosine and the anti-apoptotic sphingosine 1-phosphate molecule. Ceramide and sphingosine metabolism therefore appears as a pivotal regulatory pathway in the determination of cell fate. PMID:14708343

  7. Human skeletal muscle ceramide content is not a major factor in muscle insulin sensitivity

    DEFF Research Database (Denmark)

    Skovbro, M; Baranowski, M; Skov-Jensen, C;

    2008-01-01

    AIMS/HYPOTHESIS: In skeletal muscle, ceramides may be involved in the pathogenesis of insulin resistance through an attenuation of insulin signalling. This study investigated total skeletal muscle ceramide fatty acid content in participants exhibiting a wide range of insulin sensitivities. METHODS...

  8. Immobilization of phospholipase C for the production of ceramide from sphingomyelin hydrolysis

    DEFF Research Database (Denmark)

    Zhang, Long; Hellgren, Lars; Xu, Xuebing

    2007-01-01

    The immobilization of Clostridium perfringens phospholipase C was studied for the first time and the catalytic properties of the immobilized enzyme were investigated for the hydrolysis of sphingomyelin to produce ceramide. Ceramide is of great commercial potentials in cosmetic and pharmaceutical...

  9. Influence of cholesterol and ceramide VI on the structure of multilamellar lipid membranes at water exchange

    International Nuclear Information System (INIS)

    The structural changes in the multilamellar lipid membranes of dipalmitoylphosphatidylcholine (DPPC)/cholesterol and DPPC/ceramide VI binary systems during hydration and dehydration have been studied by neutron diffraction. The effect of cholesterol and ceramide on the kinetics of water exchange in DPPC membranes is characterized. Compared to pure DPPC, membranes of binary systems swell faster during hydration (with a characteristic time of ∼30 min). Both compounds, ceramide VI and cholesterol, similarly affect the hydration of DPPC membranes, increasing the repeat distance due to the bilayer growth. However, in contrast to cholesterol, ceramide significantly reduces the thickness of the membrane water layer. The introduction of cholesterol into a DPPC membrane slows down the change in the parameters of the bilayer internal structure during dehydration. In the DPPC/ceramide VI/cholesterol ternary system (with a molar cholesterol concentration of 40%), cholesterol is partially released from the lamellar membrane structure into the crystalline phase.

  10. GIPC: Glycosyl Inositol Phospho Ceramides, the major sphingolipids on earth.

    Science.gov (United States)

    Gronnier, Julien; Germain, Véronique; Gouguet, Paul; Cacas, Jean-Luc; Mongrand, Sébastien

    2016-04-01

    What are the most abundant sphingolipids on earth? The answer is Glycosyl Inositol Phosphoryl Ceramides (GIPCs) present in fungi and the green lineage. In this review, we discuss the putative role of plant GIPCs in the lipid bilayer asymmetry, in the lateral organization of membrane rafts and in the very long chain fatty acid inter-leaflet coupling of lipids in the plant plasma membrane (PM). A special focus on the structural similarities -and putative functions- of GIPCs is discussed by comparison with animal gangliosides, structural homologs of plant GIPCs. PMID:27074617

  11. Ultraviolet (UV and Hydrogen Peroxide Activate Ceramide-ER Stress-AMPK Signaling Axis to Promote Retinal Pigment Epithelium (RPE Cell Apoptosis

    Directory of Open Access Journals (Sweden)

    Jin Yao

    2013-05-01

    Full Text Available Ultraviolet (UV radiation and reactive oxygen species (ROS impair the physiological functions of retinal pigment epithelium (RPE cells by inducing cell apoptosis, which is the main cause of age-related macular degeneration (AMD. The mechanism by which UV/ROS induces RPE cell death is not fully addressed. Here, we observed the activation of a ceramide-endoplasmic reticulum (ER stress-AMP activated protein kinase (AMPK signaling axis in UV and hydrogen peroxide (H2O2-treated RPE cells. UV and H2O2 induced an early ceramide production, profound ER stress and AMPK activation. Pharmacological inhibitors against ER stress (salubrinal, ceramide production (fumonisin B1 and AMPK activation (compound C suppressed UV- and H2O2-induced RPE cell apoptosis. Conversely, cell permeable short-chain C6 ceramide and AMPK activator AICAR (5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide mimicked UV and H2O2’s effects and promoted RPE cell apoptosis. Together, these results suggest that UV/H2O2 activates the ceramide-ER stress-AMPK signaling axis to promote RPE cell apoptosis.

  12. Separation and Detection of Ceramides by HPLC Followed by Evaporative Light-Scattering Detection and Thin Layer Chromatography

    Institute of Scientific and Technical Information of China (English)

    张琳; 周全; 傅学奇; 陈国强

    2002-01-01

    Ceramides are important signaling molecules involved in a variety of cellular processes, including cell growth, differentiation, and apoptosis. Currently, different methods are used for ceramide analysis, some of which are insensitive or cumbersome. This paper described methods utilizing thin layer chromatography (TLC) and high-performance liquid chromatography (HPLC) followed by evaporative light scattering detection (ELSD) to detect ceramide directly in cell extracts without derivatization, which was proved to be efficient and reproducible. Five kinds of ceramides were used as standards. Both TLC and normal-phase HPLC/ELSD results indicate that yeast contains several kinds of ceramides.

  13. Regulation of Neuronal Stem Cell Proliferation in the Hippocampus by Endothelial Ceramide

    Directory of Open Access Journals (Sweden)

    Anne Gulbins

    2016-08-01

    Full Text Available Background/Aims: Major depressive disorder is one of the most common diseases in western countries. The disease is mainly defined by its psychiatric symptoms. However, the disease has also many symptoms outside the central nervous system, in particular cardiovascular symptoms. Recent studies demonstrated that the acid sphingomyelinase/ceramide system plays an important role in the development of major depressive disorder and functions as a target of antidepressants. Methods: Here, we investigated (i whether ceramide accumulates in endothelial cells in the neurogenetic zone of the hippocampus after glucocorticosterone-mediated stress, (ii whether ceramide is released into the extracellular space of the hippocampus and (iii whether extracellular ceramide inhibits neuronal proliferation. Ceramide was determined in endothelial cell culture supernatants or extracellular hippocampus extracts by a kinase assay. Endothelial ceramide in the hippocampus was analyzed by confocal microscopy of brain sections stained with Cy3-labelled anti-ceramide antibodies and FITC-Isolectin B4. Neuronal proliferation was measured by incubation of pheochromocytoma neuronal cells with culture supernatants and extracellular hippocampus extracts. Results: Treatment of cultured endothelial cells with glucocorticosterone induces a release of ceramide into the supernatant. Likewise, treatment of mice with glucocorticosterone triggers a release of ceramide into the extracellular space of the hippocampus. The release of ceramide is inhibited by concomitant treatment with the antidepressant amitriptyline, which also inhibits the activity of the acid sphingomyelinase. Studies employing confocal microscopy revealed that ceramide is formed and accumulates exclusively in endothelial cells in the hippocampus of stressed mice, a process that was again prevented by co-application of amitriptyline. Ceramide released in the culture supernatant or into the extracellular space of the

  14. Ceramide Signaling and Metabolism in Pathophysiological States of the Lung.

    Science.gov (United States)

    Petrache, Irina; Berdyshev, Evgeny V

    2016-01-01

    Following the discovery of ceramide as the central signaling and metabolic relay among sphingolipids, studies of its involvement in lung health and pathophysiology have exponentially increased. In this review, we highlight key studies in the context of recent progress in metabolomics and translational research methodologies. Evidence points toward an important role for the ceramide/sphingosine-1-phosphate rheostat in maintaining lung cell survival, vascular barrier function, and proper host response to airway microbial infections. Sphingosine kinase 1 has emerged as an important determinant of sphingosine-1-phosphate lung levels, which, when aberrantly high, contribute to lung fibrosis, maladaptive vascular remodeling, and allergic asthma. New sphingolipid metabolites have been discovered as potential biomarkers of several lung diseases. Although multiple acute and chronic lung pathological conditions involve perturbations in sphingolipid signaling and metabolism, there are specific patterns, unique sphingolipid species, enzymes, metabolites, and receptors, which have emerged that deepen our understanding of lung pathophysiology and inform the development of new therapies for lung diseases. PMID:26667073

  15. Assaying Ceramide Synthase Activity In Vitro and in Living Cells Using Liquid Chromatography-Mass Spectrometry.

    Science.gov (United States)

    Lim, Xin Ying; Pickford, Russell; Don, Anthony S

    2016-01-01

    Sphingolipids are one the major lipid families in eukaryotes, incorporating a diverse array of structural and signaling lipids such as sphingomyelin and gangliosides. The core lipid component for all complex sphingolipids is ceramide, a diacyl lipid consisting of a variable length fatty acid linked through an amide bond to a long chain base such as sphingosine or dihydrosphingosine. This reaction is catalyzed by a family of six ceramide synthases (CERS1-6), each of which preferentially catalyzes the synthesis of ceramides with different fatty acid chain lengths. Ceramides are themselves potent cellular and physiological signaling molecules heavily implicated in diabetes and neurodegenerative diseases, making it important for researchers to have access to sensitive and accurate assays for ceramide synthase activity. This chapter describes methods for assaying ceramide synthase activity in cell or tissue lysates, or in cultured cells (in situ), using liquid chromatography-tandem mass spectrometry (LC-MS/MS) as the readout. LC-MS/MS is a very sensitive and accurate means for assaying ceramide synthase reaction products. PMID:26552671

  16. Diversity and Complexity of Ceramide Generation After Exposure of Jurkat Leukemia Cells to Irradiation

    International Nuclear Information System (INIS)

    Purpose: To define which intracellular pools of sphingomyelin and ceramide are involved in the triggering of apoptosis of Jurkat leukemia cells in response to γ-ray exposure. Methods and Materials: We examined the kinetics of ceramide generation at the whole-cell level and in different subcellular compartments (plasma membrane rafts, mitochondria, and endoplasmic reticulum) after irradiation with photons. Ceramide was measured by high-performance liquid chromatography or after pulse labeling experiments, and the presence of sphingomyelinase within mitochondria was assessed by electron microscopy. Results: Irradiation of Jurkat leukemia cells resulted in the sequential triggering of sphingomyelin hydrolysis, followed by de novo synthesis that led to a late ceramide response (from 24 h) correlated with the triggering of apoptosis. At the subcellular level, pulse-label experiments, using [3H]-palmitate as a precursor, strengthened the involvement of the radiation-induced sphingomyelin breakdown and revealed a very early peak (15 min) of ceramide in plasma membrane rafts. A second peak in mitochondria was measured 4 h after irradiation, resulting from an increase of the sphingomyelin content relating to the targeting of acid sphingomyelinase toward this organelle. Conclusion: These data confirm that ceramide is a major determinant in the triggering of radiation-induced apoptosis and highlight the complexity of the sequential compartment-specific ceramide-mediated response of Jurkat leukemia cells to γ-rays

  17. Proteome-wide Identification of Novel Ceramide-binding Proteins by Yeast Surface cDNA Display and Deep Sequencing.

    Science.gov (United States)

    Bidlingmaier, Scott; Ha, Kevin; Lee, Nam-Kyung; Su, Yang; Liu, Bin

    2016-04-01

    Although the bioactive sphingolipid ceramide is an important cell signaling molecule, relatively few direct ceramide-interacting proteins are known. We used an approach combining yeast surface cDNA display and deep sequencing technology to identify novel proteins binding directly to ceramide. We identified 234 candidate ceramide-binding protein fragments and validated binding for 20. Most (17) bound selectively to ceramide, although a few (3) bound to other lipids as well. Several novel ceramide-binding domains were discovered, including the EF-hand calcium-binding motif, the heat shock chaperonin-binding motif STI1, the SCP2 sterol-binding domain, and the tetratricopeptide repeat region motif. Interestingly, four of the verified ceramide-binding proteins (HPCA, HPCAL1, NCS1, and VSNL1) and an additional three candidate ceramide-binding proteins (NCALD, HPCAL4, and KCNIP3) belong to the neuronal calcium sensor family of EF hand-containing proteins. We used mutagenesis to map the ceramide-binding site in HPCA and to create a mutant HPCA that does not bind to ceramide. We demonstrated selective binding to ceramide by mammalian cell-produced wild type but not mutant HPCA. Intriguingly, we also identified a fragment from prostaglandin D2synthase that binds preferentially to ceramide 1-phosphate. The wide variety of proteins and domains capable of binding to ceramide suggests that many of the signaling functions of ceramide may be regulated by direct binding to these proteins. Based on the deep sequencing data, we estimate that our yeast surface cDNA display library covers ∼60% of the human proteome and our selection/deep sequencing protocol can identify target-interacting protein fragments that are present at extremely low frequency in the starting library. Thus, the yeast surface cDNA display/deep sequencing approach is a rapid, comprehensive, and flexible method for the analysis of protein-ligand interactions, particularly for the study of non-protein ligands. PMID

  18. SIRT3 Deacetylates Ceramide Synthases: IMPLICATIONS FOR MITOCHONDRIAL DYSFUNCTION AND BRAIN INJURY.

    Science.gov (United States)

    Novgorodov, Sergei A; Riley, Christopher L; Keffler, Jarryd A; Yu, Jin; Kindy, Mark S; Macklin, Wendy B; Lombard, David B; Gudz, Tatyana I

    2016-01-22

    Experimental evidence supports the role of mitochondrial ceramide accumulation as a cause of mitochondrial dysfunction and brain injury after stroke. Herein, we report that SIRT3 regulates mitochondrial ceramide biosynthesis via deacetylation of ceramide synthase (CerS) 1, 2, and 6. Reciprocal immunoprecipitation experiments revealed that CerS1, CerS2, and CerS6, but not CerS4, are associated with SIRT3 in cerebral mitochondria. Furthermore, CerS1, -2, and -6 are hyperacetylated in the mitochondria of SIRT3-null mice, and SIRT3 directly deacetylates the ceramide synthases in a NAD(+)-dependent manner that increases enzyme activity. Investigation of the SIRT3 role in mitochondrial response to brain ischemia/reperfusion (IR) showed that SIRT3-mediated deacetylation of ceramide synthases increased enzyme activity and ceramide accumulation after IR. Functional studies demonstrated that absence of SIRT3 rescued the IR-induced blockade of the electron transport chain at the level of complex III, attenuated mitochondrial outer membrane permeabilization, and decreased reactive oxygen species generation and protein carbonyls in mitochondria. Importantly, Sirt3 gene ablation reduced the brain injury after IR. These data support the hypothesis that IR triggers SIRT3-dependent deacetylation of ceramide synthases and the elevation of ceramide, which could inhibit complex III, leading to increased reactive oxygen species generation and brain injury. The results of these studies highlight a novel mechanism of SIRT3 involvement in modulating mitochondrial ceramide biosynthesis and suggest an important role of SIRT3 in mitochondrial dysfunction and brain injury after experimental stroke. PMID:26620563

  19. Immobilization of phospholipase C for the production of ceramide from sphingomyelin hydrolysis

    DEFF Research Database (Denmark)

    Zhang, Long; Hellgren, Lars; Xu, Xuebing

    2007-01-01

    The immobilization of Clostridium perfringens phospholipase C was studied for the first time and the catalytic properties of the immobilized enzyme were investigated for the hydrolysis of sphingomyelin to produce ceramide. Ceramide is of great commercial potentials in cosmetic and pharmaceutical...... industries such as in hair and skin care products, due to its major role in maintaining the water-retaining properties of the epidermis. The feasibility of enzymatic production of ceramide through hydrolysis of sphingomyelin has previously been proven. In order to improve the reusability of the enzyme, the...

  20. Effect of Laser and LED on Enzymatic Production of Ceramide

    DEFF Research Database (Denmark)

    Hongyu, Zhang; Zhang, Long; Tidemand-Lichtenberg, Peter;

    2011-01-01

    An enzyme (Phospholipase C Type I from Clostridium perfringens) was exposed to 0-810J/cm2 of energy using laser light at wavelengths 808 nm, 532nm, 1064 nm, and 1342 nm and two LED light sources at wavelengths 810 nm and 640 nm. Enzyme responses were evaluated by measuring ceramide concentration...... using HPTLC (high performance thin-layer chromatography) at 0.5, 1, 2, 3, 4, 6, 17, 24 h after irradiation. The duration of effect was evaluated from the experimental data. The results show that enzyme activity can be increased by using both laser and LED sources whose wavelength is located within...... a certain range. The effect depends on the energy and wavelength of the light. The increase in enzyme activity continued for about 4 h after irradiation. This study shows that the duration of irradiation should be included as one of the main laser parameters when reporting on the effects of laser...

  1. Kinetic study of sphingomyelin hydrolysis for ceramide production

    DEFF Research Database (Denmark)

    Zhang, Long; Hellgren, Lars; Xu, Xuebing

    2008-01-01

    reaction at 65 °C. The reactions for both the soluble and immobilized enzymes followed Michaelis–Menten kinetics. Km's for the soluble and immobilized enzymes were 1.07 ± 0.32 and 1.26 ± 0.19 mM, respectively. The value of Vmax was markedly decreased by the immobilization without much change in Km, as if...... cosmetic and pharmaceutical industries such as in hair and skin care products. The enzymatic hydrolysis of sphingomyelin has been proved to be a feasible method to produce ceramide. The kinetic performance of sphingomyelin hydrolysis in the optimal two-phase (water:organic solvent) reaction system was...... investigated to elucidate the possible reaction mechanism and also to further improve the hydrolysis performance. Enzyme in solution had less thermal stability than the enzyme powder and the immobilized enzyme. The thermal inactivation of phospholipase C in all the three forms did not follow the first order...

  2. Exercise and training effects on ceramide metabolism in human skeletal muscle

    DEFF Research Database (Denmark)

    Helge, Jørn Wulff; Dobrzyn, Agnieszka; Saltin, Bengt;

    2004-01-01

    In rat skeletal muscle prolonged exercise affects the content and composition of ceramides, but in human skeletal muscle no data are available on this compound. Our aim was to examine the content of ceramide- and sphingomyelin fatty acids and neutral, Mg(2+)-dependent sphingomyelinase activity...... was excised from the vastus lateralis. Ceramide and sphingomyelin were isolated using thin-layer chromatography. The content of individual ceramide fatty acids and sphingomyelin fatty acids was measured by means of gas-liquid chromatography. The activity of neutral, Mg(2+)-dependent sphingomyelinase......(2+)-dependent sphingomyelinase activity was similar in the two groups at rest and a similar reduction was observed after exercise in both groups (untrained from 2.19 +/- 0.08 to 1.78 +/- 0.08 and trained from 2.31 +/- 0.12 to 1.80 +/- 0.09 nmol (mg protein) (-1) h(-1); P

  3. Functional loss of two ceramide synthases elicits autophagy-dependent lifespan extension in C. elegans

    DEFF Research Database (Denmark)

    Mosbech, Mai-Britt; Kruse, Rikke; Harvald, Eva Bang; Olsen, Anne Sofie Braun; Gallego, Sandra Fernandez; Hannibal-Bach, Hans Kristian; Ejsing, Christer S.; Færgeman, Nils J

    2013-01-01

    Ceramide and its metabolites constitute a diverse group of lipids, which play important roles as structural entities of biological membranes as well as regulators of cellular growth, differentiation, and development. The C. elegans genome comprises three ceramide synthase genes; hyl-1, hyl-2, and...... lagr-1. HYL-1 function is required for synthesis of ceramides and sphingolipids containing very long acyl-chains (≥C24), while HYL-2 is required for synthesis of ceramides and sphingolipids containing shorter acyl-chains (≤C22). Here we show that functional loss of HYL-2 decreases lifespan, while loss...... of HYL-1 or LAGR-1 does not affect lifespan. We show that loss of HYL-1 and LAGR-1 functions extend lifespan in an autophagy-dependent manner, as knock down of the autophagy-associated gene ATG-12 abolishes hyl-1;lagr-1 longevity. The transcription factors PHA-4/FOXA, DAF-16/FOXO, and SKN-1 are also...

  4. Regulation of secretory transport by protein kinase D–mediated phosphorylation of the ceramide transfer protein

    Science.gov (United States)

    Fugmann, Tim; Hausser, Angelika; Schöffler, Patrik; Schmid, Simone; Pfizenmaier, Klaus; Olayioye, Monilola A.

    2007-01-01

    Protein kinase D (PKD) has been identified as a crucial regulator of secretory transport at the trans-Golgi network (TGN). Recruitment and activation of PKD at the TGN is mediated by the lipid diacylglycerol, a pool of which is generated by sphingomyelin synthase from ceramide and phosphatidylcholine. The nonvesicular transfer of ceramide from the endoplasmic reticulum to the Golgi complex is mediated by the lipid transfer protein CERT (ceramide transport). In this study, we identify CERT as a novel in vivo PKD substrate. Phosphorylation on serine 132 by PKD decreases the affinity of CERT toward its lipid target phosphatidylinositol 4-phosphate at Golgi membranes and reduces ceramide transfer activity, identifying PKD as a regulator of lipid homeostasis. We also show that CERT, in turn, is critical for PKD activation and PKD-dependent protein cargo transport to the plasma membrane. Thus, the interdependence of PKD and CERT is key to the maintenance of Golgi membrane integrity and secretory transport. PMID:17591919

  5. Regulation of secretory transport by protein kinase D-mediated phosphorylation of the ceramide transfer protein.

    Science.gov (United States)

    Fugmann, Tim; Hausser, Angelika; Schöffler, Patrik; Schmid, Simone; Pfizenmaier, Klaus; Olayioye, Monilola A

    2007-07-01

    Protein kinase D (PKD) has been identified as a crucial regulator of secretory transport at the trans-Golgi network (TGN). Recruitment and activation of PKD at the TGN is mediated by the lipid diacylglycerol, a pool of which is generated by sphingomyelin synthase from ceramide and phosphatidylcholine. The nonvesicular transfer of ceramide from the endoplasmic reticulum to the Golgi complex is mediated by the lipid transfer protein CERT (ceramide transport). In this study, we identify CERT as a novel in vivo PKD substrate. Phosphorylation on serine 132 by PKD decreases the affinity of CERT toward its lipid target phosphatidylinositol 4-phosphate at Golgi membranes and reduces ceramide transfer activity, identifying PKD as a regulator of lipid homeostasis. We also show that CERT, in turn, is critical for PKD activation and PKD-dependent protein cargo transport to the plasma membrane. Thus, the interdependence of PKD and CERT is key to the maintenance of Golgi membrane integrity and secretory transport. PMID:17591919

  6. Ceramide formation mediated by acid sphingomyelinase facilitates endosomal escape of caliciviruses.

    Science.gov (United States)

    Shivanna, Vinay; Kim, Yunjeong; Chang, Kyeong-Ok

    2015-09-01

    Our recent results demonstrated that bile acids facilitate virus escape from the endosomes into the cytoplasm for successful replication of porcine enteric calicivirus (PEC). We report a novel finding that bile acids can be substituted by cold treatment for endosomal escape and virus replication. This endosomal escape by cold treatment or bile acids is associated with ceramide formation by acid sphingomyelinase (ASM). ASM catalyzes hydrolysis of sphingomyelin into ceramide, which is known to destabilize lipid bilayer. Treatment of LLC-PK cells with bile acids or cold led to ceramide formation, and small molecule antagonists or siRNA of ASM blocked ceramide formation in the endosomes and significantly reduced PEC replication. Inhibition of ASM resulted in the retention of PEC, feline calicivirus or murine norovirus in the endosomes in correlation with reduced viral replication. These results suggest the importance of viral escape from the endosomes for the replication of various caliciviruses. PMID:25985440

  7. Effect of monoglycerides and fatty acids on a ceramide bilayer.

    Science.gov (United States)

    Akinshina, Anna; Das, Chinmay; Noro, Massimo G

    2016-07-14

    Monoglycerides and unsaturated fatty acids, naturally present in trace amounts in the stratum corneum (top layer of skin) lipid matrix, are commonly used in pharmaceutical, cosmetic and health care formulations. However, a detailed molecular understanding of how the oil additives get incorporated into the skin lipids from topical application and, once incorporated, how they affect the properties and integrity of the lipid matrix remains unexplored. Using ceramide 2 bilayers as skin lipid surrogates, we use a series of molecular dynamics simulations with six different natural oil ingredients at multiple concentrations to investigate the effect of the oils on the properties and stability of the bilayers. The six oils: monoolein, monostearin, monoelaidin, oleic acid, stearic acid and linoleic acid - all having the same length of the alkyl chain, C18, but a varying degree of saturation, allow us to systematically address the effect of unsaturation in the additives. Our results show that at low oil concentration (∼5%) the mixed bilayers containing any of the oils and ceramide 2 (CER2) become more rigid than pure CER2 bilayers due to more efficient lipid packing. Better packing also results in the formation of larger numbers of hydrogen bonds between the lipids, which occurs at the expense of the hydrogen bonds between lipids and water. The mixed bilayers with saturated or trans-unsaturated oils remain stable over the whole range of oil concentration. In contrast, the presence of the oils with at least one cis-double bond leads to bilayer instability and complete loss of bilayer structure at the oil content of about 50-65%. Two cis-double bonds in the lipid tail induce bilayer disruption at even lower concentration (∼30%). The mixed bilayers remain in the gel phase (without melting to a fluid phase) until the phase transition to a non-bilayer phase occurs. We also demonstrate that the stability of the bilayer strongly correlates with the order parameter of the lipid

  8. Clinical use of a ceramide-based moisturizer for treating dogs with atopic dermatitis

    OpenAIRE

    Jung, Ji-Young; Nam, Eui-Hwa; Park, Seol-hee; Han, Seung-Hee; HWANG, Cheol-Yong

    2013-01-01

    In humans, skin barrier dysfunction is thought to be responsible for enhanced penetration of allergens. Similar to conditions seen in humans, canine atopic dermatitis (CAD) is characterized by derangement of corneocytes and disorganization of intercellular lipids in the stratum corenum (SC) with decreased ceramide levels. This study was designed to evaluate the effects of a moisturizer containing ceramide on dogs with CAD. Dogs (n = 20, 3~8 years old) with mild to moderate clinical signs were...

  9. Synthesis and Characterization of Long-Chain Tartaric Acid Diamides as Novel Ceramide-Like Compounds

    Directory of Open Access Journals (Sweden)

    Krisztina Takács-Novák

    2010-02-01

    Full Text Available Ceramides play a crucial role in the barrier function of the skin as well as in transmembrane signaling. In this study long aliphatic chain tartaric acid diamides able to replace ceramides in an in vitro model of the stratum corneum lipid matrix due to their similar physico-chemical properties were synthesized from diacetoxysuccinic anhydride in four steps. Their pro-apoptotic effect on fibroblast cells was also investigated.

  10. Ceramide and S1P signaling in embryonic stem cell differentiation

    OpenAIRE

    Bieberich, Erhard

    2012-01-01

    Recent studies show that bioactive lipids are important regulators for stem cell survival and differentiation. The sphingolipid ceramide and its derivative, sphingosine-1-phosphate (S1P), can act synergistically on embryonic stem (ES) cell differentiation. We show here simple methods to analyze sphingolipids in differentiating ES cells and to use ceramide and S1P analogs for the guided differentiation of mouse ES cells toward neuronal and glial lineage.

  11. The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

    OpenAIRE

    Becker, Katrin Anne; Riethmüller, Joachim; Zhang, Yang; Gulbins, Erich

    2010-01-01

    Sphingolipids and in particular ceramide have been shown to be critically involved in the response to many receptor-mediated, but also receptor-independent, mainly stress stimuli. Recent studies demonstrate that ceramide plays an important role in the pathogenesis of cystic fibrosis, a hereditary metabolic disorder caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator. Patients with cystic fibrosis suffer from chronic pulmonary inflammation and microbial lung infectio...

  12. Stress-Induced Cell Death Is Mediated by Ceramide Synthesis in Neurospora crassa▿

    OpenAIRE

    Plesofsky, Nora S.; Levery, Steven B.; Castle, Sherry A.; Brambl, Robert

    2008-01-01

    The combined stresses of moderate heat shock (45°C) and analog-induced glucose deprivation constitute a lethal stress for Neurospora crassa. We found that this cell death requires fatty acid synthesis and the cofactor biotin. In the absence of the cofactor, the stressed cells are particularly sensitive to exogenous ceramide, which is lethal at low concentrations. When we extracted endogenous sphingolipids, we found that unique ceramides were induced (i) by the inhibitory glucose analog 2-deox...

  13. Phospholipase C-catalyzed sphingomyelin hydrolysis in a membrane reactor for ceramide production

    DEFF Research Database (Denmark)

    Zhang, Long; Liang, Shanshan; Hellgren, Lars; Jonsson, Gunnar Eigil; Xu, Xuebing

    2008-01-01

    A membrane reactor for the production of ceramide through sphingomyelin hydrolysis with phospholipase C from Clostridium perfringens was studied for the first time. Ceramide has raised a large interest as an active component in both pharmaceutical and cosmetic industry. The enzymatic hydrolysis o...... study demonstrated the improved enzyme reusability, the fast immobilization process, the straightforward up-scaling and the combination of the hydrolysis with the product separation in the membrane reactor developed....

  14. Sphingosine Kinase Inhibitors as Maintenance Therapy of Glioblastoma After Ceramide-Induced Response.

    Science.gov (United States)

    Sordillo, Laura A; Sordillo, Peter P; Helson, Lawrence

    2016-05-01

    Ceramide and sphingosine 1-phosphate (S1P) are sphingolipid metabolites with important signaling functions. Ceramides promote apoptosis, whereas S1P favors proliferation, angiogenesis and cell survival. The balance between these opposing signaling functions is referred to as the sphingolipid rheostat. A shift in this balance toward S1P is seen in glioblastoma (GBM) and other cancers, and results in tumor cell survival and resistance to chemotherapy. Sphingosine kinase (SK), the enzyme responsible for transforming sphingosine into S1P, plays the critical role in modulating the balance between S1P and ceramides. Chemotherapeutic agents or radiation therapy may induce short-term responses in GBM patients by increasing ceramide levels. However, we believe that the enzyme SK may cause the increased ceramide to be metabolized to S1P, restoring the abnormally high S1P to ceramide balance, and that this may be part of the reason for the near-100% recurrence rate of GBM. The use of maintenance therapy with an SK inhibitor, in patients with GBM who have tumor reduction or stable disease after therapy, should be investigated. PMID:27127108

  15. Nanoemulsification of pseudo-ceramide by molecular association with mannosylerythritol lipid.

    Science.gov (United States)

    Kim, Min Kyung; Jeong, Eun Seon; Kim, Kwang Nyeon; Park, Seung Han; Kim, Jin Woong

    2014-04-01

    Ceramide molecules in water-based solutions readily attract each other to form molecular crystals, which seriously hampers to diversify their formulations. This paper describes a facile method that allows fabrication of stable ceramide emulsions through an effective molecular association with a lipid having an asymmetric molecular geometry. The lipid considered in this study is mannosylerythritol lipid (MEL). MEL is specialized in having a unique molecular structure containing sugar alcohol erythritol as a hydrophilic part and two alkyl chains with different number of carbons as hydrophobic moieties. Our particular interest has been focused on experimentally demonstrating how MEL interacts with pseudo-ceramide molecules by observing phase properties, emulsion morphology, and suspension stability. The pseudo-ceramide emulsions prepared with MEL show remarkably improved dispersion stability without either formation of molecular crystals or changes in particle sizes even after storing them for a long time. This suggests that MEL readily associates with the pseudo-ceramide due to the hydrophobic interaction, while it makes a break in the continuity of the molecular assembly of the pseudo-ceramide molecules themselves due to the geometric hindrance coming from MEL's asymmetric molecular structure. PMID:24290102

  16. Ceramide levels regulated by carnitine palmitoyltransferase 1C control dendritic spine maturation and cognition.

    Science.gov (United States)

    Carrasco, Patricia; Sahún, Ignasi; McDonald, Jerome; Ramírez, Sara; Jacas, Jordi; Gratacós, Esther; Sierra, Adriana Y; Serra, Dolors; Herrero, Laura; Acker-Palmer, Amparo; Hegardt, Fausto G; Dierssen, Mara; Casals, Núria

    2012-06-15

    The brain-specific isoform carnitine palmitoyltransferase 1C (CPT1C) has been implicated in the hypothalamic regulation of food intake and energy homeostasis. Nevertheless, its molecular function is not completely understood, and its role in other brain areas is unknown. We demonstrate that CPT1C is expressed in pyramidal neurons of the hippocampus and is located in the endoplasmic reticulum throughout the neuron, even inside dendritic spines. We used molecular, cellular, and behavioral approaches to determine CPT1C function. First, we analyzed the implication of CPT1C in ceramide metabolism. CPT1C overexpression in primary hippocampal cultured neurons increased ceramide levels, whereas in CPT1C-deficient neurons, ceramide levels were diminished. Correspondingly, CPT1C knock-out (KO) mice showed reduced ceramide levels in the hippocampus. At the cellular level, CPT1C deficiency altered dendritic spine morphology by increasing immature filopodia and reducing mature mushroom and stubby spines. Total protrusion density and spine head area in mature spines were unaffected. Treatment of cultured neurons with exogenous ceramide reverted the KO phenotype, as did ectopic overexpression of CPT1C, indicating that CPT1C regulation of spine maturation is mediated by ceramide. To study the repercussions of the KO phenotype on cognition, we performed the hippocampus-dependent Morris water maze test on mice. Results show that CPT1C deficiency strongly impairs spatial learning. All of these results demonstrate that CPT1C regulates the levels of ceramide in the endoplasmic reticulum of hippocampal neurons, and this is a relevant mechanism for the correct maturation of dendritic spines and for proper spatial learning. PMID:22539351

  17. Ceramide Levels Regulated by Carnitine Palmitoyltransferase 1C Control Dendritic Spine Maturation and Cognition*

    Science.gov (United States)

    Carrasco, Patricia; Sahún, Ignasi; McDonald, Jerome; Ramírez, Sara; Jacas, Jordi; Gratacós, Esther; Sierra, Adriana Y.; Serra, Dolors; Herrero, Laura; Acker-Palmer, Amparo; Hegardt, Fausto G.; Dierssen, Mara; Casals, Núria

    2012-01-01

    The brain-specific isoform carnitine palmitoyltransferase 1C (CPT1C) has been implicated in the hypothalamic regulation of food intake and energy homeostasis. Nevertheless, its molecular function is not completely understood, and its role in other brain areas is unknown. We demonstrate that CPT1C is expressed in pyramidal neurons of the hippocampus and is located in the endoplasmic reticulum throughout the neuron, even inside dendritic spines. We used molecular, cellular, and behavioral approaches to determine CPT1C function. First, we analyzed the implication of CPT1C in ceramide metabolism. CPT1C overexpression in primary hippocampal cultured neurons increased ceramide levels, whereas in CPT1C-deficient neurons, ceramide levels were diminished. Correspondingly, CPT1C knock-out (KO) mice showed reduced ceramide levels in the hippocampus. At the cellular level, CPT1C deficiency altered dendritic spine morphology by increasing immature filopodia and reducing mature mushroom and stubby spines. Total protrusion density and spine head area in mature spines were unaffected. Treatment of cultured neurons with exogenous ceramide reverted the KO phenotype, as did ectopic overexpression of CPT1C, indicating that CPT1C regulation of spine maturation is mediated by ceramide. To study the repercussions of the KO phenotype on cognition, we performed the hippocampus-dependent Morris water maze test on mice. Results show that CPT1C deficiency strongly impairs spatial learning. All of these results demonstrate that CPT1C regulates the levels of ceramide in the endoplasmic reticulum of hippocampal neurons, and this is a relevant mechanism for the correct maturation of dendritic spines and for proper spatial learning. PMID:22539351

  18. Hydrogen peroxide/ceramide/Akt signaling axis play a critical role in the antileukemic potential of sanguinarine.

    Science.gov (United States)

    Rahman, Anees; Thayyullathil, Faisal; Pallichankandy, Siraj; Galadari, Sehamuddin

    2016-07-01

    Dysregulation of apoptosis is a prime hallmark of leukemia. Therefore, drugs which restore the sensitivity of leukemic cells to apoptotic stimuli are promising candidates in the treatment of leukemia. Recently, we have demonstrated that sanguinarine (SNG), a benzophenanthridine alkaloid, isolated from Sanguinaria canadensis induces ROS-dependent ERK1/2 activation and autophagic cell death in human malignant glioma cells (Pallichankandy et al., 2015; [43]). In this study, we investigated the antileukemic potential of SNG in vitro, and further examined the molecular mechanisms of SNG-induced cell death. In human leukemic cells, SNG activated apoptotic cell death pathway characterized by activation of caspase cascade, DNA fragmentation and down-regulation of anti-apoptotic proteins. Importantly, we have identified a crucial role for hydrogen peroxide (H2O2)-dependent ceramide (Cer) generation in the facilitation of SNG-induced apoptosis. Additionally, we have found that SNG inhibits Akt, a key anti-apoptotic protein kinase by dephosphorylating it at Ser(473), leading to the dephosphorylation of its downstream targets, GSK3β and mTOR. Interestingly, inhibition of Cer generation, using acid sphingomyelinase inhibitor, significantly reduced the SNG-induced Akt dephosphorylation and apoptosis, whereas, activation of Cer generation using inhibitors of acid ceramidase and glucosylceramide synthase enhanced it. Furthermore, using a group of ceramide activated protein phosphatases (CAPPs) inhibitor (calyculin A, Okadaic acid, and phosphatidic acid), the involvement of protein phosphatase 1 form of CAPP in SNG-induced Akt dephosphorylation and apoptosis was demonstrated. Altogether, these results underscore a critical role for H2O2-Cer-Akt signaling axis in the antileukemic action of SNG. PMID:27154977

  19. Comprehensive quantification of ceramide species in human stratum corneum.

    Science.gov (United States)

    Masukawa, Yoshinori; Narita, Hirofumi; Sato, Hirayuki; Naoe, Ayano; Kondo, Naoki; Sugai, Yoshiya; Oba, Tsuyoshi; Homma, Rika; Ishikawa, Junko; Takagi, Yutaka; Kitahara, Takashi

    2009-08-01

    One of the key challenges in lipidomics is to quantify lipidomes of interest, as it is practically impossible to collect all authentic materials covering the targeted lipidomes. For diverse ceramides (CER) in human stratum corneum (SC) that play important physicochemical roles in the skin, we developed a novel method for quantification of the overall CER species by improving our previously reported profiling technique using normal-phase liquid chromatography-electrospray ionization-mass spectrometry (NPLC-ESI-MS). The use of simultaneous selected ion monitoring measurement of as many as 182 kinds of molecular-related ions enables the highly sensitive detection of the overall CER species, as they can be analyzed in only one SC-stripped tape as small as 5 mm x 10 mm. To comprehensively quantify CERs, including those not available as authentic species, we designed a procedure to estimate their levels using relative responses of representative authentic species covering the species targeted, considering the systematic error based on intra-/inter-day analyses. The CER levels obtained by this method were comparable to those determined by conventional thin-layer chromatography (TLC), which guarantees the validity of this method. This method opens lipidomics approaches for CERs in the SC. PMID:19349641

  20. Ceramides and cytotoxic constituents from Ficus glumosa Del. (Moraceae)

    International Nuclear Information System (INIS)

    Chemical investigation of the stem bark of Ficus glumosa (Moraceae) yielded two new ceramides (2R,7E)-2-hydroxy-N-[(2S,3S,4R)-1,3,4-trihydroxyhexadecan-2-yl] hexacos-7-enamide and (2R)-N-{(2S,3S,4R,9Z)-1-O-[(β-D-glucopyranosyl]-3,4-dihydroxyheptadec -9-en-2-yl}-2-hydroxypentacosanamide together with twenty one known compounds. The structures were established using NMR data, mass spectrometry, chemical transformation and by comparison with the reported data. Twenty one compounds were further tested against the prostate cancer PC-3 cell line and six of them revealed cytotoxic effect. Dongnoside E was the most active compound with an IC50 0.75 μmol L-1against the cancer cells line PC-3 while the reference drug doxorubicin displayed 0.91 μmol L-1. This compound also proved to inhibit the cell growth of the fibrosarcoma cancer HT1080 (IC50 0.7 μmol L-1). (author)

  1. Ceramides and cytotoxic constituents from Ficus glumosa Del. (Moraceae)

    Energy Technology Data Exchange (ETDEWEB)

    Nana, Frederic; Sandjo, Louis Pergaud; Keumedjio, Felix; Ambassa, Pantaleon [Department of Organic Chemistry, University of Yaounde I, Yaounde (Cameroon); Malik, Rizwana [H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi (Pakistan); Kuete, Victor; Choudhary, Muhammad Iqbal [Department of Biochemistry, University of Dschang, Dschang (Cameroon); Rincheval, Vincent [Laboratoire de Genetique et Biologie Cellulaire Batiment Fermat, University of Versailles, St Quentin-en-Yvelines (France); Ngadjui, Bonaventure Tchaleu [Department of Pharmaceutical Sciences and Traditional Pharmacopeia, Faculty of Medicine and Biomedical Sciences, University of Yaounde I, Yaounde (Cameroon)

    2012-03-15

    Chemical investigation of the stem bark of Ficus glumosa (Moraceae) yielded two new ceramides (2R,7E)-2-hydroxy-N-[(2S,3S,4R)-1,3,4-trihydroxyhexadecan-2-yl] hexacos-7-enamide and (2R)-N-{l_brace}(2S,3S,4R,9Z)-1-O-[({beta}-D-glucopyranosyl]-3,4-dihydroxyheptadec -9-en-2-yl{r_brace}-2-hydroxypentacosanamide together with twenty one known compounds. The structures were established using NMR data, mass spectrometry, chemical transformation and by comparison with the reported data. Twenty one compounds were further tested against the prostate cancer PC-3 cell line and six of them revealed cytotoxic effect. Dongnoside E was the most active compound with an IC{sub 50} 0.75 {mu}mol L{sup -1}against the cancer cells line PC-3 while the reference drug doxorubicin displayed 0.91 {mu}mol L{sup -1}. This compound also proved to inhibit the cell growth of the fibrosarcoma cancer HT1080 (IC{sub 50} 0.7 {mu}mol L{sup -1}). (author)

  2. Sphingomyelinase D activity in model membranes: structural effects of in situ generation of ceramide-1-phosphate.

    Directory of Open Access Journals (Sweden)

    Roberto P Stock

    Full Text Available The toxicity of Loxosceles spider venom has been attributed to a rare enzyme, sphingomyelinase D, which transforms sphingomyelin to ceramide-1-phosphate. The bases of its inflammatory and dermonecrotic activity, however, remain unclear. In this work the effects of ceramide-1-phosphate on model membranes were studied both by in situ generation of this lipid using a recombinant sphingomyelinase D from the spider Loxosceles laeta and by pre-mixing it with sphingomyelin and cholesterol. The systems of choice were large unilamellar vesicles for bulk studies (enzyme kinetics, fluorescence spectroscopy and dynamic light scattering and giant unilamellar vesicles for fluorescence microscopy examination using a variety of fluorescent probes. The influence of membrane lateral structure on the kinetics of enzyme activity and the consequences of enzyme activity on the structure of target membranes containing sphingomyelin were examined. The findings indicate that: 1 ceramide-1-phosphate (particularly lauroyl ceramide-1-phosphate can be incorporated into sphingomyelin bilayers in a concentration-dependent manner and generates coexistence of liquid disordered/solid ordered domains, 2 the activity of sphingomyelinase D is clearly influenced by the supramolecular organization of its substrate in membranes and, 3 in situ ceramide-1-phosphate generation by enzymatic activity profoundly alters the lateral structure and morphology of the target membranes.

  3. Apoptosis of human colon carcinoma HT-29 cells induced by ceramide

    Institute of Scientific and Technical Information of China (English)

    Xiao-Feng Zhang; Bai-Xiang Li; Chun-Yan Dong; Rui Ren

    2006-01-01

    AIM: To investigate the effect of exogenous ceramideinduced apoptosis on human colon carcinoma HT-29cells.METHODS: Light microscope, transmission electron microscope and fluorescence microscope were used to observe the morphology change of apoptosis in HT-29cells. Agarose gel electrophoresis was performed to detect the DNA fragment. Mitochondrial function was detected by MTT assay. mRNA expression of Bcl-2 family gene members was determined by reverse transcription polymerase chain reaction (RT-PCR) assay.RESULTS: After C2-ceramide treatment, typical characteristics of apoptosis, such as nuclear chromatin breakage, apoptotic body and DNA ladder, could be observed. After exposure to 50 μmol/L C2-ceramide for 12 and 24 h, cell apoptosis was 64.1% and 81.3% respectively, which had a time-and dose-effect relationship. Mitochondrial function started to decrease from 6 h after exposure to ceramide. Meanwhile,ceramide up-regulated or down-regulated the mRNA expression of Bcl-2 family gene members.CONCLUSION: Ceramide induces apoptosis of human colon carcinoma HT-29 cells by affecting the expression of Bcl-2 family gene members and impacting the mitochondrial function.

  4. Sphingomyelinase D activity in model membranes: structural effects of in situ generation of ceramide-1-phosphate

    DEFF Research Database (Denmark)

    Stock, Roberto; Brewer, Jonathan R.; Wagner, Kerstin;

    2012-01-01

    The toxicity of Loxosceles spider venom has been attributed to a rare enzyme, sphingomyelinase D, which transforms sphingomyelin to ceramide-1-phosphate. The bases of its inflammatory and dermonecrotic activity, however, remain unclear. In this work the effects of ceramide-1-phosphate on model...... membranes were studied both by in situ generation of this lipid using a recombinant sphingomyelinase D from the spider Loxosceles laeta and by pre-mixing it with sphingomyelin and cholesterol. The systems of choice were large unilamellar vesicles for bulk studies (enzyme kinetics, fluorescence spectroscopy...... of sphingomyelinase D is clearly influenced by the supramolecular organization of its substrate in membranes and, 3) in situ ceramide-1-phosphate generation by enzymatic activity profoundly alters the lateral structure and morphology of the target membranes....

  5. Acid ceramidase and the treatment of ceramide diseases: The expanding role of enzyme replacement therapy.

    Science.gov (United States)

    Schuchman, Edward H

    2016-09-01

    Ceramides are a diverse group of sphingolipids that play important roles in many biological processes. Acid ceramidase (AC) is one key enzyme that regulates ceramide metabolism. Early research on AC focused on the fact that it is the enzyme deficient in the rare genetic disorder, Farber Lipogranulomatosis. Recent research has revealed that deficiency of the same enzyme is responsible for a rare form of spinal muscular atrophy associated with myoclonic epilepsy (SMA-PME). Due to their diverse role in biology, accumulation of ceramides also has been implicated in the pathobiology of many other common diseases, including infectious lung diseases, diabetes, cancers and others. This has revealed the potential of AC as a therapy for many of these diseases. This review will focus on the biology of AC and the potential role of this enzyme in the treatment of human disease. PMID:27155573

  6. Alpha Particles Induce Apoptosis through the Sphingomyelin Pathway

    OpenAIRE

    Seideman, Jonathan H.; Stancevic, Branka; Rotolo, Jimmy A.; McDevitt, Michael R.; Howell, Roger W.; Kolesnick, Richard N; Scheinberg, David A.

    2011-01-01

    The sphingomyelin pathway involves the enzymatic cleavage of sphingomyelin to produce ceramide, a second messenger that serves as a key mediator in the rapid apoptotic response to various cell stressors. Low-linear energy transfer (LET) γ radiation can initiate this pathway, independent of DNA damage, via the cell membrane. Whether short-ranged, high-LET a particles, which are of interest as potent environmental carcinogens, radiotherapies and potential components of dirty bombs, can act thro...

  7. Influence of calcium on ceramide-1-phosphate monolayers.

    Science.gov (United States)

    Oliveira, Joana S L; Brezesinski, Gerald; Hill, Alexandra; Gericke, Arne

    2016-01-01

    Ceramide-1-phosphate (C1P) plays an important role in several biological processes, being identified as a key regulator of many protein functions. For instance, it acts as a mediator of inflammatory responses. The mediation of the inflammation process happens due to the interaction of C1P with the C2 domain of cPLA2α, an effector protein that needs the presence of submicromolar concentrations of calcium ions. The aim of this study was to determine the phase behaviour and structural properties of C1P in the presence and absence of millimolar quantities of calcium in a well-defined pH environment. For that purpose, we used monomolecular films of C1P at the soft air/liquid interface with calcium ions in the subphase. The pH was varied to change the protonation degree of the C1P head group. We used surface pressure versus molecular area isotherms coupled with other monolayer techniques as Brewster angle microscopy (BAM), infrared reflection-absorption spectroscopy (IRRAS) and grazing incidence X-ray diffraction (GIXD). The isotherms indicate that C1P monolayers are in a condensed state in the presence of calcium ions, regardless of the pH. At higher pH without calcium ions, the monolayer is in a liquid-expanded state due to repulsion between the negatively charged phosphate groups of the C1P molecules. When divalent calcium ions are added, they are able to bridge the highly charged phosphate groups, enhancing the regular arrangement of the head groups. Similar solidification of the monolayer structure can be seen in the presence of a 150 times larger concentration of monovalent sodium ions. Therefore, calcium ions have clearly a strong affinity for the phosphomonoester of C1P. PMID:26977381

  8. Hypertension is associated with marked alterations in sphingolipid biology: a potential role for ceramide.

    Directory of Open Access Journals (Sweden)

    Léon J A Spijkers

    Full Text Available BACKGROUND: Hypertension is, amongst others, characterized by endothelial dysfunction and vascular remodeling. As sphingolipids have been implicated in both the regulation of vascular contractility and growth, we investigated whether sphingolipid biology is altered in hypertension and whether this is reflected in altered vascular function. METHODS AND FINDINGS: In isolated carotid arteries from spontaneously hypertensive rats (SHR and normotensive Wistar-Kyoto (WKY rats, shifting the ceramide/S1P ratio towards ceramide dominance by administration of a sphingosine kinase inhibitor (dimethylsphingosine or exogenous application of sphingomyelinase, induced marked endothelium-dependent contractions in SHR vessels (DMS: 1.4±0.4 and SMase: 2.1±0.1 mN/mm; n = 10, that were virtually absent in WKY vessels (DMS: 0.0±0.0 and SMase: 0.6±0.1 mN/mm; n = 9, p<0.05. Imaging mass spectrometry and immunohistochemistry indicated that these contractions were most likely mediated by ceramide and dependent on iPLA(2, cyclooxygenase-1 and thromboxane synthase. Expression levels of these enzymes were higher in SHR vessels. In concurrence, infusion of dimethylsphingosine caused a marked rise in blood pressure in anesthetized SHR (42±4%; n = 7, but not in WKY (-12±10%; n = 6. Lipidomics analysis by mass spectrometry, revealed elevated levels of ceramide in arterial tissue of SHR compared to WKY (691±42 vs. 419±27 pmol, n = 3-5 respectively, p<0.05. These pronounced alterations in SHR sphingolipid biology are also reflected in increased plasma ceramide levels (513±19 pmol WKY vs. 645±25 pmol SHR, n = 6-12, p<0.05. Interestingly, we observed similar increases in ceramide levels (correlating with hypertension grade in plasma from humans with essential hypertension (185±8 pmol vs. 252±23 pmol; n = 18 normotensive vs. n = 19 hypertensive patients, p<0.05. CONCLUSIONS: Hypertension is associated with marked alterations in vascular

  9. Analysis of ceramide metabolites in differentiating epidermal keratinocytes treated with calcium or vitamin C

    OpenAIRE

    Kim, Juyoung; Yun, Hyejeong; Cho, Yunhi

    2011-01-01

    Ceramides (Cer) comprise the major constituent of sphingolipids in the epidermis and are known to play diverse roles in the outermost layers of the skin including water retention and provision of a physical barrier. In addition, they can be hydrolyzed into free sphingoid bases such as C18 sphingosine (SO) and C18 sphinganine (SA) or can be further metabolized to C18 So-1-phosphate (S1P) and C18 Sa-1-phosphate (Sa1P) in keratinocytes. The significance of ceramide metabolites emerged from studi...

  10. Bioassay-guided fractionation of extracts from Codiaeum variegatum against Entamoeba histolytica discovers compounds that modify expression of ceramide biosynthesis related genes.

    Science.gov (United States)

    Mfotie Njoya, Emmanuel; Weber, Christian; Hernandez-Cuevas, Nora Adriana; Hon, Chung-Chau; Janin, Yves; Kamini, Melanie F G; Moundipa, Paul F; Guillén, Nancy

    2014-01-01

    Leaves of Codiaeum variegatum ("garden croton") are used against bloody diarrhoea by local populations in Cameroon. This study aims to search for the active components from C. variegatum against Entamoeba histolytica, and thereby initiate the study of their mechanism of action. A bioassay-guided screening of the aqueous extracts from C. variegatum leaves and various fractions was carried out against trophozoites of E. histolytica axenic culture. We found that the anti-amoebic activity of extracts changed with respect to the collection criteria of leaves. Thereby, optimal conditions were defined for leaves' collection to maximise the anti-amoebic activity of the extracts. A fractionation process was performed, and we identified several sub-fractions (or isolated compounds) with significantly higher anti-amoebic activity compared to the unfractionated aqueous extract. Anti-amoebic activity of the most potent fraction was confirmed with the morphological characteristics of induced death in trophozoites, including cell rounding and lysis. Differential gene expression analysis using high-throughput RNA sequencing implies the potential mechanism of its anti-amoebic activity by targeting ceramide, a bioactive lipid involved in disturbance of biochemical processes within the cell membrane including differentiation, proliferation, cell growth arrest and apoptosis. Regulation of ceramide biosynthesis pathway as a target for anti-amoebic compounds is a novel finding which could be an alternative for drug development against E. histolytica. PMID:24416462

  11. Bioassay-guided fractionation of extracts from Codiaeum variegatum against Entamoeba histolytica discovers compounds that modify expression of ceramide biosynthesis related genes.

    Directory of Open Access Journals (Sweden)

    Emmanuel Mfotie Njoya

    Full Text Available Leaves of Codiaeum variegatum ("garden croton" are used against bloody diarrhoea by local populations in Cameroon. This study aims to search for the active components from C. variegatum against Entamoeba histolytica, and thereby initiate the study of their mechanism of action. A bioassay-guided screening of the aqueous extracts from C. variegatum leaves and various fractions was carried out against trophozoites of E. histolytica axenic culture. We found that the anti-amoebic activity of extracts changed with respect to the collection criteria of leaves. Thereby, optimal conditions were defined for leaves' collection to maximise the anti-amoebic activity of the extracts. A fractionation process was performed, and we identified several sub-fractions (or isolated compounds with significantly higher anti-amoebic activity compared to the unfractionated aqueous extract. Anti-amoebic activity of the most potent fraction was confirmed with the morphological characteristics of induced death in trophozoites, including cell rounding and lysis. Differential gene expression analysis using high-throughput RNA sequencing implies the potential mechanism of its anti-amoebic activity by targeting ceramide, a bioactive lipid involved in disturbance of biochemical processes within the cell membrane including differentiation, proliferation, cell growth arrest and apoptosis. Regulation of ceramide biosynthesis pathway as a target for anti-amoebic compounds is a novel finding which could be an alternative for drug development against E. histolytica.

  12. CD95/Fas-induced ceramide formation proceeds with slow kinetics and is not blocked by caspase-3/CPP32 inhibition.

    Science.gov (United States)

    Tepper, A D; Cock, J G; de Vries, E; Borst, J; van Blitterswijk, W J

    1997-09-26

    The current confusion regarding the relevance of endogenous ceramide in mediating CD95/Fas-induced apoptosis is based mainly on (i) discrepancies in kinetics of the ceramide response between different studies using the same apoptotic stimulus and (ii) the observation that late ceramide formation (hours) often parallels apoptosis onset. We investigated CD95-induced ceramide formation in Jurkat cells, using two methods (radiolabeling/thin layer chromatography and benzoylation/high performance liquid chromatography), which, unlike the commonly used diglyceride kinase assay, discriminate between ceramide species and de novo formed dihydroceramide. We demonstrate that ceramide accumulates after several hours, reaching a 7-fold increase after 8 h, kinetics closely paralleling apoptosis induction. No fast response was observed, not even in the presence of inhibitors of ceramide metabolism. The majority ( approximately 70%) of the ceramide response remained unaffected when apoptosis was completely inhibited at the level of caspase-3/CPP32 processing by the inhibitor peptide DEVD-CHO. Exogenous cell-permeable C2-ceramide induced the proteolytic processing of caspase-3, albeit with somewhat slower kinetics than with CD95. DEVD-CHO dose-dependently inhibited C2-ceramide- or exogenous sphingomyelinase-induced apoptosis. The results support the idea that ceramide acts in conjunction with the caspase cascade in CD95-induced apoptosis. PMID:9305886

  13. The interaction between the pleckstrin homology domain of ceramide kinase and phosphatidylinositol 4,5-bisphosphate regulates the plasma membrane targeting and ceramide 1-phosphate levels

    International Nuclear Information System (INIS)

    Ceramide kinase (CERK) converts ceramide to ceramide-1-phosphate (C1P), which has recently emerged as a new bioactive molecule capable of regulating diverse cellular functions. The N-terminus of the CERK protein encompasses a sequence motif known as a pleckstrin homology (PH) domain. Although the PH domain was previously demonstrated to be an important domain for the subcellular localization of CERK, the precise properties of this domain remained unclear. In this study, we reveal that the PH domain of CERK exhibits high affinity for phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), among other lipids. Furthermore, in COS7 cells, GFP-fused CERK translocated rapidly from the cytoplasm to the plasma membrane in response to hyper-osmotic stress, which is known to increase the intracellular PI(4,5)P2 levels, whereas a PH domain deletion mutant did not. Additionally, in [32P]orthophosphate-labeled COS7 cells, the translocation of CERK to the plasma membrane induced a 2.8-fold increase in C1P levels. The study presented here provides insight into the crucial role of the CERK-PH domain in plasma membrane targeting, through its binding to PI(4,5)P2, and subsequent induction of C1P production in the vicinity of the membrane

  14. The novel HDAC inhibitor AR-42-induced anti-colon cancer cell activity is associated with ceramide production

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Weihong; Xu, Bin; Yao, Yiting; Yu, Xiaoling [Department of Clinical Laboratory, Tongren Hospital, Shanghai (China); Shen, Jie, E-mail: tongrensj163@163.com [Department of Administrative, Tongren Hospital, No. 786 Yuyuan Road, Changning District, Shanghai (China)

    2015-08-07

    In the current study, we investigated the potential activity of AR-42, a novel histone deacetylase (HDAC) inhibitor, against colon cancer cells. Our in vitro results showed that AR-42 induced ceramide production, exerted potent anti-proliferative and pro-apoptotic activities in established (SW-620 and HCT-116 lines) and primary human colon cancer cells. Exogenously-added sphingosine 1-phosphate (S1P) suppressed AR-42-induced activity, yet a cell-permeable ceramide (C4) facilitated AR-42-induced cytotoxicity against colon cancer cells. In addition, AR-42-induced ceramide production and anti-colon cancer cell activity were inhibited by the ceramide synthase inhibitor fumonisin B1, but were exacerbated by PDMP, which is a ceramide glucosylation inhibitor. In vivo, oral administration of a single dose of AR-42 dramatically inhibited SW-620 xenograft growth in severe combined immunodeficient (SCID) mice, without inducing overt toxicities. Together, these results show that AR-42 dramatically inhibits colon cancer cell proliferation in vitro and in vivo, and ceramide production might be the key mechanism responsible for its actions. - Highlights: • AR-42 is anti-proliferative against primary/established colon cancer cells. • AR-42 induces significant apoptotic death in primary/established colon cancer cells. • Ceramide production mediates AR-42-induced cytotoxicity in colon cancer cells. • AR-42 oral administration potently inhibits SW-620 xenograft growth in SCID mice.

  15. The novel HDAC inhibitor AR-42-induced anti-colon cancer cell activity is associated with ceramide production

    International Nuclear Information System (INIS)

    In the current study, we investigated the potential activity of AR-42, a novel histone deacetylase (HDAC) inhibitor, against colon cancer cells. Our in vitro results showed that AR-42 induced ceramide production, exerted potent anti-proliferative and pro-apoptotic activities in established (SW-620 and HCT-116 lines) and primary human colon cancer cells. Exogenously-added sphingosine 1-phosphate (S1P) suppressed AR-42-induced activity, yet a cell-permeable ceramide (C4) facilitated AR-42-induced cytotoxicity against colon cancer cells. In addition, AR-42-induced ceramide production and anti-colon cancer cell activity were inhibited by the ceramide synthase inhibitor fumonisin B1, but were exacerbated by PDMP, which is a ceramide glucosylation inhibitor. In vivo, oral administration of a single dose of AR-42 dramatically inhibited SW-620 xenograft growth in severe combined immunodeficient (SCID) mice, without inducing overt toxicities. Together, these results show that AR-42 dramatically inhibits colon cancer cell proliferation in vitro and in vivo, and ceramide production might be the key mechanism responsible for its actions. - Highlights: • AR-42 is anti-proliferative against primary/established colon cancer cells. • AR-42 induces significant apoptotic death in primary/established colon cancer cells. • Ceramide production mediates AR-42-induced cytotoxicity in colon cancer cells. • AR-42 oral administration potently inhibits SW-620 xenograft growth in SCID mice

  16. Physical properties of ceramides: effect of fatty acid hydroxylation.

    Science.gov (United States)

    Shah, J; Atienza, J M; Rawlings, A V; Shipley, G G

    1995-09-01

    The structural and thermotropic properties of alpha-hydroxy fatty acid (HFA) and non-hydroxy fatty acid (NFA) ceramides (CER) have been studied using differential scanning calorimetry (DSC) and X-ray diffraction techniques. The DSC of anhydrous HFA-CER shows a single, sharp reversible transition at 95.6 degrees C (delta H = 15.3 kcal/mol). At intermediate hydrations HFA-CER exhibited more complex behavior but at maximum hydration only a single reversible transition is observed at 80.0 degrees C (delta H = 8.5 kcal/mol). X-ray diffraction of hydrated (74% water) HFA-CER at 20 degrees C shows a lamellar structure with a bilayer periodicity d = 60.7 Angstrum; a single wide angle reflection at 4.2 Angstrum is characteristic of hexagonal chain packing. Above the main transition temperature at 91 degrees C, a hexagonal (HII) phase is observed. In contrast, DSC of anhydrous NFA-CER demonstrates two thermal transitions at 81.3 degrees C (delta H = 6.8 kcal/mol) and 85.9 degrees C (delta H = 3.5 kcal/mol). With increasing hydration, both transitions shift towards lower temperatures; at maximum hydration, on heating, the endothermic transitions occur at 72.7 degrees C (delta H = 9.8 kcal/mol) and 81.1 degrees C (delta H = 4.0 kcal/mol). On cooling, there is hysteresis of both transitions. X-ray diffraction of NFA-CER (80% water) at 20 degrees C shows a well-ordered lamellar structure with a bilayer periodicity d = 58.6 Angstrum and three wide-angle reflections at 4.6 Angstrum, 4.2 Angstrum, and 3.8 Angstrum. At 77 degrees C (between the two transitions), again a lamellar structure exists with reduced bilayer periodicity d = 53.1 Angstrum and four wide-angle reflections at 4.6 Angstrum, 4.2 Angstrum, and 3.8 Angstrum are observed. Above the second transition, only a single low angle reflection at 30.0 Angstrum is observed; a diffuse reflection at 4.6 Angstrum is indicative of a melted chain phase. Thus, HFA-CER exhibits a simple phase behavior involving the reversible

  17. Ceramide formation is involved in Lactobacillus acidophilus-induced IFN-beta response in dendritic cells

    DEFF Research Database (Denmark)

    Fuglsang, Eva; Henningsen, Louise; Frøkiær, Hanne

    of sphingomyelin to ceramide by acid sphingomyelinase (ASMase) at the outer leaflet of the PM is a key event in endocytosis of gram-positive Lactobacillus acidophilus (L. acidophilus) and the subsequent induction of IFN-beta in DCs and, as the gram-negative Escherichia coli (E. coli) does not induce appreciable...

  18. The challenge to verify ceramide's role of apoptosis induction in human cardiomyocytes - a pilot study

    Directory of Open Access Journals (Sweden)

    Voth Vladimir

    2011-03-01

    Full Text Available Abstract Background Cardioplegia and reperfusion of the myocardium may be associated with cardiomyocyte apoptosis and subsequent myocardial injury. In order to establish a pharmacological strategy for the prevention of these events, this study aimed to verify the reliability of our human cardiac model and to evaluate the pro-apoptotic properties of the sphingolipid second messenger ceramide and the anti-apoptotic properties of the acid sphingomyelinase inhibitor amitryptiline during simulated cardioplegia and reperfusion ex vivo. Methods Cardiac biopsies were retrieved from the right auricle of patients undergoing elective CABG before induction of cardiopulmonary bypass. Biopsies were exposed to ex vivo conditions of varying periods of cp/rep (30/10, 60/20, 120/40 min. Groups: I (untreated control, n = 10, II (treated control cp/rep, n = 10, III (cp/rep + ceramide, n = 10, IV (cp/rep + amitryptiline, n = 10 and V (cp/rep + ceramide + amitryptiline, n = 10. For detection of apoptosis anti-activated-caspase-3 and PARP-1 cleavage immunostaining were employed. Results In group I the percentage of apoptotic cardiomyocytes was significantly (p Conclusion Ceramid induces and amitryptiline suppresses apoptosis significantly in our ex vivo setting. This finding warrants further studies aiming to evaluate potential beneficial effects of selective inhibition of apoptosis inducing mediators on the suppression of ischemia/reperfusion injury in clinical settings.

  19. A Hypothesis Concerning a Potential Involvement of Ceramide in Apoptosis and Acantholysis Induced by Pemphigus Autoantibodies

    Directory of Open Access Journals (Sweden)

    Wendy B. Bollag

    2010-01-01

    Full Text Available Autoimmune diseases affect more than 50 million Americans, resulting in significant healthcare costs. Most autoimmune diseases occur sporadically; however, endemic pemphigus foliaceus (EPF is an autoimmune skin disease localized to specific geographic loci. EPF, and the related diseases pemphigus vulgaris (PV and pemphigus foliaceus (PF, are characterized by skin lesions and autoantibodies to molecules found on epidermal keratinocytes. A variant of EPF in patients from El Bagre, Colombia, South America, has recently been reported to be distinct from previously described loci in Brazil and Tunisia epidemiologically and immunologically. As in PF and EPF, El Bagre EPF patients exhibit autoantibodies towards desmoglein-1, a cell adhesion molecule critical for maintaining epidermal integrity. An association of El Bagre EPF with sun exposure has been detected, and ultraviolet irradiation also exacerbates symptoms in PV, PF and EPF. Our hypothesis is that: (1 the autoantibodies generate pathology through an alteration in ceramide metabolism in targeted keratinocytes, resulting in apoptosis and/or cell death and acantholysis, but only when the cell's ability to metabolize ceramide is exceeded, and (2 apoptosis in response to this altered ceramide metabolism is initiated and/or exacerbated by other agents that increase ceramide levels, such as cytokines, ultraviolet irradiation, and senescence.

  20. Phytoceramide in vertebrate tissues: one step chromatography separation for molecular characterization of ceramide species.

    Directory of Open Access Journals (Sweden)

    Somsankar Dasgupta

    Full Text Available Ceramide is a precursor for complex sphingolipids in vertebrates, while plants contain phytoceramide. By using a novel chromatography purification method we show that phytoceramide comprises a significant proportion of animal sphingolipids. Total ceramide including phytoceramide from mouse tissue (brain, heart, liver lipid extracts and cell culture (mouse primary astrocytes, human oligodendroglioma cells was eluted as a single homogenous fraction, and then analyzed by thin layer chromatography, and further characterized by gas chromatography-mass spectrometry (GC-MS. We detected a unique band that migrated between non-hydroxy fatty acyl ceramide and hydroxy fatty acyl ceramide, and identified it as phytoceramide. Using RT-PCR, we confirmed that mouse tissues expressed desaturase 2, an enzyme that has been reported to generate phytoceramide from dihydroceramide. Previously, only trace amounts of phytoceramide were reported in vertebrate intestine, kidney, and skin. While its function is still elusive, this is the first report of phytoceramide characterization in glial cells and vertebrate brain, heart, and liver.

  1. In vivo metabolism of fumonisin B1 to N-acylated ceramide-like compounds

    Science.gov (United States)

    Fumonisins are toxic and carcinogenic mycotoxins found in corn-based foods. Fumonisin B1 (FB1) metabolism to ceramide-like cytotoxic N-acylated FB1 (NAFB1) compounds has been shown in vitro, but in vivo metabolism has not been reported. Therefore, male Sprague-Dawley rats (2/group) were given 5 da...

  2. Biochemical methods for quantifying sphingolipids: ceramide, sphingosine, sphingosine kinase-1 activity, and sphingosine-1-phosphate.

    Science.gov (United States)

    Brizuela, Leyre; Cuvillier, Olivier

    2012-01-01

    Sphingolipids (ceramide, sphingosine, and sphingosine-1-phosphate) are bioactive lipids with important biological functions in proliferation, apoptosis, angiogenesis, and inflammation. Herein, we describe easy and rapid biochemical methods with the use of radiolabeled molecules ((3)H, (32)P) for their mass determination. Quantitation of sphingosine kinase-1 activity, the most studied isoform, is also included. PMID:22528435

  3. Human Trabecular Meshwork Sphingolipid and Ceramide Profiles and Potential Latent Fungal Commensalism

    OpenAIRE

    Aljohani, Ayman J.; Edwards, Genea; Guerra, Yenifer; Dubovy, Sander; Miller, Darlene; Lee, Richard K; Bhattacharya, Sanjoy K.

    2014-01-01

    The mass spectrometry-identified sphingolipids and ceramides in the trabecular meshwork (TM) showed presence of nonmammalian sphingoid base Fumonisins. Taken together with Gomori methenamine silver staining and DNA amplification, this suggests widespread latent commensalism by Fusarium species in the human TM.

  4. Stress-induced cell death is mediated by ceramide synthesis in Neurospora crassa

    DEFF Research Database (Denmark)

    Plesofsky, Nora S; Levery, Steven B; Castle, Sherry A; Brambl, Robert

    2008-01-01

    )-phytoceramide is not made by germinating asexual spores subjected to the same heat and carbon stress. Since these spores, unlike growing cells, do not die from the stresses, this suggests a possible connection between synthesis of the dual-stress-induced ceramide and cell death. This connection is supported by the...

  5. Aureobasidin A arrests growth of yeast cells through both ceramide intoxication and deprivation of essential inositolphosphorylceramides

    DEFF Research Database (Denmark)

    Cerantola, Vanessa; Guillas, Isabelle; Roubaty, Carole;

    2009-01-01

    All mature Saccharomyces cerevisiae sphingolipids comprise inositolphosphorylceramides containing C26:0 or C24:0 fatty acids and either phytosphingosine or dihydrosphingosine. Here we analysed the lipid profile of lag1Delta lac1Delta mutants lacking acyl-CoA-dependent ceramide synthesis, which re...

  6. Neutral sphingomyelinase-2, acid sphingomyelinase, and ceramide levels in COPD patients compared to controls

    Directory of Open Access Journals (Sweden)

    Lea SR

    2016-09-01

    Full Text Available Simon R Lea,1,* Hannah J Metcalfe,1,* Jonathan Plumb,1 Christian Beerli,2 Chris Poll,3 Dave Singh,1 Katharine H Abbott-Banner3 1Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, The University of Manchester and University Hospital of South Manchester, NHS Foundation Trust, Manchester, UK; 2Novartis Pharma AG, Postfach, Basel, Switzerland; 3Respiratory Diseases, Novartis Institute for Biomedical Research, Horsham, West Sussex, UK *These authors contributed equally to this work Background: Increased pulmonary ceramide levels are suggested to play a causative role in lung diseases including COPD. Neutral sphingomyelinase-2 (nSMase-2 and acid SMase (aSMase, which hydrolyze sphingomyelin to produce ceramide, are activated by a range of cellular stresses, including inflammatory cytokines and pathogens, but notably cigarette smoke appears to only activate nSMase-2. Our primary objective was to investigate nSMase-2 and aSMase protein localization and quantification in lung tissue from nonsmokers (NS, smokers (S, and COPD patients. In addition, various ceramide species (C16, C18, and C20 were measured in alveolar macrophages from COPD patients versus controls. Materials and methods: Patients undergoing surgical resection for suspected or confirmed lung cancer were recruited, and nSMase-2 and aSMase protein was investigated in different areas of lung tissue (small airways, alveolar walls, subepithelium, and alveolar macrophages by immunohistochemistry. Ceramide species were measured in alveolar macrophages from COPD patients and controls by mass spectrometry. Results: nSMase-2 and aSMase were detected in the majority of small airways. There was a significant increase in nSMase-2 immunoreactivity in alveolar macrophages from COPD patients (54% compared with NS (31.7% (P<0.05, and in aSMase immunoreactivity in COPD (68.2% and S (69.5% alveolar macrophages compared with NS (52.4% (P

  7. 4,8-Sphingadienine and 4-hydroxy-8-sphingenine activate ceramide production in the skin

    Directory of Open Access Journals (Sweden)

    Shirakura Yoshiyuki

    2012-08-01

    Full Text Available Abstract Background Ingestion of glucosylceramide improves transepidermal water loss (TEWL from the skin, but the underlying mechanism by which a small amount of dietary glucosylceramide can vastly improve skin conditions remains unclear. In a previous report, glucosylceramides were shown to be digested to sphingoids, which were shown to be absorbed through the intestinal epithelium. Based on these observations, we hypothesized that sphingoids are the key molecules facilitating endogenous ceramide production. In this study, we assessed the effect of 4,8-sphingadienine (d18:2 and 4-hydroxy-8-sphingenine (t18:1, derived from konjac glucosylceramide, on stimulating ceramide production. Methods Konjac glucosylceramide acidolysis was performed using hydrochloric acid; the resulting d18:2 and t18:1 were fractionated by column chromatography. Real-time quantitative RT-PCR was performed to assess the effect of d18:2 and t18:1 on gene expression in normal human epidermal keratinocytes, while their effect on the nuclear receptor, peroxisome proliferator-activated receptor (PPARγ, was measured using a receptor-cofactor assay system. The effect of d18:2 and t18:1 on stimulating ceramide production was evaluated using HPTLC analysis in a 3-dimensional human skin model. Results We noted the upregulation of genes related to de novo ceramide synthesis as well as of those encoding the elongases of very long-chain fatty acids by d18:2 and t18:1, but not by glucosylceramide and 4-sphingenine. Both these sphingoids also facilitated the expression of PPARβ/δ and PPARγ; moreover, they also demonstrated ligand activity for PPARγ. These results indicated that d18:2 and t18:1 promote the differentiation of keratinocytes. Analysis of the lipids within the 3-dimensional human skin model indicated that treatment with d18:2 and t18:1 not only upregulated gene expression but also increased ceramide production. Conclusions The sphingoids d18:2 and t18:1 activated genes

  8. Chronic Voluntary Ethanol Consumption Induces Favorable Ceramide Profiles in Selectively Bred Alcohol-Preferring (P Rats.

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    Jessica Godfrey

    Full Text Available Heavy alcohol consumption has detrimental neurologic effects, inducing widespread neuronal loss in both fetuses and adults. One proposed mechanism of ethanol-induced cell loss with sufficient exposure is an elevation in concentrations of bioactive lipids that mediate apoptosis, including the membrane sphingolipid metabolites ceramide and sphingosine. While these naturally-occurring lipids serve as important modulators of normal neuronal development, elevated levels resulting from various extracellular insults have been implicated in pathological apoptosis of neurons and oligodendrocytes in several neuroinflammatory and neurodegenerative disorders. Prior work has shown that acute administration of ethanol to developing mice increases levels of ceramide in multiple brain regions, hypothesized to be a mediator of fetal alcohol-induced neuronal loss. Elevated ceramide levels have also been implicated in ethanol-mediated neurodegeneration in adult animals and humans. Here, we determined the effect of chronic voluntary ethanol consumption on lipid profiles in brain and peripheral tissues from adult alcohol-preferring (P rats to further examine alterations in lipid composition as a potential contributor to ethanol-induced cellular damage. P rats were exposed for 13 weeks to a 20% ethanol intermittent-access drinking paradigm (45 ethanol sessions total or were given access only to water (control. Following the final session, tissues were collected for subsequent chromatographic analysis of lipid content and enzymatic gene expression. Contrary to expectations, ethanol-exposed rats displayed substantial reductions in concentrations of ceramides in forebrain and heart relative to non-exposed controls, and modest but significant decreases in liver cholesterol. qRT-PCR analysis showed a reduction in the expression of sphingolipid delta(4-desaturase (Degs2, an enzyme involved in de novo ceramide synthesis. These findings indicate that ethanol intake levels

  9. Myriocin prevents muscle ceramide accumulation but not muscle fiber atrophy during short-term mechanical unloading.

    Science.gov (United States)

    Salaun, Erwann; Lefeuvre-Orfila, Luz; Cavey, Thibault; Martin, Brice; Turlin, Bruno; Ropert, Martine; Loreal, Olivier; Derbré, Frédéric

    2016-01-15

    Bedridden patients in intensive care unit or after surgery intervention commonly develop skeletal muscle weakness. The latter is promoted by a variety of prolonged hospitalization-associated conditions. Muscle disuse is the most ubiquitous and contributes to rapid skeletal muscle atrophy and progressive functional strength reduction. Disuse causes a reduction in fatty acid oxidation, leading to its accumulation in skeletal muscle. We hypothesized that muscle fatty acid accumulation could stimulate ceramide synthesis and promote skeletal muscle weakness. Therefore, the present study was designed to determine the effects of sphingolipid metabolism on skeletal muscle atrophy induced by 7 days of disuse. For this purpose, male Wistar rats were treated with myriocin, an inhibitor of de novo synthesis of ceramides, and subjected to hindlimb unloading (HU) for 7 days. Soleus muscles were assayed for fiber diameter, ceramide levels, protein degradation, and apoptosis signaling. Serum and liver were removed to evaluate the potential hepatoxicity of myriocin treatment. We found that HU increases content of saturated C16:0 and C18:0 ceramides and decreases soleus muscle weight and fiber diameter. HU increased the level of polyubiquitinated proteins and induced apoptosis in skeletal muscle. Despite a prevention of C16:0 and C18:0 muscle accumulation, myriocin treatment did not prevent skeletal muscle atrophy and concomitant induction of apoptosis and proteolysis. Moreover, myriocin treatment increased serum transaminases and induced hepatocyte necrosis. These data highlight that inhibition of de novo synthesis of ceramides during immobilization is not an efficient strategy to prevent skeletal muscle atrophy and exerts adverse effects like hepatotoxicity. PMID:26542521

  10. Functional loss of two ceramide synthases elicits autophagy-dependent lifespan extension in C. elegans.

    Directory of Open Access Journals (Sweden)

    Mai-Britt Mosbech

    Full Text Available Ceramide and its metabolites constitute a diverse group of lipids, which play important roles as structural entities of biological membranes as well as regulators of cellular growth, differentiation, and development. The C. elegans genome comprises three ceramide synthase genes; hyl-1, hyl-2, and lagr-1. HYL-1 function is required for synthesis of ceramides and sphingolipids containing very long acyl-chains (≥C24, while HYL-2 is required for synthesis of ceramides and sphingolipids containing shorter acyl-chains (≤C22. Here we show that functional loss of HYL-2 decreases lifespan, while loss of HYL-1 or LAGR-1 does not affect lifespan. We show that loss of HYL-1 and LAGR-1 functions extend lifespan in an autophagy-dependent manner, as knock down of the autophagy-associated gene ATG-12 abolishes hyl-1;lagr-1 longevity. The transcription factors PHA-4/FOXA, DAF-16/FOXO, and SKN-1 are also required for the observed lifespan extension, as well as the increased number of autophagosomes in hyl-1;lagr-1 animals. Both autophagic events and the transcription factors PHA-4/FOXA, DAF-16, and SKN-1 have previously been associated with dietary restriction-induced longevity. Accordingly, we find that hyl-1;lagr-1 animals display reduced feeding, increased resistance to heat, and reduced reproduction. Collectively, our data suggest that specific sphingolipids produced by different ceramide synthases have opposing roles in determination of C. elegans lifespan. We propose that loss of HYL-1 and LAGR-1 result in dietary restriction-induced autophagy and consequently prolonged longevity.

  11. Role of Sphingolipid Mediator Ceramide in Obesity and Renal Injury in Mice Fed a High-Fat DietS⃞

    OpenAIRE

    Boini, Krishna M.; Zhang, Chun; Xia, Min; Poklis, Justin L.; Li, Pin-Lan

    2010-01-01

    The present study tested a hypothesis that excess accumulation of sphingolipid, ceramide, its metabolites, or a combination contributes to the development of obesity and associated kidney damage. Liquid chromatography/mass spectrometry analysis demonstrated that C57BL/6J mice on the high-fat diet (HFD) had significantly increased plasma total ceramide levels compared with animals fed a low-fat diet (LFD)...

  12. Suppression of sphingomyelin synthase 1 by small interference RNA is associated with enhanced ceramide production and apoptosis after photodamage

    OpenAIRE

    Separovic, Duska; Semaan, Louie; Tarca, Adi L.; Maitah, Ma’In Yehya Awad; Hanada, Kentaro; Bielawski, Jacek; Villani, Maristella; Luberto, Chiara

    2008-01-01

    We have shown that overexpression of SMS1, an enzyme that converts de novo ceramide into sphingomyelin, is accompanied by attenuated ceramide response and apoptotic resistance after photodamage with the photosensitizer Pc 4 (photodynamic therapy; PDT). To test whether SMS1 overexpression-related effects after PDT can be reversed, in this study SMS1 was downregulated in Jurkat T lymphoma/leukemia cells using small inhibitory RNA (siRNA) for SMS1. Compared to scrambled (control) siRNA-transfect...

  13. Topical effects of N-acetyl-L-hydroxyproline on ceramide synthesis and alleviation of pruritus

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    Hashizume E

    2013-02-01

    Full Text Available Erika Hashizume,1 Tetsuo Nakano,2 Ayako Kamimura,1 Koji Morishita31Healthcare Products Development Center, Kyowa Hakko Bio, Tsukuba, Ibaraki, 2Technical Research Laboratories, Kyowa Hakko Bio, Hofu, Yamaguchi, 3Technology Development and Research Department, Kyowa Hakko Bio, Tokyo, JapanPurpose: N-acetyl-l-hydroxyproline (AHYP is an acetylated form of l-hydroxyproline that is used to treat skin ulcers and porphyria cutanea tarda. Its other biological and physiological effects on the skin have not been elucidated. We investigated the effects of AHYP on the skin-barrier function, focusing on ceramide synthesis and the effects of topical AHYP on atopic dermatitis.Materials and methods: AHYP was applied to a three-dimensional cultured skin model. Ceramides were quantified by high-performance thin-layer chromatography. Serine palmitoyltransferase (SPT is the rate-limiting enzyme in de novo ceramide synthesis, and the mRNA of its long-chain base subunit 1 (SPTLC1 was evaluated by quantitative reverse-transcription polymerase chain reaction. A clinical trial in the form of an intraindividual, comparative, double-blind, randomized, vehicle-controlled test involving 15 female subjects suffering from slight atopic dermatitis was performed. Subjects applied 1% (w/w AHYP cream to one forearm and a control cream to the other forearm twice daily for 4 weeks. Skin condition was evaluated by measuring transepidermal water loss (TEWL. Dermatological observations were made by a dermatologist, and subjects evaluated their own pruritus intensity before beginning treatment and 4 weeks after the start of treatment.Results: SPTLC1 expression and ceramide synthesis were significantly increased in an AHYP-treated skin model (P < 0.05. In the clinical trial, no adverse effects were observed in any subjects. TEWL was increased in the control-treated region of the forearm (P < 0.05 after 4 weeks' application, whereas there was no change in the AHYP-treated region of the

  14. The Permeability Enhancing Mechanism of DMSO in Ceramide Bilayers Simulated by Molecular Dynamics

    OpenAIRE

    Notman, Rebecca; den Otter, Wouter K.; Noro, Massimo G.; Briels, W. J.; Anwar, Jamshed

    2007-01-01

    The lipids of the topmost layer of the skin, the stratum corneum, represent the primary barrier to molecules penetrating the skin. One approach to overcoming this barrier for the purpose of delivery of active molecules into or via the skin is to employ chemical permeability enhancers, such as dimethylsulfoxide (DMSO). How these molecules exert their effect at the molecular level is not understood. We have investigated the interaction of DMSO with gel-phase bilayers of ceramide 2, the predomin...

  15. Ceramide Stimulates ABCA12 Expression via Peroxisome Proliferator-activated Receptor δ in Human Keratinocytes*

    OpenAIRE

    Jiang, Yan J.; Uchida, Yoshikazu; Lu, Biao; Kim, Peggy; Mao, Cungui; Akiyama, Masashi; Elias, Peter M.; Holleran, Walter M.; Grunfeld, Carl; Feingold, Kenneth R.

    2009-01-01

    ABCA12 (ATP binding cassette transporter, family 12) is a cellular membrane transporter that facilitates the delivery of glucosylceramides to epidermal lamellar bodies in keratinocytes, a process that is critical for permeability barrier formation. Following secretion of lamellar bodies into the stratum corneum, glucosylceramides are metabolized to ceramides, which comprise ∼50% of the lipid in stratum corneum. Gene mutations of ABCA12 underlie harlequin ichthyosis, a devastating skin disorde...

  16. Induction of a Hardening Phenomenon and Quantitative Changes of Ceramides in Stratum Corneum

    OpenAIRE

    Park, Sook Young; Kim, Jin Hye; Cho, Soo Ick; Kim, Kyeong Il; Cho, Hee Jin; Park, Chun Wook; Lee, Cheol Heon; Kim, Hye One

    2014-01-01

    Background Hardening phenomenon of human skin after repeated exposure to the irritants is well-known, but the precise mechanism remains elusive. Objective To modify the previous experimental model of hardening phenomenon by repeated applications of two different concentrations of sodium lauryl sulfate (SLS) solutions to Korean healthy volunteers and to investigate the quantitative changes of ceramides in stratum corneum before and after chronic repeated irritation. Methods Eight hundred micro...

  17. Comprehensive quantification of ceramide species in human stratum corneum[S

    OpenAIRE

    Masukawa, Yoshinori; Narita, Hirofumi; Sato, Hirayuki; Naoe, Ayano; Kondo, Naoki; Sugai, Yoshiya; Oba, Tsuyoshi; Homma, Rika; Ishikawa, Junko; Takagi, Yutaka; Kitahara, Takashi

    2009-01-01

    One of the key challenges in lipidomics is to quantify lipidomes of interest, as it is practically impossible to collect all authentic materials covering the targeted lipidomes. For diverse ceramides (CER) in human stratum corneum (SC) that play important physicochemical roles in the skin, we developed a novel method for quantification of the overall CER species by improving our previously reported profiling technique using normal-phase liquid chromatog­raphy-electrospray ionization-mass spec...

  18. Fumonisin concentration and ceramide synthase inhibitory activity of corn, masa, and tortilla chips.

    Science.gov (United States)

    Voss, Kenneth A; Norred, William P; Meredith, Filmore I; Riley, Ronald T; Stephen Saunders, D

    2006-07-01

    Nixtamalization removes fumonisins from corn and reduces their amounts in masa and tortilla products. Fumonisin concentrations and potential toxicity could be underestimated, however, if unknown but biologically active fumonisins are present. Therefore, the relative amounts of fumonisins in extracts of fumonisin-contaminated corn and its masa and tortilla chip nixtamalization products were determined with an in vitro ceramide synthase inhibition bioassay using increased sphinganine (Sa) and sphinganine to sphingosine ratio (Sa/So) as endpoints. African green monkey kidney cells (Vero cells ATCC CCL-81) were grown in 1-ml wells and exposed to 4 microl of the concentrated extracts for 48 h. The corn extract inhibited ceramide synthase as Sa (mean = 132 pmol/well) and Sa/So (mean = 2.24) were high compared to vehicle controls (Sa = 9 pmol/well; Sa/So = 0.10). Inhibitory activity (mean Sa = 14-24 pmol/well; mean Sa/So = 0.17-0.28) of the masa and tortilla chip extracts were reduced > or = 80% compared to the corn extract. Results were corroborated in a second experiment in which Sa and Sa/So of the wells treated with masa or tortilla chip extracts were reduced > or = 89% compared to those treated with the corn extract. Masa and tortilla chip FB1 concentrations (4-7 ppm) were reduced about 80-90% compared to the corn (30 ppm) when the materials were analyzed by high-performance liquid chromatography (HPLC). Therefore, nixtamalization reduced both the measured amount of FB1 and the ceramide synthase inhibitory activity of masa and tortilla chips extracts. The results further suggest that the masa and tortilla chip extracts did not contain significant amounts of unknown fumonisins having ceramide synthase inhibitory activity. PMID:16760143

  19. Hyperosmolarity-induced lipid droplet formation depends on ceramide production by neutral sphingomyelinase 2[S

    OpenAIRE

    Robciuc, Alexandra; Hyötyläinen, Tuulia; Jauhiainen, Matti; Holopainen, Juha M.

    2012-01-01

    Hyperosmolarity (HO) imposes a remarkable stress on membranes, especially in tissues in direct contact with the external environment. Our efforts were focused on revealing stress-induced lipid changes that precede the inflammatory cytokine response in human corneal epithelial cells exposed to increasing osmolarity. We used a lipidomic analysis that detected significant and systematic changes in the lipid profile, highly correlated with sodium concentrations in the medium. Ceramides and trigly...

  20. Accumulation of Ordered Ceramide-Cholesterol Domains in Farber Disease Fibroblasts

    OpenAIRE

    Ferreira, Natalia Santos; Goldschmidt-Arzi, Michal; Sabanay, Helena; Storch, Judith; Levade, Thierry; Ribeiro, Maria Gil; Addadi, Lia; Futerman, Anthony H.

    2013-01-01

    Farber disease is an inherited metabolic disorder caused by mutations in the acid ceramidase gene, which leads to ceramide accumulation in lysosomes. Farber disease patients display a wide variety of symptoms with most patients eventually displaying signs of nervous system dysfunction. We now present a novel tool that could potentially be used to distinguish between the milder and more severe forms of the disease, namely, an antibody that recognizes a mixed monolayer or bilayer of cholesterol...

  1. Functions of Ceramide Synthase Paralogs YPR114w and YJR116w of Saccharomyces cerevisiae.

    Directory of Open Access Journals (Sweden)

    Shamroop K Mallela

    Full Text Available Ceramide is synthesized in yeast by two redundant acyl-CoA dependent synthases, Lag1 and Lac1. In lag1∆ lac1∆ cells, free fatty acids and sphingoid bases are elevated, and ceramides are produced through the redundant alkaline ceramidases Ypc1 and Ydc1, working backwards. Even with all four of these genes deleted, cells are surviving and continue to contain small amounts of complex sphingolipids. Here we show that these residual sphingolipids are not synthesized by YPR114w or YJR116w, proteins of unknown function showing a high degree of homology to Lag1 and Lac1. Indeed, the hextuple lag1∆ lac1∆ ypc1∆ ydc1∆ ypr114w∆ yjr116w∆ mutant still contains ceramides and complex sphingolipids. Yjr116w∆ exhibit an oxygen-dependent hypersensitivity to Cu2+ due to an increased mitochondrial production of reactive oxygen species (ROS and a mitochondrially orchestrated programmed cell death in presence of copper, but also a general copper hypersensitivity that cannot be counteracted by the antioxidant N-acetyl-cysteine (NAC. Myriocin efficiently represses the synthesis of sphingoid bases of ypr114w∆, but not its growth. Both yjr116w∆ and ypr114w∆ have fragmented vacuoles and produce less ROS than wild type, before and after diauxic shift. Ypr114w∆/ypr114w∆ have an increased chronological life span. Thus, Yjr116w and Ypr114w are related, but not functionally redundant.

  2. Analysis of Skeletal Muscle Torque Capacity and Circulating Ceramides in Patients with Advanced Heart Failure

    Science.gov (United States)

    Brunjes, Danielle L.; Dunlop, Mark; Wu, Christina; Jones, Meaghan; Kato, Tomoko S.; Kennel, Peter J.; Armstrong, Hilary F.; Choo, Tse-Hwei; Bartels, Matthew N.; Forman, Daniel E.; Mancini, Donna M.; Schulze, P. Christian

    2016-01-01

    Background Heart failure (HF)-related exercise intolerance is thought to be perpetuated by peripheral skeletal muscle functional, structural, and metabolic abnormalities. We analyzed specific dynamics of muscle contraction in patients with HF compared with healthy, sedentary controls. Methods Isometric and isokinetic muscle parameters were measured in the dominant upper and lower limbs of 45 HF patients and 15 healthy age-matched controls. Measurements included peak torque normalized to body weight, work normalized to body weight, power, time to peak torque, and acceleration and deceleration to maximum strength times. Body morphometry (dual energy X-ray absorptiometry scan) and circulating fatty acids and ceramides (lipodomics) were analyzed in a subset of subjects (18 HF and 9 controls). Results Extension and flexion time-to-peak torque was longer in the lower limbs of HF patients. Furthermore, acceleration and deceleration times in the lower limbs were also prolonged in HF subjects. HF subjects had increased adiposity and decreased lean muscle mass compared with controls. Decreased circulating unsaturated fatty acids and increased ceramides were found in subjects with HF. Conclusions Delayed torque development suggests skeletal muscle impairments that may reflect abnormal neuromuscular functional coupling. These impairments may be further compounded by increased adiposity and inflammation associated with increased ceramides. PMID:26879888

  3. Induction of membrane ceramides: a novel strategy to interfere with T lymphocyte cytoskeletal reorganisation in viral immunosuppression.

    Directory of Open Access Journals (Sweden)

    Evelyn Gassert

    2009-10-01

    Full Text Available Silencing of T cell activation and function is a highly efficient strategy of immunosuppression induced by pathogens. By promoting formation of membrane microdomains essential for clustering of receptors and signalling platforms in the plasma membrane, ceramides accumulating as a result of membrane sphingomyelin breakdown are not only essential for assembly of signalling complexes and pathogen entry, but also act as signalling modulators, e. g. by regulating relay of phosphatidyl-inositol-3-kinase (PI3K signalling. Their role in T lymphocyte functions has not been addressed as yet. We now show that measles virus (MV, which interacts with the surface of T cells and thereby efficiently interferes with stimulated dynamic reorganisation of their actin cytoskeleton, causes ceramide accumulation in human T cells in a neutral (NSM and acid (ASM sphingomyelinase-dependent manner. Ceramides induced by MV, but also bacterial sphingomyelinase, efficiently interfered with formation of membrane protrusions and T cell spreading and front/rear polarisation in response to beta1 integrin ligation or alphaCD3/CD28 activation, and this was rescued upon pharmacological or genetic ablation of ASM/NSM activity. Moreover, membrane ceramide accumulation downmodulated chemokine-induced T cell motility on fibronectin. Altogether, these findings highlight an as yet unrecognised concept of pathogens able to cause membrane ceramide accumulation to target essential processes in T cell activation and function by preventing stimulated actin cytoskeletal dynamics.

  4. Serum sphingolipidomic analyses reveal an upregulation of C16-ceramide and sphingosine-1-phosphate in hepatocellular carcinoma.

    Science.gov (United States)

    Grammatikos, Georgios; Schoell, Niklas; Ferreirós, Nerea; Bon, Dimitra; Herrmann, Eva; Farnik, Harald; Köberle, Verena; Piiper, Albrecht; Zeuzem, Stefan; Kronenberger, Bernd; Waidmann, Oliver; Pfeilschifter, Josef

    2016-04-01

    We have recently shown that major alterations of serum sphingolipid metabolites in chronic liver disease associate significantly with the stage of liver fibrosis in corresponding patients. In the current study we assessed via mass spectrometry serum concentrations of sphingolipid metabolites in a series of 122 patients with hepatocellular carcinoma (HCC) compared to an age- and sex-matched series of 127 patients with cirrhosis. We observed a highly significant upregulation of long and very long chain ceramides (C16-C24) in the serum of patients with HCC as compared to patients with cirrhosis (P < 0.001). Accordingly, dihydro-ceramides, synthetic precursors of ceramides and notably sphingosine, sphingosine-1-phosphate (S1P) and sphinganine-1-phosphate (SA1P) were upregulated in patients with HCC (P < 0.001). Especially the diagnostic accuracy of C16-ceramide and S1P, assessed by receiver operating curve (ROC) analysis, showed a higher area under the curve (AUC) value as compared to alpha fetoprotein (AFP) (0.999 and 0.985 versus 0.823, P < 0.001 respectively). In conclusion, serum levels of sphingolipid metabolites show a significant upregulation in patients with HCC as compared to patients with cirrhosis. Particularly C16-ceramide and S1P may serve as novel diagnostic markers for the identification of HCC in patients with liver diseases. Our data justify further investigations on the role of sphingolipids in HCC. PMID:26933996

  5. Ceramide content is higher in type I compared to type II fibers in obesity and type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Kristensen, Ditte Bech; Prats Gavalda, Clara; Ara, Ignacio; Dela, Flemming; Helge, Jørn W; Larsen, Steen

    2012-01-01

    control subjects, were performed. A fasting blood sample was obtained and plasma insulin and glucose determined. A muscle biopsy was obtained from deltoideus and vastus lateralis, and fiber-type ceramide content was determined by fluorescence immunohistochemistry. Insulin sensitivity estimated by Quicki......This study investigated fiber-type-specific muscle ceramide content in obese subjects and type 2 diabetes patients. Two substudies, one which compared type 2 diabetes patients to both lean- and obese BMI-matched subjects and the other study which compared lean body-matched post-obese, obese, and...... index was higher in lean compared to type 2 diabetes patients and obese controls. Also in control and post-obese subjects, a higher insulin sensitivity was observed compared to obese subjects. Ceramide content was consistently higher in type I than in type II muscle fibers and higher in deltoideus than...

  6. Mechanisms of lung endothelial barrier disruption induced by cigarette smoke: role of oxidative stress and ceramides.

    Science.gov (United States)

    Schweitzer, Kelly S; Hatoum, Hadi; Brown, Mary Beth; Gupta, Mehak; Justice, Matthew J; Beteck, Besem; Van Demark, Mary; Gu, Yuan; Presson, Robert G; Hubbard, Walter C; Petrache, Irina

    2011-12-01

    The epithelial and endothelial cells lining the alveolus form a barrier essential for the preservation of the lung respiratory function, which is, however, vulnerable to excessive oxidative, inflammatory, and apoptotic insults. Whereas profound breaches in this barrier function cause pulmonary edema, more subtle changes may contribute to inflammation. The mechanisms by which cigarette smoke (CS) exposure induce lung inflammation are not fully understood, but an early alteration in the epithelial barrier function has been documented. We sought to investigate the occurrence and mechanisms by which soluble components of mainstream CS disrupt the lung endothelial cell barrier function. Using cultured primary rat microvascular cell monolayers, we report that CS induces endothelial cell barrier disruption in a dose- and time-dependent manner of similar magnitude to that of the epithelial cell barrier. CS exposure triggered a mechanism of neutral sphingomyelinase-mediated ceramide upregulation and p38 MAPK and JNK activation that were oxidative stress dependent and that, along with Rho kinase activation, mediated the endothelial barrier dysfunction. The morphological changes in endothelial cell monolayers induced by CS included actin cytoskeletal rearrangement, junctional protein zonula occludens-1 loss, and intercellular gap formation, which were abolished by the glutathione modulator N-acetylcysteine and ameliorated by neutral sphingomyelinase inhibition. The direct application of ceramide recapitulated the effects of CS, by disrupting both endothelial and epithelial cells barrier, by a mechanism that was redox and apoptosis independent and required Rho kinase activation. Furthermore, ceramide induced dose-dependent alterations of alveolar microcirculatory barrier in vivo, measured by two-photon excitation microscopy in the intact rat. In conclusion, soluble components of CS have direct endothelial barrier-disruptive effects that could be ameliorated by glutathione

  7. A single prior bout of exercise protects against palmitate-induced insulin resistance despite an increase in total ceramide content.

    Science.gov (United States)

    Thrush, A Brianne; Harasim, Ewa; Chabowski, Adrian; Gulli, Roberto; Stefanyk, Leslie; Dyck, David J

    2011-05-01

    Ceramide accumulation has been implicated in the impairment of insulin-stimulated glucose transport in skeletal muscle following saturated fatty acid (FA) exposure. Importantly, a single bout of exercise can protect against acute lipid-induced insulin resistance. The mechanism by which exercise protects against lipid-induced insulin resistance is not completely known but may occur through a redirection of FA toward triacylglycerol (TAG) and away from ceramide and diacylglycerol (DAG). Therefore, in the current study, an in vitro preparation was used to examine whether a prior bout of exercise could confer protection against palmitate-induced insulin resistance and whether the pharmacological [50 μM fumonisin B(1) (FB1)] inhibition of ceramide synthesis in the presence of palmitate could mimic the protective effect of exercise. Soleus muscle of sedentary (SED), exercised (EX), and SED in the presence of FB1 (SED+FB1) were incubated with or without 2 mM palmitate for 4 h. This 2-mM palmitate exposure impaired insulin-stimulated glucose transport (-28%, P TAG accumulation in the SED group (P TAG (P net increase in ceramide content in response to palmitate exposure in the EX group was not different compared with SED, despite the maintenance of insulin sensitivity. The incubation of soleus from SED rats with FB1 (SED+FB1) prevented the detrimental effects of palmitate and caused a redirection of FA toward TAG accumulation (P < 0.05). Therefore, this research suggests that although inhibiting ceramide accumulation can prevent the detrimental effects of palmitate, a single prior bout of exercise appears to protect against palmitate-induced insulin resistance, which may be independent of changes in ceramide content. PMID:21325642

  8. Involvement of neutral sphingomyelinase in the angiotensin II signaling pathway.

    Science.gov (United States)

    Bautista-Pérez, Rocio; del Valle-Mondragón, Leonardo; Cano-Martínez, Agustina; Pérez-Méndez, Oscar; Escalante, Bruno; Franco, Martha

    2015-05-15

    The possibility that angiotensin II (ANG II) exerts its effects through the activation of neutral sphingomyelinase (nSMase) has not been tested in kidneys. The results of the present study provide evidence for the activity and expression of nSMase in rat kidneys. In isolated perfused rat kidney, ANG II-induced renal vasoconstriction was inhibited by GW4869, an inhibitor of nSMase. We used nSMase for investigating the signal transduction downstream of ceramide. nSMase constricted the renal vasculature. An inhibitor of ceramidase (CDase), N-oleoylethanolamine (OEA), enhanced either ANG II- or nSMase-induced renal vasoconstriction. To demonstrate the interaction between the nSMase and cytosolic phospholipase A2 (cPLA2) signal transduction pathways, we evaluated the response to nSMase in the presence and absence of inhibitors of arachidonic acid (AA) metabolism: arachidonyl trifluoromethyl ketone (AACOCF3), an inhibitor of cPLA2; 5,8,11,14-eicosatetraynoic acid (ETYA), an inhibitor of all AA pathways; indomethacin, an inhibitor of cyclooxygenase (COX); furegrelate, a thromboxane A2 (TxA2)-synthase inhibitor; and SQ29548, a TxA2-receptor antagonist. In these experiments, the nSMase-induced renal vasoconstriction decreased. ANG II or nSMase was associated with an increase in the release of thromboxane B2 (TxB2) in the renal perfusate of isolated perfused rat kidney. In addition, the coexpression of the ceramide with cPLA2, was found in the smooth muscle layer of intrarenal vessels. Our results suggest that ANG II stimulates ceramide formation via the activation of nSMase; thus ceramide may indirectly regulate vasoactive processes that modulate the activity of cPLA2 and the release of TxA2. PMID:25354938

  9. Control of Glucosylceramide Production and Morphogenesis by the Bar1 Ceramide Synthase in Fusarium graminearum

    OpenAIRE

    Rittenour, William R.; Chen, Ming; Edgar B. Cahoon; Harris, Steven D.

    2011-01-01

    The contribution of plasma membrane proteins to the virulence of plant pathogenic fungi is poorly understood. Accordingly, the objective of this study was to characterize the acyl-CoA dependent ceramide synthase Bar1 (previously implicated in plasma membrane organization) in the wheat pathogen Fusarium graminearum. The role of Bar1 in mediating cell membrane organization was confirmed as ΔBAR1 mutants failed to display a distinct sterol-rich domain at the hyphal tip. The ΔBAR1 mutants were no...

  10. A tendem mass spectrometric approach for determining the structure of molecular species of ceramide in the marine sponge, Haliclona cribricutis

    Digital Repository Service at National Institute of Oceanography (India)

    Tilvi, S.; Majik, M.; Naik, C.G.

    ). Informative patterns are described by Lee et al. employing LC/ESI-MS in both positive- and negative-ionization modes to identify the structures of both sphingoid base and N-acyl chains of ceramides and also of an impurity in cosmetics. 12 Kerwin et al....K.-Y. Ng and A.M. Hetherington, “Sphingolipids, new players in plant signaling”, Trends Plant Sci. 8, 317 (2003). 4. K. Venkayaraman and A.H. Futerman, “Ceramide as a second messenger: sticky solutions to sticky problems”, Trends Cell Biol. 10, 408...

  11. Comparative atomic-scale hydration of the ceramide and phosphocholine headgroup in solution and bilayer environments.

    Science.gov (United States)

    Gillams, Richard J; Lorenz, Christian D; McLain, Sylvia E

    2016-06-14

    Previous studies have used neutron diffraction to elucidate the hydration of the ceramide and the phosphatidylcholine headgroup in solution. These solution studies provide bond-length resolution information on the system, but are limited to liquid samples. The work presented here investigates how the hydration of ceramide and phosphatidylcholine headgroups in a solution compares with that found in a lipid bilayer. This work shows that the hydration patterns seen in the solution samples provide valuable insight into the preferential location of hydrating water molecules in the bilayer. There are certain subtle differences in the distribution, which result from a combination of the lipid conformation and the lipid-lipid interactions within the bilayer environment. The lipid-lipid interactions in the bilayer will be dependent on the composition of the bilayer, whereas the restricted exploration of conformational space is likely to be applicable in all membrane environments. The generalized description of hydration gathered from the neutron diffraction studies thus provides good initial estimation for the hydration pattern, but this can be further refined for specific systems. PMID:27306021

  12. Comparative atomic-scale hydration of the ceramide and phosphocholine headgroup in solution and bilayer environments

    Science.gov (United States)

    Gillams, Richard J.; Lorenz, Christian D.; McLain, Sylvia E.

    2016-06-01

    Previous studies have used neutron diffraction to elucidate the hydration of the ceramide and the phosphatidylcholine headgroup in solution. These solution studies provide bond-length resolution information on the system, but are limited to liquid samples. The work presented here investigates how the hydration of ceramide and phosphatidylcholine headgroups in a solution compares with that found in a lipid bilayer. This work shows that the hydration patterns seen in the solution samples provide valuable insight into the preferential location of hydrating water molecules in the bilayer. There are certain subtle differences in the distribution, which result from a combination of the lipid conformation and the lipid-lipid interactions within the bilayer environment. The lipid-lipid interactions in the bilayer will be dependent on the composition of the bilayer, whereas the restricted exploration of conformational space is likely to be applicable in all membrane environments. The generalized description of hydration gathered from the neutron diffraction studies thus provides good initial estimation for the hydration pattern, but this can be further refined for specific systems.

  13. HOS3, an ELO-Like Gene, Inhibits Effects of ABA and Implicates a S-1-P/Ceramide Control System for Abiotic Stress Responses in Arabidopsis thaliana

    Institute of Scientific and Technical Information of China (English)

    Tanya M. Quist; Irina Sokolchik; Huazhong Shi; Robert J. Joly; Ray A. Bressan; Albino Maggio; Meena Narsimhan; Xia Li

    2009-01-01

    A hyper-osmotically sensitive mutant of Arabidopsis thaliana, designated hos3-1 (high expression of osmotically responsive genes), was identified based on its hyper-luminescence of RD29A:LUC promoter fusion plants upon treatment with NaCI and ABA. These responses implicate the disrupted gene as a direct or indirect negative regulator of the RD29A stress-responsive pathway. By sequencing the flanking regions of the T-DNA borders, it was determined that the disrupted gene is at locus At4g36830, annotated as encoding a putative protein with high homology to CIG30 (ELO2/FEN1).CIG30 has been implicated in synthesis of very long chain fatty acids (VLCFA), which are essential precursors for sphingolipids and ceramides. Altered stress responses characteristic of ABA-hypersensitivity, including reduced root growth inhibition and reduced germination with ABA treatment and reduced water loss from leaves, were exhibited by allelic hos3-1 and hos3-2 mutants. The hos3-2 mutant is partially suppressed in its transcript abundance and is inherited as a recessive trait. Further, the HOS30RF under the control of the 35SCaMV promoter restored wild-type NaCI- and ABA-root growth sensitivity as well as RD29A:LUC luminescence in mutant plants. We also show here that the HOS3 wild-type gene functionally complements the sensitivity of elo2 and elo3 yeast mutants to monensin. Furthermore, both hos3-1 and hos3-2 alleles shared increased sensitivity to the herbicide Metolachlor, which inhibits acyl chain elongation in synthesis of VLCFA, and HOS3 functionally complemented both elo2 and elo3 and restored levels of VLCFA. Together, these data establish that HOS3 inhibits ABA-mediated stress responses and implicate the VLCFA pathway and products as control points for several aspects of abiotic stress signaling and responses. The results also provide support for a role of ceramide in the control of stomatal behavior.

  14. Differential activation of acid sphingomyelinase and ceramide release determines invasiveness of Neisseria meningitidis into brain endothelial cells.

    Directory of Open Access Journals (Sweden)

    Alexander Simonis

    2014-06-01

    Full Text Available The interaction with brain endothelial cells is central to the pathogenicity of Neisseria meningitidis infections. Here, we show that N. meningitidis causes transient activation of acid sphingomyelinase (ASM followed by ceramide release in brain endothelial cells. In response to N. meningitidis infection, ASM and ceramide are displayed at the outer leaflet of the cell membrane and condense into large membrane platforms which also concentrate the ErbB2 receptor. The outer membrane protein Opc and phosphatidylcholine-specific phospholipase C that is activated upon binding of the pathogen to heparan sulfate proteoglycans, are required for N. meningitidis-mediated ASM activation. Pharmacologic or genetic ablation of ASM abrogated meningococcal internalization without affecting bacterial adherence. In accordance, the restricted invasiveness of a defined set of pathogenic isolates of the ST-11/ST-8 clonal complex into brain endothelial cells directly correlated with their restricted ability to induce ASM and ceramide release. In conclusion, ASM activation and ceramide release are essential for internalization of Opc-expressing meningococci into brain endothelial cells, and this segregates with invasiveness of N. meningitidis strains.

  15. Loss of ceramide synthase 2 activity, necessary for myelin biosynthesis, precedes tau pathology in the cortical pathogenesis of Alzheimer's disease.

    Science.gov (United States)

    Couttas, Timothy A; Kain, Nupur; Suchowerska, Alexandra K; Quek, Lake-Ee; Turner, Nigel; Fath, Thomas; Garner, Brett; Don, Anthony S

    2016-07-01

    The anatomical progression of neurofibrillary tangle pathology throughout Alzheimer's disease (AD) pathogenesis runs inverse to the pattern of developmental myelination, with the disease preferentially affecting thinly myelinated regions. Myelin is comprised 80% of lipids, and the prototypical myelin lipids, galactosylceramide, and sulfatide are critical for neurological function. We observed severe depletion of galactosylceramide and sulfatide in AD brain tissue, which can be traced metabolically to the loss of their biosynthetic precursor, very long chain ceramide. The synthesis of very long chain ceramides is catalyzed by ceramide synthase 2 (CERS2). We demonstrate a significant reduction in CERS2 activity as early as Braak stage I/II in temporal cortex, and Braak stage III/IV in hippocampus and frontal cortex, indicating that loss of myelin-specific ceramide synthase activity precedes neurofibrillary tangle pathology in cortical regions. These findings open a new vista on AD pathogenesis by demonstrating a defect in myelin lipid biosynthesis at the preclinical stages of the disease. We posit that, over time, this defect contributes significantly to myelin deterioration, synaptic dysfunction, and neurological decline. PMID:27255818

  16. The ceramide inhibitor fumonisin B1 mitigates the pulmonary effects of low-dose diesel exhaust inhalation in mice.

    Science.gov (United States)

    Shaheen, Hazem M; Onoda, Atsuto; Shinkai, Yusuke; Nakamura, Masayuki; El-Ghoneimy, Ashraf A; El-Sayed, Yasser S; Takeda, Ken; Umezawa, Masakazu

    2016-10-01

    Recent studies have suggested that inhalation of diesel exhaust (DE), a major source of air pollution, results in pulmonary alterations; however, the effects of DE at low concentrations are poorly understood. Therefore, this study was conducted to elucidate the pulmonary effects of low-level exposure to DE and the potential role of a ceramide de novo biosynthesis inhibitor, fumonisin B1 (FB1) to ameliorate the DE-toxicity. Male C57BL/6J mice underwent 1- or 7-day experiments (4 equal groups/experiment) and were assigned to the control, DE (0.1mg/m(3)), FB1 (6.75mg/kg body weight SC at days 0, 3 and 6) or DE+FB1 groups. DE and/or FB1 treatment had no effect on the expression of Nos2, a biomarker of oxidative stress. Ceramide production in the bronchial epithelial cells and Sphk1 mRNA expression were induced in the lung after the 7-day DE exposure and were partially suppressed by the FB1 treatment. Additionally, the effects of DE on SP-A and SP-D mRNA expression were also suppressed by the FB1 treatment. These results suggest that ceramide and Sphk1 may be sensitive biomarkers for low-level DE-induced pulmonary effects. Collectively, ceramide likely contributes to the DE-induced early stage of airway inflammation, which is considered a potential pulmonary target during low-level DE exposure. PMID:27376354

  17. Ceramide targets xIAP and cIAP1 to sensitize metastatic colon and breast cancer cells to apoptosis induction to suppress tumor progression

    International Nuclear Information System (INIS)

    Ceramide is a bioeffector that mediates various cellular processes, including apoptosis. However, the mechanism underlying ceramide function in apoptosis is apparently cell type-dependent and is not well-understood. We aimed at identifying molecular targets of ceramide in metastatic human colon and breast cancer cells, and determining the efficacy of ceramide analog in suppression of colon and breast cancer metastasis. The activity of and mechanism underlying ceramide as a cytotoxic agent, and as a sensitizer for Fas-mediated apoptosis was analyzed in human cell lines established from primary or metastatic colon and breast cancers. The efficacy of ceramide analog LCL85 in suppression of metastasis was examined in preclinical mouse tumor models. Exposure of human colon carcinoma cells to ceramide analog LCL85 results in apoptosis in a dose-dependent manner. Interestingly, a sublethal dose of LCL85 increased C16 ceramide content and overcame tumor cell resistance to Fas-mediated apoptosis. Subsequently, treatment of tumor cells with exogenous C16 ceramide resulted in increased tumor cell sensitivity to Fas-mediated apoptosis. LCL85 resembles Smac mimetic BV6 in sensitization of colon carcinoma cells to Fas-mediated apoptosis by inducing proteasomal degradation of cIAP1 and xIAP proteins. LCL85 also decreased xIAP1 and cIAP1 protein levels and sensitized metastatic human breast cancer cells to Fas-mediated apoptosis. Silencing xIAP and cIAP1 with specific siRNAs significantly increased the metastatic human colon carcinoma cell sensitivity to Fas-mediated apoptosis, suggesting that IAP proteins mediate apoptosis resistance in metastatic human colon carcinoma cells and ceramide induces IAP protein degradation to sensitize the tumor cells to apoptosis induction. Consistent with its apoptosis sensitization activity, subtoxic doses of LCL85 suppressed colon carcinoma cell metastatic potential in an experimental lung metastasis mouse model, as well as breast cancer growth

  18. Role of sphingolipid mediator ceramide in obesity and renal injury in mice fed a high-fat diet.

    Science.gov (United States)

    Boini, Krishna M; Zhang, Chun; Xia, Min; Poklis, Justin L; Li, Pin-Lan

    2010-09-01

    The present study tested a hypothesis that excess accumulation of sphingolipid, ceramide, its metabolites, or a combination contributes to the development of obesity and associated kidney damage. Liquid chromatography/mass spectrometry analysis demonstrated that C57BL/6J mice on the high-fat diet (HFD) had significantly increased plasma total ceramide levels compared with animals fed a low-fat diet (LFD). Treatment of mice with the acid sphingomyelinase (ASMase) inhibitor amitriptyline significantly attenuated the HFD-induced plasma ceramide levels. Corresponding to increase in plasma ceramide, the HFD significantly increased the body weight gain, plasma leptin concentration, urinary total protein and albumin excretion, glomerular damage index, and adipose tissue ASMase activity compared with the LFD-fed mice. These HFD-induced changes were also significantly attenuated by treatment of mice with amitriptyline. In addition, the decline of plasma glucose concentration after an intraperitoneal injection of insulin (0.15 U/kg b.wt.) was more sustained in mice on the HFD with amitriptyline than on the HFD alone. Intraperitoneal injection of glucose (3 g/kg b.wt.) resulted in a slow increase followed by a rapid decrease in the plasma glucose concentration in LFD and HFD plus amitriptyline-treated mice, but such blood glucose response was not observed in HFD-fed mice. Immunofluorescence analysis demonstrated a decrease in the podocin and an increase in the desmin in the glomeruli of HFD-fed mice compared with the LFD and HFD plus amitriptyline-treated mice. In conclusion, our results reveal a pivotal role for ceramide biosynthesis in obesity, metabolic syndrome, and associated kidney damage. PMID:20543095

  19. New ceramide from the aerial part of Tinospora oblongifolia with cytotoxic activities.

    Science.gov (United States)

    Samita, Fidelis; Ochieng, Charles O; Owuor, Philip O; Manguro, Lawrence A O

    2014-01-01

    A new ceramide, 2,3-dihydroxy-N-[(2S,3S,4R)-1,3,4-trihydroxyicosan-2-yl[tetracosanamide (1) along with four known compounds: 2-(4'-hydroxyphenyl)-ethyl lignocerate (2), docosyl-3,4-dihydroxy-trans-cinnamate (3), β-sitosterol (4) and β-sitosterol glycoside (5) were isolated from Tinospora oblongifolia (Menispermaceae). Their structures were determined on the basis of spectroscopic methods, mass spectrometry analysis as well as chemical transformation and by comparing their physical and spectral data with those reported in the literature. Compound 1 exhibited strong cytotoxic activity against KB cells with IC50 = 3.4 μM although less than that of camptothecin IC50 = 0.3 μM (positive control). PMID:24635055

  20. Cholesterol Depletion from a Ceramide/Cholesterol Mixed Monolayer: A Brewster Angle Microscope Study

    KAUST Repository

    Mandal, Pritam

    2016-06-01

    Cholesterol is crucial to the mechanical properties of cell membranes that are important to cells’ behavior. Its depletion from the cell membranes could be dramatic. Among cyclodextrins (CDs), methyl beta cyclodextrin (MβCD) is the most efficient to deplete cholesterol (Chol) from biomembranes. Here, we focus on the depletion of cholesterol from a C16 ceramide/cholesterol (C16-Cer/Chol) mixed monolayer using MβCD. While the removal of cholesterol by MβCD depends on the cholesterol concentration in most mixed lipid monolayers, it does not depend very much on the concentration of cholesterol in C16-Cer/Chol monolayers. The surface pressure decay during depletion were described by a stretched exponential that suggested that the cholesterol molecules are unable to diffuse laterally and behave like static traps for the MβCD molecules. Cholesterol depletion causes morphology changes of domains but these disrupted monolayers domains seem to reform even when cholesterol level was low.

  1. Mesophase formation by ceramides and cholesterol: a model for stratum corneum lipid packing?

    Science.gov (United States)

    Parrott, D T; Turner, J E

    1993-04-22

    Previous X-ray diffraction and electron microscopy experiments have suggested that there is an unusual double bilayer structure formed by stratum corneum lipids, with a lamellar spacing of about 131 A (White, S.H., Mirejovsky, D. and King, G.I. (1988) Biochemistry 27, 3725-3732; Hou, S.Y.E., Mitra, A.K., White, S.H., Menon, G.K., Ghadially, R. and Elias, P.M. (1991) J. Invest. Dermatol. 96, 215-223; Bouwstra, J.A., De Vries, M.A., Gouris, G.S., Bras, W., Brussee, J. and Ponec, M. (1991) J. Controlled Release 15, 209-220). Two contradictory models have been proposed for this structure. In the Downing model, used to explain electron microscopy observations, acylceramides are vital, acting as a 'lynch-pin' and holding the lipid layers together (Swartzendruber, W.C., Kitko, D.J., Madison, K.C. and Downing, D.T. (1989) J. Invest. Dermatol. 92, 251-257). Alternatively, to explain X-ray diffraction results from intact corneum, protein intercallation into the lipid bilayers is suggested, since an electron dense region wider than can be accounted for by lipid headgroups alone, is required (Bouwstra, J.A., De Vries, M.A., Gouris, G.S., Bras, W., Brussee, J. and Ponec, M. (1991) J. Controlled Release 15, 209-220). Thus, existing models require the presence of either acylceramides or protein. We describe how a similar structure can be prepared in vitro using mixtures of cholesterol and ceramides. Cholesterol induces a novel double-bilayer structure in ceramides II, and IV. This result is in conflict with the existing literature which cites acylceramides, or protein as instrumental in maintaining the in vivo structure of the phase. Characterisation has been carried out using optical microscopy and synchrotron X-ray diffraction. PMID:8476922

  2. Ceramide 1-phosphate regulates cell migration and invasion of human pancreatic cancer cells.

    Science.gov (United States)

    Rivera, Io-Guané; Ordoñez, Marta; Presa, Natalia; Gangoiti, Patricia; Gomez-Larrauri, Ana; Trueba, Miguel; Fox, Todd; Kester, Mark; Gomez-Muñoz, Antonio

    2016-02-15

    Pancreatic cancer is an aggressive and devastating disease characterized by invasiveness, rapid progression and profound resistance to treatment. Despite years of intense investigation, the prognosis of this type of cancer is poor and there is no efficacious treatment to overcome the disease. Using human PANC-1 and MIA PaCa-2 cells, we demonstrate that the bioactive sphingolipid ceramide 1-phosphate (C1P) increases pancreatic cancer cell migration and invasion. Treatment of these cells with selective inhibitors of phosphatidylinositol 3-kinase (PI3K), Akt1, or mammalian target of rapamycin 1 (mTOR1), or with specific siRNAs to silence the genes encoding these kinases, resulted in potent inhibition of C1P-induced cell migration and invasion. Likewise, the extracellularly regulated kinases 1 and 2 (ERK1-2), and the small GTPase RhoA, which regulates cytoskeleton reorganization, were also found to be implicated in C1P-stimulated ROCK1-dependent cancer cell migration and invasion. In addition, pre-treatment of the cancer cells with pertussis toxin abrogated C1P-induced cell migration, suggesting the intervention of a Gi protein-coupled receptor in this process. Pancreatic cancer cells engineered to overexpress ceramide kinase (CerK), the enzyme responsible for C1P biosynthesis in mammalian cells, showed enhanced spontaneous cell migration that was potently blocked by treatment with the selective CerK inhibitor NVP-231, or by treatment with specific CerK siRNA. Moreover, overexpression of CerK with concomitant elevations in C1P enhanced migration of pancreatic cancer cells. Collectively, these data demonstrate that C1P is a key regulator of pancreatic cancer cell motility, and suggest that targeting CerK expression/activity and C1P may be relevant factors for controlling pancreatic cancer cell dissemination. PMID:26707801

  3. Membrane Organization and Ionization Behavior of the Minor but Crucial Lipid Ceramide-1-Phosphate

    Energy Technology Data Exchange (ETDEWEB)

    Kooijman, Edgar E.; Sot, Jesus; Montes, L.-Ruth; Alonso, Alicia; Gericke, Arne; de Kruijff, Ben; Kumar, Satyendra; Goni, Felix M. (Utrecht); (Kent); (Basque)

    2008-08-06

    Ceramide-1-phosphate (Cer-1-P), one of the simplest of all sphingophospholipids, occurs in minor amounts in biological membranes. Yet recent evidence suggests important roles of this lipid as a novel second messenger with crucial tasks in cell survival and inflammatory responses. We present a detailed description of the physical chemistry of this hitherto little explored membrane lipid. At full hydration Cer-1-P forms a highly organized subgel (crystalline) bilayer phase (L{sub c}) at low temperature, which transforms into a regular gel phase (L{sub {beta}}) at {approx}45 C, with the gel to fluid phase transition (L{sub {beta}}-L{sub {alpha}}) occurring at {approx}65 C. When incorporated at 5mol % in a phosphatidylcholine bilayer, the pK{sub a2} of Cer-1-P, 7.39{+-}0.03, lies within the physiological pH range. Inclusion of phosphatidylethanolamine in the phosphatidylcholine bilayer, at equimolar ratio, dramatically reduces the pK{sub a2} to 6.64{+-}0.03. We explain these results in light of the novel electrostatic/hydrogen bond switch model described recently for phosphatidic acid. In mixtures with dielaidoylphosphatidylethanolamine, small concentrations of Cer-1-P cause a large reduction of the lamellar-to-inverted hexagonal phase transition temperature, suggesting that Cer-1-P induces, like phosphatidic acid, negative membrane curvature in these types of lipid mixtures. These properties place Cer-1-P in a class more akin to certain glycerophospholipids (phosphatidylethanolamine, phosphatidic acid) than to any other sphingolipid. In particular, the similarities and differences between ceramide and Cer-1-P may be relevant in explaining some of their physiological roles.

  4. Membrane organization and ionization behavior of the minor but crucial lipid ceramide-1-phosphate.

    Science.gov (United States)

    Kooijman, Edgar E; Sot, Jesús; Montes, L-Ruth; Alonso, Alicia; Gericke, Arne; de Kruijff, Ben; Kumar, Satyendra; Goñi, Felix M

    2008-06-01

    Ceramide-1-phosphate (Cer-1-P), one of the simplest of all sphingophospholipids, occurs in minor amounts in biological membranes. Yet recent evidence suggests important roles of this lipid as a novel second messenger with crucial tasks in cell survival and inflammatory responses. We present a detailed description of the physical chemistry of this hitherto little explored membrane lipid. At full hydration Cer-1-P forms a highly organized subgel (crystalline) bilayer phase (L(c)) at low temperature, which transforms into a regular gel phase (L(beta)) at approximately 45 degrees C, with the gel to fluid phase transition (L(beta)-L(alpha)) occurring at approximately 65 degrees C. When incorporated at 5 mol % in a phosphatidylcholine bilayer, the pK(a2) of Cer-1-P, 7.39 +/- 0.03, lies within the physiological pH range. Inclusion of phosphatidylethanolamine in the phosphatidylcholine bilayer, at equimolar ratio, dramatically reduces the pK(a2) to 6.64 +/- 0.03. We explain these results in light of the novel electrostatic/hydrogen bond switch model described recently for phosphatidic acid. In mixtures with dielaidoylphosphatidylethanolamine, small concentrations of Cer-1-P cause a large reduction of the lamellar-to-inverted hexagonal phase transition temperature, suggesting that Cer-1-P induces, like phosphatidic acid, negative membrane curvature in these types of lipid mixtures. These properties place Cer-1-P in a class more akin to certain glycerophospholipids (phosphatidylethanolamine, phosphatidic acid) than to any other sphingolipid. In particular, the similarities and differences between ceramide and Cer-1-P may be relevant in explaining some of their physiological roles. PMID:18296489

  5. Saturated- and n-6 polyunsaturated-fat diets each induce ceramide accumulation in mouse skeletal muscle: reversal and improvement of glucose tolerance by lipid metabolism inhibitors.

    Science.gov (United States)

    Frangioudakis, G; Garrard, J; Raddatz, K; Nadler, J L; Mitchell, T W; Schmitz-Peiffer, C

    2010-09-01

    Lipid-induced insulin resistance is associated with intracellular accumulation of inhibitory intermediates depending on the prevalent fatty acid (FA) species. In cultured myotubes, ceramide and phosphatidic acid (PA) mediate the effects of the saturated FA palmitate and the unsaturated FA linoleate, respectively. We hypothesized that myriocin (MYR), an inhibitor of de novo ceramide synthesis, would protect against glucose intolerance in saturated fat-fed mice, while lisofylline (LSF), a functional inhibitor of PA synthesis, would protect unsaturated fat-fed mice. Mice were fed diets enriched in saturated fat, n-6 polyunsaturated fat, or chow for 6 wk. Saline, LSF (25 mg/kg x d), or MYR (0.3 mg/kg x d) were administered by mini-pumps in the final 4 wk. Glucose homeostasis was examined by glucose tolerance test. Muscle ceramide and PA were analyzed by mass spectrometry. Expression of LASS isoforms (ceramide synthases) was evaluated by immunoblotting. Both saturated and polyunsaturated fat diets increased muscle ceramide and induced glucose intolerance. MYR and LSF reduced ceramide levels in saturated and unsaturated fat-fed mice. Both inhibitors also improved glucose tolerance in unsaturated fat-fed mice, but only LSF was effective in saturated fat-fed mice. The discrepancy between ceramide and glucose tolerance suggests these improvements may not be related directly to changes in muscle ceramide and may involve other insulin-responsive tissues. Changes in the expression of LASS1 were, however, inversely correlated with alterations in glucose tolerance. The demonstration that LSF can ameliorate glucose intolerance in vivo independent of the dietary FA type indicates it may be a novel intervention for the treatment of insulin resistance. PMID:20660065

  6. Saturated- and n-6 Polyunsaturated-Fat Diets Each Induce Ceramide Accumulation in Mouse Skeletal Muscle: Reversal and Improvement of Glucose Tolerance by Lipid Metabolism Inhibitors

    OpenAIRE

    Frangioudakis, G.; J. Garrard; Raddatz, K.; Nadler, J L; Mitchell, T. W.; Schmitz-Peiffer, C.

    2010-01-01

    Lipid-induced insulin resistance is associated with intracellular accumulation of inhibitory intermediates depending on the prevalent fatty acid (FA) species. In cultured myotubes, ceramide and phosphatidic acid (PA) mediate the effects of the saturated FA palmitate and the unsaturated FA linoleate, respectively. We hypothesized that myriocin (MYR), an inhibitor of de novo ceramide synthesis, would protect against glucose intolerance in saturated fat-fed mice, while lisofylline (LSF), a funct...

  7. Thermodynamic Insights and Conceptual Design of Skin-Sensitive Chitosan Coated Ceramide/PLGA Nanodrug for Regeneration of Stratum Corneum on Atopic Dermatitis

    Science.gov (United States)

    Jung, Sang-Myung; Yoon, Gwang Heum; Lee, Hoo Chul; Jung, Moon Hee; Yu, Sun Il; Yeon, Seung Ju; Min, Seul Ki; Kwon, Yeo Seon; Hwang, Jin Ha; Shin, Hwa Sung

    2015-01-01

    Atopic dermatitis (AD) is a complex skin disease primarily characterized by psoriasis of the stratum corneum. AD drugs have usually been used in acidic and hydrophilic solvents to supply moisture and prevent lipid defects. Ceramide is a typical treatment agent to regenerate the stratum corneum and relieve symptoms of AD. However, ceramide has limitation on direct use for skin because of its low dispersion properties in hydrophilic phase and side effects at excessive treatment. In this study, ceramide imbedded PLGA nanoparticles were developed with chitosan coating (Chi-PLGA/Cer) to overcome this problem. The chitosan coating enhanced initial adherence to the skin and prevented the initial burst of ceramide, but was degraded by the weakly acidic nature of skin, resulting in controlled release of ceramide with additional driving force of the squeezed PLGA nanoparticles. Additionally, the coating kinetics of chitosan were controlled by manipulating the reaction conditions and then mathematically modeled. The Chi-PLGA/Cer was not found to be cytotoxic and ceramide release was controlled by pH, temperature, and chitosan coating. Finally, Chi-PLGA/Cer was demonstrated to be effective at stratum corneum regeneration in a rat AD model. Overall, the results presented herein indicated that Chi-PLGA/Cer is a novel nanodrug for treatment of AD. PMID:26666701

  8. C16-Ceramide Analog Combined with Pc 4 Photodynamic Therapy Evokes Enhanced Total Ceramide Accumulation, Promotion of DEVDase Activation in the Absence of Apoptosis, and Augmented Overall Cell Killing

    Directory of Open Access Journals (Sweden)

    Duska Separovic

    2011-01-01

    Full Text Available Because of the failure of single modality approaches, combination therapy for cancer treatment is a promising alternative. Sphingolipid analogs, with or without anticancer drugs, can improve tumor response. C16-pyridinium ceramide analog LCL30, was used in combination with photodynamic therapy (PDT, an anticancer treatment modality, to test the hypothesis that the combined treatment will trigger changes in the sphingolipid profile and promote cell death. Using SCCVII mouse squamous carcinoma cells, and the silicone phthalocyanine Pc 4 for PDT, we showed that combining PDT with LCL30 (PDT/LCL30 was more effective than individual treatments in raising global ceramide levels, as well as in reducing dihydrosphingosine levels. Unlike LCL30, PDT, alone or combined, increased total dihydroceramide levels. Sphingosine levels were unaffected by LCL30, but were abolished after PDT or the combination. LCL30-triggered rise in sphingosine-1-phosphate was reversed post-PDT or the combination. DEVDase activation was evoked after PDT or LCL30, and was promoted post- PDT/LCL30. Neither mitochondrial depolarization nor apoptosis were observed after any of the treatments. Notably, treatment with the combination resulted in augmented overall cell killing. Our data demonstrate that treatment with PDT/LCL30 leads to enhanced global ceramide levels and DEVDase activation in the absence of apoptosis, and promotion of total cell killing.

  9. Effects of topical corticosteroid and tacrolimus on ceramides and irritancy to sodium lauryl sulphate in healthy skin

    DEFF Research Database (Denmark)

    Jungersted, Jakob Mutanu; Høgh, Julie Kaae; Hellegren, Lars I;

    2011-01-01

    The skin barrier, located in the stratum corneum, is influenced mainly by the lipid and protein composition of this layer. In eczematous diseases impairment of the skin barrier is thought to be of prime importance. Topical anti-inflammatory drugs and emollients are the most widely used eczema...... twice daily for one week with betamethasone, tacrolimus, emollient, or left untreated, respectively. After one week each area was challenged with a 24 h sodium lauryl sulphate patch test. The lipids were collected using the cyanoacrylate method and evaluated by high performance thin layer chromatography....... For evaluation of the skin barrier, transepidermal water loss, erythema and electrical capacitance were measured. The ceramide/cholesterol ratio was increased in betamethasone- (p¿=¿0.008) and tacrolimus-treated (p¿=¿0.025) skin compared with emollient-treated skin. No differences in ceramide...

  10. Bioactives of Artemisia dracunculus L. Mitigate the Role of Ceramides in Attenuating Insulin Signaling in Rat Skeletal Muscle Cells

    OpenAIRE

    Diana N Obanda; Hernandez, Amy; RIBNICKY, DAVID; Yu, Yongmei; Zhang, Xian H.; Wang, Zhong Q.; Cefalu, William T.

    2012-01-01

    Ectopic lipids in peripheral tissues have been implicated in attenuating insulin action in vivo. The botanical extract of Artemisia dracunculus L. (PMI 5011) improves insulin action, yet the precise mechanism is not known. We sought to determine whether the mechanism by which PMI 5011 improves insulin signaling is through regulation of lipid metabolism. After differentiation, cells were separately preincubated with free fatty acids (FFAs) and ceramide C2, and the effects on glycogen content, ...

  11. Hypocrellin B and paclitaxel-encapsulated hyaluronic acid-ceramide nanoparticles for targeted photodynamic therapy in lung cancer.

    Science.gov (United States)

    Chang, Ji-Eun; Cho, Hyun-Jong; Yi, Eunjue; Kim, Dae-Duk; Jheon, Sanghoon

    2016-05-01

    To increase the therapeutic efficacy of photodynamic therapy (PDT) in treating lung cancer, we developed both photosensitizer and anticancer drug encapsulated hyaluronic acid-ceramide nanoparticles. Based on our previous study, a co-delivery system of photosensitizers and anticancer agents greatly improves the therapeutic effect of PDT. Furthermore, hyaluronic acid-ceramide-based nanoparticles are ideal targeting carriers for lung cancer. In vitro phototoxicity in A549 (human lung adenocarcinoma) cells and in vivo antitumor efficacy in A549 tumor-bearing mice treated with hypocrellin B (HB)-loaded nanoparticles (HB-NPs) or hypocrellin B and paclitaxel loaded nanoparticles (HB-P-NPs) were evaluated. Cell viability assay, microscopic analysis and FACS analysis were performed for the in vitro studies and HB-P-NPs showed enhanced phototoxicity compared with HB-NPs. In the animal study, the tumor volume change and the histological analysis was studied and the anticancer efficacy improved in the order of free HBceramide nanoparticle-based targeted delivery improved the effects of PDT in lung cancer in mice. PMID:26967521

  12. Absence of perilipin 2 prevents hepatic steatosis, glucose intolerance and ceramide accumulation in alcohol-fed mice.

    Directory of Open Access Journals (Sweden)

    Rotonya M Carr

    Full Text Available Perilipin 2 (Plin2 is a lipid droplet protein that has roles in both lipid and glucose homeostasis. An increase in Plin2 in liver is associated with the development of steatosis, glucose intolerance, and ceramide accumulation in alcoholic liver disease. We investigated the role of Plin2 on energy balance and glucose and lipid homeostasis in wildtype and Plin2 knockout (Plin2KO mice chronically fed a Lieber-DeCarli liquid ethanol or control diet for six weeks.We performed in vivo measurements of energy intake and expenditure; body composition; and glucose tolerance. After sacrifice, liver was dissected for histology and lipid analysis.We found that neither genotype nor diet had a significant effect on final weight, body composition, or energy intake between WT and Plin2KO mice fed alcohol or control diets. Additionally, alcohol feeding did not affect oxygen consumption or carbon dioxide production in Plin2KO mice. We performed glucose tolerance testing and observed that alcohol feeding failed to impair glucose tolerance in Plin2KO mice. Most notably, absence of Plin2 prevented hepatic steatosis and ceramide accumulation in alcohol-fed mice. These changes were related to downregulation of genes involved in lipogenesis and triglyceride synthesis.Plin2KO mice chronically fed alcohol are protected from hepatic steatosis, glucose intolerance, and hepatic ceramide accumulation, suggesting a critical pathogenic role of Plin2 in experimental alcoholic liver disease.

  13. The role of ceramides 1 and 2 in the stratum corneum lipid organisation.

    Science.gov (United States)

    Bouwstra, J A; Cheng, K; Gooris, G S; Weerheim, A; Ponec, M

    1996-05-20

    A mixture of ceramide 1 and ceramide 2 (CER(1 + 2)) was isolated from pig stratum corneum and mixed in various molar ratios with cholesterol (CHOL) or with CHOL and palmitic acid (PA). The mixtures were hydrated in a buffer solution of pH 5.0 and their phase behaviour was studied by wide- and small-angle X-ray diffraction. The small-angle diffraction curve of the CHOL/CER(1 + 2) mixture at a molar ratio of 0.4 revealed the presence of only one peak at a spacing of 6.7 nm. Increasing the amount of CHOL to a molar ratio of 0.6 was accompanied by a shift of this peak to a smaller spacing (5.7 nm) and the appearance of two weak peaks at 11.8 and 4.1 nm spacings. Increasing the CHOL content to an equimolar ratio resulted in the appearance of two lamellar phases with periodicities of 5.5 and 12 nm, respectively. In a CHOL/CER(1 + 2) mixture at a molar ratio of 2 the periodicities of the two phases were 5.6 and 12 nm, respectively. From these observations it was concluded that the CHOL/CER(1 + 2) mixtures exerted similar phase behaviour, as reported earlier for intact SC (Bouwstra et al. (1995) J. Lipid Res. 36, 496-504) and for mixtures (Bouwstra et al. (1996) J. Lipid Res., in press) prepared from CHOL and total ceramide fraction (CER) isolated from pig stratum corneum. However, in the CHOL/CER mixtures a lower relative amount of CHOL was required to acquire these lamellar phases, indicating that at low CHOL contents, CER 3, 4, 5 and 6 play a crucial role in the formation of the lamellar phases. Furthermore, the solubility of CHOL in the mixtures increased in the presence of CER 1, suggesting its important role for the barrier function of the skin. When palmitic acid (PA) was included, the phase behaviour of the CHOL/CER(1 + 2)/PA mixture was more complex. Next to two lamellar phases, an additional phase with a spacing of 3.77 nm was observed, never seen in intact stratum corneum. In the absence of CHOL, the wide-angle diffraction pattern of the CER(1 + 2) revealed one

  14. Control of glucosylceramide production and morphogenesis by the Bar1 ceramide synthase in Fusarium graminearum.

    Directory of Open Access Journals (Sweden)

    William R Rittenour

    Full Text Available The contribution of plasma membrane proteins to the virulence of plant pathogenic fungi is poorly understood. Accordingly, the objective of this study was to characterize the acyl-CoA dependent ceramide synthase Bar1 (previously implicated in plasma membrane organization in the wheat pathogen Fusarium graminearum. The role of Bar1 in mediating cell membrane organization was confirmed as ΔBAR1 mutants failed to display a distinct sterol-rich domain at the hyphal tip. The ΔBAR1 mutants were non-pathogenic when inoculated onto wheat heads, and their in vitro growth also was severely perturbed. ΔBAR1 mutants were incapable of producing perithecia (sexual fruiting structures and only produced macroconidia (asexual spores in the presence of NaCl. Sphingolipid analyses indicated that Bar1 is specifically necessary for the production of glucosylceramides in both F. graminearum and Aspergillus nidulans. Interestingly, glucosylceramides appear to mediate sensitivity to heat stable antifungal factor (HSAF, as, in addition to ΔBAR1 mutants, a glucosylceramide synthase deficient mutant of Yarrowia lipolytica is also resistant to HSAF.

  15. Control of glucosylceramide production and morphogenesis by the Bar1 ceramide synthase in Fusarium graminearum.

    Science.gov (United States)

    Rittenour, William R; Chen, Ming; Cahoon, Edgar B; Harris, Steven D

    2011-01-01

    The contribution of plasma membrane proteins to the virulence of plant pathogenic fungi is poorly understood. Accordingly, the objective of this study was to characterize the acyl-CoA dependent ceramide synthase Bar1 (previously implicated in plasma membrane organization) in the wheat pathogen Fusarium graminearum. The role of Bar1 in mediating cell membrane organization was confirmed as ΔBAR1 mutants failed to display a distinct sterol-rich domain at the hyphal tip. The ΔBAR1 mutants were non-pathogenic when inoculated onto wheat heads, and their in vitro growth also was severely perturbed. ΔBAR1 mutants were incapable of producing perithecia (sexual fruiting structures) and only produced macroconidia (asexual spores) in the presence of NaCl. Sphingolipid analyses indicated that Bar1 is specifically necessary for the production of glucosylceramides in both F. graminearum and Aspergillus nidulans. Interestingly, glucosylceramides appear to mediate sensitivity to heat stable antifungal factor (HSAF), as, in addition to ΔBAR1 mutants, a glucosylceramide synthase deficient mutant of Yarrowia lipolytica is also resistant to HSAF. PMID:21559419

  16. A deficiency of ceramide biosynthesis causes cerebellar purkinje cell neurodegeneration and lipofuscin accumulation.

    Directory of Open Access Journals (Sweden)

    Lihong Zhao

    2011-05-01

    Full Text Available Sphingolipids, lipids with a common sphingoid base (also termed long chain base backbone, play essential cellular structural and signaling functions. Alterations of sphingolipid levels have been implicated in many diseases, including neurodegenerative disorders. However, it remains largely unclear whether sphingolipid changes in these diseases are pathological events or homeostatic responses. Furthermore, how changes in sphingolipid homeostasis shape the progression of aging and neurodegeneration remains to be clarified. We identified two mouse strains, flincher (fln and toppler (to, with spontaneous recessive mutations that cause cerebellar ataxia and Purkinje cell degeneration. Positional cloning demonstrated that these mutations reside in the Lass1 gene. Lass1 encodes (dihydroceramide synthase 1 (CerS1, which is highly expressed in neurons. Both fln and to mutations caused complete loss of CerS1 catalytic activity, which resulted in a reduction in sphingolipid biosynthesis in the brain and dramatic changes in steady-state levels of sphingolipids and sphingoid bases. In addition to Purkinje cell death, deficiency of CerS1 function also induced accumulation of lipofuscin with ubiquitylated proteins in many brain regions. Our results demonstrate clearly that ceramide biosynthesis deficiency can cause neurodegeneration and suggest a novel mechanism of lipofuscin formation, a common phenomenon that occurs during normal aging and in some neurodegenerative diseases.

  17. Sphingosine Kinase 2 and Ceramide Transport as Key Targets of the Natural Flavonoid Luteolin to Induce Apoptosis in Colon Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Loubna Abdel Hadi

    Full Text Available The plant flavonoid luteolin exhibits different biological effects, including anticancer properties. Little is known on the molecular mechanisms underlying its actions in colorectal cancer (CRC. Here we investigated the effects of luteolin on colon cancer cells, focusing on the balance between ceramide and sphingosine-1-phosphate (S1P, two sphingoid mediators with opposite roles on cell fate. Using cultured cells, we found that physiological concentrations of luteolin induce the elevation of ceramide, followed by apoptotic death of colon cancer cells, but not of differentiated enterocytes. Pulse studies revealed that luteolin inhibits ceramide anabolism to complex sphingolipids. Further experiments led us to demonstrate that luteolin induces an alteration of the endoplasmic reticulum (ER-Golgi flow of ceramide, pivotal to its metabolic processing to complex sphingolipids. We report that luteolin exerts its action by inhibiting both Akt activation, and sphingosine kinase (SphK 2, with the consequent reduction of S1P, an Akt stimulator. S1P administration protected colon cancer cells from luteolin-induced apoptosis, most likely by an intracellular, receptor-independent mechanism. Overall this study reveals for the first time that the dietary flavonoid luteolin exerts toxic effects on colon cancer cells by inhibiting both S1P biosynthesis and ceramide traffic, suggesting its dietary introduction/supplementation as a potential strategy to improve existing treatments in CRC.

  18. Improved insulin sensitivity after exercise training is linked to reduced plasma C14:0 ceramide in obesity and type 2 diabetes

    DEFF Research Database (Denmark)

    Kasumov, Takhar; Solomon, Thomas; Hwang, Calvin; Huang, Hazel; Haus, Jacob M; Zhang, Renliang; Kirwan, John P

    2015-01-01

     = 0.009) ceramide were negatively correlated with the increase in insulin sensitivity. CONCLUSIONS: Ceramides are linked to exercise training-induced improvements in insulin sensitivity, and plasma C14:0 ceramide may provide a specific target for investigating lipid-related insulin resistance in......OBJECTIVE: To assess the effect of exercise training on insulin sensitivity and plasma ceramides in obesity and type 2 diabetes (T2D). METHODS: Twenty-four adults with obesity and normal glucose tolerance (NGT, n = 14) or diabetes (n = 10) were studied before and after a 12-week supervised exercise......-training program (5 days/week, 1 h/day, 80-85% of maximum heart rate). Changes in body composition were assessed using hydrostatic weighing and computed tomography. Peripheral tissue insulin sensitivity was assessed by a 40 mU/m(2) /min hyperinsulinemic euglycemic clamp. Plasma ceramides (C14:0, C16:0, C18:0, C18...

  19. Muscle ceramide content is similar after 3 weeks’ consumption of fat or carbohydrate diet in a crossover design in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Helge, J. W.; Tobin, L.; Drachmann, Tue;

    2012-01-01

    This study aimed at investigating the effect of prolonged adaptation to fat- or carbohydrate-rich diet on muscle ceramide in type 2 diabetes patients, using a longitudinal crossover study. Eleven type 2 diabetes patients consumed isocaloric fat- or carbohydrate-rich diet for 3 weeks in random order...... sensitivity, muscle glycogen, triacylglycerol and ceramide content were similar. Plasma adiponectin concentration was significantly higher after fat compared with carbohydrate-rich diet. Results indicated that following fat-rich diet intake muscle ceramide and triacylglycerol concentrations were not different...... compared with that after carbohydrate-rich diet. Furthermore, plasma adiponectin concentration was higher after fat-rich compared with carbohydrate-rich diet, but insulin sensitivity remained similar despite the major difference in dietary macronutrient composition....

  20. Tetanus Toxin Hc Fragment Induces the Formation of Ceramide Platforms and Protects Neuronal Cells against Oxidative Stress.

    Directory of Open Access Journals (Sweden)

    Roger Cubí

    Full Text Available Tetanus toxin (TeTx is the protein, synthesized by the anaerobic bacteria Clostridium tetani, which causes tetanus disease. TeTx gains entry into target cells by means of its interaction with lipid rafts, which are membrane domains enriched in sphingomyelin and cholesterol. However, the exact mechanism of host membrane binding remains to be fully established. In the present study we used the recombinant carboxyl terminal fragment from TeTx (Hc-TeTx, the domain responsible for target neuron binding, showing that Hc-TeTx induces a moderate but rapid and sustained increase in the ceramide/sphingomyelin ratio in primary cultures of cerebellar granule neurons and in NGF-differentiated PC12 cells, as well as induces the formation of ceramide platforms in the plasma membrane. The mentioned increase is due to the promotion of neutral sphingomyelinase activity and not to the de novo synthesis, since GW4869, a specific neutral sphingomyelinase inhibitor, prevents neutral sphingomyelinase activity increase and formation of ceramide platforms. Moreover, neutral sphingomyelinase inhibition with GW4869 prevents Hc-TeTx-triggered signaling (Akt phosphorylation, as well as the protective effect of Hc-TeTx on PC12 cells subjected to oxidative stress, while siRNA directed against nSM2 prevents protection by Hc-TeTx of NSC-34 cells against oxidative insult. Finally, neutral sphingomyelinase activity seems not to be related with the internalization of Hc-TeTx into PC12 cells. Thus, the presented data shed light on the mechanisms triggered by TeTx after membrane binding, which could be related with the events leading to the neuroprotective action exerted by the Hc-TeTx fragment.

  1. Tetanus Toxin Hc Fragment Induces the Formation of Ceramide Platforms and Protects Neuronal Cells against Oxidative Stress.

    Science.gov (United States)

    Cubí, Roger; Candalija, Ana; Ortega, Arturo; Gil, Carles; Aguilera, José

    2013-01-01

    Tetanus toxin (TeTx) is the protein, synthesized by the anaerobic bacteria Clostridium tetani, which causes tetanus disease. TeTx gains entry into target cells by means of its interaction with lipid rafts, which are membrane domains enriched in sphingomyelin and cholesterol. However, the exact mechanism of host membrane binding remains to be fully established. In the present study we used the recombinant carboxyl terminal fragment from TeTx (Hc-TeTx), the domain responsible for target neuron binding, showing that Hc-TeTx induces a moderate but rapid and sustained increase in the ceramide/sphingomyelin ratio in primary cultures of cerebellar granule neurons and in NGF-differentiated PC12 cells, as well as induces the formation of ceramide platforms in the plasma membrane. The mentioned increase is due to the promotion of neutral sphingomyelinase activity and not to the de novo synthesis, since GW4869, a specific neutral sphingomyelinase inhibitor, prevents neutral sphingomyelinase activity increase and formation of ceramide platforms. Moreover, neutral sphingomyelinase inhibition with GW4869 prevents Hc-TeTx-triggered signaling (Akt phosphorylation), as well as the protective effect of Hc-TeTx on PC12 cells subjected to oxidative stress, while siRNA directed against nSM2 prevents protection by Hc-TeTx of NSC-34 cells against oxidative insult. Finally, neutral sphingomyelinase activity seems not to be related with the internalization of Hc-TeTx into PC12 cells. Thus, the presented data shed light on the mechanisms triggered by TeTx after membrane binding, which could be related with the events leading to the neuroprotective action exerted by the Hc-TeTx fragment. PMID:23826362

  2. Probiotic sonicates selectively induce mucosal immune cells apoptosis through ceramide generation via neutral sphingomyelinase.

    Directory of Open Access Journals (Sweden)

    Sandra Angulo

    Full Text Available BACKGROUND: Probiotics appear to be beneficial in inflammatory bowel disease, but their mechanism of action is incompletely understood. We investigated whether probiotic-derived sphingomyelinase mediates this beneficial effect. METHODOLOGY/PRINCIPAL FINDINGS: Neutral sphingomyelinase (NSMase activity was measured in sonicates of the probiotic L. brevis (LB and S. thermophilus (ST and the non-probiotic E. coli (EC and E. faecalis (EF. Lamina propria mononuclear cells (LPMC were obtained from patients with Crohn's disease (CD and Ulcerative Colitis (UC, and peripheral blood mononuclear cells (PBMC from healthy volunteers, analysing LPMC and PBMC apoptosis susceptibility, reactive oxygen species (ROS generation and JNK activation. In some experiments, sonicates were preincubated with GSH or GW4869, a specific NSMase inhibitor. NSMase activity of LB and ST was 10-fold that of EC and EF sonicates. LB and ST sonicates induced significantly more apoptosis of CD and UC than control LPMC, whereas EC and EF sonicates failed to induce apoptosis. Pre-stimulation with anti-CD3/CD28 induced a significant and time-dependent increase in LB-induced apoptosis of LPMC and PBMC. Exposure to LB sonicates resulted in JNK activation and ROS production by LPMC. NSMase activity of LB sonicates was completely abrogated by GW4869, causing a dose-dependent reduction of LB-induced apoptosis. LB and ST selectively induced immune cell apoptosis, an effect dependent on the degree of cell activation and mediated by bacterial NSMase. CONCLUSIONS: These results suggest that induction of immune cell apoptosis is a mechanism of action of some probiotics, and that NSMase-mediated ceramide generation contributes to the therapeutic effects of probiotics.

  3. Implication of matrix metalloproteinases 2 and 9 in ceramide 1-phosphate-stimulated macrophage migration.

    Science.gov (United States)

    Ordoñez, Marta; Rivera, Io-Guané; Presa, Natalia; Gomez-Muñoz, Antonio

    2016-08-01

    Cell migration is a complex biological function involved in both physiologic and pathologic processes. Although this is a subject of intense investigation, the mechanisms by which cell migration is regulated are not completely understood. In this study we show that the bioactive sphingolipid ceramide 1-phosphate (C1P), which is involved in inflammatory responses, causes upregulation of metalloproteinases (MMP) -2 and -9 in J774A.1 macrophages. This effect was shown to be dependent on stimulation of phosphatidylinositol 3-kinase (PI3K) and extracellularly regulated kinases 1-2 (ERK1-2) as demonstrated by treating the cells with specific siRNA to knockdown the p85 regulatory subunit of PI3K, or ERK1-2. Inhibition of MMP-2 or MMP-9 pharmacologically or with specific siRNA to silence the genes encoding these MMPs abrogated C1P-stimulated macrophage migration. Also, C1P induced actin polymerization and potently increased phosphorylation of the focal adhesion protein paxillin, which are essential factors in the regulation of cell migration. As expected, blockade of paxillin activation with specific siRNA significantly reduced actin polymerization. In addition, inhibition of actin polymerization with cytochalasin D completely blocked C1P-induced MMP-2 and -9 expression as well as C1P-stimulated macrophage migration. It was also observed that pertussis toxin (Ptx) inhibited Akt, ERK1-2, and paxillin phosphorylation, and completely blocked cell migration. The latter findings support the notion that C1P-stimulated macrophage migration is a receptor mediated effect, and point to MMP-2 and -9 as possible therapeutic targets to control inflammation. PMID:27164414

  4. Structural and thermotropic properties of synthetic C16:0 (palmitoyl) ceramide: effect of hydration.

    Science.gov (United States)

    Shah, J; Atienza, J M; Duclos, R I; Rawlings, A V; Dong, Z; Shipley, G G

    1995-09-01

    Differential scanning calorimetry (DSC) and X-ray diffraction techniques have been used to investigate the structure and thermotropic properties of synthetic, non-hydroxy fatty acid (16:0) ceramide (NFA(C16)CER) as a function of hydration. Anhydrous NFA(C16)CER shows a single, broad endothermic transition at 95.4 degrees C (delta H = 10.4 kcal/mol). On hydration, a broad exothermic transition appears at approximately 50-70 degrees C while the main endothermic transition decreases to 90.0 degrees C (delta H = 13.8 kcal/mol). The enthalpy of the exothermic transition increases with hydration to a maximum value, delta H = 4.8 kcal/mol. This polymorphic phase behavior depends on the low temperature incubation time and prior cooling rate. X-ray diffraction of fully hydrated NFA(C16)CER at 26 degrees C, shows a well-ordered lamellar phase with a bilayer periodicity d = 46.9 A. At 68 degrees C, above the first exothermic transition, X-ray diffraction shows again a lamellar phase with reduced bilayer periodicity d = 41.8 A and an increased number of both lamellar and wide-angle reflections indicative of enhanced layer and chain packing order, respectively. At 90.0 degrees C, above the main transition, the diffraction pattern shows a broad, intense reflection at 29.9 A and a diffuse reflection at 4.6 A, indicative of a melted chain phase. On cooling, NFA(C16)CER exhibits polymorphic phase behavior involving the conversion of the melted chain phase to a metastable bilayer phase. On heating, this metastable phase undergoes an exothermic transition to a stable bilayer phase; on further heating, NFA(C16)CER converts endothermically to the melted-chain phase.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8558082

  5. Absence of Perilipin 2 Prevents Hepatic Steatosis, Glucose Intolerance and Ceramide Accumulation in Alcohol-Fed Mice

    OpenAIRE

    Carr, Rotonya M.; Peralta, Giselle; Yin, Xiaoyan; Ahima, Rexford S.

    2014-01-01

    Background Perilipin 2 (Plin2) is a lipid droplet protein that has roles in both lipid and glucose homeostasis. An increase in Plin2 in liver is associated with the development of steatosis, glucose intolerance, and ceramide accumulation in alcoholic liver disease. We investigated the role of Plin2 on energy balance and glucose and lipid homeostasis in wildtype and Plin2 knockout (Plin2KO) mice chronically fed a Lieber-DeCarli liquid ethanol or control diet for six weeks. Methods We performed...

  6. Acyl-CoA-binding protein, Acb1p, is required for normal vacuole function and ceramide synthesis in Saccharomyces cerevisiae

    DEFF Research Database (Denmark)

    Færgeman, Nils J.; Feddersen, Søren; Christiansen, Janne K;

    2004-01-01

    In the present study, we show that depletion of acyl-CoA-binding protein, Acb1p, in yeast affects ceramide levels, protein trafficking, vacuole fusion and structure. Vacuoles in Acb1p-depleted cells are multi-lobed, contain significantly less of the SNAREs (soluble N -ethylmaleimide......-sensitive fusion protein attachment protein receptors) Nyv1p, Vam3p and Vti1p, and are unable to fuse in vitro. Mass spectrometric analysis revealed a dramatic reduction in the content of ceramides in whole-cell lipids and in vacuoles isolated from Acb1p-depleted cells. Maturation of yeast aminopeptidase I and...

  7. Ceramide Kinase Contributes to Proliferation but not to Prostaglandin E2 Formation in Renal Mesangial Cells and Fibroblasts

    Directory of Open Access Journals (Sweden)

    Oleksandr Pastukhov

    2014-06-01

    Full Text Available Background/Aims: Ceramide kinase (CerK catalyzes the generation of the sphingolipid ceramide-1-phosphate (C1P which regulates various cellular functions including cell growth and death, and inflammation. Here, we used a novel catalytic inhibitor of CerK, NVP-231, and CerK knockout cells to investigate the contribution of CerK to proliferation and inflammation in renal mesangial cells and fibroblasts. Methods: Cells were treated with NVP-231 and [3H]-thymidine incorporation into DNA, [3H]-arachidonic acid release, prostaglandin E2 (PGE2 synthesis, cell cycle distribution, and apoptosis were determined. Results: Treatment of rat mesangial cells and mouse renal fibroblasts with NVP-231 decreased DNA synthesis, but not of agonist-stimulated arachidonic acid release or PGE2 synthesis. Similarly, proliferation but not arachidonic acid release or PGE2 synthesis was reduced in CERK knockout renal fibroblasts. The anti-proliferative effect of NVP-231 on mesangial cells was due to M phase arrest as determined using the mitosis markers phospho-histone H3, cdc2 and polo-like kinase-1, and induction of apoptosis. Moreover, loss of CerK sensitized cells towards stress-induced apoptosis. Conclusions: Our data demonstrate that CerK induces proliferation but not PGE2 formation of renal mesangial cells and fibroblasts, and suggest that targeted CerK inhibition has potential for treating mesangioproliferative kidney diseases.

  8. Ceramide synthase inhibition causes accumulation of 1-deoxysphinganine: biosynthesis of a novel category of bioactive sphingoid bases in diverse mammalian cell linesa and mice

    Science.gov (United States)

    Fumonisins (FB) are mycotoxins that inhibit ceramide synthases (CerS) and cause animal and plant disease. Inhibition of CerS results in a rapid increases in sphinganine (Sa), an intermediate of de novo sphingolipid biosynthesis, sphinganine 1-phosphate, and a previously unidentified metabolite tha...

  9. Inhibition of ceramide glucosylation sensitizes lung cancer cells to ABC294640, a first-in-class small molecule SphK2 inhibitor.

    Science.gov (United States)

    Guan, Shuhong; Liu, Yuan Y; Yan, Tingzan; Zhou, Jun

    2016-08-01

    Sphingosine kinase 2 (SphK2) is proposed as a novel oncotarget for lung cancer. Here, we studied the anti-lung cancer cell activity by ABC294640, a first-in-class SphK2 inhibitor. We showed that ABC294640 suppressed growth of primary and A549 human lung cancer cells, but sparing SphK2-low lung epithelial cells. Inhibition of SphK2 by ABC294640 increased ceramide accumulation, but decreased pro-survival sphingosine-1-phosphate (S1P) content, leading to lung cancer cell apoptosis activation. Significantly, we show that glucosylceramide synthase (GCS) might be a major resistance factor of ABC294640. The GCS inhibitor 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) or GCS shRNA/siRNA knockdown facilitated ABC294640-induced ceramide production and lung cancer cell apoptosis. Reversely, forced overexpression of GCS reduced ABC294640's sensitivity, resulting in decreased ceramide accumulation and apoptosis induction in A549 cells. These findings provide further evidences to support that targeting SphK2 by ABC294640 may be a rational treatment option for lung cancer. Ceramide glucosylation inhibition may further sensitize lung cancer cells to ABC294640. PMID:27221045

  10. Apoptosis and the activity of ceramide, Bax and Bcl-2 in the lungs of neonatal rats exposed to limited and prolonged hyperoxia

    Directory of Open Access Journals (Sweden)

    Bitar Fadi F

    2006-07-01

    Full Text Available Abstract Background The aim of the study is to examine the effect of limited and prolonged hyperoxia on neonatal rat lung. This is done by examining the morphologic changes of apoptosis, the expression of ceramide, an important mediator of apoptosis, the expression of inflammatory mediators represented by IL-1β and the expression of 2 proto-oncogenes that appear to modulate apoptosis (Bax and Bcl-2. Methods Newborn rats were placed in chambers containing room air or oxygen above 90% for 7 days. The rats were sacrificed at 3, 7 or 14 days and their lungs removed. Sections were fixed, subjected to TUNEL, Hoechst, and E-Cadherin Staining. Sections were also incubated with anti-Bcl-2 and anti-Bax antisera. Bcl-2 and Bax were quantitated by immunohistochemistry. Lipids were extracted, and ceramide measured through a modified diacylglycerol kinase assay. RT-PCR was utilized to assess IL-1β expression. Results TUNEL staining showed significant apoptosis in the hyperoxia-exposed lungs at 3 days only. Co-staining of the apoptotic cells with Hoechst, and E-Cadherin indicated that apoptotic cells were mainly epithelial cells. The expression of Bax and ceramide was significantly higher in the hyperoxia-exposed lungs at 3 and 14 days of age, but not at 7 days. Bcl-2 was significantly elevated in the hyperoxia-exposed lungs at 3 and 14 days. IL-1β expression was significantly increased at 14 days. Conclusion Exposure of neonatal rat lung to hyperoxia results in early apoptosis documented by TUNEL assay. The early rise in Bax and ceramide appears to overcome the anti-apoptotic activity of Bcl-2. Further exposure did not result in late apoptotic changes. This suggests that apoptotic response to hyperoxia is time sensitive. Prolonged hyperoxia results in acute lung injury and the shifting balance of ceramide, Bax and Bcl-2 may be related to the evolution of the inflammatory process.

  11. Metronomic Ceramide Analogs Inhibit Angiogenesis in Pancreatic Cancer through Up-regulation of Caveolin-1 and Thrombospondin-1 and Down-regulation of Cyclin D1

    Directory of Open Access Journals (Sweden)

    Guido Bocci

    2012-09-01

    Full Text Available AIMS: To evaluate the antitumor and antiangiogenic activity of metronomic ceramide analogs and their relevant molecular mechanisms. METHODS: Human endothelial cells [human dermal microvascular endothelial cells and human umbilical vascular endothelial cell (HUVEC] and pancreatic cancer cells (Capan-1 and MIA PaCa-2 were treated with the ceramide analogs (C2, AL6, C6, and C8, at low concentrations for 144 hours to evaluate any antiproliferative and proapoptotic effects and inhibition of migration and to measure the expression of caveolin-1 (CAV-1 and thrombospondin-1 (TSP-1 mRNAs by real-time reverse transcription-polymerase chain reaction. Assessment of extracellular signal-regulated kinases 1 and 2 (ERK1/2 and Akt phosphorylation and of CAV-1 and cyclin D1 protein expression was performed by ELISA. Maximum tolerated dose (MTD gemcitabine was compared against metronomic doses of the ceramide analogs by evaluating the inhibition of MIA PaCa-2 subcutaneous tumor growth in nude mice. RESULTS: Metronomic ceramide analogs preferentially inhibited cell proliferation and enhanced apoptosis in endothelial cells. Low concentrations of AL6 and C2 caused a significant inhibition of HUVEC migration. ERK1/2 and Akt phosphorylation were significantly decreased after metronomic ceramide analog treatment. Such treatment caused the overexpression of CAV-1 and TSP-1 mRNAs and proteins in endothelial cells, whereas cyclin D1 protein levels were reduced. The antiangiogenic and antitumor impact in vivo of metronomic C2 and AL6 regimens was similar to that caused by MTD gemcitabine. CONCLUSIONS: Metronomic C2 and AL6 analogs have antitumor and antiangiogenic activity, determining the up-regulation of CAV-1 and TSP-1 and the suppression of cyclin D1.

  12. Modest phenotypic improvements in ASA-deficient mice with only one UDP-galactose:ceramide-galactosyltransferase gene

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    De Deyn PP

    2006-08-01

    Full Text Available Summary Background Arylsulfatase A (ASA-deficient mice are a model for the lysosomal storage disorder metachromatic leukodystrophy. This lipidosis is characterised by the lysosomal accumulation of the sphingolipid sulfatide. Storage of this lipid is associated with progressive demyelination. We have mated ASA-deficient mice with mice heterozygous for a non-functional allele of UDP-galactose:ceramide-galactosyltransferase (CGT. This deficiency is known to lead to a decreased synthesis of galactosylceramide and sulfatide, which should reduce sulfatide storage and improve pathology in ASA-deficient mice. Results ASA-/- CGT+/- mice, however, showed no detectable decrease in sulfatide storage. Neuronal degeneration of cells in the spiral ganglion of the inner ear, however, was decreased. Behavioural tests showed small but clear improvements of the phenotype in ASA-/- CGT+/- mice. Conclusion Thus the reduction of galactosylceramide and sulfatide biosynthesis by genetic means overall causes modest improvements of pathology.

  13. Platelet activating factor-induced ceramide micro-domains drive endothelial NOS activation and contribute to barrier dysfunction.

    Directory of Open Access Journals (Sweden)

    Sanda Predescu

    Full Text Available The spatial and functional relationship between platelet activating factor-receptor (PAF-R and nitric oxide synthase (eNOS in the lateral plane of the endothelial plasma membrane is poorly characterized. In this study, we used intact mouse pulmonary endothelial cells (ECs as well as endothelial plasma membrane patches and subcellular fractions to define a new microdomain of plasmalemma proper where the two proteins colocalize and to demonstrate how PAF-mediated nitric oxide (NO production fine-tunes ECs function as gatekeepers of vascular permeability. Using fluorescence microscopy and immunogold labeling electron microscopy (EM on membrane patches we demonstrate that PAF-R is organized as clusters and colocalizes with a subcellular pool of eNOS, outside recognizable vesicular profiles. Moreover, PAF-induced acid sphingomyelinase activation generates a ceramide-based microdomain on the external leaflet of plasma membrane, inside of which a signalosome containing eNOS shapes PAF-stimulated NO production. Real-time measurements of NO after PAF-R ligation indicated a rapid (5 to 15 min increase in NO production followed by a > 45 min period of reduction to basal levels. Moreover, at the level of this new microdomain, PAF induces a dynamic phosphorylation/dephosphorylation of Ser, Thr and Tyr residues of eNOS that correlates with NO production. Altogether, our findings establish the existence of a functional partnership PAF-R/eNOS on EC plasma membrane, at the level of PAF-induced ceramide plasma membrane microdomains, outside recognized vesicular profiles.

  14. IL-1beta-Induced iNOS Expression, NO Release and Loss in Metabolic Cell Viability Are Resistant to Inhibitors of Ceramide Synthase and Sphingomyelinase in INS 832/13 Cells

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    Rajakrishnan Veluthakal

    2006-11-01

    Full Text Available Context Emerging evidence indicates regulatory roles for ceramide in the metabolic dysfunction of the islet beta cell. Recently, potential similarities between IL-1beta and ceramide on their effects on islet beta cell have been reported, including reduction in mitochondrial membrane potential and loss in metabolic cell viability.Objective Herein, we investigated whether IL-1beta-induced nitric oxide synthetase (iNOS expression, nitric oxide (NO release and loss in metabolic cell viability require ceramide biosynthesis either via the activation of sphingomyelinase or ceramide synthase.Setting Insulin-secreting INS 832/13 cells.Results We found that two structurally-distinct inhibitors of sphingomyelinase activation (e.g., 3-O-methylsphingomyelin or desipramine or ceramide biosynthesis inhib-itor (e.g., fumonisin failed to exert clear effects on IL-1beta-induced iNOS expression, NO release and loss in cell viability.Conclusions Taken together, our findings indicate that neither the sphingomyelinase nor the ceramide synthase activation is required for IL-1beta-induced metabolic abnormalities in insulin-secreting INS 832/13 cells.

  15. Ceramide 1-phosphate induces neointimal formation via cell proliferation and cell cycle progression upstream of ERK1/2 in vascular smooth muscle cells

    International Nuclear Information System (INIS)

    Ceramide 1-phosphate (C1P) is a novel bioactive sphingolipid formed by ceramide kinase (CERK)-catalyzed phosphorylation of ceramide. It has been implicated in the regulation of such vital pathophysiological functions as phagocytosis and inflammation, but there have been no reports ascribing a biological function to CERK in vascular disorders. Here the potential role of CERK/C1P in neointimal formation was investigated using rat aortic vascular smooth muscle cells (VSMCs) in primary culture and a rat carotid injury model. Exogenous C8-C1P stimulated cell proliferation, DNA synthesis, and cell cycle progression of rat aortic VSMCs in primary culture. In addition, wild-type CERK-transfected rat aortic VSMCs induced a marked increase in rat aortic VSMC proliferation and [3H]-thymidine incorporation when compared to empty vector transfectant. C8-C1P markedly activated extracellular signal-regulated kinase 1 and 2 (ERK1/2) within 5 min, and the activation could be prevented by U0126, a MEK inhibitor. Also, K1, a CERK inhibitor, decreased the ERK1/2 phosphorylation and cell proliferation on platelet-derived growth factor (PDGF)-stimulated rat aortic VSMCs. CERK expression and C1P levels were found to be potently increased during neointimal formation using a rat carotid injury model. However, ceramide levels decreased during the neointimal formation process. These findings suggest that C1P can induce neointimal formation via cell proliferation through the regulation of the ERK1/2 protein in rat aortic VSMCs and that CERK/C1P may regulate VSMC proliferation as an important pathogenic marker in the development of cardiovascular disorders.

  16. Serum Ceramide Kinase as a Biomarker of Cognitive Functions, and the Effect of Using Two Slimming Dietary Therapies in Obese Middle Aged Females

    OpenAIRE

    Maha I.A. Moaty; Suzanne Fouad; Salwa M. El Shebini; Yusr M. I. Kazem; Nihad H. Ahmed; Magda S. Mohamed; Hussein, Ahmed M. S.; Atiat M. Arafa; Laila M. Hanna; Salwa T. Tapozada

    2015-01-01

    AIM: Highlighting the impact of obesity on mental and cognitive functions using serum ceramide kinase enzyme concentration as a biomarker for cognitive evaluation in the middle aged females, and also targeting to control the obesity and simultaneously postponing the deterioration of the cognitive functions, by implementing two slimming dietary therapies each incorporating different functional ingredients known to boost cognition. SUBJECTS AND METHODS: Ninety six obese middle aged females, ...

  17. Resuscitation of wild-type p53 expression by disrupting ceramide glycosylation: a novel approach to target mutant p53 tumors

    OpenAIRE

    Liu, Yong-Yu

    2011-01-01

    Mutant p53 is frequently detected in cancers lose of its ability in tumor suppression and gain of function in promoting tumor progression. Restoration of p53 functions by replacement of wild-type p53 and inhibition of its degradation or increment of its transcriptional activity has been applied in prevention and treatment of cancers. Recent evidence indicates that disrupting ceramide glycosylation can resuscitate wild-type p53 expression and p53-dependent apoptosis in mutant p53 tumors. Actin...

  18. Ceramide 1-phosphate induces neointimal formation via cell proliferation and cell cycle progression upstream of ERK1/2 in vascular smooth muscle cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Tack-Joong, E-mail: ktj@yonsei.ac.kr [Division of Biological Science and Technology, College of Science and Technology, Yonsei University, Wonju 220-710 (Korea, Republic of); Kang, Yeo-Jin [Division of Biological Science and Technology, College of Science and Technology, Yonsei University, Wonju 220-710 (Korea, Republic of); Lim, Yong [College of Pharmacy, Chungbuk National University, Cheongju 361-763 (Korea, Republic of); Lee, Hyoung-Woo [Division of Biological Science and Technology, College of Science and Technology, Yonsei University, Wonju 220-710 (Korea, Republic of); College of Pharmacy, Chungbuk National University, Cheongju 361-763 (Korea, Republic of); Bae, Kiho [Division of Biological Science and Technology, College of Science and Technology, Yonsei University, Wonju 220-710 (Korea, Republic of); Lee, Youn-Sun; Yoo, Jae-Myung; Yoo, Hwan-Soo; Yun, Yeo-Pyo [College of Pharmacy, Chungbuk National University, Cheongju 361-763 (Korea, Republic of)

    2011-08-15

    Ceramide 1-phosphate (C1P) is a novel bioactive sphingolipid formed by ceramide kinase (CERK)-catalyzed phosphorylation of ceramide. It has been implicated in the regulation of such vital pathophysiological functions as phagocytosis and inflammation, but there have been no reports ascribing a biological function to CERK in vascular disorders. Here the potential role of CERK/C1P in neointimal formation was investigated using rat aortic vascular smooth muscle cells (VSMCs) in primary culture and a rat carotid injury model. Exogenous C8-C1P stimulated cell proliferation, DNA synthesis, and cell cycle progression of rat aortic VSMCs in primary culture. In addition, wild-type CERK-transfected rat aortic VSMCs induced a marked increase in rat aortic VSMC proliferation and [{sup 3}H]-thymidine incorporation when compared to empty vector transfectant. C8-C1P markedly activated extracellular signal-regulated kinase 1 and 2 (ERK1/2) within 5 min, and the activation could be prevented by U0126, a MEK inhibitor. Also, K1, a CERK inhibitor, decreased the ERK1/2 phosphorylation and cell proliferation on platelet-derived growth factor (PDGF)-stimulated rat aortic VSMCs. CERK expression and C1P levels were found to be potently increased during neointimal formation using a rat carotid injury model. However, ceramide levels decreased during the neointimal formation process. These findings suggest that C1P can induce neointimal formation via cell proliferation through the regulation of the ERK1/2 protein in rat aortic VSMCs and that CERK/C1P may regulate VSMC proliferation as an important pathogenic marker in the development of cardiovascular disorders.

  19. High-energy collision-induced dissociation of [M+Na]+ ions desorbed by fast atom bombardment of ceramides isolated from the starfish Distolasterias nipon.

    Science.gov (United States)

    Yoo, Ji Sun; Park, Taeseong; Bang, Geul; Lee, Chulhyun; Rho, Jung-Rae; Kim, Young Hwan

    2013-02-01

    Ten ceramides and four cerebrosides were extracted from the starfish Distolasterias nipon by solvent extraction, silica gel column chromatography and reversed-phase high-performance liquid chromatography. Structural identification was conducted using tandem mass spectrometry of monosodiated ions desorbed by fast atom bombardment. The complete structures of four cerebrosides were determined by a previously reported method. The high-energy collision-induced dissociation (CID) spectral characteristics of ceramides with various structures depend on the number and positions of double bonds on both the N-acyl and sphingoid chains, the presence of a hydroxyl group or a double bond at the C-4 position of the sphingoid chain and the presence of an α-hydroxy group on the N-acyl chain. The high-energy CID of the monosodiated ion, [M+Na](+), of each ceramide molecular species generated abundant ions, providing information on the composition of the fatty acyl chains and sphingoid long-chain bases. Each homologous ion series along the fatty acyl group and aliphatic chain of the sphingoid base was used for locating the double-bond positions of both chains and hydroxyl groups on the sphingoid base chain. The double-bond positions were also confirmed by the m/z values of abundant allylic even- and odd-electron ions, and the intensity ratio of the T ion peak relative to the O ion peak. This technique could determine the complete structures of ceramides and cerebrosides in an extract mixture and has great potential for determining other sphingolipids isolated from various biological sources. PMID:23378088

  20. Persistence of HCV in Acutely-Infected Patients Depletes C24-Ceramide and Upregulates Sphingosine and Sphinganine Serum Levels.

    Science.gov (United States)

    Grammatikos, Georgios; Dietz, Julia; Ferreiros, Nerea; Koch, Alexander; Dultz, Georg; Bon, Dimitra; Karakasiliotis, Ioannis; Lutz, Thomas; Knecht, Gaby; Gute, Peter; Herrmann, Eva; Zeuzem, Stefan; Mavromara, Penelope; Sarrazin, Christoph; Pfeilschifter, Josef

    2016-01-01

    Hepatitis C virus (HCV) substantially affects lipid metabolism, and remodeling of sphingolipids appears to be essential for HCV persistence in vitro. The aim of the current study is the evaluation of serum sphingolipid variations during acute HCV infection. We enrolled prospectively 60 consecutive patients with acute HCV infection, most of them already infected with human immunodeficiency virus (HIV), and serum was collected at the time of diagnosis and longitudinally over a six-month period until initiation of antiviral therapy or confirmed spontaneous clearance. Quantification of serum sphingolipids was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Spontaneous clearance was observed in 11 out of 60 patients (18.3%), a sustained viral response (SVR) in 43 out of 45 patients (95.5%) receiving an antiviral treatment after follow-up, whereas persistence of HCV occurred in six out of 60 patients (10%). C24-ceramide (C24-Cer)-levels increased at follow-up in patients with spontaneous HCV eradication (p < 0.01), as compared to baseline. Sphingosine and sphinganine values were significantly upregulated in patients unable to clear HCV over time compared to patients with spontaneous clearance of HCV infection on follow-up (p = 0.013 and 0.006, respectively). In summary, the persistence of HCV after acute infection induces a downregulation of C24Cer and a simultaneous elevation of serum sphingosine and sphinganine concentrations. PMID:27304952

  1. Priming with ceramide-1 phosphate promotes the therapeutic effect of mesenchymal stem/stromal cells on pulmonary artery hypertension.

    Science.gov (United States)

    Lim, Jisun; Kim, YongHwan; Heo, Jinbeom; Kim, Kang-Hyun; Lee, Seungun; Lee, Sei Won; Kim, Kyunggon; Kim, In-Gyu; Shin, Dong-Myung

    2016-04-22

    Some molecules enriched in damaged organs can contribute to tissue repair by stimulating the mobilization of stem cells. These so-called "priming" factors include bioactive lipids, complement components, and cationic peptides. However, their therapeutic significance remains to be determined. Here, we show that priming of mesenchymal stromal/stem cells (MSCs) with ceramide-1 phosphate (C1P), a bioactive lipid, enhances their therapeutic efficacy in pulmonary artery hypertension (PAH). Human bone marrow (BM)-derived MSCs treated with 100 or 200 μM C1P showed improved migration activity in Transwell assays compared with non-primed MSCs and concomitantly activated MAPK(p42/44) and AKT signaling cascades. Although C1P priming had little effect on cell surface marker phenotypes and the multipotency of MSCs, it potentiated their proliferative, colony-forming unit-fibroblast, and anti-inflammatory activities. In a monocrotaline-induced PAH animal model, a single administration of human MSCs primed with C1P significantly attenuated the PAH-related increase in right ventricular systolic pressure, right ventricular hypertrophy, and thickness of α-smooth muscle actin-positive cells around the vessel wall. Thus, this study shows that C1P priming increases the effects of MSC therapy by enhancing the migratory, self-renewal, and anti-inflammatory activity of MSCs and that MSC therapy optimized with priming protocols might be a promising option for the treatment of PAH patients. PMID:26993164

  2. Molecular pathways

    DEFF Research Database (Denmark)

    Cox, Thomas R; Erler, Janine Terra

    2014-01-01

    45% of deaths in the developed world are linked to fibrotic disease. Fibrosis and cancer are known to be inextricably linked; however, we are only just beginning to understand the common and overlapping molecular pathways between the two. Here, we discuss what is known about the intersection of...... fibrosis and cancer, with a focus on cancer metastasis, and highlight some of the exciting new potential clinical targets that are emerging from analysis of the molecular pathways associated with these two devastating diseases. Clin Cancer Res; 20(14); 3637-43. ©2014 AACR....

  3. Apoptosis and the activity of ceramide, Bax and Bcl-2 in the lungs of neonatal rats exposed to limited and prolonged hyperoxia

    OpenAIRE

    Bitar Fadi F; Nasser Michel; Panjarian Shoghag; Khayat Aline; Bitar Hala; Dbaibo Ghassan S; Husari Ahmad W; El-Sabban Marwan; Zaatari Ghazi; Mroueh Salman M

    2006-01-01

    Abstract Background The aim of the study is to examine the effect of limited and prolonged hyperoxia on neonatal rat lung. This is done by examining the morphologic changes of apoptosis, the expression of ceramide, an important mediator of apoptosis, the expression of inflammatory mediators represented by IL-1β and the expression of 2 proto-oncogenes that appear to modulate apoptosis (Bax and Bcl-2). Methods Newborn rats were placed in chambers containing room air or oxygen above 90% for 7 da...

  4. Designing pathways

    DEFF Research Database (Denmark)

    Scheuer, John Damm

    2010-01-01

    The theoretical background in this chapter is organizational studies and especially theories about design and design processes in organizations. The concept of design is defined as a particular kind of work aimed at making arrangements in order to change existing situations into desired ones. The...... illustrative case example is the introduction of clinical pathways in a psychiatric department. The contribution to a general core of design research is the development of the concept of design work and a critical discussion of the role of technological rules in design work....

  5. Controlled Penetration of a Novel Dimeric Ceramide into and across the Stratum Corneum Using Microemulsions and Various Types of Semisolid Formulations.

    Science.gov (United States)

    Neubert, Reinhard H H; Sonnenberger, Stefan; Dobner, Bodo; Gray, Charles W; Barger, K Natalie; Sevi-Maxwell, Kara; Sommer, Elfi; Wohlrab, Johannes

    2016-01-01

    Ceramides (CERs) are integral parts of the intercellular lipid lamellae of the stratum corneum (SC), which is responsible for the barrier function of the skin. Many skin diseases such as atopic dermatitis and psoriasis are associated with the depletion or disturbance of the level of CERs in the SC. Administration of an exogenous novel dimeric ceramide (dCER) deep into the SC may help to stabilize the SC barrier substantially and to treat some skin disease conditions. Consequently, with the help of the existing technology, it might be possible to formulate various pharmaceutical dosage forms that can facilitate penetration of dCER into the SC. Therefore, the penetration of dCER was studied using a high-performance liquid chromatography/atmospheric-pressure ionization/mass spectrometry method for the detection and quantification of exogenous dCER in the SC as well as other skin layers. Penetration studies were carried out in the Franz diffusion cell using excised human skin ex vivo. Penetration of dCER was studied with 3 model formulations: a colloidal formulation (microemulsion), a cream formulation with ethoxydiglycol as penetration enhancer and a nanoformulation. The highest concentrations of dCER in the different skin layers were found after application of the cream with penetration enhancer. Surprisingly, the lowest concentrations of dCER in the different skin layers were found after application of the microemulsion. PMID:27193887

  6. Serum Ceramide Kinase as a Biomarker of Cognitive Functions, and the Effect of Using Two Slimming Dietary Therapies in Obese Middle Aged Females

    Science.gov (United States)

    Moaty, Maha I. A.; Fouad, Suzanne; El Shebini, Salwa M.; Kazem, Yusr M. I.; Ahmed, Nihad H.; Mohamed, Magda S.; Hussein, Ahmed M. S.; Arafa, Atiat M.; Hanna, Laila M.; Tapozada, Salwa T.

    2015-01-01

    AIM: Highlighting the impact of obesity on mental and cognitive functions using serum ceramide kinase enzyme concentration as a biomarker for cognitive evaluation in the middle aged females, and also targeting to control the obesity and simultaneously postponing the deterioration of the cognitive functions, by implementing two slimming dietary therapies each incorporating different functional ingredients known to boost cognition. SUBJECTS AND METHODS: Ninety six obese middle aged females, divided into two groups volunteered to follow a low caloric balanced diet combined with two bread supplements composed essentially of barley flour and wheat germ mixed with either 5% turmeric, group (A); or with 5% ginger, group (B) for 4 weeks, phase (1); to be followed by the hypocaloric diet alone for another 4 weeks, phase (2). RESULTS: By the end of phase (1), the biochemical analysis showed a positive response of the levels of C-peptide and modified homeostatic model assessment of insulin resistance; also increased levels of the serum ceramide kinase enzyme, coupled with improved cognitive functions tests. Improvement of the relevant metabolic profile, fasting blood glucose, blood pressure and the anthropometric measurements was detected. CONCLUSION: Using dietary therapy supported by special formulas which contain active ingredients succeeded in reducing weight and improving both the metabolic profile and the cognitive functions. PMID:27275191

  7. N,N-Dimethylsphingosine is a potent competitive inhibitor of sphingosine kinase but not of protein kinase C: modulation of cellular levels of sphingosine 1-phosphate and ceramide.

    Science.gov (United States)

    Edsall, L C; Van Brocklyn, J R; Cuvillier, O; Kleuser, B; Spiegel, S

    1998-09-15

    Sphingosine 1-phosphate (SPP), a lipid second messenger formed by the action of sphingosine kinase, has been implicated in regulating diverse biological processes, including growth, survival, and differentiation. N,N-Dimethylsphingosine (DMS) inhibits sphingosine kinase and has been used to investigate the biological roles of SPP; however, little is known of the mechanism of inhibition of sphingosine kinase by DMS. In addition, DMS has been shown to inhibit protein kinase C in vitro. Here we report that DMS is a competitive inhibitor of sphingosine kinase from U937 monoblastic leukemia cells, Swiss 3T3 fibroblasts, and PC12 pheochromocytoma cells. DMS decreases basal levels of SPP and prevents increases in SPP in response to physiological stimuli known to activate sphingosine kinase. DMS also effectively increases cellular levels of ceramide in a variety of cell types, and resetting of the ceramide/SPP rheostat may account for the pro-apoptotic effects of DMS. Moreover, DMS, at concentrations which effectively inhibit sphingosine kinase, has no effect on protein kinase C activity or its membrane translocation. Thus, DMS acts as a specific competitive inhibitor of sphingosine kinase in diverse cell types and is a useful tool to elucidate the role of SPP as an intracellular second messenger. PMID:9737868

  8. Dimyristoylphosphatidylcholine/C16 : 0-ceramide binary liposomes studied by differential scanning calorimetry and wide- and small-angle X-ray scattering

    DEFF Research Database (Denmark)

    Holopainen, J.M.; Lemmich, J.; Richter, F.; Mouritsen, O.G.; Rapp, G.; Kinnunen, P.K.J.

    2000-01-01

    hydrated binary membranes composed of dimyristoylphosphatidylcholine (DMPC) and N-palmitoyl-ceramide (C16:0-ceramide, up to a mole fraction X-cer = 0.35) were resolved in further detail by high-sensitivity differential scanning calorimetry (DSC) and x-ray diffraction. Both methods reveal very strong...... studied compositions there is an endotherm in the region close to the T-m for DMPC. At X-cer greater than or equal to 0.03 a second endotherm is evident at higher temperatures, starting at 32.1 degrees C and reaching 54.6 degrees C at X-cer = 0.30. X-ray small-angle reflection heating scans reveal a...... lamellar phase within the temperature range of 15-60 degrees C, regardless of composition. The pretransition is observed up to X-cer < 0.18, together with an increase in T-p. In the gel phase the lamellar repeat distance d increases from similar to 61 Angstrom at X-cer = 0.03, to 67 Angstrom at X-cer = 0...

  9. Liposomal short-chain C6 ceramide induces potent anti-osteosarcoma activity in vitro and in vivo.

    Science.gov (United States)

    Zhai, Lei; Sun, Nan; Han, Zhe; Jin, Hai-chao; Zhang, Bo

    Osteosarcoma (OS) remains one deadly disease for many affected patients. The search for novel and more efficient anti-OS agents is urgent. In the current study, we demonstrated that liposome-packed C6 ceramide exerted potent cytotoxic effect against established (U2OS and MG-63 lines) and primary human OS cells. Meanwhile, the liposomal C6 (ceramide) induced caspase-mediated apoptotic death in OS cells. Liposomal C6 was significantly more potent than conventional free C6 in inhibiting OS cells, yet it was safe to non-cancerous bone cells (primary murine osteoblasts or human MLO-Y4 osteocytic cells). At the signaling level, we showed that liposomal C6 potently inhibited Akt activation in OS cells. Further studies revealed that a low dose of liposomal C6 dramatically sensitized the in vitro anti-OS activity of two conventional chemodrugs: methotrexate (MTX) and doxorubicin. In vivo, intravenous injection of liposomal C6 inhibited Akt activation and suppressed U2OS xenograft growth in nude mice without causing apparent toxicities. Meanwhile, when given at a low-dose (5 mg/kg body weight), liposomal C6 dramatically sensitized MTX's anti-U2OS activity in vivo. Collectively, our data demonstrate that liposomal C6 exerts potent anti-tumor activity in preclinical OS models. PMID:26505795

  10. Carbon nanoparticles induce ceramide- and lipid raft-dependent signalling in lung epithelial cells: a target for a preventive strategy against environmentally-induced lung inflammation

    Directory of Open Access Journals (Sweden)

    Peuschel Henrike

    2012-12-01

    Full Text Available Abstract Background Particulate air pollution in lung epithelial cells induces pathogenic endpoints like proliferation, apoptosis, and pro-inflammatory reactions. The activation of the epidermal growth factor receptor (EGFR is a key event responsible for signalling events involving mitogen activated protein kinases specific for these endpoints. The molecular events leading to receptor activation however are not well understood. These events are relevant for the toxicological evaluation of inhalable particles as well as for potential preventive strategies in situations when particulate air pollution cannot be avoided. The current study therefore had the objective to elucidate membrane-coupled events leading to EGFR activation and the subsequent signalling cascade in lung epithelial cells. Furthermore, we aimed to identify the molecular target of ectoine, a biophysical active substance which we described to prevent carbon nanoparticle-induced lung inflammation. Methods Membrane signalling events were investigated in isolated lipid rafts from lung epithelial cells with regard to lipid and protein content of the signalling platforms. Using positive and negative intervention approaches, lipid raft changes, subsequent signalling events, and lung inflammation were investigated in vitro in lung epithelial cells (RLE-6TN and in vivo in exposed animals. Results Carbon nanoparticle treatment specifically led to an accumulation of ceramides in lipid rafts. Detailed analyses demonstrated a causal link of ceramides and subsequent EGFR activation coupled with a loss of the receptor in the lipid raft fractions. In vitro and in vivo investigations demonstrate the relevance of these events for carbon nanoparticle-induced lung inflammation. Moreover, the compatible solute ectoine was able to prevent ceramide-mediated EGFR phosphorylation and subsequent signalling as well as lung inflammation in vivo. Conclusion The data identify a so far unknown event in pro

  11. Mechanisms of Mycotoxin-Induced Neurotoxicity through Oxidative Stress-Associated Pathways

    Directory of Open Access Journals (Sweden)

    Koji Uetsuka

    2011-08-01

    Full Text Available Among many mycotoxins, T-2 toxin, macrocyclic trichothecenes, fumonisin B1 (FB1 and ochratochin A (OTA are known to have the potential to induce neurotoxicity in rodent models. T-2 toxin induces neuronal cell apoptosis in the fetal and adult brain. Macrocyclic trichothecenes bring about neuronal cell apoptosis and inflammation in the olfactory epithelium and olfactory bulb. FB1 induces neuronal degeneration in the cerebral cortex, concurrent with disruption of de novo ceramide synthesis. OTA causes acute depletion of striatal dopamine and its metabolites, accompanying evidence of neuronal cell apoptosis in the substantia nigra, striatum and hippocampus. This paper reviews the mechanisms of neurotoxicity induced by these mycotoxins especially from the viewpoint of oxidative stress-associated pathways.

  12. In Vitro Palmitate Treatment of Myotubes from Postmenopausal Women Leads to Ceramide Accumulation, Inflammation and Affected Insulin Signaling

    DEFF Research Database (Denmark)

    Abildgaard, Julie; Henstridge, Darren C; Pedersen, Anette Tønnes;

    2014-01-01

    Menopause is associated with an increased incidence of insulin resistance and metabolic diseases. In a chronic palmitate treatment model, we investigated the role of skeletal muscle fatty acid exposure in relation to the metabolic deterioration observed with menopause. Human skeletal muscle...... satellite cells were isolated from premenopausal (n = 6) and postmenopausal (n = 5) women. In an in vitro model, the myotubes were treated with palmitate (300 µM) for one-, two- or three days during differentiation. Effects on lipid accumulation, inflammation and insulin signaling were studied. Palmitate......, post-myotubes showed a blunted insulin stimulated phosphorylation of AS160 in response to chronic palmitate treatment compared with pre-myotubes (p = 0.02). The increased intramyocellular ceramide content in the post-myotubes was associated with a significantly higher mRNA expression of Serine...

  13. Influence of ceramide 2 on in vitro skin permeation and retention of 5-ALA and its ester derivatives, for Photodynamic Therapy

    Directory of Open Access Journals (Sweden)

    Maria Bernadete Riemma Pierre

    2009-03-01

    Full Text Available Photodynamic therapy (PDT based on topical 5-aminolevulinic acid (5-ALA, an endogenous precursor of protoporphyrin, is an interesting approach for the treatment of skin cancer. However, 5-ALA is a hydrophilic molecule and such a characteristic limits its appropriate cutaneous penetration and retention. In this way, more lipophilic molecules, such as esterified 5-ALA derivatives, have been under investigation in order to improve the skin penetration of this molecule. Drug formulation can also alter 5-ALA skin penetration. Therefore, the aim of this work was to study the influence of ceramide 2 - the main lipid of the SC- on the cutaneous delivery of 5-ALA and its ester derivatives in vitro, using Franz diffusion cell. The skin permeation of all studied drugs was decreased in the presence of ceramide, representing a desirable characteristic in order to avoid the risk of systemic side effects. Nevertheless, the SC and [epidermis + dermis] retention after 16 h has also been decreased in the presence of ceramide, as compared to control. In conclusion, ceramide was not a good adjuvant, meaning that research of other vehicles could be useful to improve cutaneous delivery of 5-ALA.A Terapia Fotodinâmica (TFD tópica com um precursor das porfirinas endógenas, o ácido 5-aminolevulínico (5-ALA, constitui uma nova modalidade para o tratamento do câncer de pele. Entretanto, o 5-ALA é uma molécula hidrofílica, o que limita sua penetração e retenção cutânea apropriadas. Moléculas mais lipofílicas, tais como derivados esterificados do 5-ALA, estão sob intensa investigação para melhorar a penetração cutânea desta molécula. A formulação que contém o fármaco também pode alterar a penetração cutânea do 5-ALA. Desta forma, o objetivo deste trabalho foi estudar a influência da ceramida 2 - o principal lipídeo do EC- sobre a penetração cutânea de 5-ALA e seus derivados esterificados usando células de difusão de Franz. A permea

  14. Distinct roles of two ceramide synthases, CaLag1p and CaLac1p, in the morphogenesis of Candida albicans

    DEFF Research Database (Denmark)

    Cheon, Seon Ah; Bal, Jyotiranjan; Song, Yunkyoung;

    2012-01-01

    Lag1p and Lac1p catalyse ceramide synthesis in Saccharomyces cerevisiae. This study shows that Lag1 family proteins are generally required for polarized growth in hemiascomycetous yeast. However, in contrast to S. cerevisiae where these proteins are functionally redundant, C. albicans Lag1p (CaLag1......p) and Lac1p (CaLac1p) are functionally distinct. Lack of CaLag1p, but not CaLac1p, caused severe defects in the growth and hyphal morphogenesis of C. albicans. Deletion of CaLAG1 decreased expression of the hypha-specific HWP1 and ECE1 genes. Moreover, overexpression of CaLAG1 induced pseudohyphal....... albicans....

  15. Depletion of ceramides with very long chain fatty acids causes defective skin permeability barrier function, and neonatal lethality in ELOVL4 deficient mice

    Directory of Open Access Journals (Sweden)

    Wenmei Li, Roger Sandhoff, Mari Kono, Patricia Zerfas, Vickie Hoffmann, Bryan Char-Hoa Ding, Richard L. Proia, Chu-Xia Deng

    2007-01-01

    Full Text Available Very long chain fatty acids (VLCFA, either free or as components of glycerolipids and sphingolipids, are present in many organs. Elongation of very long chain fatty acids-4 (ELOVL4 belongs to a family of 6 members of putative fatty acid elongases that are involved in the formation of VLCFA. Mutations in ELOVL4 were found to be responsible for an autosomal dominant form of Stargardt's-like macular dystrophy (STGD3 in human. We have previously disrupted the mouse Elovl4 gene, and found that Elovl4+/- mice were developmentally normal, suggesting that haploinsufficiency of ELOVL4 is not a cause for the juvenile retinal degeneration in STGD3 patients. However, Elovl4-/- mice died within several hours of birth for unknown reason(s. To study functions of ELOVL4 further, we have explored the causes for the postnatal lethality in Elovl4-/- mice. Our data indicated that the mutant mice exhibited reduced thickness of the dermis, delayed differentiation of keratinocytes, and abnormal structure of the stratum corneum. We showed that all Elovl4-/- mice exhibited defective skin water permeability barrier function, leading to the early postnatal death. We further showed that the absence of ELOVL4 results in depletion in the epidermis of ceramides with ω-hydroxy very long chain fatty acids (≥C28 and accumulation of ceramides with non ω-hydroxy fatty acids of C26, implicating C26 fatty acids as possible substrates of ELOVL4. These data demonstrate that ELOVL4 is required for VLCFA synthesis that is essential for water permeability barrier function of skin.

  16. CD40L induces multidrug resistance to apoptosis in breast carcinoma and lymphoma cells through caspase independent and dependent pathways

    Directory of Open Access Journals (Sweden)

    Blay Jean-Yves

    2006-03-01

    Full Text Available Abstract Background CD40L was found to reduce doxorubicin-induced apoptosis in non Hodgkin's lymphoma cell lines through caspase-3 dependent mechanism. Whether this represents a general mechanism for other tumor types is unknown. Methods The resistance induced by CD40L against apoptosis induced by a panel of cytotoxic chemotherapeutic drugs in non Hodgkin's lymphoma and breast carcinoma cell lines was investigated. Results Doxorubicin, cisplatyl, etoposide, vinblastin and paclitaxel increased apoptosis in a dose-dependent manner in breast carcinoma as well as in non Hodgkin's lymphoma cell lines. Co-culture with irradiated L cells expressing CD40L significantly reduced the percentage of apoptotic cells in breast carcinoma and non Hodgkin's lymphoma cell lines treated with these drugs. In breast carcinoma cell lines, these 5 drugs induced an inconsistent increase of caspase-3/7 activity, while in non Hodgkin's lymphoma cell lines all 5 drugs increased caspase-3/7 activity up to 28-fold above baseline. Co-culture with CD40L L cells reduced (-39% to -89% the activation of caspase-3/7 induced by these agents in all 5 non Hodgkin's lymphoma cell lines, but in none of the 2 breast carcinoma cell lines. Co culture with CD40L L cells also blocked the apoptosis induced by exogenous ceramides in breast carcinoma and non Hodgkin's lymphoma cell lines through a caspase-3-like, 8-like and 9-like dependent pathways. Conclusion These results indicate that CD40L expressed on adjacent non tumoral cells induces multidrug resistance to cytotoxic agents and ceramides in both breast carcinoma and non Hodgkin's lymphoma cell lines, albeit through a caspase independent and dependent pathway respectively.

  17. Andrographolide, a Novel NF-κB Inhibitor, Induces Vascular Smooth Muscle Cell Apoptosis via a Ceramide-p47phox-ROS Signaling Cascade

    Directory of Open Access Journals (Sweden)

    Yu-Ying Chen

    2013-01-01

    Full Text Available Atherosclerosis is linked with the development of many cardiovascular complications. Abnormal proliferation of vascular smooth muscle cells (VSMCs plays a crucial role in the development of atherosclerosis. Accordingly, the apoptosis of VSMCs, which occurs in the progression of vascular proliferation, may provide a beneficial strategy for managing cardiovascular diseases. Andrographolide, a novel nuclear factor-κB inhibitor, is the most active and critical constituent isolated from the leaves of Andrographis paniculata. Recent studies have indicated that andrographolide is a potential therapeutic agent for treating cancer through the induction of apoptosis. In this study, the apoptosis-inducing activity and mechanisms in andrographolide-treated rat VSMCs were characterized. Andrographolide significantly induced reactive oxygen species (ROS formation, p53 activation, Bax, and active caspase-3 expression, and these phenomena were suppressed by pretreating the cells with N-acetyl-L-cysteine, a ROS scavenger, or diphenylene iodonium, a nicotinamide adenine dinucleotide phosphate (NADPH oxidase (Nox inhibitor. Furthermore, p47phox, a Nox subunit protein, was phosphorylated in andrographolide-treated rat VSMCs. However, pretreatment with 3-O-methyl-sphingomyelin, a neutral sphingomyelinase inhibitor, significantly inhibited andrographolide-induced p47phox phosphorylation as well as Bax and active caspase-3 expression. Our results collectively demonstrate that andrographolide-reduced cell viability can be attributed to apoptosis in VSMCs, and this apoptosis-inducing activity was associated with the ceramide-p47phox-ROS signaling cascade.

  18. Critical Role of COI1-Dependent Jasmonate Pathway in AAL toxin induced PCD in Tomato Revealed by Comparative Proteomics

    Science.gov (United States)

    Zhang, Min; Koh, Jin; Liu, Lihong; Shao, Zhiyong; Liu, Haoran; Hu, Songshen; Zhu, Ning; Dufresne, Craig P.; Chen, Sixue; Wang, Qiaomei

    2016-01-01

    Alternaria alternata f.sp. Lycopersici (AAL) toxin induces programmed cell death (PCD) in susceptible tomato (Solanum lycopersicum) leaves. Jasmonate (JA) promotes AAL toxin induced PCD in a COI1 (coronatine insensitive 1, JA receptor)-dependent manner by enhancement of reactive oxygen species (ROS) production. To further elucidate the underlying mechanisms of this process, we performed a comparative proteomic analysis using tomato jasmonic acid insensitive1 ( jai1), the receptor mutant of JA, and its wild type (WT) after AAL toxin treatment with or without JA treatment. A total of 10367 proteins were identified in tomato leaves using isobaric tags for relative and absolute quantitation (iTRAQ) quantitative proteomics approach. 2670 proteins were determined to be differentially expressed in response to AAL toxin and JA. Comparison between AAL toxin treated jai1 and its WT revealed the COI1-dependent JA pathway regulated proteins, including pathways related to redox response, ceramide synthesis, JA, ethylene (ET), salicylic acid (SA) and abscisic acid (ABA) signaling. Autophagy, PCD and DNA damage related proteins were also identified. Our data suggest that COI1-dependent JA pathway enhances AAL toxin induced PCD through regulating the redox status of the leaves, other phytohormone pathways and/or important PCD components. PMID:27324416

  19. Down-regulation of T lymphocyte activation in vitro and in vivo induced by glycoinositolphospholipids from Trypanosoma cruzi. Assignment of the T cell-suppressive determinant to the ceramide domain.

    Science.gov (United States)

    Gomes, N A; Previato, J O; Zingales, B; Mendonça-Previato, L; DosReis, G A

    1996-01-15

    The major surface glycoinositolphospholipid (GIPL) from Trypanosoma cruzi was purified and assessed in mouse T cell function assays. Purified GIPLs from T. cruzi strains Y and G, but not from a plant trypanosomatid (Phytomonas serpens), markedly blocked in vitro CD4+ and CD8+ T cell mitogenesis induced by bacterial superantigen and anti-TCR;CD3 Abs. Secretion of IL-2, but not of IL-4, bioactivity, was reduced by GIPLs. T. cruzi, but not P. serpens, GIPL also blocked recall cellular responses to T. cruiz. GIPLs from T. cruzi, but not from P. serpens, blocked in vivo regional lymph node T cell activation induced by anti-CD3 mAb. Blockage led to loss of IL-2 responsiveness, with inhibition of CD25 expression on both CD4+ and CD8+ subsets. Isolated phosphoinositol oligosaccharides from GIPLs had no effect on in vitro CD4+ T cell mitogenesis. Isolated ceramide from T. cruzi GIPLs contained mainly N-lignoceroyldihydrosphingosine and blocked CD4+ T cell activation in vitro with the same potency as the intact GIPL. Standard N-palmitoylsphingosine, but not N-palmitoyldihydrosphingosine, blocked CD4+ T cell mitogenesis. A longer fatty acid chain, such as in standard N-lignoceroyldihydrosphingosine, or in the natural trypanosomal GIPL-derived ceramide, however, conferred full inhibitory effects on CD4+ T cells. These results demonstrate that T. cruzi GIPL has T cell immunomodulatory activity in vitro and in vivo, and that this novel activity maps to the ceramide domain. These findings could have implications for immunologic disturbances induced in the host by the causative agent of Chagas' disease. PMID:8543814

  20. Determination of Functional Ceramide Lipids in Beet and By-products%甜菜及副产品中功能性神经酰胺脂质的测定

    Institute of Scientific and Technical Information of China (English)

    热娜古丽·木沙; 魏佼

    2013-01-01

    Using beet, beet pulp and beet molasses as raw material,extraction and determination of it's functional ceramide, to provide a theoretical basis for the extraction and utilization of ceramide. The result show total lipid contents in beet, beet pulp and beet molasses in raw material is 0.4 %, 0.7 % and 0.1 %, respectively. The proportion of polar lipid in total lipid is 44.7 %, 55.6 % and 54.8 %, respectively. In molasses, glycolipids accounted for the highest proportion of total lipids, up to 19.4%. TLC analysis proved that in beet and beet pulp contain the functional ceramide lipids. The ceramide content of beet pup was slightly higher than the beet, the result of 0.46 mg/g and 0.35 mg/g,but extremely low in molasses (<0.1 mg/g).%  以甜菜、甜菜渣和甜菜糖蜜为原料,提取测定其功能性成分神经酰胺的含量,为提取利用神经酰胺提供理论依据。结果表明,甜菜、甜菜渣及甜菜糖蜜原物中的总脂质含量分别为0.4%、0.7%及0.1%。总脂质中极性脂质的比例分别为44.7%、55.6%和54.8%。甜菜糖蜜中糖脂占总脂质中的比例最高,达19.4%。TLC分析初步检测出甜菜和甜菜渣中含有功能性脂质神经酰胺;甜菜渣中神经酰胺含量略高于甜菜,分别为0.46 mg/g和0.35 mg/g,但在甜菜糖蜜中含量极少(<0.1 mg/g)。

  1. Structure elucidation of the blood group B like and blood group I active octaantennary ceramide tetracontasaccharide from rabbit erythrocyte membranes by two-dimensional 1H NMR spectroscopy at 600 MHz

    International Nuclear Information System (INIS)

    The primary structure of the ceramide tetracontasaccharide (1) from rabbit erythrocyte membranes has been determined with the aid of 600-MHz two-dimensional phase-sensitive correlated, totally correlated (TOCSY, homonuclear Hartmann-Hahn), relayed coherence transfer, triple quantum filtered, and nuclear Overhauser enhancement 1H NMR spectra. It was shown that obtaining subspectra of the constituent sugar residues from a totally correlated spectrum and assigning the resonances occurring in these subspectra by analyzing the relevant cross-peaks in phase-sensitive correlated spectra is the most efficient way for establishing complex oligosaccharide structures. This analysis has shown 1 to be the highest homologue of the multiantennary neolactoglycosphingolipids

  2. Molecular trapping of a fluorescent ceramide analogue at the Golgi apparatus of fixed cells: interaction with endogenous lipids provides a trans-Golgi marker for both light and electron microscopy

    OpenAIRE

    1989-01-01

    We have previously shown that a fluorescent derivative of ceramide, N- (epsilon-7-nitrobenz-2-oxa-1,3-diazol-4-yl-aminocaproyl)-D-eryth ro- sphingosin e (C6-NBD-Cer), vitally stains the Golgi apparatus of cells (Lipsky, N. G., and R. E. Pagano. 1985. Science (Wash. DC). 228:745- 747). In the present paper we demonstrate that C6-NBD-Cer also accumulates at the Golgi apparatus of fixed cells and we explore the mechanism by which this occurs. When human skin fibroblasts were fixed with glutarald...

  3. Immunomodulatory Pathways and Metabolism

    OpenAIRE

    Bhargava, Prerna

    2012-01-01

    Energy metabolism plays a vital role in normal physiology, adaptive responses and host defense mechanisms. Research throughout the last decade has shown evidence that immune pathways communicate with metabolic pathways to alter the metabolic status in response to physiological or pathological signals. In this thesis, I will explore how immunomodulatory molecules affect metabolic homeostasis and conversely, how metabolic sensing pathways modulate immune responses. The first part my work utiliz...

  4. The caveolae-mediated sv40 entry pathway bypasses the golgi complex en route to the endoplasmic reticulum

    Directory of Open Access Journals (Sweden)

    Kuksin Dmitry

    2005-04-01

    Full Text Available Abstract Background Simian virus 40 (SV40 enters cells via an atypical caveolae-mediated endocytic pathway, which delivers the virus to a new intermediary compartment, the caveosome. The virus then is believed to go directly from the caveosome to the endoplasmic reticulum. Cholera toxin likewise enters via caveolae and traffics to caveosomes. But, in contrast to SV40, cholera toxin is transported from caveosomes to the endoplasmic reticulum via the Golgi. For that reason, and because the caveosome and Golgi may have some common markers, we revisited the issue of whether SV40 might access the endoplasmic reticulum via the Golgi. Results We confirmed our earlier finding that SV40 co localizes with the Golgi marker β-COP. However, we show that the virus does not co localize with the more discriminating Golgi markers, golgin 97 and BODIPY-ceramide. Conclusion The caveolae-mediated SV40 entry pathway does not intersect the Golgi. SV40 is seen to co localize with β-COP because that protein is a marker for caveosomes as well as the Golgi. Moreover, these results are consistent with the likelihood that the caveosome is a sorting organelle. In addition, there are at least two distinct but related routes by which a ligand might traffic from the caveosome to the ER; one route involving transport through the Golgi, and another pathway that does not involve the Golgi.

  5. Descoberta de novas suberinases através de uma abordagem metagenómica

    OpenAIRE

    Bordadágua, João Nuno Lágio

    2013-01-01

    A espécie de formigas, Crematogaster scutellaris, nidifica na cortiça de sobreiros (Quercus suber L.), escavando galerias extensas que diminuem o valor comercial deste produto. Acredita-se que a degradação da cortiça é efetuada por enzimas digestivas secretadas pelas glândulas da própria formiga, como também por microrganismos simbiontes presentes no seu sistema digestivo intestinal – o microbioma intestinal. Tendo em conta que a cortiça é composta maioritariamente por suberina, o objetivo pr...

  6. Metagenes Associated with Survival in Non-Small Cell Lung Cancer

    OpenAIRE

    Egon Urgard; Tõnu Vooder; Urmo Võsa; Kristjan Välk; Mingming Liu; Cheng Luo; Fabian Hoti; Retlav Roosipuu; Tarmo Annilo; Jukka Laine; Frenz, Christopher M.; Liqing Zhang; Andres Metspalu

    2011-01-01

    NSCLC (non-small cell lung cancer) comprises about 80% of all lung cancer cases worldwide. Surgery is most effective treatment for patients with early-stage disease. However, 30%–55% of these patients develop recurrence within 5 years. Therefore, markers that can be used to accurately classify early-stage NSCLC patients into different prognostic groups may be helpful in selecting patients who should receive specific therapies. A previously published dataset was used to evaluate gene expressio...

  7. Consistent metagenes from cancer expression profiles yield agent specific predictors of chemotherapy response

    DEFF Research Database (Denmark)

    Li, Qiyuan; Eklund, Aron Charles; Birkbak, Nicolai Juul;

    2011-01-01

    BACKGROUND: Genome scale expression profiling of human tumor samples is likely to yield improved cancer treatment decisions. However, identification of clinically predictive or prognostic classifiers can be challenging when a large number of genes are measured in a small number of tumors. RESULTS...

  8. Migration pathways in soils

    International Nuclear Information System (INIS)

    This study looked at diffusive migration through three types of deformation; the projectile pathways, hydraulic fractures of the sediments and faults, and was divided into three experimental areas: autoradiography, the determination of diffusion coefficients and electron microscopy of model projectile pathways in clay. For the autoradiography, unstressed samples were exposed to two separate isotopes, Pm-147 (a possible model for Am behaviour) and the poorly sorbed iodide-125. The results indicated that there was no enhanced migration through deformed kaolin samples nor through fractured Great Meteor East (GME) sediment, although some was evident through the projectile pathways in GME and possibly through the GME sheared samples. The scanning electron microscopy of projectile pathways in clay showed that emplacement of a projectile appeared to have no effect on the orientation of particles at distances greater than two projectile radii from the centre of a projectile pathway. It showed that the particles were not simply aligned with the direction of motion of the projectile but that, the closer to the surface of a particular pathway, the closer the particles lay to their original orientation. This finding was of interest from two points of view: i) the ease of migration of a pollutant along the pathway, and ii) possible mechanisms of hole closure. It was concluded that, provided that there is no advective migration, the transport of radionuclides through sediments containing these defects would not be significantly more rapid than in undeformed sediments. (author)

  9. DMPD: Regulatory pathways in inflammation. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17967718 Regulatory pathways in inflammation. Mantovani A, Garlanda C, Locati M, Ro....html) (.csml) Show Regulatory pathways in inflammation. PubmedID 17967718 Title Regulatory pathways in infl

  10. Poly-L-ornithine promotes preferred differentiation of neural stem/progenitor cells via ERK signalling pathway

    Science.gov (United States)

    Ge, Hongfei; Tan, Liang; Wu, Pengfei; Yin, Yi; Liu, Xin; Meng, Hui; Cui, Gaoyu; Wu, Nan; Lin, Jiangkai; Hu, Rong; Feng, Hua

    2015-10-01

    Neural stem/progenitor cells (NSPCs) replacement therapies are the most attractive strategies to restore an injured brain. Key challenges of such therapies are enriching NSPCs and directing them differentiation into specific neural cell types. Here, three biomaterial substrates Poly-L-ornithine (PO), Poly-L-lysine (PLL) and fibronectin (FN) were investigated for their effects on proliferation and differentiation of rat NSPCs, and the underlying mechanisms were also explored. The results showed PO significantly increased NSPCs proliferation and induced preferred differentiation, compared with PLL and FN. Checking protein markers of several neural cell subtypes, it is showed PO significantly induced NSPCs expressing Doublecortin (DCX) and Olig2, one for neuroblasts and young neurons and the other for young oligodendrocytes. It is suggested the ERK signaling pathway was involving in this process because an ERK antagonist U0126 could inhibit PO’s effects mentioned above, as well as an ERK pathway agonist Ceramide C6 could enhance them. Given that both neurons and oligodendrocytes are the most vulnerable cells in many neurological diseases, PO-induced preferred differentiation into neurons and oligodendrocytes is a potential paradigm for NSPCs-based therapies.

  11. Dexter energy transfer pathways.

    Science.gov (United States)

    Skourtis, Spiros S; Liu, Chaoren; Antoniou, Panayiotis; Virshup, Aaron M; Beratan, David N

    2016-07-19

    Energy transfer with an associated spin change of the donor and acceptor, Dexter energy transfer, is critically important in solar energy harvesting assemblies, damage protection schemes of photobiology, and organometallic opto-electronic materials. Dexter transfer between chemically linked donors and acceptors is bridge mediated, presenting an enticing analogy with bridge-mediated electron and hole transfer. However, Dexter coupling pathways must convey both an electron and a hole from donor to acceptor, and this adds considerable richness to the mediation process. We dissect the bridge-mediated Dexter coupling mechanisms and formulate a theory for triplet energy transfer coupling pathways. Virtual donor-acceptor charge-transfer exciton intermediates dominate at shorter distances or higher tunneling energy gaps, whereas virtual intermediates with an electron and a hole both on the bridge (virtual bridge excitons) dominate for longer distances or lower energy gaps. The effects of virtual bridge excitons were neglected in earlier treatments. The two-particle pathway framework developed here shows how Dexter energy-transfer rates depend on donor, bridge, and acceptor energetics, as well as on orbital symmetry and quantum interference among pathways. PMID:27382185

  12. Pathways of tau fibrillization.

    Science.gov (United States)

    Kuret, Jeff; Chirita, Carmen N; Congdon, Erin E; Kannanayakal, Theresa; Li, Guibin; Necula, Mihaela; Yin, Haishan; Zhong, Qi

    2005-01-01

    New methods for analyzing tau fibrillization have yielded insights into the biochemical transitions involved in the process. Here we review the parallels between the sequential progression of tau fibrillization observed macroscopically in Alzheimer's disease (AD) lesions and the pathway of tau aggregation observed in vitro with purified tau preparations. In addition, pharmacological agents for further dissection of fibrillization mechanism and lesion formation are discussed. PMID:15615636

  13. New pathways into headship?

    OpenAIRE

    Higham, Rob; Early, Peter; Coldwell, Michael; Stevens, Anna; Brown, Chris

    2015-01-01

    There continues to be something of a conundrum in the recruitment of headteachers in England. While “a very large majority of headteachers report being satisfied with their jobs” (Micklewright et al 2014: 17), headteacher recruitment and retention remain major challenges for school governors and policy makers. In this context, the New Pathways into Headship project was commissioned by the National College for Teaching and Leadership (NCTL) in January 2013. Tasked with considering new or a...

  14. Pathway analysis of IMC

    DEFF Research Database (Denmark)

    Skrypnyuk, Nataliya; Nielson, Flemming; Pilegaard, Henrik

    We present the ongoing work on the pathway analysis of a stochastic calculus. Firstly we present a particular stochastic calculus that we have chosen for our modeling - the Interactive Markov Chains calculus, IMC for short. After that we specify a few restrictions that we have introduced into the...... syntax of IMC in order to make our analysis feasible. Finally we describe the analysis itself together with several theoretical results that we have proved for it....

  15. Expression of ceramide galactosy transferase in sciatic nerve of rats with diabetic peripheral neuropathy after electroacupuncture at Zusanli and Shenshu points

    Institute of Scientific and Technical Information of China (English)

    Hongsheng Dong; Yunyun Zhang; Yin Shi; Min Zheng; Qiujuan Zhang

    2006-01-01

    BACKGROUND: Ceramide galactosyltransferase (GGT) protein and mRNA expression defect can cause the abnormal morphology and slowing conduction velocity of peripheral nerve. Morphologic change and functional disorder of myelin sheath and axon appear when diabetic peripheral neuropathy (DPN) occurs. Whether electroacupuncture at Zusanli(ST 36) and Shenshu(BL 32) points can enhance the expression of CGT protein and mRNA in the DPN tissue?OBJECTIVE: To observe the effect of electroacupuncture at Zusanli and Shenshu points on motor, sensory conduction velocity and CGT mRNA and its protein expression of sciatic nerve in rats with DPN.DESIGN: A randomized and controlled animal experiment.SETTING: Department of Neurology and Central Laboratory, Yueyang Hospital of Traditional Chinese & Western Medicine, Shanghai University of Traditional Chinese Medicine.MATERIALS : Totally 60 healthy male Wistar rats of clean grade, aged 4 month, with body mass of 200 to 220 g, were enrolled in this study. Streptozotocin (STZ, Sigma Company of USA, Batch No. S-0130).METHODS: This study was carried out in the Animal Experimental Center and Central Laboratory, YueyangHospital of Traditional Chinese & Western Medicine during February 2005 to March 2006. ① Fifteen rats were randomly chosen,serving as normal group.All the other rets were intraperitoneally injected once with STZ to develop experimental diabetic rat models. If fasting blood glucose was ≥ 15 mmol/L,sensory nerve and motor nerve conduction velocity of sciatic nerve was obviously slowed, tail-swaying temperature threshold was increased and myelinated nerve fiber of sciatic nerve changed, DPN models were successful. The successful model rats were randomly assigned into 3 groups: model group, control group(electroacupuncture at non-meridian-non-acupoint)and electroacupuncture group [electroacupuncture at Zusanli and Shenshu points], with 15 rats each. The rats in the normal group and model group were untouched. In the

  16. Pathways with PathWhiz.

    Science.gov (United States)

    Pon, Allison; Jewison, Timothy; Su, Yilu; Liang, Yongjie; Knox, Craig; Maciejewski, Adam; Wilson, Michael; Wishart, David S

    2015-07-01

    PathWhiz (http://smpdb.ca/pathwhiz) is a web server designed to create colourful, visually pleasing and biologically accurate pathway diagrams that are both machine-readable and interactive. As a web server, PathWhiz is accessible from almost any place and compatible with essentially any operating system. It also houses a public library of pathways and pathway components that can be easily viewed and expanded upon by its users. PathWhiz allows users to readily generate biologically complex pathways by using a specially designed drawing palette to quickly render metabolites (including automated structure generation), proteins (including quaternary structures, covalent modifications and cofactors), nucleic acids, membranes, subcellular structures, cells, tissues and organs. Both small-molecule and protein/gene pathways can be constructed by combining multiple pathway processes such as reactions, interactions, binding events and transport activities. PathWhiz's pathway replication and propagation functions allow for existing pathways to be used to create new pathways or for existing pathways to be automatically propagated across species. PathWhiz pathways can be saved in BioPAX, SBGN-ML and SBML data exchange formats, as well as PNG, PWML, HTML image map or SVG images that can be viewed offline or explored using PathWhiz's interactive viewer. PathWhiz has been used to generate over 700 pathway diagrams for a number of popular databases including HMDB, DrugBank and SMPDB. PMID:25934797

  17. Aquatic pathway 1

    International Nuclear Information System (INIS)

    This first part of the study discusses problems of exposure due to the emission of radioactive substances into the environment via the water pathway. Discussion is started with a paper on the fundamentals of calculation and another paper on the results of preliminary radiological model calculations. The colloquium will assess the present state of knowledge, helps to find an agreement between divergent opinions and determine open questions and possible solutions. Ten main problems have been raised, most of which pertain to site conditions. They are trated as sub-investigations by individual participants or working groups. The findings will be discussed in further colloquia. (orig.)

  18. WikiPathways: capturing the full diversity of pathway knowledge.

    Science.gov (United States)

    Kutmon, Martina; Riutta, Anders; Nunes, Nuno; Hanspers, Kristina; Willighagen, Egon L; Bohler, Anwesha; Mélius, Jonathan; Waagmeester, Andra; Sinha, Sravanthi R; Miller, Ryan; Coort, Susan L; Cirillo, Elisa; Smeets, Bart; Evelo, Chris T; Pico, Alexander R

    2016-01-01

    WikiPathways (http://www.wikipathways.org) is an open, collaborative platform for capturing and disseminating models of biological pathways for data visualization and analysis. Since our last NAR update, 4 years ago, WikiPathways has experienced massive growth in content, which continues to be contributed by hundreds of individuals each year. New aspects of the diversity and depth of the collected pathways are described from the perspective of researchers interested in using pathway information in their studies. We provide updates on extensions and services to support pathway analysis and visualization via popular standalone tools, i.e. PathVisio and Cytoscape, web applications and common programming environments. We introduce the Quick Edit feature for pathway authors and curators, in addition to new means of publishing pathways and maintaining custom pathway collections to serve specific research topics and communities. In addition to the latest milestones in our pathway collection and curation effort, we also highlight the latest means to access the content as publishable figures, as standard data files, and as linked data, including bulk and programmatic access. PMID:26481357

  19. Columbia River pathway report

    International Nuclear Information System (INIS)

    This report summarizes the river-pathway portion of the first phase of the Hanford Environmental Dose Reconstruction (HEDR) Project. The HEDR Project is estimating radiation doses that could have been received by the public from the Department of Energy's Hanford Site, in southeastern Washington State. Phase 1 of the river-pathway dose reconstruction effort sought to determine whether dose estimates could be calculated for populations in the area from above the Hanford Site at Priest Rapids Dam to below the site at McNary Dam from January 1964 to December 1966. Of the potential sources of radionuclides from the river, fish consumption was the most important. Doses from drinking water were lower at Pasco than at Richland and lower at Kennewick than at Pasco. The median values of preliminary dose estimates calculated by HEDR are similar to independent, previously published estimates of average doses to Richland residents. Later phases of the HEDR Project will address dose estimates for periods other than 1964--1966 and for populations downstream of McNary Dam. 17 refs., 19 figs., 1 tab

  20. Signaling Pathways in Melanogenesis

    Directory of Open Access Journals (Sweden)

    Stacey A. N. D’Mello

    2016-07-01

    Full Text Available Melanocytes are melanin-producing cells found in skin, hair follicles, eyes, inner ear, bones, heart and brain of humans. They arise from pluripotent neural crest cells and differentiate in response to a complex network of interacting regulatory pathways. Melanins are pigment molecules that are endogenously synthesized by melanocytes. The light absorption of melanin in skin and hair leads to photoreceptor shielding, thermoregulation, photoprotection, camouflage and display coloring. Melanins are also powerful cation chelators and may act as free radical sinks. Melanin formation is a product of complex biochemical events that starts from amino acid tyrosine and its metabolite, dopa. The types and amounts of melanin produced by melanocytes are determined genetically and are influenced by a variety of extrinsic and intrinsic factors such as hormonal changes, inflammation, age and exposure to UV light. These stimuli affect the different pathways in melanogenesis. In this review we will discuss the regulatory mechanisms involved in melanogenesis and explain how intrinsic and extrinsic factors regulate melanin production. We will also explain the regulatory roles of different proteins involved in melanogenesis.

  1. Signaling Pathways in Melanogenesis.

    Science.gov (United States)

    D'Mello, Stacey A N; Finlay, Graeme J; Baguley, Bruce C; Askarian-Amiri, Marjan E

    2016-01-01

    Melanocytes are melanin-producing cells found in skin, hair follicles, eyes, inner ear, bones, heart and brain of humans. They arise from pluripotent neural crest cells and differentiate in response to a complex network of interacting regulatory pathways. Melanins are pigment molecules that are endogenously synthesized by melanocytes. The light absorption of melanin in skin and hair leads to photoreceptor shielding, thermoregulation, photoprotection, camouflage and display coloring. Melanins are also powerful cation chelators and may act as free radical sinks. Melanin formation is a product of complex biochemical events that starts from amino acid tyrosine and its metabolite, dopa. The types and amounts of melanin produced by melanocytes are determined genetically and are influenced by a variety of extrinsic and intrinsic factors such as hormonal changes, inflammation, age and exposure to UV light. These stimuli affect the different pathways in melanogenesis. In this review we will discuss the regulatory mechanisms involved in melanogenesis and explain how intrinsic and extrinsic factors regulate melanin production. We will also explain the regulatory roles of different proteins involved in melanogenesis. PMID:27428965

  2. The Chordin Morphogenetic Pathway.

    Science.gov (United States)

    De Robertis, Edward M; Moriyama, Yuki

    2016-01-01

    The ancestral Chordin/bone morphogenetic protein (BMP) signaling pathway that establishes dorsal-ventral (D-V) patterning in animal development is one of the best understood morphogenetic gradients, and is established by multiple proteins that interact with each other in the extracellular space-including several BMPs, Chordin, Tolloid, Ont-1, Crossveinless-2, and Sizzled. The D-V gradient is adjusted redundantly by regulating the synthesis of its components, by direct protein-protein interactions between morphogens, and by long-range diffusion. The entire embryo participates in maintaining the D-V BMP gradient, so that for each action in the dorsal side there is a reaction in the ventral side. A gradient of Chordin is formed in the extracellular matrix that separates ectoderm from endomesoderm, called Brachet's cleft in Xenopus. The Chordin/BMP pathway is self-organizing and able to scale pattern in the dorsal half of bisected embryos or in Spemann dorsal lip transplantation experiments. PMID:26970622

  3. The Reactome pathway Knowledgebase.

    Science.gov (United States)

    Fabregat, Antonio; Sidiropoulos, Konstantinos; Garapati, Phani; Gillespie, Marc; Hausmann, Kerstin; Haw, Robin; Jassal, Bijay; Jupe, Steven; Korninger, Florian; McKay, Sheldon; Matthews, Lisa; May, Bruce; Milacic, Marija; Rothfels, Karen; Shamovsky, Veronica; Webber, Marissa; Weiser, Joel; Williams, Mark; Wu, Guanming; Stein, Lincoln; Hermjakob, Henning; D'Eustachio, Peter

    2016-01-01

    The Reactome Knowledgebase (www.reactome.org) provides molecular details of signal transduction, transport, DNA replication, metabolism and other cellular processes as an ordered network of molecular transformations-an extended version of a classic metabolic map, in a single consistent data model. Reactome functions both as an archive of biological processes and as a tool for discovering unexpected functional relationships in data such as gene expression pattern surveys or somatic mutation catalogues from tumour cells. Over the last two years we redeveloped major components of the Reactome web interface to improve usability, responsiveness and data visualization. A new pathway diagram viewer provides a faster, clearer interface and smooth zooming from the entire reaction network to the details of individual reactions. Tool performance for analysis of user datasets has been substantially improved, now generating detailed results for genome-wide expression datasets within seconds. The analysis module can now be accessed through a RESTFul interface, facilitating its inclusion in third party applications. A new overview module allows the visualization of analysis results on a genome-wide Reactome pathway hierarchy using a single screen page. The search interface now provides auto-completion as well as a faceted search to narrow result lists efficiently. PMID:26656494

  4. Polyurethane film dressings and ceramide 2-containing hydrocolloid dressing reduce the risk of pressure ulcer development in high-risk patients undergoing surgery: a matched case-control study

    Directory of Open Access Journals (Sweden)

    Kohta M

    2015-02-01

    Full Text Available Masushi Kohta,1 Kazumi Sakamoto,2 Tsunao Oh-i31Medical Engineering Laboratory, ALCARE Co, Ltd, Sumida-ku, Tokyo, 2Department of Nursing, 3Department of Dermatology, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, JapanBackground: Numerous clinical challenges regarding adhesive dressings have shown that using an adhesive dressing could minimize or prevent superficial skin loss in patients at risk of developing pressure ulcers. However, evidence that polyurethane film dressings and ceramide 2-containing hydrocolloid dressing can reduce the risk of pressure ulcer development in high-risk patients undergoing surgery is limited. Therefore, we assessed the effects of application of these dressings for reducing the risk of pressure ulcer development in these patients and identified other risk factors.Methods: A matched case-control study was conducted involving 254 patients at high risk for pressure ulcer development at one acute care hospital in Japan. No patients in this study had a pressure ulcer at the start of the study. Thirty-one patients developed a pressure ulcer during surgery, and these patients were defined as cases. Controls were randomly matched for sex and age (±4 years, from which 62 patients were selected. Medical records were obtained for preoperative factors, including age, sex, body mass index, diabetes mellitus, albumin, total protein, C-reactive protein, white cell count, red cell count, and hemoglobin, and for intraoperative factors, including dressing application, operation time, body position, and surgery type. The odds ratio (OR and 95% confidence interval (CI were determined to identify risk factors for pressure ulcer development in patients undergoing surgery.Results: By multiple logistic regression analysis, there was a significantly reduced risk of pressure ulcer development for patients who had dressing applications as compared with those without dressing applications (OR 0.063; 95% CI 0.012–0.343; P=0

  5. Pathways to Global Markets

    DEFF Research Database (Denmark)

    Smith, David E.; Mitry, Darryl J.

    2011-01-01

    . An important case study is McDonald‘s corporation, the world‘s largest fast food restaurant chain. This company has employed divergent marketing and economic strategies in both domestic and the international markets to become a leader in the global marketplace. An overview of the company‘s background......, organizational structures, mission and vision illustrate McDonald‘s strategic focus on its proactive evolution from a small drive-through operation to a global fast-food giant. The strategy is based on its ability to adapt to the cultural differences of the markets that McDonald‘s serves while preserving its......For marketing and economic researchers, an important aspect of globalization is the degree to which various consumer behavior dimensions and consumption patterns in different parts of the world are becoming similar, and how multinational companies have identified pathways to global success...

  6. Summer 2014 Pathways Report

    Science.gov (United States)

    Hand, Zachary

    2014-01-01

    Over the summer I had the exciting opportunity to work for NASA at the Kennedy Space Center as a Mission Assurance Engineering intern. When I was offered a position in mission assurance for the Safety and Mission Assurance directorate's Launch Services Division, I didn't really know what I would be doing, but I knew it would be an excellent opportunity to learn and grow professionally. In this report I will provide some background information on the Launch Services Division, as well as detail my duties and accomplishments during my time as an intern. Additionally, I will relate the significance of my work experience to my current academic work and future career goals. This report contains background information on Mission Assurance Engineering, a description of my duties and accomplishments over the summer of 2014, and relates the significance of my work experience to my school work and future career goals. It is a required document for the Pathways program.

  7. Exposures from aquatic pathways

    International Nuclear Information System (INIS)

    Methods for estimation aquatic pathways contribution to the total population exposure are discussed. Aquatic pathways are the major factor for radionuclides spreading from the Chernobyl Exclusion zone. An annual outflow of 90Sr and 137Cs comprised 10-20 TBq and 2-4 TBq respectively and the population exposed by this effluence constitutes almost 30 million people. The dynamic of doses from 90Sr and 'Cs, which Dnieper water have to delivered, is calculated. The special software has been developed to simulate the process of dose formation in the of diverse Dnieper regions. Regional peculiarities of municipal tap, fishing and irrigation are considered. Seventy-year prediction of dose structure and function of dose forming is performed. The exposure is estimated for 12 regions of the Dnieper basin and the Crimea. The maximal individual annual committed effective doses due to the use of water by ordinary members of the population in Kiev region from 90Sr and 137Cs in 1986 are 1.7*10-5 Sv and 2.7*10-5 Sv respectively. A commercial fisherman on Kiev reservoir in 1986 received 4.7*10-4 Sv and 5*10-3 Sv from 90Sr and 137Cs, respectively. The contributions to the collective cumulative (over 70 years) committed effective dose (CCCED70) of irrigation, municipal tap water and fish consumption for members of the population respectively are 18%, 43%, 39% in Kiev region, 8%, 25%, 67% in Poltava region, and 50%, 50%, 0% (consumption of Dnieper fish is absent) in the Crimea. The predicted contribution of the Strontium-90 to CCCED70 resulting from the use of water is 80%. The CCCED70 to the population of the Dnieper regions (32.5 million people) is 3000 person-Sv due to the use the Dnieper water

  8. Combinatorial pathway assembly in yeast

    Directory of Open Access Journals (Sweden)

    Khalil Essani

    2015-10-01

    Full Text Available With the emergence of synthetic biology and the vast knowledge about individual biocatalytic reactions, the challenge nowadays is to implement whole natural or synthetic pathways into microorganisms. For this purpose balanced enzyme activities throughout the pathway need to be achieved in addition to simple functional gene expression to avoid bottlenecks and to obtain high titers of the desired product. As the optimization of pathways in a specific biological context is often hard to achieve by rational design, combinatorial approaches have been developed to address this issue. Here, current strategies and proof of concepts for combinatorial pathway assembly in yeasts are reviewed. By exploiting its ability to join multiple DNA fragments in a very efficient and easy manner, the yeast Saccharomyces cerevisiae does not only constitute an attractive host for heterologous pathway expression, but also for assembling pathways by recombination in vivo.

  9. Pathways to man

    International Nuclear Information System (INIS)

    The study of radionuclide pathways leading to man generally has the goal of allowing us to predict human exposure from measurements of the radionuclide concentration in some segment of the environment. This modelling process provides a valuable tool in both the regulatory and health protection fields. However, most of the models in the regulatory field and in the health physics profession were designed to maximize exposure estimates. It is preferable to have scientifically defensible estimates and to add suitable safety factors at the end. Thus we are still faced with the development and validation of suitable models for many of the radionuclides of interest. The most useful models will include means of assessing variability and uncertainty. In this case variability might be considered as the differences in behavior due to age, sex or other factors in animals or man and those differences among plant species or animal species that determine their uptake factors. The uncertainty, on the other hand, would be the estimate of possible error in the experimental measurements. Model parameters would always have some variability even for site-specific cases and broad averages for population groups would have to include a factor expressing the possible variabilty and uncertainity. Thus any exposure calculation would have to be expressed with some range and valid assessments of this range are required

  10. Pathway Interaction Database (PID) —

    Science.gov (United States)

    The National Cancer Institute (NCI) in collaboration with Nature Publishing Group has established the Pathway Interaction Database (PID) in order to provide a highly structured, curated collection of information about known biomolecular interactions and key cellular processes assembled into signaling pathways.

  11. KeyPathwayMinerWeb

    DEFF Research Database (Denmark)

    List, Markus; Alcaraz, Nicolas; Dissing-Hansen, Martin;

    2016-01-01

    We present KeyPathwayMinerWeb, the first online platform for de novo pathway enrichment analysis directly in the browser. Given a biological interaction network (e.g. protein-protein interactions) and a series of molecular profiles derived from one or multiple OMICS studies (gene expression, for...... instance), KeyPathwayMiner extracts connected sub-networks containing a high number of active or differentially regulated genes (proteins, metabolites) in the molecular profiles. The web interface at (http://keypathwayminer.compbio.sdu.dk) implements all core functionalities of the KeyPathwayMiner tool set...... such as data integration, input of background knowledge, batch runs for parameter optimization and visualization of extracted pathways. In addition to an intuitive web interface, we also implemented a RESTful API that now enables other online developers to integrate network enrichment as a web service...

  12. Signaling pathways in diabetic nephropathy.

    Science.gov (United States)

    Kawanami, Daiji; Matoba, Keiichiro; Utsunomiya, Kazunori

    2016-10-01

    Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD), however, specific treatment for DN has not yet been elucidated. Therefore, it is critically important to understand the molecular mechanism underlying DN to develop cause-related therapeutic strategy. To date, various factors such as hemodynamic changes and metabolic pathways have been shown to be involved in the pathogenesis of DN. Excessive glucose influx activates cellular signaling pathways, including the diacylglycerol (DAG)-protein kinase C (PKC) pathway, advanced glycation end-products (AGE), polyol pathway, hexosamine pathway and oxidative stress. These factors interact with one another, thereby facilitating inflammatory processes, leading to the development of glomerulosclerosis under diabetic conditions. In addition to metabolic pathways, Rho-kinase, an effector of small-GTPase binding protein Rho, has been implicated as an important factor in the pathogenesis of DN. A number of studies have demonstrated that Rho-kinase plays key roles in the development of DN by inducing endothelial dysfunction, mesangial excessive extracellular matrix (ECM) production, podocyte abnormality, and tubulointerstitial fibrosis. In this review article, we describe our current understanding of the signaling pathways in DN. PMID:27094540

  13. Metabolic pathway engineering of the toluene degradation pathway

    OpenAIRE

    Regan, L.

    1995-01-01

    This thesis addresses the problem of how to examine a metabolic pathway and identify what are the key elements, specifically with respect to rate-limitation. The aim is to be able to analyze a pathway, identify the bottlenecks and implement genetic modifications to remove these bottlenecks. This is done by defining the system of interest and developing a predictive model using kinetic data. The model predictions can then be verified using fermentation data and genetic technique...

  14. Pathways with PathWhiz

    OpenAIRE

    Pon, Allison; Jewison, Timothy; Su, Yilu; Liang, Yongjie; Knox, Craig; Maciejewski, Adam; Wilson, Michael; Wishart, David S.

    2015-01-01

    PathWhiz (http://smpdb.ca/pathwhiz) is a web server designed to create colourful, visually pleasing and biologically accurate pathway diagrams that are both machine-readable and interactive. As a web server, PathWhiz is accessible from almost any place and compatible with essentially any operating system. It also houses a public library of pathways and pathway components that can be easily viewed and expanded upon by its users. PathWhiz allows users to readily generate biologically complex pa...

  15. Multiple pathways regulate shoot branching

    Directory of Open Access Journals (Sweden)

    Catherine eRameau

    2015-01-01

    Full Text Available Shoot branching patterns result from the spatio-temporal regulation of axillary bud outgrowth. Numerous endogenous, developmental and environmental factors are integrated at the bud and plant levels to determine numbers of growing shoots. Multiple pathways that converge to common integrators are most probably involved. We propose several pathways involving not only the classical hormones auxin, cytokinins and strigolactones, but also other signals with a strong influence on shoot branching such as gibberellins, sugars or molecular actors of plant phase transition. We also deal with recent findings about the molecular mechanisms and the pathway involved in the response to shade as an example of an environmental signal controlling branching. We propose the TCP transcription factor TB1/BRC1 and the polar auxin transport stream in the stem as possible integrators of these pathways. We finally discuss how modeling can help to represent this highly dynamic system by articulating knowledges and hypothesis and calculating the phenotype properties they imply.

  16. Signalling pathways in endometrial cancer

    OpenAIRE

    Markowska, Anna; Pawałowska, Monika; Lubin, Jolanta; Markowska, Janina

    2014-01-01

    Carcinogenesis is a multistage process, during which the activity of signalling pathways responsible for cell cycle regulation and division is disrupted which leads to inhibition of apoptosis and enhanced proliferation. Improper activation of Wnt/β-catenin and PI3K. Akt pathways play essential role in endometrial cancers (EC), mainly type I. Mutations in APC, axin or CTNBB1 may lead to β-catenin overactivation leading to excessive gene expression. PTEN inactivation, mutations in the PIK3CA or...

  17. Vestibular pathways involved in cognition

    Directory of Open Access Journals (Sweden)

    Martin Hitier

    2014-07-01

    Full Text Available Recent discoveries have emphasized the role of the vestibular system in cognitive processes such as memory, spatial navigation and bodily self-consciousness. A precise understanding of the vestibular pathways involved is essential to understand the consequences of vestibular diseases for cognition, as well as develop therapeutic strategies to facilitate recovery. The knowledge of the “vestibular cortical projections areas”, defined as the cortical areas activated by vestibular stimulation, has dramatically increased over the last several years from both anatomical and functional points of view. Four major pathways have been hypothesized to transmit vestibular information to the vestibular cortex: 1 the vestibulo-thalamo-cortical pathway, which probably transmits spatial information about the environment via the parietal, entorhinal and perirhinal cortices to the hippocampus and is associated with spatial representation and self-versus object motion distinctions; 2 the pathway from the dorsal tegmental nucleus via the lateral mammillary nucleus, the anterodorsal nucleus of the thalamus to the entorhinal cortex, which transmits information for estimations of the head direction; 3 the pathway via the nucleus reticularis pontis oralis, the supramammillary nucleus and the medial septum to the hippocampus, which transmits information supporting hippocampal theta rhythm and memory; and 4 a possible pathway via the cerebellum, and the ventral lateral nucleus of the thalamus (perhaps to the parietal cortex, which transmits information for spatial learning. Finally a new pathway is hypothesized via the basal ganglia, potentially involved in spatial learning and spatial memory. From these pathways, progressively emerges the anatomical network of vestibular cognition.

  18. A New Sphingolipid from the Fungus Paxillus panuoides

    Institute of Scientific and Technical Information of China (English)

    GAO Jin-Ming; ZHANG Zeng-Qiang; LIU Ji-Kai

    2003-01-01

    @@ The ceramides, cleavage products of various sphingolipids, including gangliosides and cerebrosides, are in volved in various signal transduction pathways. Many extracellular stresses, such as tumor necrosis factors-α (TNFα) and human immunodeficiency virus (HIV) have been shown to activate sphingomyelinases that release ceramides which inhibit cell growth and induce apoptosis. Because of the importance of ceramides, chemistry and biology of ceramides have been the vital subject of the latest research in recent years. [1~4

  19. Coherence in electron transfer pathways.

    Science.gov (United States)

    Skourtis, Spiros S; Beratan, David N; Waldeck, David H

    2011-01-01

    Central to the view of electron-transfer reactions is the idea that nuclear motion generates a transition state geometry at which the electron/hole amplitude propagates coherently from the electron donor to the electron acceptor. In the weakly coupled or nonadiabatic regime, the electron amplitude tunnels through an electronic barrier between the donor and acceptor. The structure of the barrier is determined by the covalent and noncovalent interactions of the bridge. Because the tunneling barrier depends on the nuclear coordinates of the reactants (and on the surrounding medium), the tunneling barrier is highly anisotropic, and it is useful to identify particular routes, or pathways, along which the transmission amplitude propagates. Moreover, when more than one such pathway exists, and the paths give rise to comparable transmission amplitude magnitudes, one may expect to observe quantum interferences among pathways if the propagation remains coherent. Given that the effective tunneling barrier height and width are affected by the nuclear positions, the modulation of the nuclear coordinates will lead to a modulation of the tunneling barrier and hence of the electron flow. For long distance electron transfer in biological and biomimetic systems, nuclear fluctuations, arising from flexible protein moieties and mobile water bridges, can become quite significant. We discuss experimental and theoretical results that explore the quantum interferences among coupling pathways in electron-transfer kinetics; we emphasize recent data and theories associated with the signatures of chirality and inelastic processes, which are manifested in the tunneling pathway coherence (or absence of coherence). PMID:23833692

  20. Aberrant Signaling Pathways in Glioma

    Energy Technology Data Exchange (ETDEWEB)

    Nakada, Mitsutoshi, E-mail: nakada@ns.m.kanazawa-u.ac.jp; Kita, Daisuke; Watanabe, Takuya; Hayashi, Yutaka [Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641 (Japan); Teng, Lei [Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641 (Japan); Department of Neurosurgery, The First Clinical College of Harbin Medical University, Nangang, Harbin 150001 (China); Pyko, Ilya V.; Hamada, Jun-Ichiro [Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641 (Japan)

    2011-08-10

    Glioblastoma multiforme (GBM), a WHO grade IV malignant glioma, is the most common and lethal primary brain tumor in adults; few treatments are available. Median survival rates range from 12–15 months. The biological characteristics of this tumor are exemplified by prominent proliferation, active invasiveness, and rich angiogenesis. This is mainly due to highly deregulated signaling pathways in the tumor. Studies of these signaling pathways have greatly increased our understanding of the biology and clinical behavior of GBM. An integrated view of signal transduction will provide a more useful approach in designing novel therapies for this devastating disease. In this review, we summarize the current understanding of GBM signaling pathways with a focus on potential molecular targets for anti-signaling molecular therapies.

  1. Aberrant Signaling Pathways in Glioma

    International Nuclear Information System (INIS)

    Glioblastoma multiforme (GBM), a WHO grade IV malignant glioma, is the most common and lethal primary brain tumor in adults; few treatments are available. Median survival rates range from 12–15 months. The biological characteristics of this tumor are exemplified by prominent proliferation, active invasiveness, and rich angiogenesis. This is mainly due to highly deregulated signaling pathways in the tumor. Studies of these signaling pathways have greatly increased our understanding of the biology and clinical behavior of GBM. An integrated view of signal transduction will provide a more useful approach in designing novel therapies for this devastating disease. In this review, we summarize the current understanding of GBM signaling pathways with a focus on potential molecular targets for anti-signaling molecular therapies

  2. UniPathway: a resource for the exploration and annotation of metabolic pathways.

    Science.gov (United States)

    Morgat, Anne; Coissac, Eric; Coudert, Elisabeth; Axelsen, Kristian B; Keller, Guillaume; Bairoch, Amos; Bridge, Alan; Bougueleret, Lydie; Xenarios, Ioannis; Viari, Alain

    2012-01-01

    UniPathway (http://www.unipathway.org) is a fully manually curated resource for the representation and annotation of metabolic pathways. UniPathway provides explicit representations of enzyme-catalyzed and spontaneous chemical reactions, as well as a hierarchical representation of metabolic pathways. This hierarchy uses linear subpathways as the basic building block for the assembly of larger and more complex pathways, including species-specific pathway variants. All of the pathway data in UniPathway has been extensively cross-linked to existing pathway resources such as KEGG and MetaCyc, as well as sequence resources such as the UniProt KnowledgeBase (UniProtKB), for which UniPathway provides a controlled vocabulary for pathway annotation. We introduce here the basic concepts underlying the UniPathway resource, with the aim of allowing users to fully exploit the information provided by UniPathway. PMID:22102589

  3. The lectin pathway of complement

    DEFF Research Database (Denmark)

    Ballegaard, Vibe Cecilie Diederich; Haugaard, Anna Karen; Garred, P;

    2014-01-01

    The pattern recognition molecules of the lectin complement pathway are important components of the innate immune system with known functions in host-virus interactions. This paper summarizes current knowledge of how these intriguing molecules, including mannose-binding lectin (MBL), Ficolin-1, -2...

  4. Signalling pathways in endometrial cancer.

    Science.gov (United States)

    Markowska, Anna; Pawałowska, Monika; Lubin, Jolanta; Markowska, Janina

    2014-01-01

    Carcinogenesis is a multistage process, during which the activity of signalling pathways responsible for cell cycle regulation and division is disrupted which leads to inhibition of apoptosis and enhanced proliferation. Improper activation of Wnt/β-catenin and PI3K. Akt pathways play essential role in endometrial cancers (EC), mainly type I. Mutations in APC, axin or CTNBB1 may lead to β-catenin overactivation leading to excessive gene expression. PTEN inactivation, mutations in the PIK3CA or Akt result in increased transmission in the PI3K/Akt pathway, apoptosis inhibition, intensive cell division, mTOR excitation. In non-endometrioid cancers, key mutations include suppressor gene TP53 responsible for repairing damaged DNA or apoptosis initiation. Irregularities in gene P16, encoding a protein forming the p16-cyclinD/CDK-pRb have also been described. Understanding the complex relations between specific proteins taking part in signal transduction of the abovementioned pathways is key to research on drugs used in targeted therapy. PMID:25520571

  5. Critical nodes in signalling pathways

    DEFF Research Database (Denmark)

    Taniguchi, Cullen M; Emanuelli, Brice; Kahn, C Ronald

    2006-01-01

    Physiologically important cell-signalling networks are complex, and contain several points of regulation, signal divergence and crosstalk with other signalling cascades. Here, we use the concept of 'critical nodes' to define the important junctions in these pathways and illustrate their unique ro...

  6. Rapid prototype extruded conductive pathways

    Energy Technology Data Exchange (ETDEWEB)

    Bobbitt, III, John T.

    2016-06-21

    A process of producing electrically conductive pathways within additively manufactured parts and similar parts made by plastic extrusion nozzles. The process allows for a three-dimensional part having both conductive and non-conductive portions and allows for such parts to be manufactured in a single production step.

  7. Reverse Engineering Adverse Outcome Pathways

    Energy Technology Data Exchange (ETDEWEB)

    Perkins, Edward; Chipman, J.K.; Edwards, Stephen; Habib, Tanwir; Falciani, Francesco; Taylor, Ronald C.; Van Aggelen, Graham; Vulpe, Chris; Antczak, Philipp; Loguinov, Alexandre

    2011-01-30

    The toxicological effects of many stressors are mediated through unknown, or poorly characterized, mechanisms of action. We describe the application of reverse engineering complex interaction networks from high dimensional omics data (gene, protein, metabolic, signaling) to characterize adverse outcome pathways (AOPs) for chemicals that disrupt the hypothalamus-pituitary-gonadal endocrine axis in fathead minnows. Gene expression changes in fathead minnow ovaries in response to 7 different chemicals, over different times, doses, and in vivo versus in vitro conditions were captured in a large data set of 868 arrays. We examined potential AOPs of the antiandrogen flutamide using two mutual information theory methods, ARACNE and CLR to infer gene regulatory networks and potential adverse outcome pathways. Representative networks from these studies were used to predict a network path from stressor to adverse outcome as a candidate AOP. The relationship of individual chemicals to an adverse outcome can be determined by following perturbations through the network in response to chemical treatment leading to the nodes associated with the adverse outcome. Identification of candidate pathways allows for formation of testable hypotheses about key biologic processes, biomarkers or alternative endpoints, which could be used to monitor an adverse outcome pathway. Finally, we identify the unique challenges facing the application of this approach in ecotoxicology, and attempt to provide a road map for the utilization of these tools. Key Words: mechanism of action, toxicology, microarray, network inference

  8. Molecular Pathways: Targeting DNA Repair Pathway Defects Enriched in Metastasis.

    Science.gov (United States)

    Corcoran, Niall M; Clarkson, Michael J; Stuchbery, Ryan; Hovens, Christopher M

    2016-07-01

    The maintenance of a pristine genome, free from errors, is necessary to prevent cellular transformation and degeneration. When errors in DNA are detected, DNA damage repair (DDR) genes and their regulators are activated to effect repair. When these DDR pathways are themselves mutated or aberrantly downregulated, cancer and neurodegenerative disorders can ensue. Multiple lines of evidence now indicate, however, that defects in key regulators of DNA repair pathways are highly enriched in human metastasis specimens and hence may be a key step in the acquisition of metastasis and the ability of localized disease to disseminate. Some of the key regulators of checkpoints in the DNA damage response are the TP53 protein and the PARP enzyme family. Targeting of these pathways, especially through PARP inhibition, is now being exploited therapeutically to effect significant clinical responses in subsets of individuals, particularly in patients with ovarian cancer or prostate cancer, including cancers with a marked metastatic burden. Targeting DNA repair-deficient tumors with drugs that take advantage of the fundamental differences between normal repair-proficient cells and repair-deficient tumors offers new avenues for treating advanced disease in the future. Clin Cancer Res; 22(13); 3132-7. ©2016 AACR. PMID:27169997

  9. Reactome from a WikiPathways Perspective.

    Science.gov (United States)

    Bohler, Anwesha; Wu, Guanming; Kutmon, Martina; Pradhana, Leontius Adhika; Coort, Susan L; Hanspers, Kristina; Haw, Robin; Pico, Alexander R; Evelo, Chris T

    2016-05-01

    Reactome and WikiPathways are two of the most popular freely available databases for biological pathways. Reactome pathways are centrally curated with periodic input from selected domain experts. WikiPathways is a community-based platform where pathways are created and continually curated by any interested party. The nascent collaboration between WikiPathways and Reactome illustrates the mutual benefits of combining these two approaches. We created a format converter that converts Reactome pathways to the GPML format used in WikiPathways. In addition, we developed the ComplexViz plugin for PathVisio which simplifies looking up complex components. The plugin can also score the complexes on a pathway based on a user defined criterion. This score can then be visualized on the complex nodes using the visualization options provided by the plugin. Using the merged collection of curated and converted Reactome pathways, we demonstrate improved pathway coverage of relevant biological processes for the analysis of a previously described polycystic ovary syndrome gene expression dataset. Additionally, this conversion allows researchers to visualize their data on Reactome pathways using PathVisio's advanced data visualization functionalities. WikiPathways benefits from the dedicated focus and attention provided to the content converted from Reactome and the wealth of semantic information about interactions. Reactome in turn benefits from the continuous community curation available on WikiPathways. The research community at large benefits from the availability of a larger set of pathways for analysis in PathVisio and Cytoscape. The pathway statistics results obtained from PathVisio are significantly better when using a larger set of candidate pathways for analysis. The conversion serves as a general model for integration of multiple pathway resources developed using different approaches. PMID:27203685

  10. Molecular pathways towards psychiatric disorders

    International Nuclear Information System (INIS)

    The observed fibrillar-neuronal organization of the cerebral cortex suggests that in the aetiology of certain psychiatric disorders the genomic response of the neuron to the challenge presented by stress or insults at various stages of development, is to set off a programmed chain of molecular events (or ''pathways''), as demonstrated in previous genetic studies. The understanding of these pathways is important in order to enhance our ability to influence these illnesses, and are hypothesized to be initiated by a nucleolar mechanism for inducing abnormal synthesis of the nerve growth factor (NGF). The hypothesis is used to approach tentatively the still open question regarding the pathogenesis of mental retardation (MR) and senile dementia (SD). (author). 25 refs

  11. Developmental pathways of motor dysfunction.

    Science.gov (United States)

    Kleven, Gale A; Bellinger, Seanceray A

    2015-05-01

    Recent evidence has revealed unique patterns of behavioral development after prenatal insult similar to those outlined in studies of adult metabolic dysfunction after prenatal malnutrition. The hallmark features of this Developmental Pathway include a prenatal insult to the nervous system (environmental or genetic) followed by a period of Silent Vulnerability, where no or few functional deficits are observed, and finally emergence of later dysfunction. Possible mechanisms leading to later dysfunction from prenatal insult may include secondary or cascade effects due to the timing of prenatal insults relative to later developing structures in the brain. Methods best employed to study the mechanisms of these pathways are microgenetic and longitudinal designs that include behavioral assessment during the prenatal period of development, and animal models such as the guinea pig. PMID:25864561

  12. Parkinson's disease: insights from pathways

    OpenAIRE

    Cookson, Mark R.; Bandmann, Oliver

    2010-01-01

    Parkinson's disease (PD) typically presents in sporadic fashion, but the identification of disease-causing mutations in monogenically inherited PD genes has provided crucial insight into the pathogenesis of this disorder. Mutations in autosomal recessively inherited genes, namely parkin, PINK1 and DJ-1, typically lead to early onset parkinsonism. At least two of these genes (PINK1 and parkin) appear to work in the same pathway related to maintenance of mitochondrial functional integrity under...

  13. Glycosyltransferase efficiently controls phenylpropanoid pathway

    OpenAIRE

    Kulma Anna; Korobczak-Sosna Alina; Aksamit-Stachurska Anna; Szopa Jan

    2008-01-01

    Abstract Background In a previous study, anthocyanin levels in potato plants were increased by manipulating genes connected with the flavonoid biosynthesis pathway. However, starch content and tuber yield were dramatically reduced in the transgenic plants, which over-expressed dihydroflavonol reductase (DFR). Results Transgenic plants over-expressing dihydroflavonol reductase (DFR) were subsequently transformed with the cDNA coding for the glycosyltransferase (UGT) of Solanum sogarandinum in ...

  14. New Pathways for Alimentary Mucositis

    OpenAIRE

    Keefe, Dorothy M. K.; Joanne M. Bowen

    2008-01-01

    Alimentary mucositis is a major dose-limiting toxicity associated with anticancer treatment. It is responsible for reducing patient quality of life and represents a significant economic burden in oncology. The pathobiology of alimentary mucositis is extremely complex, and an increased understanding of mechanisms and pathway interactions is required to rationally design improved therapies. This review describes the latest advances in defining mechanisms of alimentary mucositis pathobiology in ...

  15. Vestibular pathways involved in cognition

    OpenAIRE

    Martin Hitier

    2014-01-01

    Recent discoveries have emphasized the role of the vestibular system in cognitive processes such as memory, spatial navigation and bodily self-consciousness. A precise understanding of the vestibular pathways involved is essential to understand the consequences of vestibular diseases for cognition, as well as develop therapeutic strategies to facilitate recovery. The knowledge of the “vestibular cortical projections areas”, defined as the cortical areas activated by vestibular stimulation, ha...

  16. Imbalanced kynurenine pathway in schizophrenia.

    Science.gov (United States)

    Kegel, Magdalena E; Bhat, Maria; Skogh, Elisabeth; Samuelsson, Martin; Lundberg, Kristina; Dahl, Marja-Liisa; Sellgren, Carl; Schwieler, Lilly; Engberg, Göran; Schuppe-Koistinen, Ina; Erhardt, Sophie

    2014-01-01

    Several studies suggest a role for kynurenic acid (KYNA) in the pathophysiology of schizophrenia. It has been proposed that increased brain KYNA levels in schizophrenia result from a pathological shift in the kynurenine pathway toward enhanced KYNA formation, away from the other branch of the pathway leading to quinolinic acid (QUIN). Here we investigate the levels of QUIN in cerebrospinal fluid (CSF) of patients with schizophrenia and healthy controls, and relate those to CSF levels of KYNA and other kynurenine metabolites from the same individuals. CSF QUIN levels from stable outpatients treated with olanzapine (n = 22) and those of controls (n = 26) were analyzed using liquid chromatography-mass spectrometry. No difference in CSF QUIN levels between patients and controls was observed (20.6 ± 1.5 nM vs. 18.2 ± 1.1 nM, P = 0.36). CSF QUIN was positively correlated to CSF kynurenine and CSF KYNA in patients but not in controls. The CSF QUIN/KYNA ratio was lower in patients than in controls (P = 0.027). In summary, the present study offers support for an over-activated and imbalanced kynurenine pathway, favoring the production of KYNA over QUIN in patients with schizophrenia. PMID:25288889

  17. Fragmentation pathways of polymer ions.

    Science.gov (United States)

    Wesdemiotis, Chrys; Solak, Nilüfer; Polce, Michael J; Dabney, David E; Chaicharoen, Kittisak; Katzenmeyer, Bryan C

    2011-01-01

    Tandem mass spectrometry (MS/MS) is increasingly applied to synthetic polymers to characterize chain-end or in-chain substituents, distinguish isobaric and isomeric species, and determine macromolecular connectivities and architectures. For confident structural assignments, the fragmentation mechanisms of polymer ions must be understood, as they provide guidelines on how to deduce the desired information from the fragments observed in MS/MS spectra. This article reviews the fragmentation pathways of synthetic polymer ions that have been energized to decompose via collisionally activated dissociation (CAD), the most widely used activation method in polymer analysis. The compounds discussed encompass polystyrenes, poly(2-vinyl pyridine), polyacrylates, poly(vinyl acetate), aliphatic polyester copolymers, polyethers, and poly(dimethylsiloxane). For a number of these polymers, several substitution patterns and architectures are considered, and questions regarding the ionization agent and internal energy of the dissociating precursor ions are also addressed. Competing and consecutive dissociations are evaluated in terms of the structural insight they provide about the macromolecular structure. The fragmentation pathways of the diverse array of polymer ions examined fall into three categories, viz. (1) charge-directed fragmentations, (2) charge-remote rearrangements, and (3) charge-remote fragmentations via radical intermediates. Charge-remote processes predominate. Depending on the ionizing agent and the functional groups in the polymer, the incipient fragments arising by pathways (1)-(3) may form ion-molecule complexes that survive long enough to permit inter-fragment hydrogen atom, proton, or hydride transfers. PMID:20623599

  18. Dual Pathways to Prospective Remembering

    Directory of Open Access Journals (Sweden)

    Mark A Mcdaniel

    2015-07-01

    Full Text Available According to the multiprocess framework (McDaniel & Einstein, 2000, the cognitive system can support prospective memory (PM retrieval through two general pathways. One pathway depends on top-down attentional control processes that maintain activation of the intention and/or monitor the environment for the triggering or target cues that indicate that the intention should be executed. A second pathway depends on (bottom-up spontaneous retrieval processes, processes that are often triggered by a PM target cue; critically spontaneous retrieval is assumed to not require monitoring or active maintenance of the intention. Given demand characteristics associated with experimental settings, however, participants are often inclined to monitor, thereby potentially masking discovery of bottom-up spontaneous retrieval processes. In this article, we discuss parameters of laboratory PM paradigms to discourage monitoring and review recent behavioral evidence from such paradigms that implicate spontaneous retrieval in PM. We then re-examine the neuro-imaging evidence from the lens of the multiprocess framework and suggest some critical modifications to existing neuro-cognitive interpretations of the neuro-imaging results. These modifications illuminate possible directions and refinements for further neuro-imaging investigations of PM.

  19. Quantifying macromolecular conformational transition pathways

    Science.gov (United States)

    Seyler, Sean; Kumar, Avishek; Thorpe, Michael; Beckstein, Oliver

    2015-03-01

    Diverse classes of proteins function through large-scale conformational changes that are challenging for computer simulations. A range of fast path-sampling techniques have been used to generate transitions, but it has been difficult to compare paths from (and assess the relative strengths of) different methods. We introduce a comprehensive method (pathway similarity analysis, PSA) for quantitatively characterizing and comparing macromolecular pathways. The Hausdorff and Fréchet metrics (known from computational geometry) are used to quantify the degree of similarity between polygonal curves in configuration space. A strength of PSA is its use of the full information available from the 3 N-dimensional configuration space trajectory without requiring additional specific knowledge about the system. We compare a sample of eleven different methods for the closed-to-open transitions of the apo enzyme adenylate kinase (AdK) and also apply PSA to an ensemble of 400 AdK trajectories produced by dynamic importance sampling MD and the Geometrical Pathways algorithm. We discuss the method's potential to enhance our understanding of transition path sampling methods, validate them, and help guide future research toward deeper physical insights into conformational transitions.

  20. Synergy between methylerythritol phosphate pathway and mevalonate pathway for isoprene production in Escherichia coli.

    Science.gov (United States)

    Yang, Chen; Gao, Xiang; Jiang, Yu; Sun, Bingbing; Gao, Fang; Yang, Sheng

    2016-09-01

    Isoprene, a key building block of synthetic rubber, is currently produced entirely from petrochemical sources. In this work, we engineered both the methylerythritol phosphate (MEP) pathway and the mevalonate (MVA) pathway for isoprene production in E. coli. The synergy between the MEP pathway and the MVA pathway was demonstrated by the production experiment, in which overexpression of both pathways improved the isoprene yield about 20-fold and 3-fold, respectively, compared to overexpression of the MEP pathway or the MVA pathway alone. The (13)C metabolic flux analysis revealed that simultaneous utilization of the two pathways resulted in a 4.8-fold increase in the MEP pathway flux and a 1.5-fold increase in the MVA pathway flux. The synergy of the dual pathway was further verified by quantifying intracellular flux responses of the MEP pathway and the MVA pathway to fosmidomycin treatment and mevalonate supplementation. Our results strongly suggest that coupling of the complementary reducing equivalent demand and ATP requirement plays an important role in the synergy of the dual pathway. Fed-batch cultivation of the engineered strain overexpressing the dual pathway resulted in production of 24.0g/L isoprene with a yield of 0.267g/g of glucose. The synergy of the MEP pathway and the MVA pathway also successfully increased the lycopene productivity in E. coli, which demonstrates that it can be used to improve the production of a broad range of terpenoids in microorganisms. PMID:27174717

  1. Ceramide profile in hypohidrotic ectodermal dysplasia

    DEFF Research Database (Denmark)

    Jungersted, J. M.; Høgh, Julie Kaae; Hellgren, Lars; Agnert, T.; Jemec, G. B. E.

    2012-01-01

    with HED (n = 7) and patients with AD (n = 21), using cyanoacrylate to take biopsy samples from the stratum corneum. Lipids were extracted from the biopsies and analysed using high‐performance thin‐layer chromatography. Results. The lipid profiles of HED and AD were similar in distribution, apart from...

  2. Mechanisms and impact of ceramide phosphoethanolamine biosynthesis

    NARCIS (Netherlands)

    Hentes Vacaru, A.M.

    2009-01-01

    Sphingolipids represent an essential class of membrane molecules in eukaryotic cells. They are primarily found in the outer leaflet of the plasma membrane where they help create a rigid and impermeable barrier to the extracellular environment. While sphingomyelin (SM) is the most abundant sphingolip

  3. Hand eczema and stratum corneum ceramides

    DEFF Research Database (Denmark)

    Jungersted, J. M.; Høgh, Julie Kaae; Hellgren, Lars;

    2015-01-01

    Index (HECSI), and skin barrier susceptibility was assessed by measuring transepidermal water loss (TEWL) after a 24-hour patch test with sodium lauryl sulfate (SLS). Results: No statistically significant difference was found between groups for the lipid analysis or for skin susceptibility to SLS. We...

  4. 线纹香茶菜地下部分甾体与神经酰胺类成分%Steroidal and Ceramide Constituents from Underground Part of Isodon lophanthoides

    Institute of Scientific and Technical Information of China (English)

    徐伟; 孙俊哲; 赵明早; 王靖雯; 董相; 姜北

    2016-01-01

    目的:对线纹香茶菜(Isodon lophanthoides)地下部分化学成分进行研究。方法:采用硅胶、Sephadex LH-20等多种柱层析方法对线纹香茶菜地下部分进行分离纯化,并运用现代波谱学技术与理化性质等手段对分离的化合物进行结构鉴定。结果:从线纹香茶菜地下部分70%丙酮-水提取物的乙酸乙酯部位分离得到5个甾体类化合物和2个神经酰胺类化合物,分别鉴定为:豆甾-4-烯-3-酮(1)、豆甾醇(2)、7α-羟基谷甾醇(3)、胡萝卜苷(4)、5α,6β-二羟基胡萝卜苷(5)、(2S,3S,4R,8E)-2-[(2′R)-2′-羟基-二十四酰氨基]-8-十八烯-1,3,4-三醇(6)、(2S,3R,4E,8Z)-1-O-β-D-葡萄糖-2-[(2′R)-2′-羟基-二十四酰氨基]-4,8-十八二烯-1,3-二醇(7)。结论:化合物1、3、5~7为首次从该植物中分离得到,其中化合物5~7为首次从该属植物地下部分分离得到。%Objective: To explore the chemical constituents from the underground part of Isodon lophanthoides. Methods: The compounds were isolated and purified by silica gel and Sephadex LH-20 column chromatography. Their structures were identified by various spectral analysis and physicochemical properties. Results: Five steroidal compounds and two ceramide compounds were obtained from ethyl acetate fraction of 70% acetone-water extract of the Isodon lophanthoides underground part and identified as stigmast-4-ene-3-one(1), stigmasterol(2), 7α-hydroxysitosterol(3), daucosterol(4), 5α, 6β-dihydroxy-daucosterol(5),(2S, 3S, 4R, 8E)-2-[(2′R)-2-hydroxytetracosanoylamino]-1, 3, 4-octadecanetriol-8-ene(6), and 1-O-β-D-glucopyranosyl-(2S, 3R, 4E, 8Z)-2-[(2′R)-2-hydroxytetracosanoylamino]-1,3-octadecanediol-4, 8-diene(7). Conclusion:All of these compounds except for 2 and 4 were isolated from this plant for the first time, while the compounds 5-7 were firstly obtained from the underground part of Isodon

  5. Apoptotic engulfment pathway and schizophrenia.

    LENUS (Irish Health Repository)

    Chen, Xiangning

    2009-01-01

    BACKGROUND: Apoptosis has been speculated to be involved in schizophrenia. In a previously study, we reported the association of the MEGF10 gene with the disease. In this study, we followed the apoptotic engulfment pathway involving the MEGF10, GULP1, ABCA1 and ABCA7 genes and tested their association with the disease. METHODOLOGY\\/PRINCIPAL FINDINGS: Ten, eleven and five SNPs were genotyped in the GULP1, ABCA1 and ABCA7 genes respectively for the ISHDSF and ICCSS samples. In all 3 genes, we observed nominally significant associations. Rs2004888 at GULP1 was significant in both ISHDSF and ICCSS samples (p = 0.0083 and 0.0437 respectively). We sought replication in independent samples for this marker and found highly significant association (p = 0.0003) in 3 Caucasian replication samples. But it was not significant in the 2 Chinese replication samples. In addition, we found a significant 2-marker (rs2242436 * rs3858075) interaction between the ABCA1 and ABCA7 genes in the ISHDSF sample (p = 0.0022) and a 3-marker interaction (rs246896 * rs4522565 * rs3858075) amongst the MEGF10, GULP1 and ABCA1 genes in the ICCSS sample (p = 0.0120). Rs3858075 in the ABCA1 gene was involved in both 2- and 3-marker interactions in the two samples. CONCLUSIONS\\/SIGNIFICANCE: From these data, we concluded that the GULP1 gene and the apoptotic engulfment pathway are involved in schizophrenia in subjects of European ancestry and multiple genes in the pathway may interactively increase the risks to the disease.

  6. Oxylipin Pathway in Rice and Arabidopsis

    Institute of Scientific and Technical Information of China (English)

    E. Wassim Chehab; John V. Perea; Banu Gopalan; Steve Theg; Katayoon Dehesh

    2007-01-01

    Plants have evolved complex signaling pathways to coordinate responses to developmental and environmental information. The oxylipin pathway is one pivotal lipid-based signaling network, composed of several competing branch pathways, that determines the plant's ability to adapt to various stimuli. Activation of the oxylipin pathway induces the de novo synthesis of biologically active metabolltes called "oxylipins". The relative levels of these metabolltes are a distinct indicator of each plant species and determine the ability of plants to adapt to different stimuli. The two major branches of the oxylipln pathway, allene oxide synthase (AOS) and hydroperoxide lyase (HPL) are responsible for production of the signaling compounds,jasmonates and aldehydes respectively. Here, we compare and contrast the regulation of AOS and HPL branch pathways in rice and Arabidopsis as model monocotyledonous and dicotyledonous systems. These analyses provide new Insights into the evolution of JAs and aldehydes signaling pathways, and the complex network of processes responsible for stress adaptations in monocots and dicots.

  7. Regulation of SREBPs by Sphingomyelin in Adipocytes via a Caveolin and Ras-ERK-MAPK-CREB Signaling Pathway.

    Directory of Open Access Journals (Sweden)

    Nehman Makdissy

    Full Text Available Sterol response element binding protein (SREBP is a key transcription factor in insulin and glucose metabolism. We previously demonstrated that elevated levels of membrane sphingomyelin (SM were related to peroxisome proliferator-activated receptor-γ (PPARγ, which is a known target gene of SREBP-1 in adipocytes. However, the role of SM in SREBP expression in adipocytes remains unknown. In human abdominal adipose tissue from obese women with various concentrations of fasting plasma insulin, SREBP-1 proteins decreased in parallel with increases in membrane SM levels. An inverse correlation was found between the membrane SM content and the levels of SREBP-1c/ERK/Ras/PPARγ/CREB proteins. For the first time, we demonstrate the effects of SM and its signaling pathway in 3T3-F442A adipocytes. These cells were enriched or unenriched with SM in a range of concentrations similar to those observed in obese subjects by adding exogenous natural SMs (having different acyl chain lengths or by inhibiting neutral sphingomyelinase. SM accumulated in caveolae of the plasma membrane within 24 h and then in the intracellular space. SM enrichment decreased SREBP-1 through the inhibition of extracellular signal-regulated protein kinase (ERK but not JNK or p38 mitogen-activated protein kinase (MAPK. Ras/Raf-1/MEK1/2 and KSR proteins, which are upstream mediators of ERK, were down-regulated, whereas SREBP-2/caveolin and cholesterol were up-regulated. In SM-unmodulated adipocytes treated with DL-1-Phenyl-2-Palmitoylamino-3-morpholino-1-propanol (PPMP, where the ceramide level increased, the expression levels of SREBPs and ERK were modulated in an opposite direction relative to the SM-enriched cells. SM inhibited the insulin-induced expression of SREBP-1. Rosiglitazone, which is an anti-diabetic agent and potent activator of PPARγ, reversed the effects of SM on SREBP-1, PPARγ and CREB. Taken together, these findings provide novel insights indicating that excess

  8. [Clinical pathway "Acute Coronary Syndrome"].

    Science.gov (United States)

    Grimm, W; Maisch, B

    2006-07-01

    The clinical pathway "acute coronary syndrome" of the university hospital Marburg describes the guideline-conform and consented management of patients with ST-segment elevation infarct (STEMI), non-ST-segment elevation infarct (NSTEMI) and Troponin negative unstable angina. A 12-lead ECG recording is made and read in all patients within 10 minutes. All patients with STEMI undergo immediate revascularisation using primary percutanuous catheter intervention (PCI) after administration of basic medical therapy. Primary PCI is also used in all patients with NSTEMI, persistent chest pain, rhythm or hemodynamic instability. Patients with unstable angina, who became free of symptoms after application of basic medication, but who have additional risk factors undergo cardiac catheterisation within 48 hours. Acute myocardial infarction can be ruled out in patients with twofold negative cardiac troponin levels during 6-12 hours. In the absence of further symptoms, these patiens undergo differential diagnostic evaluation of cardiac and extracardiac causes of chest pain. The introduction of this clinical pathway 2 years ago, which was consented before by the hospital board and the clinical directors, has lead to a remarkable improvement in the clinical decision-making at the emergency room of the hospital and reduced the door to intervention time considerably. PMID:16763796

  9. Pathway analysis of coronary atherosclerosis.

    Science.gov (United States)

    King, Jennifer Y; Ferrara, Rossella; Tabibiazar, Raymond; Spin, Joshua M; Chen, Mary M; Kuchinsky, Allan; Vailaya, Aditya; Kincaid, Robert; Tsalenko, Anya; Deng, David Xing-Fei; Connolly, Andrew; Zhang, Peng; Yang, Eugene; Watt, Clifton; Yakhini, Zohar; Ben-Dor, Amir; Adler, Annette; Bruhn, Laurakay; Tsao, Philip; Quertermous, Thomas; Ashley, Euan A

    2005-09-21

    Large-scale gene expression studies provide significant insight into genes differentially regulated in disease processes such as cancer. However, these investigations offer limited understanding of multisystem, multicellular diseases such as atherosclerosis. A systems biology approach that accounts for gene interactions, incorporates nontranscriptionally regulated genes, and integrates prior knowledge offers many advantages. We performed a comprehensive gene level assessment of coronary atherosclerosis using 51 coronary artery segments isolated from the explanted hearts of 22 cardiac transplant patients. After histological grading of vascular segments according to American Heart Association guidelines, isolated RNA was hybridized onto a customized 22-K oligonucleotide microarray, and significance analysis of microarrays and gene ontology analyses were performed to identify significant gene expression profiles. Our studies revealed that loss of differentiated smooth muscle cell gene expression is the primary expression signature of disease progression in atherosclerosis. Furthermore, we provide insight into the severe form of coronary artery disease associated with diabetes, reporting an overabundance of immune and inflammatory signals in diabetics. We present a novel approach to pathway development based on connectivity, determined by language parsing of the published literature, and ranking, determined by the significance of differentially regulated genes in the network. In doing this, we identify highly connected "nexus" genes that are attractive candidates for therapeutic targeting and followup studies. Our use of pathway techniques to study atherosclerosis as an integrated network of gene interactions expands on traditional microarray analysis methods and emphasizes the significant advantages of a systems-based approach to analyzing complex disease. PMID:15942018

  10. Pulmonary gas conducting interstitial pathway

    International Nuclear Information System (INIS)

    In spite of the growing efforts oriented towards revealing different aspects of emphysema, the persistence of the emphysematous or emphysema-like changes (ELCs) is not explored yet in the open literature. In this study we demonstrate the persistence of an ELC for 22 years in a spontaneous pneumothorax (SP) patient which indicates a hitherto unknown gas supply to the ELC. For this purpose we used high resolution computed tomography (HRCT) images processed into three-dimensional (3D) geometry. By the same token, not only a long persistence but also the volume increase of this ELC between 2002 and 2010 was demonstrated. The 3D geometry visualized an aerated interstitial structure between the sites of supposed gas leakage at the wall of the third generation airways and the ELC. This potential gas conducting interstitial pathway is not a continuation and has neither the form nor the structure of a bronchus. The finding suggests that in this patient the intrabronchial gas passes through the bronchial wall and via a gas conducting interstitial pathway reaches the ELC. Despite the availability of the presently employed techniques for at least 15 years, such case and phenomenon have not been described previously. The retrieval of the patient suggests that the findings could be relevant for a considerable proportion of the population

  11. Combustion kinetics and reaction pathways

    Energy Technology Data Exchange (ETDEWEB)

    Klemm, R.B.; Sutherland, J.W. [Brookhaven National Laboratory, Upton, NY (United States)

    1993-12-01

    This project is focused on the fundamental chemistry of combustion. The overall objectives are to determine rate constants for elementary reactions and to elucidate the pathways of multichannel reactions. A multitechnique approach that features three independent experiments provides unique capabilities in performing reliable kinetic measurements over an exceptionally wide range in temperature, 300 to 2500 K. Recent kinetic work has focused on experimental studies and theoretical calculations of the methane dissociation system (CH{sub 4} + Ar {yields} CH{sub 3} + H + Ar and H + CH{sub 4} {yields} CH{sub 3} + H{sub 2}). Additionally, a discharge flow-photoionization mass spectrometer (DF-PIMS) experiment is used to determine branching fractions for multichannel reactions and to measure ionization thresholds of free radicals. Thus, these photoionization experiments generate data that are relevant to both reaction pathways studies (reaction dynamics) and fundamental thermochemical research. Two distinct advantages of performing PIMS with high intensity, tunable vacuum ultraviolet light at the National Synchrotron Light Source are high detection sensitivity and exceptional selectivity in monitoring radical species.

  12. Transneuronal pathways to the vestibulocerebellum

    Science.gov (United States)

    Kaufman, G. D.; Mustari, M. J.; Miselis, R. R.; Perachio, A. A.

    1996-01-01

    The alpha-herpes virus (pseudorabies, PRV) was used to observe central nervous system (CNS) pathways associated with the vestibulocerebellar system. Retrograde transneuronal migration of alpha-herpes virions from specific lobules of the gerbil and rat vestibulo-cerebellar cortex was detected immunohistochemically. Using a time series analysis, progression of infection along polyneuronal cerebellar afferent pathways was examined. Pressure injections of > 20 nanoliters of a 10(8) plaque forming units (pfu) per ml solution of virus were sufficient to initiate an infectious locus which resulted in labeled neurons in the inferior olivary subnuclei, vestibular nuclei, and their afferent cell groups in a progressive temporal fashion and in growing complexity with increasing incubation time. We show that climbing fibers and some other cerebellar afferent fibers transported the virus retrogradely from the cerebellum within 24 hours. One to three days after cerebellar infection discrete cell groups were labeled and appropriate laterality within crossed projections was preserved. Subsequent nuclei labeled with PRV after infection of the flocculus/paraflocculus, or nodulus/uvula, included the following: vestibular (e.g., z) and inferior olivary nuclei (e.g., dorsal cap), accessory oculomotor (e.g., Darkschewitsch n.) and accessory optic related nuclei, (e.g., the nucleus of the optic tract, and the medial terminal nucleus); noradrenergic, raphe, and reticular cell groups (e.g., locus coeruleus, dorsal raphe, raphe pontis, and the lateral reticular tract); other vestibulocerebellum sites, the periaqueductal gray, substantia nigra, hippocampus, thalamus and hypothalamus, amygdala, septal nuclei, and the frontal, cingulate, entorhinal, perirhinal, and insular cortices. However, there were differences in the resulting labeling between infection in either region. Double-labeling experiments revealed that vestibular efferent neurons are located adjacent to, but are not included

  13. Post-Communist Welfare Pathways

    DEFF Research Database (Denmark)

    Cerami, Alfio; Vanhuysse, Pieter

    This collection adopts novel theoretical approaches to study the diverse welfare state pathways that have evolved across Central and Eastern Europe since the fall of communism in 1989. Going beyond existing path dependency and neo-institutionalist explanations, it highlights the role of explanatory...... factors such as micro-causal mechanisms, ideas, discourses, path departures, power politics, and elite strategies. This book includes contributions from leading international Experts such as Claus Offe, Robert Kaufman, Stefan Haggard, Tomasz Inglot, and Mitchell Orenstein, to examine welfare in specific...... lie ahead for welfare state regimes in Central and Eastern Europe. Praise and reviews “'In this conceptually-sophisticated, richly-informed volume, Cerami and Vanhuysse bring together an exceptional group of scholars to debate path dependence and institutional transformation in CEE welfare states. The...

  14. Shadows Along the Spiritual Pathway.

    Science.gov (United States)

    Humphrey, Caroline

    2015-12-01

    Contemporary spirituality discourses tend to assume that a canopy of light and love overarches all spiritual pathways. Unfortunately, the dark side of humanity cannot be spirited away so easily, and aberrations of personal spiritual development, interpersonal spiritual relationships and new spiritual movements can often be traced to the denial, repression and return of our dark side. Transpersonal psychology offers a way of approaching, reframing and redeeming the unconscious depths of our psyche, with its metaphors of shadows and daimons on the one hand, and its therapeutic practices for symbolically containing and transcending polarities on the other. In its absence, any spirituality which eulogises holistic growth is likely to engender the reverse effect. PMID:25794547

  15. [Stress and the kynurenine pathway].

    Science.gov (United States)

    Majláth, Zsófia; Vécsei, László

    2015-08-30

    The kynurenine pathway is the main route of tryptophan degradation which gives rise to several neuroactive metabolites. Kynurenic acid is an endogenous antagonist of excitatory receptors, which proved to be neuroprotective in the preclinical settings. Kynurenines have been implicated in the neuroendocrine regulatory processes. Stress induces several alterations in the kynurenine metabolism and this process may contribute to the development of stress-related pathological processes. Irritable bowel disease and gastric ulcer are well-known disorders which are related to psychiatric comorbidity and stress. In experimental conditions kynurenic acid proved to be beneficial by reducing inflammatory processes and normalizing microcirculation in the bowel. Further investigations are needed to better understand the relations of stress and the kynurenines, with the aim of developing novel therapeutic tools for stress-related pathologies. PMID:26299831

  16. Reaction pathways of propene pyrolysis.

    Science.gov (United States)

    Qu, Yena; Su, Kehe; Wang, Xin; Liu, Yan; Zeng, Qingfeng; Cheng, Laifei; Zhang, Litong

    2010-05-01

    The gas-phase reaction pathways in preparing pyrolytic carbon with propene pyrolysis have been investigated in detail with a total number of 110 transition states and 50 intermediates. The structure of the species was determined with density functional theory at B3PW91/6-311G(d,p) level. The transition states and their linked intermediates were confirmed with frequency and the intrinsic reaction coordinates analyses. The elementary reactions were explored in the pathways of both direct and the radical attacking decompositions. The energy barriers and the reaction energies were determined with accurate model chemistry method at G3(MP2) level after an examination of the nondynamic electronic correlations. The heat capacities and entropies were obtained with statistical thermodynamics. The Gibbs free energies at 298.15 K for all the reaction steps were reported. Those at any temperature can be developed with classical thermodynamics by using the fitted (as a function of temperature) heat capacities. It was found that the most favorable paths are mainly in the radical attacking chain reactions. The chain was proposed with 26 reaction steps including two steps of the initialization of the chain to produce H and CH(3) radicals. For a typical temperature (1200 K) adopted in the experiments, the highest energy barriers were found in the production of C(3) to be 203.4 and 193.7 kJ/mol. The highest energy barriers for the production of C(2) and C were found 174.1 and 181.4 kJ/mol, respectively. These results are comparable with the most recent experimental observation of the apparent activation energy 201.9 +/- 0.6 or 137 +/- 25 kJ/mol. PMID:20082392

  17. Pathway-Based Functional Analysis of Metagenomes

    Science.gov (United States)

    Bercovici, Sivan; Sharon, Itai; Pinter, Ron Y.; Shlomi, Tomer

    Metagenomic data enables the study of microbes and viruses through their DNA as retrieved directly from the environment in which they live. Functional analysis of metagenomes explores the abundance of gene families, pathways, and systems, rather than their taxonomy. Through such analysis researchers are able to identify those functional capabilities most important to organisms in the examined environment. Recently, a statistical framework for the functional analysis of metagenomes was described that focuses on gene families. Here we describe two pathway level computational models for functional analysis that take into account important, yet unaddressed issues such as pathway size, gene length and overlap in gene content among pathways. We test our models over carefully designed simulated data and propose novel approaches for performance evaluation. Our models significantly improve over current approach with respect to pathway ranking and the computations of relative abundance of pathways in environments.

  18. Stochasticity in the yeast mating pathway

    International Nuclear Information System (INIS)

    We report stochastic simulations of the yeast mating signal transduction pathway. The effects of intrinsic and external noise, the influence of cell-to-cell difference in the pathway capacity, and noise propagation in the pathway have been examined. The stochastic temporal behaviour of the pathway is found to be robust to the influence of inherent fluctuations, and intrinsic noise propagates in the pathway in a uniform pattern when the yeasts are treated with pheromones of different stimulus strengths and of varied fluctuations. In agreement with recent experimental findings, extrinsic noise is found to play a more prominent role than intrinsic noise in the variability of proteins. The occurrence frequency for the reactions in the pathway are also examined and a more compact network is obtained by dropping most of the reactions of least occurrence

  19. Coherent band pathways between knots and links

    CERN Document Server

    Buck, Dorothy

    2014-01-01

    We categorise coherent band (aka nullification) pathways between knots and 2-component links. Additionally, we characterise the minimal coherent band pathways (with intermediates) between any two knots or 2-component links with small crossing number. We demonstrate these band surgeries for knots and links with small crossing number. We apply these results to place lower bounds on the minimum number of recombinant events separating DNA configurations, restrict the recombination pathways and determine chirality and/or orientation of the resulting recombinant DNA molecules.

  20. The Lectin Pathway of Complement and Biocompatibility

    DEFF Research Database (Denmark)

    Hein, Estrid; Garred, Peter

    2015-01-01

    activation, the coagulation system and the complement system. The complement system is an important part of the initial immune response and consists of fluid phase molecules in the blood stream. Three different activation pathways can initiate the complement system, the lectin, the classical and the...... been broadly documented. However, the specific role of lectin pathway and the pattern recognition molecules initiating the pathway has only been transiently investigated. Here we review the current data on the field....

  1. Driving and dementia: a clinical decision pathway

    OpenAIRE

    Carter, Kirsty; Monaghan, Sophie; O'Brien, John; Teodorczuk, Andrew; Mosimann, Urs; Taylor, John-Paul

    2014-01-01

    Objective This study aimed to develop a pathway to bring together current UK legislation, good clinical practice and appropriate management strategies that could be applied across a range of healthcare settings. Methods The pathway was constructed by a multidisciplinary clinical team based in a busy Memory Assessment Service. A process of successive iteration was used to develop the pathway, with input and refinement provided via survey and small group meetings with individuals from a wide ra...

  2. Driving and dementia: a clinical decision pathway

    OpenAIRE

    Carter, Kirsty; Monaghan, Sophie; O'Brien, John; Teodorczuk, Andrew; Mosimann, Urs Peter; Taylor, John-Paul

    2014-01-01

    OBJECTIVE This study aimed to develop a pathway to bring together current UK legislation, good clinical practice and appropriate management strategies that could be applied across a range of healthcare settings. METHODS The pathway was constructed by a multidisciplinary clinical team based in a busy Memory Assessment Service. A process of successive iteration was used to develop the pathway, with input and refinement provided via survey and small group meetings with individuals fr...

  3. Cyclic energy pathways in ecological food webs

    OpenAIRE

    B. D. Fath; Halnes, G.

    2007-01-01

    Standard ecology textbooks typically maintain that nutrients cycle, but energy flows in unidirectional chains. However, here we use a new metric that allows for the identification and quantification of cyclic energy pathways. Some of these important pathways occur due to the contribution of dead organic matter to detrital pools and those organisms that feed on them, reintroducing some of that energy back into the food web. Recognition of these cyclic energy pathways profoundly impacts many ...

  4. The metabolic pathway collection: an update.

    OpenAIRE

    Galimova, M; Goryanin, I; Gretchkin, Y; Ivanova, N.; Komarov, Y; Maltsev, N.; Mikhailova, N.; Nenashev, V; Overbeek, R; Panyushkina, E; Pronevitch, L; Selkov, E

    1997-01-01

    The Metabolic Pathway Collection from EMP is an extraction of data from the larger Enzymes and Metabolic Pathways database (EMP). This extraction has been made publicly available in the hope that others will find it useful for a variety of purposes. The original release in October 1995 contained 1814 distinct pathways. The current collection contains 2180. Metabolic reconstructions for the first completely sequenced organisms-Haemophilus influenzae,Mycoplasma genitalium,Saccharomyces cerevisi...

  5. Designing Imprint Rolls for Fluid Pathway Fabrication

    OpenAIRE

    Vijayaraghavan, Athulan; Dornfeld, David A

    2007-01-01

    This paper discusses a novel method for designing imprint rolls for the fabrication of fluid pathways. Roller imprint processes have applications in diverse areas including fuel cell manufacturing and microfluidic device fabrication. Robust design methods are required for developing imprint rolls with optimal features. In the method discussed in this paper, the rolls are designed procedurally with the fluid pathway design given as input. The pathways are decomposed into repeating features (or...

  6. Pathway-PDT: a flexible pathway analysis tool for nuclear families

    OpenAIRE

    Park, Yo Son; Schmidt, Michael; Martin, Eden R.; Pericak-Vance, Margaret A.; Chung, Ren-Hua

    2013-01-01

    Background Pathway analysis based on Genome-Wide Association Studies (GWAS) data has become popular as a secondary analysis strategy. Although many pathway analysis tools have been developed for case–control studies, there is no tool that can use all information from raw genotypes in general nuclear families. We developed Pathway-PDT, which uses the framework of Pedigree Disequilibrium Test (PDT) for general family data, to perform pathway analysis based on raw genotypes in family-based GWAS....

  7. Inconsistent pathways of household waste

    International Nuclear Information System (INIS)

    The aim of this study was to provide policy-makers and waste management planners with information about how recycling programs affect the quantities of specific materials recycled and disposed of. Two questions were addressed: which factors influence household waste generation and pathways? and how reliable are official waste data? Household waste flows were studied in 35 Swedish municipalities, and a wide variation in the amount of waste per capita was observed. When evaluating the effect of different waste collection policies, it was found to be important to identify site-specific factors influencing waste generation. Eleven municipal variables were investigated in an attempt to explain the variation. The amount of household waste per resident was higher in populous municipalities and when net commuting was positive. Property-close collection of dry recyclables led to increased delivery of sorted metal, plastic and paper packaging. No difference was seen in the amount of separated recyclables per capita when weight-based billing for the collection of residual waste was applied, but the amount of residual waste was lower. Sixteen sources of error in official waste statistics were identified and the results of the study emphasize the importance of reliable waste generation and composition data to underpin waste management policies.

  8. Glycosyltransferase efficiently controls phenylpropanoid pathway

    Directory of Open Access Journals (Sweden)

    Kulma Anna

    2008-03-01

    Full Text Available Abstract Background In a previous study, anthocyanin levels in potato plants were increased by manipulating genes connected with the flavonoid biosynthesis pathway. However, starch content and tuber yield were dramatically reduced in the transgenic plants, which over-expressed dihydroflavonol reductase (DFR. Results Transgenic plants over-expressing dihydroflavonol reductase (DFR were subsequently transformed with the cDNA coding for the glycosyltransferase (UGT of Solanum sogarandinum in order to obtain plants with a high anthocyanin content without reducing tuber yield and quality. Based on enzyme studies, the recombinant UGT is a 7-O-glycosyltransferase whose natural substrates include both anthocyanidins and flavonols such as kaempferol and quercetin. In the super-transformed plants, tuber production was much higher than in the original transgenic plants bearing only the transgene coding for DFR, and was almost the same as in the control plants. The anthocyanin level was lower than in the initial plants, but still higher than in the control plants. Unexpectedly, the super-transformed plants also produced large amounts of kaempferol, chlorogenic acid, isochlorogenic acid, sinapic acid and proanthocyanins. Conclusion In plants over-expressing both the transgene for DFR and the transgene for UGT, the synthesis of phenolic acids was diverted away from the anthocyanin branch. This represents a novel approach to manipulating phenolic acids synthesis in plants.

  9. Nicotinic receptors in addiction pathways.

    Science.gov (United States)

    Leslie, Frances M; Mojica, Celina Y; Reynaga, Daisy D

    2013-04-01

    Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that consist of pentameric combinations of α and β subunits. These receptors are widely distributed throughout the brain and are highly expressed in addiction circuitry. The role of nAChRs in regulating neuronal activity and motivated behavior is complex and varies both in and among brain regions. The rich diversity of central nAChRs has hampered the characterization of their structure and function with use of classic pharmacological techniques. However, recent molecular approaches using null mutant mice with specific regional lentiviral re-expression, in combination with neuroanatomical and electrophysiological techniques, have allowed the elucidation of the influence of different nAChR types on neuronal circuit activity and behavior. This review will address the influence of nAChRs on limbic dopamine circuitry and the medial habenula-interpeduncular nucleus complex, which are critical mediators of reinforced behavior. Characterization of the mechanisms underlying regulation of addiction pathways by endogenous cholinergic transmission and by nicotine may lead to the identification of new therapeutic targets for treating tobacco dependence and other addictions. PMID:23247824

  10. Racial discrimination & health: pathways & evidence.

    Science.gov (United States)

    Ahmed, Ameena T; Mohammed, Selina A; Williams, David R

    2007-10-01

    This review provides an overview of the existing empirical research of the multiple ways by which discrimination can affect health. Institutional mechanisms of discrimination such as restricting marginalized groups to live in undesirable residential areas can have deleterious health consequences by limiting socio-economic status (SES) and creating health-damaging conditions in residential environments. Discrimination can also adversely affect health through restricting access to desirable services such as medical care and creating elevated exposure to traditional stressors such as unemployment and financial strain. Central to racism is an ideology of inferiority that can adversely affect non-dominant groups because some members of marginalized populations will accept as true the dominant society's ideology of their group's inferiority. Limited empirical research indicates that internalized racism is inversely related to health. In addition, the existence of these negative stereotypes can lead dominant group members to consciously and unconsciously discriminate against the stigmatized. An overview of the growing body of research examining the ways in which psychosocial stress generated by subjective experiences of discrimination can affect health is also provided. We review the evidence from the United States and other societies that suggest that the subjective experience of discrimination can adversely affect health and health enhancing behaviours. Advancing our understanding of the relationship between discrimination and health requires improved assessment of the phenomenon of discrimination and increased attention to identifying the psychosocial and biological pathways that may link exposure to discrimination to health status. PMID:18032807

  11. DMPD: Pathways connecting inflammation and cancer. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18325755 Pathways connecting inflammation and cancer. Allavena P, Garlanda C, Borre...llo MG, Sica A, Mantovani A. Curr Opin Genet Dev. 2008 Feb;18(1):3-10. Epub 2008 Mar 5. (.png) (.svg) (.html) (.csml) Show Pathways... connecting inflammation and cancer. PubmedID 18325755 Title Pathways connecting infl

  12. DMPD: LPS/TLR4 signal transduction pathway. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18304834 LPS/TLR4 signal transduction pathway. Lu YC, Yeh WC, Ohashi PS. Cytokine. ...2008 May;42(2):145-51. Epub 2008 Mar 4. (.png) (.svg) (.html) (.csml) Show LPS/TLR4 signal transduction path...way. PubmedID 18304834 Title LPS/TLR4 signal transduction pathway. Authors Lu YC, Yeh WC, Ohashi PS. Publica

  13. DMPD: Regulation of mitochondrial antiviral signaling pathways. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18549796 Regulation of mitochondrial antiviral signaling pathways. Moore CB, Ting J...P. Immunity. 2008 Jun;28(6):735-9. (.png) (.svg) (.html) (.csml) Show Regulation of mitochondrial antiviral ...signaling pathways. PubmedID 18549796 Title Regulation of mitochondrial antiviral signaling pathways. Author

  14. DMPD: Signaling pathways activated by microorganisms. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17303405 Signaling pathways activated by microorganisms. Takeuchi O, Akira S. Curr ...Opin Cell Biol. 2007 Apr;19(2):185-91. Epub 2007 Feb 15. (.png) (.svg) (.html) (.csml) Show Signaling pathwa...ys activated by microorganisms. PubmedID 17303405 Title Signaling pathways activated by microorganisms. Auth

  15. DMPD: Parallel pathways of virus recognition. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 16713969 Parallel pathways of virus recognition. Tenoever BR, Maniatis T. Immunity.... 2006 May;24(5):510-2. (.png) (.svg) (.html) (.csml) Show Parallel pathways of virus recognition. PubmedID 1...6713969 Title Parallel pathways of virus recognition. Authors Tenoever BR, Maniatis T. Publication Immunity.

  16. DMPD: All is not Toll: new pathways in DNA recognition. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 16446382 All is not Toll: new pathways in DNA recognition. Wagner H, Bauer S. J Exp... Med. 2006 Feb 20;203(2):265-8. Epub 2006 Jan 30. (.png) (.svg) (.html) (.csml) Show All is not Toll: new pa...thways in DNA recognition. PubmedID 16446382 Title All is not Toll: new pathways in DNA recognition. Authors

  17. Modeling biochemical pathways in the gene ontology.

    Science.gov (United States)

    Hill, David P; D'Eustachio, Peter; Berardini, Tanya Z; Mungall, Christopher J; Renedo, Nikolai; Blake, Judith A

    2016-01-01

    The concept of a biological pathway, an ordered sequence of molecular transformations, is used to collect and represent molecular knowledge for a broad span of organismal biology. Representations of biomedical pathways typically are rich but idiosyncratic presentations of organized knowledge about individual pathways. Meanwhile, biomedical ontologies and associated annotation files are powerful tools that organize molecular information in a logically rigorous form to support computational analysis. The Gene Ontology (GO), representing Molecular Functions, Biological Processes and Cellular Components, incorporates many aspects of biological pathways within its ontological representations. Here we present a methodology for extending and refining the classes in the GO for more comprehensive, consistent and integrated representation of pathways, leveraging knowledge embedded in current pathway representations such as those in the Reactome Knowledgebase and MetaCyc. With carbohydrate metabolic pathways as a use case, we discuss how our representation supports the integration of variant pathway classes into a unified ontological structure that can be used for data comparison and analysis. PMID:27589964

  18. Insight Projects: PATHway and Replay overview

    OpenAIRE

    Monaghan, David; Walsh, Deirdre; Ahmadi, Amin

    2015-01-01

    An overview of current projects within Insight presented during the Insight Summer Research Event, including PATHway: Technology enabled behavioural change as a pathway towards better self-management of CVD and RePLAY: Digitally Capturing Unique skills in European Traditional Sports and Games.

  19. Women's Work Pathways Across the Life Course.

    Science.gov (United States)

    Damaske, Sarah; Frech, Adrianne

    2016-04-01

    Despite numerous changes in women's employment in the latter half of the twentieth century, women's employment continues to be uneven and stalled. Drawing from data on women's weekly work hours in the National Longitudinal Survey of Youth (NLSY79), we identify significant inequality in women's labor force experiences across adulthood. We find two pathways of stable full-time work for women, three pathways of part-time employment, and a pathway of unpaid labor. A majority of women follow one of the two full-time work pathways, while fewer than 10% follow a pathway of unpaid labor. Our findings provide evidence of the lasting influence of work-family conflict and early socioeconomic advantages and disadvantages on women's work pathways. Indeed, race, poverty, educational attainment, and early family characteristics significantly shaped women's work careers. Work-family opportunities and constraints also were related to women's work hours, as were a woman's gendered beliefs and expectations. We conclude that women's employment pathways are a product of both their resources and changing social environment as well as individual agency. Significantly, we point to social stratification, gender ideologies, and work-family constraints, all working in concert, as key explanations for how women are "tracked" onto work pathways from an early age. PMID:27001314

  20. Fuel Pathway Integration Technical Team Roadmap

    Energy Technology Data Exchange (ETDEWEB)

    None

    2013-06-01

    The Fuel Pathway Integration Technical Team (FPITT) supports the U.S. DRIVE Partnership (the Partnership) in the identification and evaluation of implementation scenarios for fuel cell technology pathways, including hydrogen and fuel cell electric vehicles in the transportation sector, both during a transition period and in the long term.

  1. A brain cancer pathway in clinical practice

    DEFF Research Database (Denmark)

    Laursen, Emilie Lund; Rasmussen, Birthe Krogh

    2012-01-01

    Danish healthcare seeks to improve cancer survival through improved diagnostics, rapid treatment and increased focus on cancer prevention and early help-seeking. In neuro-oncology, this has resulted in the Integrated Brain Cancer Pathway (IBCP). The paper explores how the pathway works in the...

  2. Calcium influx pathways in rat pancreatic ducts

    DEFF Research Database (Denmark)

    Hug, M J; Pahl, C; Novak, I

    1996-01-01

    A number of agonists increase intracellular Ca2+ activity, [Ca2+]i, in pancreatic ducts, but the influx/efflux pathways and intracellular Ca2+ stores in this epithelium are unknown. The aim of the present study was to characterise the Ca2+ influx pathways, especially their pH sensitivity, in nati...

  3. Wood ethanol and synthetic natural gas pathways

    International Nuclear Information System (INIS)

    This report provided details of updates to the wood ethanol pathway recently added to the GHGenius model, an analytical tool used to analyze emissions from conventional and alternative fuel combustion processes. The pathway contains data developed by the United States Department of Energy. A number of co-products were added to the wood and agricultural residue pathways, including furfural, xylitol, lignin, and glycerol. New chemical inputs included nitrogen gas, ammonia, enzymes and yeast. Biological ethanol pathways were reviewed, and separate inputs for wood, agricultural residues, corn ethanol, and wheat ethanol were added. The model was updated to reflect current research conducted on the gasification of wood and the upgrading of the gas to produce pipeline quality natural gas. New process developments in producing pipeline quality gas from coal were also added. The ability to model enzyme consumption was added to all ethanol pathways. 25 refs., 41 tabs., 8 figs

  4. Wood ethanol and synthetic natural gas pathways

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2006-11-30

    This report provided details of updates to the wood ethanol pathway recently added to the GHGenius model, an analytical tool used to analyze emissions from conventional and alternative fuel combustion processes. The pathway contains data developed by the United States Department of Energy. A number of co-products were added to the wood and agricultural residue pathways, including furfural, xylitol, lignin, and glycerol. New chemical inputs included nitrogen gas, ammonia, enzymes and yeast. Biological ethanol pathways were reviewed, and separate inputs for wood, agricultural residues, corn ethanol, and wheat ethanol were added. The model was updated to reflect current research conducted on the gasification of wood and the upgrading of the gas to produce pipeline quality natural gas. New process developments in producing pipeline quality gas from coal were also added. The ability to model enzyme consumption was added to all ethanol pathways. 25 refs., 41 tabs., 8 figs.

  5. The metabolic pathway collection: an update.

    Science.gov (United States)

    Selkov, E; Galimova, M; Goryanin, I; Gretchkin, Y; Ivanova, N; Komarov, Y; Maltsev, N; Mikhailova, N; Nenashev, V; Overbeek, R; Panyushkina, E; Pronevitch, L; Selkov, E

    1997-01-01

    The Metabolic Pathway Collection from EMP is an extraction of data from the larger Enzymes and Metabolic Pathways database (EMP). This extraction has been made publicly available in the hope that others will find it useful for a variety of purposes. The original release in October 1995 contained 1814 distinct pathways. The current collection contains 2180. Metabolic reconstructions for the first completely sequenced organisms-Haemophilus influenzae,Mycoplasma genitalium,Saccharomyces cerevisiaeandMethanococcus janaschii-are all included in the current release. All of the pathways in the collections are available as ASCII files in the form generated by the main curator, Evgeni Selkov. In addition, we are offering a more structured encoding of a subset of the collection; our initial release of this subcollection includes all of the pathways inMycoplasma genitalium, and we ultimately intend to offer the entire collection in this form as well. PMID:9016500

  6. Pathway Analysis Incorporating Protein-Protein Interaction Networks Identified Candidate Pathways for the Seven Common Diseases.

    Science.gov (United States)

    Lin, Peng-Lin; Yu, Ya-Wen; Chung, Ren-Hua

    2016-01-01

    Pathway analysis has become popular as a secondary analysis strategy for genome-wide association studies (GWAS). Most of the current pathway analysis methods aggregate signals from the main effects of single nucleotide polymorphisms (SNPs) in genes within a pathway without considering the effects of gene-gene interactions. However, gene-gene interactions can also have critical effects on complex diseases. Protein-protein interaction (PPI) networks have been used to define gene pairs for the gene-gene interaction tests. Incorporating the PPI information to define gene pairs for interaction tests within pathways can increase the power for pathway-based association tests. We propose a pathway association test, which aggregates the interaction signals in PPI networks within a pathway, for GWAS with case-control samples. Gene size is properly considered in the test so that genes do not contribute more to the test statistic simply due to their size. Simulation studies were performed to verify that the method is a valid test and can have more power than other pathway association tests in the presence of gene-gene interactions within a pathway under different scenarios. We applied the test to the Wellcome Trust Case Control Consortium GWAS datasets for seven common diseases. The most significant pathway is the chaperones modulate interferon signaling pathway for Crohn's disease (p-value = 0.0003). The pathway modulates interferon gamma, which induces the JAK/STAT pathway that is involved in Crohn's disease. Several other pathways that have functional implications for the seven diseases were also identified. The proposed test based on gene-gene interaction signals in PPI networks can be used as a complementary tool to the current existing pathway analysis methods focusing on main effects of genes. An efficient software implementing the method is freely available at http://puppi.sourceforge.net. PMID:27622767

  7. AlzPathway: a comprehensive map of signaling pathways of Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Mizuno Satoshi

    2012-05-01

    Full Text Available Abstract Background Alzheimer’s disease (AD is the most common cause of dementia among the elderly. To clarify pathogenesis of AD, thousands of reports have been accumulating. However, knowledge of signaling pathways in the field of AD has not been compiled as a database before. Description Here, we have constructed a publicly available pathway map called “AlzPathway” that comprehensively catalogs signaling pathways in the field of AD. We have collected and manually curated over 100 review articles related to AD, and have built an AD pathway map using CellDesigner. AlzPathway is currently composed of 1347 molecules and 1070 reactions in neuron, brain blood barrier, presynaptic, postsynaptic, astrocyte, and microglial cells and their cellular localizations. AlzPathway is available as both the SBML (Systems Biology Markup Language map for CellDesigner and the high resolution image map. AlzPathway is also available as a web service (online map based on Payao system, a community-based, collaborative web service platform for pathway model curation, enabling continuous updates by AD researchers. Conclusions AlzPathway is the first comprehensive map of intra, inter and extra cellular AD signaling pathways which can enable mechanistic deciphering of AD pathogenesis. The AlzPathway map is accessible at http://alzpathway.org/.

  8. Brain evolution by brain pathway duplication.

    Science.gov (United States)

    Chakraborty, Mukta; Jarvis, Erich D

    2015-12-19

    Understanding the mechanisms of evolution of brain pathways for complex behaviours is still in its infancy. Making further advances requires a deeper understanding of brain homologies, novelties and analogies. It also requires an understanding of how adaptive genetic modifications lead to restructuring of the brain. Recent advances in genomic and molecular biology techniques applied to brain research have provided exciting insights into how complex behaviours are shaped by selection of novel brain pathways and functions of the nervous system. Here, we review and further develop some insights to a new hypothesis on one mechanism that may contribute to nervous system evolution, in particular by brain pathway duplication. Like gene duplication, we propose that whole brain pathways can duplicate and the duplicated pathway diverge to take on new functions. We suggest that one mechanism of brain pathway duplication could be through gene duplication, although other mechanisms are possible. We focus on brain pathways for vocal learning and spoken language in song-learning birds and humans as example systems. This view presents a new framework for future research in our understanding of brain evolution and novel behavioural traits. PMID:26554045

  9. The Wnt pathway: emerging anticancer strategies.

    Science.gov (United States)

    Gupta, Aman; Verma, Anukriti; Mishra, Ashutosh K; Wadhwa, Gulshan; Sharma, Sanjeev K; Jain, Chakresh K

    2013-05-01

    The canonical Wnt cascade has emerged as a critical regulator of cancer cells. Activation of the Wnt signaling pathway has also been associated with stem cell, thus raising the possibility of its role in embryogenesis and in the proliferation of malignant cancer cells. Wnt pathway has been reported to be involved in normal physiological processes in adult animals and integrally associated with cancer cell growth and maintenance, thus has been harnessed to devise strategies for anticancer therapy. The presence or absence of some members in this pathway, such as β-catenin, Axin or APC, has been found to involve in different types of tumors in human beings. Dysregulation of the canonical Wnt/β-catenin signaling pathway, mostly by inactivating mutations of the APC tumor suppressor, or oncogenic mutations of β-catenin, has been implicated in colorectal tumorigenesis. Further, elevated levels of β-catenin protein, a hallmark of activated canonical Wnt pathway, have been significantly observed in common forms of human malignancies, indicating that activation of the Wnt pathway may play an important role in tumor development and hence could be a crucial consideration for drug development. The paper discusses the potential therapeutic and diagnostic strategies directing on Wnt pathways on the basis of recent patents and their analysis. PMID:23432158

  10. Pathways of Cl- transport in human fibroblasts

    International Nuclear Information System (INIS)

    Three pathways of Cl- efflux were identified in normal human fibroblasts. Twenty percent of the total Cl- efflux is via an electrically conductive pathway with an efflux constant of 0.016 min-1. This pathway is insensitive to 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) and bumetanide but is partially inhibited by anthracene-9-carboxylic acid. Twenty-five percent of the Cl- efflux occurs via Cl- with cation cotransport having an efflux constant of 0.020 min-1. This pathway is inhibited by bumetanide and is dependent on the simultaneous presence of Na+, K+, and Cl-. Under basal conditions, the energetics of this pathway indicate that it is operating close to equilibrium. Fifty percent of the Cl- efflux occurs via an anion exchange pathway having an efflux constant of 0.040 min-1 that is inhibited by DIDS or by removal of Cl- from the extracellular medium. Together these pathways account for 95% of the total Cl- efflux

  11. Dysregulation of the mevalonate pathway promotes transformation

    Science.gov (United States)

    Clendening, James W.; Pandyra, Aleks; Boutros, Paul C.; Ghamrasni, Samah El; Khosravi, Fereshteh; Trentin, Grace A.; Martirosyan, Anna; Hakem, Anne; Hakem, Razqallah; Jurisica, Igor; Penn, Linda Z.

    2010-01-01

    The importance of cancer metabolism has been appreciated for many years, but the intricacies of how metabolic pathways interconnect with oncogenic signaling are not fully understood. With a clear understanding of how metabolism contributes to tumorigenesis, we will be better able to integrate the targeting of these fundamental biochemical pathways into patient care. The mevalonate (MVA) pathway, paced by its rate-limiting enzyme, hydroxymethylglutaryl coenzyme A reductase (HMGCR), is required for the generation of several fundamental end-products including cholesterol and isoprenoids. Despite years of extensive research from the perspective of cardiovascular disease, the contribution of a dysregulated MVA pathway to human cancer remains largely unexplored. We address this issue directly by showing that dysregulation of the MVA pathway, achieved by ectopic expression of either full-length HMGCR or its novel splice variant, promotes transformation. Ectopic HMGCR accentuates growth of transformed and nontransformed cells under anchorage-independent conditions or as xenografts in immunocompromised mice and, importantly, cooperates with RAS to drive the transformation of primary mouse embryonic fibroblasts cells. We further explore whether the MVA pathway may play a role in the etiology of human cancers and show that high mRNA levels of HMGCR and additional MVA pathway genes correlate with poor prognosis in a meta-analysis of six microarray datasets of primary breast cancer. Taken together, our results suggest that HMGCR is a candidate metabolic oncogene and provide a molecular rationale for further exploring the statin family of HMGCR inhibitors as anticancer agents. PMID:20696928

  12. Electron Transfer Pathways in Cholesterol Synthesis.

    Science.gov (United States)

    Porter, Todd D

    2015-10-01

    Cholesterol synthesis in the endoplasmic reticulum requires electron input at multiple steps and utilizes both NADH and NADPH as the electron source. Four enzymes catalyzing five steps in the pathway require electron input: squalene monooxygenase, lanosterol demethylase, sterol 4α-methyl oxidase, and sterol C5-desaturase. The electron-donor proteins for these enzymes include cytochrome P450 reductase and the cytochrome b5 pathway. Here I review the evidence for electron donor protein requirements with these enzymes, the evidence for additional electron donor pathways, and the effect of deletion of these redox enzymes on cholesterol and lipid metabolism. PMID:26344922

  13. Cellular Signaling Pathways and Their Clinical Reflections

    Directory of Open Access Journals (Sweden)

    N. Ceren Sumer-Turanligil

    2010-06-01

    Full Text Available Cellular signaling pathways have important roles in cellular growth, differentiation, inflammatory response and apoptosis and in regulation of cellular responses under various chemical stimulators. Different proteins which belong to these pathways may be exposed to loss-of-function or gain-of-function mutations; this may lead to many clinical phenotypes including primarily cancer. In this review information about basic working principles of these pathways and diseases related to them are included. [Archives Medical Review Journal 2010; 19(3.000: 180-191

  14. Syngas Upgrading to Hydrocarbon Fuels Technology Pathway

    Energy Technology Data Exchange (ETDEWEB)

    Talmadge, M.; Biddy, M.; Dutta, A.; Jones, S.; Meyer, A.

    2013-03-01

    This technology pathway case investigates the upgrading of woody biomass derived synthesis gas (syngas) to hydrocarbon biofuels. While this specific discussion focuses on the conversion of syngas via a methanol intermediate to hydrocarbon blendstocks, there are a number of alternative conversion routes for production of hydrocarbons through a wide array of intermediates from syngas. Future work will also consider the variations to this pathway to determine the most economically viable and lowest risk conversion route. Technical barriers and key research needs have been identified that should be pursued for the syngas-to-hydrocarbon pathway to be competitive with petroleum-derived gasoline-, diesel- and jet-range hydrocarbon blendstocks.

  15. Computing folding pathways between RNA secondary structures.

    Science.gov (United States)

    Dotu, Ivan; Lorenz, William A; Van Hentenryck, Pascal; Clote, Peter

    2010-03-01

    Given an RNA sequence and two designated secondary structures A, B, we describe a new algorithm that computes a nearly optimal folding pathway from A to B. The algorithm, RNAtabupath, employs a tabu semi-greedy heuristic, known to be an effective search strategy in combinatorial optimization. Folding pathways, sometimes called routes or trajectories, are computed by RNAtabupath in a fraction of the time required by the barriers program of Vienna RNA Package. We benchmark RNAtabupath with other algorithms to compute low energy folding pathways between experimentally known structures of several conformational switches. The RNApathfinder web server, source code for algorithms to compute and analyze pathways and supplementary data are available at http://bioinformatics.bc.edu/clotelab/RNApathfinder. PMID:20044352

  16. Cholangiocarcinoma: molecular pathways and therapeutic opportunities.

    Science.gov (United States)

    Rizvi, Sumera; Borad, Mitesh J; Patel, Tushar; Gores, Gregory J

    2014-11-01

    Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy with limited treatment options and low survival rates. Currently, there are no curative medical therapies for CCA. Recent advances have enhanced our understanding of the genetic basis of this disease, and elucidated therapeutically relevant targets. Therapeutic efforts in development are directed at several key pathways due to genetic aberrations including receptor tyrosine kinase pathways, mutant IDH enzymes, the PI3K-AKT-mTOR pathway, and chromatin remodeling networks. A highly desmoplastic, hypovascular stroma is characteristic of CCAs and recent work has highlighted the importance of targeting this pathway via stromal myofibroblast depletion. Future efforts should concentrate on combination therapies with action against the cancer cell and the surrounding tumor stroma. As the mutational landscape of CCA is being illuminated, molecular profiling of patient tumors will enable identification of specific mutations and the opportunity to offer directed, personalized treatment options. PMID:25369307

  17. Imaging the Visual Pathway in Neuromyelitis Optica

    Directory of Open Access Journals (Sweden)

    Caspar F. Pfueller

    2011-01-01

    Full Text Available The focus of this paper is to summarize the current knowledge on visual pathway damage in neuromyelitis optica (NMO assessed by magnetic resonance imaging (MRI and optical coherence tomography (OCT.

  18. Clinical implications of hedgehog signaling pathway inhibitors

    Institute of Scientific and Technical Information of China (English)

    Hailan Liu; Dongsheng Gu; Jingwu Xie

    2011-01-01

    Hedgehog was first described in Drosophila melanogaster by the Nobel laureates Eric Wieschaus and Christiane Nusslein-Volhard. The hedgehog (Hh) pathway is a major regulator of cell differentiation,proliferation, tissue polarity, stem cell maintenance, and carcinogenesis. The first link of Hh signaling to cancer was established through studies of a rare familial disease, Gorlin syndrome, in 1996. Follow-up studies revealed activation of this pathway in basal cell carcinoma, medulloblastoma and, leukemia as well as in gastrointestinal, lung, ovarian, breast, and prostate cancer. Targeted inhibition of Hh signaling is now believed to be effective in the treatment and prevention of human cancer. The discovery and synthesis of specific inhibitors for this pathway are even more exciting. In this review, we summarize major advances in the understanding of Hh signaling pathway activation in human cancer, mouse models for studying Hhmediated carcinogenesis, the roles of Hh signaling in tumor development and metastasis, antagonists for Hh signaling and their clinical implications.

  19. The mevalonate pathway in C. Elegans

    Directory of Open Access Journals (Sweden)

    Rauthan Manish

    2011-12-01

    Full Text Available Abstract The mevalonate pathway in human is responsible for the synthesis of cholesterol and other important biomolecules such as coenzyme Q, dolichols and isoprenoids. These molecules are required in the cell for functions ranging from signaling to membrane integrity, protein prenylation and glycosylation, and energy homeostasis. The pathway consists of a main trunk followed by sub-branches that synthesize the different biomolecules. The majority of our knowledge about the mevalonate pathway is currently focused on the cholesterol synthesis branch, which is the target of the cholesterol-lowering statins; less is known about the function and regulation of the non-cholesterol-related branches. To study them, we need a biological system where it is possible to specifically modulate these metabolic branches individually or in groups. The nematode Caenorhabditis elegans (C. elegans is a promising model to study these non-cholesterol branches since its mevalonate pathway seems very well conserved with that in human except that it has no cholesterol synthesis branch. The simple genetic makeup and tractability of C. elegans makes it relatively easy to identify and manipulate key genetic components of the mevalonate pathway, and to evaluate the consequences of tampering with their activity. This general experimental approach should lead to new insights into the physiological roles of the non-cholesterol part of the mevalonate pathway. This review will focus on the current knowledge related to the mevalonate pathway in C. elegans and its possible applications as a model organism to study the non-cholesterol functions of this pathway.

  20. The Evolution of Fungal Metabolic Pathways

    OpenAIRE

    Wisecaver, Jennifer H.; Slot, Jason C.; Rokas, Antonis

    2014-01-01

    Fungi contain a remarkable range of metabolic pathways, sometimes encoded by gene clusters, enabling them to digest most organic matter and synthesize an array of potent small molecules. Although metabolism is fundamental to the fungal lifestyle, we still know little about how major evolutionary processes, such as gene duplication (GD) and horizontal gene transfer (HGT), have interacted with clustered and non-clustered fungal metabolic pathways to give rise to this metabolic versatility. We e...

  1. Sorting pathways of mitochondrial inner membrane proteins

    OpenAIRE

    Mahlke, Kerstin; Pfanner, Nikolaus; Martin, Jörg; Horwich, Arthur; Hartl, Franz-Ulrich; Neupert, Walter

    1990-01-01

    Two distinct pathways of sorting and assembly of nuclear-encoded mitochondrial inner membrane proteins are described. In the first pathway, precursor proteins that carry amino-terminal targeting signals are initially translocated via contact sites between both mitochondrial membranes into the mitochondrial matrix. They become proteolytically processed, interact with the 60-kDa heat-shock protein hsp60 in the matrix and are retranslocated to the inner membrane. The sorting of subunit 9 of Neur...

  2. The Kynurenine Pathway in Stem Cell Biology

    OpenAIRE

    Jones, Simon P; Guillemin, Gilles J; Bruce J Brew

    2013-01-01

    The kynurenine pathway (KP) is the main catabolic pathway of the essential amino acid tryptophan. The KP has been identified to play a critical role in regulating immune responses in a variety of experimental settings. It is also known to be involved in several neuroinflammatory diseases including Huntington’s disease, amyotrophic lateral sclerosis, and Alzheimer’s disease. This review considers the current understanding of the role of the KP in stem cell biology. Both of these fundamental ar...

  3. Notch Signaling Pathway and Human Placenta

    OpenAIRE

    Wei-Xiu Zhao, Jian-Hua Lin

    2012-01-01

    Notch signaling was evolutionarily conserved and critical for cell-fate determination, differentiation and many other biological processes. Growing evidences suggested that Notch signaling pathway played an important role in the mammalian placental development. All of the mammalian Notch family proteins had been identified in human placenta except Delta-like 3, which appeared to affect the axial skeletal system. However the molecular mechanisms that regulated the Notch signaling pathway remai...

  4. A More Flexible Lipoprotein Sorting Pathway

    OpenAIRE

    Chahales, Peter; Thanassi, David G.

    2015-01-01

    Lipoprotein biogenesis in Gram-negative bacteria occurs by a conserved pathway, each step of which is considered essential. In contrast to this model, LoVullo and colleagues demonstrate that the N-acyl transferase Lnt is not required in Francisella tularensis or Neisseria gonorrhoeae. This suggests the existence of a more flexible lipoprotein pathway, likely due to a modified Lol transporter complex, and raises the possibility that pathogens may regulate lipoprotein processing to modulate int...

  5. A shared pathway among supraventricular tachycardias

    Directory of Open Access Journals (Sweden)

    Moghaddam M

    1995-07-01

    Full Text Available AVNRT, (Atrioventricular nodal reentry tachycardia, atrial tachycardia and atrial flutter are 3 kinds of supraventricular tachycardia, which their mechanism are explained based on reentry. A 60-years-old man is presented with all of the above-mentioned arrhythmias, responsive to intravenous injection of adenosine. Radiofrequency ablation of the slow pathway territories cured all of them. Therefore, we suggest that there was a common pathway among all kinds of these arrhythmias, which were ablated with single RF lesion.

  6. Signaling pathways regulating murine pancreatic development

    DEFF Research Database (Denmark)

    Serup, Palle

    2012-01-01

    The recent decades have seen a huge expansion in our knowledge about pancreatic development. Numerous lineage-restricted transcription factor genes have been identified and much has been learned about their function. Similarly, numerous signaling pathways important for pancreas development have...... been identified and the specific roles have been investigated by genetic and cell biological methods. The present review presents an overview of the principal signaling pathways involved in regulating murine pancreatic growth, morphogenesis, and cell differentiation....

  7. Precursors of Young Women's Family Formation Pathways

    OpenAIRE

    Amato, Paul R.; Landale, Nancy S.; Havasevich, Tara C.; Booth, Alan; Eggebeen, David J.; Schoen, Robert; McHale, Susan M.

    2008-01-01

    We used latent class analysis to create family formation pathways for women between the ages of 18 and 23. Input variables included cohabitation, marriage, parenthood, full-time employment, and attending school. Data (n = 2,290) came from Waves I and III of the National Longitudinal Study of Adolescent Health (Add Health). The analysis revealed seven latent pathways: college-no family formation (29%), high school-no family formation (19%), cohabitation without children (15%), married mothers ...

  8. A more flexible lipoprotein sorting pathway.

    Science.gov (United States)

    Chahales, Peter; Thanassi, David G

    2015-05-01

    Lipoprotein biogenesis in Gram-negative bacteria occurs by a conserved pathway, each step of which is considered essential. In contrast to this model, LoVullo and colleagues demonstrate that the N-acyl transferase Lnt is not required in Francisella tularensis or Neisseria gonorrhoeae. This suggests the existence of a more flexible lipoprotein pathway, likely due to a modified Lol transporter complex, and raises the possibility that pathogens may regulate lipoprotein processing to modulate interactions with the host. PMID:25755190

  9. Advances in Targeting Signal Transduction Pathways

    OpenAIRE

    McCubrey, James A.; Steelman, Linda S.; Chappell, William H.; Sun, Lin; Davis, Nicole M.; Abrams, Stephen L.; Franklin, Richard A.; Cocco, Lucio; Evangelisti, Camilla; Chiarini, Francesca; Martelli, Alberto M.; Libra, Massimo; Candido, Saverio; Ligresti, Giovanni; Malaponte, Grazia

    2012-01-01

    Over the past few years, significant advances have occurred in both our understanding of the complexity of signal transduction pathways as well as the isolation of specific inhibitors which target key components in those pathways. Furthermore critical information is being accrued regarding how genetic mutations can affect the sensitivity of various types of patients to targeted therapy. Finally, genetic mechanisms responsible for the development of resistance after targeted therapy are being ...

  10. Lysosome: regulator of lipid degradation pathways

    OpenAIRE

    Settembre, Carmine; Ballabio, Andrea

    2014-01-01

    Autophagy is a catabolic pathway that has a fundamental role in the adaptation to fasting and primarily relies on the activity of the endolysosomal system, to which the autophagosome targets substrates for degradation. Recent studies have revealed that the lysosomal–autophagic pathway plays an important part in the early steps of lipid degradation. In this review, we discuss the transcriptional mechanisms underlying co-regulation between lysosome, autophagy, and other steps of lipid catabolis...

  11. Optic pathway degeneration in Japanese black cattle

    OpenAIRE

    Chiba, Shiori; FUNATO, Shingo; Horiuchi, Noriyuki; Matsumoto, Kotaro; Inokuma, Hisashi; FURUOKA, Hidefumi; Kobayashi, Yoshiyasu

    2014-01-01

    Degeneration of the optic pathway has been reported in various animal species including cattle. We experienced a case of bilateral optic tract degeneration characterized by severe gliosis in a Japanese black cattle without any obvious visual defects. To evaluate the significance, pathological nature and pathogenesis of the lesions, we examined the optic pathway in 60 cattle (41 Japanese black, 13 Holstein and 6 crossbreed) with or without ocular abnormalities. None of these animals had optic ...

  12. Genes and (common pathways underlying drug addiction.

    Directory of Open Access Journals (Sweden)

    Chuan-Yun Li

    2008-01-01

    Full Text Available Drug addiction is a serious worldwide problem with strong genetic and environmental influences. Different technologies have revealed a variety of genes and pathways underlying addiction; however, each individual technology can be biased and incomplete. We integrated 2,343 items of evidence from peer-reviewed publications between 1976 and 2006 linking genes and chromosome regions to addiction by single-gene strategies, microrray, proteomics, or genetic studies. We identified 1,500 human addiction-related genes and developed KARG (http://karg.cbi.pku.edu.cn, the first molecular database for addiction-related genes with extensive annotations and a friendly Web interface. We then performed a meta-analysis of 396 genes that were supported by two or more independent items of evidence to identify 18 molecular pathways that were statistically significantly enriched, covering both upstream signaling events and downstream effects. Five molecular pathways significantly enriched for all four different types of addictive drugs were identified as common pathways which may underlie shared rewarding and addictive actions, including two new ones, GnRH signaling pathway and gap junction. We connected the common pathways into a hypothetical common molecular network for addiction. We observed that fast and slow positive feedback loops were interlinked through CAMKII, which may provide clues to explain some of the irreversible features of addiction.

  13. The ectodysplasin pathway: from diseases to adaptations.

    Science.gov (United States)

    Sadier, Alexa; Viriot, Laurent; Pantalacci, Sophie; Laudet, Vincent

    2014-01-01

    The ectodysplasin (EDA) pathway, which is active during the development of ectodermal organs, including teeth, hairs, feathers, and mammary glands, and which is crucial for fine-tuning the developmental network controlling the number, size, and density of these structures, was discovered by studying human patients affected by anhidrotic/hypohidrotic ectodermal dysplasia. It comprises three main gene products: EDA, a ligand that belongs to the tumor necrosis factor (TNF)-α family, EDAR, a receptor related to the TNFα receptors, and EDARADD, a specific adaptor. This core pathway relies on downstream NF-κB pathway activation to regulate target genes. The pathway has recently been found to be associated with specific adaptations in natural populations: the magnitude of armor plates in sticklebacks and the hair structure in Asian human populations. Thus, despite its role in human disease, the EDA pathway is a 'hopeful pathway' that could allow adaptive changes in ectodermal appendages which, as specialized interfaces with the environment, are considered hot-spots of morphological evolution. PMID:24070496

  14. Neural pathways for visual speech perception

    Directory of Open Access Journals (Sweden)

    Lynne E Bernstein

    2014-12-01

    Full Text Available This paper examines the questions, what levels of speech can be perceived visually, and how is visual speech represented by the brain? Review of the literature leads to the conclusions that every level of psycholinguistic speech structure (i.e., phonetic features, phonemes, syllables, words, and prosody can be perceived visually, although individuals differ in their abilities to do so; and that there are visual modality-specific representations of speech qua speech in higher-level vision brain areas. That is, the visual system represents the modal patterns of visual speech. The suggestion that the auditory speech pathway receives and represents visual speech is examined in light of neuroimaging evidence on the auditory speech pathways. We outline the generally agreed-upon organization of the visual ventral and dorsal pathways and examine several types of visual processing that might be related to speech through those pathways, specifically, face and body, orthography, and sign language processing. In this context, we examine the visual speech processing literature, which reveals widespread diverse patterns activity in posterior temporal cortices in response to visual speech stimuli. We outline a model of the visual and auditory speech pathways and make several suggestions: (1 The visual perception of speech relies on visual pathway representations of speech qua speech. (2 A proposed site of these representations, the temporal visual speech area (TVSA has been demonstrated in posterior temporal cortex, ventral and posterior to multisensory posterior superior temporal sulcus (pSTS. (3 Given that visual speech has dynamic and configural features, its representations in feedforward visual pathways are expected to integrate these features, possibly in TVSA.

  15. Bacterial variations on the methionine salvage pathway

    Directory of Open Access Journals (Sweden)

    Haas Dieter

    2004-03-01

    Full Text Available Abstract Background The thiomethyl group of S-adenosylmethionine is often recycled as methionine from methylthioadenosine. The corresponding pathway has been unravelled in Bacillus subtilis. However methylthioadenosine is subjected to alternative degradative pathways depending on the organism. Results This work uses genome in silico analysis to propose methionine salvage pathways for Klebsiella pneumoniae, Leptospira interrogans, Thermoanaerobacter tengcongensis and Xylella fastidiosa. Experiments performed with mutants of B. subtilis and Pseudomonas aeruginosa substantiate the hypotheses proposed. The enzymes that catalyze the reactions are recruited from a variety of origins. The first, ubiquitous, enzyme of the pathway, MtnA (methylthioribose-1-phosphate isomerase, belongs to a family of proteins related to eukaryotic intiation factor 2B alpha. mtnB codes for a methylthioribulose-1-phosphate dehydratase. Two reactions follow, that of an enolase and that of a phosphatase. While in B. subtilis this is performed by two distinct polypeptides, in the other organisms analyzed here an enolase-phosphatase yields 1,2-dihydroxy-3-keto-5-methylthiopentene. In the presence of dioxygen an aci-reductone dioxygenase yields the immediate precursor of methionine, ketomethylthiobutyrate. Under some conditions this enzyme produces carbon monoxide in B. subtilis, suggesting a route for a new gaseous mediator in bacteria. Ketomethylthiobutyrate is finally transaminated by an aminotransferase that exists usually as a broad specificity enzyme (often able to transaminate aromatic aminoacid keto-acid precursors or histidinol-phosphate. Conclusion A functional methionine salvage pathway was experimentally demonstrated, for the first time, in P. aeruginosa. Apparently, methionine salvage pathways are frequent in Bacteria (and in Eukarya, with recruitment of different polypeptides to perform the needed reactions (an ancestor of a translation initiation factor and Ru

  16. Leptin signalling pathways in hypothalamic neurons.

    Science.gov (United States)

    Kwon, Obin; Kim, Ki Woo; Kim, Min-Seon

    2016-04-01

    Leptin is the most critical hormone in the homeostatic regulation of energy balance among those so far discovered. Leptin primarily acts on the neurons of the mediobasal part of hypothalamus to regulate food intake, thermogenesis, and the blood glucose level. In the hypothalamic neurons, leptin binding to the long form leptin receptors on the plasma membrane initiates multiple signaling cascades. The signaling pathways known to mediate the actions of leptin include JAK-STAT signaling, PI3K-Akt-FoxO1 signaling, SHP2-ERK signaling, AMPK signaling, and mTOR-S6K signaling. Recent evidence suggests that leptin signaling in hypothalamic neurons is also linked to primary cilia function. On the other hand, signaling molecules/pathways mitigating leptin actions in hypothalamic neurons have been extensively investigated in an effort to treat leptin resistance observed in obesity. These include SOCS3, tyrosine phosphatase PTP1B, and inflammatory signaling pathways such as IKK-NFκB and JNK signaling, and ER stress-mitochondrial signaling. In this review, we discuss leptin signaling pathways in the hypothalamus, with a particular focus on the most recently discovered pathways. PMID:26786898

  17. The intervention study of Danggui Yinzi decoction on the expression of gene and protein of AQP-3 and the content of ceramide in the posriasis vulgaris model of guinea pig%当归饮子对银屑病模型豚鼠神经酰胺含量、AQP-3基因及蛋白表达的干预研究

    Institute of Scientific and Technical Information of China (English)

    文谦; 李芳梅; 杨志波

    2016-01-01

    Objective To investigate the effect of Danggui Yinzi on the expression of AQP-3 gene and Cer protein of psoriasis model. Methods To establish an animal model of psoriasis vulgaris. The animals were divided into Danggui Yinzi group,methotrexate group,saline group,model control group and blank control group. Aquaporin 3 (AQP-3) of skin lesions part was detected with RT-PCR and Western blot methods and ELISA methods was used to detect the ceramide content of skin lesions part. Compared the results of the five groups, and the relationship of the expression changes of gene and protein in skin lesions and skin barrier function was analysed. Results The animal models of psoriasis vulgaris was successful In model control group,the content of ceramide and the expression of gene and protein of AQP-3 were all decreased significantly (P<0. 01). The expression index was increased in Danggui Yinzi group and methotrexate group and Danggui Yinzi group was increased obviously(P<0. 01). Conclusion Danggui Yinzi can enhance the expression of gene and protein of AQP-3 and the protein content of ceramide in skin lesions of psoriasis vulgaris model. It has a definite effect for skin barrier function of psoriasis vulgaris in animal model. The results indicate that the therapeutic effect is more effective than methotrexate medicine.%目的:探讨当归饮子对寻常型银屑病模型豚鼠皮肤神经酰胺( ceramide,Cer)含量、水通道蛋白3(aquaporin 3,AQP-3)基因及蛋白表达的干预影响。方法建立寻常型银屑病动物模型,分为当归饮子组、甲氨蝶呤组、生理盐水组、模型对照组、空白对照组,每组8只,酶联免疫吸附实验( ELISA)法检测造模皮损部位Cer含量,逆转录PCR( RT-PCR)和免疫印迹试验( Western blot)法检测造模皮损部位AQP-3基因及蛋白表达,分析寻常型银屑病动物模型皮损与皮肤屏障功能密切相关的基因及蛋白表达的变化。结果豚鼠耳部皮肤银屑病模型造模成功

  18. Molecular Pathways: Targeting the PI3K Pathway in Cancer-BET Inhibitors to the Rescue.

    Science.gov (United States)

    Stratikopoulos, Elias E; Parsons, Ramon E

    2016-06-01

    The PI3K signaling pathway is a complex and tightly regulated network that is critical for many physiologic processes, such as cell growth, proliferation, metabolism, and survival. Aberrant activation of this pathway can occur through mutation of almost any of its major nodes and has been implicated in a number of human diseases, including cancer. The high frequency of mutations in this pathway in multiple types of cancer has led to the development of small-molecule inhibitors of PI3K, several of which are currently in clinical trials. However, several feedback mechanisms either within the PI3K pathway or in compensatory pathways can render tumor cells resistant to therapy. Recently, targeting proteins of the bromodomain and extraterminal (BET) family of epigenetic readers of histone acetylation has been shown to effectively block adaptive signaling response of cancer cells to inhibitors of the PI3K pathway, which at least in some cases can restore sensitivity. BET inhibitors also enforce blockade of the MAPK, JAK/STAT, and ER pathways, suggesting they may be a rational combinatorial partner for divergent oncogenic signals that are subject to homeostatic regulation. Here, we review the PI3K pathway as a target for cancer therapy and discuss the potential use of BET inhibition to enhance the clinical efficacy of PI3K inhibitors. Clin Cancer Res; 22(11); 2605-10. ©2016 AACR. PMID:27250929

  19. DMPD: Signal integration between IFNgamma and TLR signalling pathways in macrophages. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 16920490 Signal integration between IFNgamma and TLR signalling pathways in macroph...ages. Schroder K, Sweet MJ, Hume DA. Immunobiology. 2006;211(6-8):511-24. Epub 2006 Jul 5. (.png) (.svg) (.html) (.csml) Show Signal... integration between IFNgamma and TLR signalling pathways in macrophages. PubmedID 16920490 Title Signal

  20. DMPD: Signalling pathways mediating type I interferon gene expression. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17904888 Signalling pathways mediating type I interferon gene expression. Edwards M...R, Slater L, Johnston SL. Microbes Infect. 2007 Sep;9(11):1245-51. Epub 2007 Jul 1. (.png) (.svg) (.html) (.csml) Show Signal...ling pathways mediating type I interferon gene expression. PubmedID 17904888 Title Signalli

  1. Exergetical Evaluation of Biobased Synthesis Pathways

    Directory of Open Access Journals (Sweden)

    Philipp Frenzel

    2014-01-01

    Full Text Available The vast majority of today’s chemical products are based on crude oil. An attractive and sustainable alternative feedstock is biomass. Since crude oil and biomass differ in various properties, new synthesis pathways and processes have to be developed. In order to prioritize limited resources for research and development (R & D, their economic potential must be estimated in the early stages of development. A suitable measure for an estimation of the economic potential is based on exergy balances. Different structures of synthesis pathways characterised by the chemical exergy of the main components are evaluated. Based on a detailed evaluation of the underlying processes, general recommendations for future bio-based synthesis pathways are derived.

  2. Reconstructing biochemical pathways from time course data.

    Science.gov (United States)

    Srividhya, Jeyaraman; Crampin, Edmund J; McSharry, Patrick E; Schnell, Santiago

    2007-03-01

    Time series data on biochemical reactions reveal transient behavior, away from chemical equilibrium, and contain information on the dynamic interactions among reacting components. However, this information can be difficult to extract using conventional analysis techniques. We present a new method to infer biochemical pathway mechanisms from time course data using a global nonlinear modeling technique to identify the elementary reaction steps which constitute the pathway. The method involves the generation of a complete dictionary of polynomial basis functions based on the law of mass action. Using these basis functions, there are two approaches to model construction, namely the general to specific and the specific to general approach. We demonstrate that our new methodology reconstructs the chemical reaction steps and connectivity of the glycolytic pathway of Lactococcus lactis from time course experimental data. PMID:17370261

  3. Evolutionary algorithm for metabolic pathways synthesis.

    Science.gov (United States)

    Gerard, Matias F; Stegmayer, Georgina; Milone, Diego H

    2016-06-01

    Metabolic pathway building is an active field of research, necessary to understand and manipulate the metabolism of organisms. There are different approaches, mainly based on classical search methods, to find linear sequences of reactions linking two compounds. However, an important limitation of these methods is the exponential increase of search trees when a large number of compounds and reactions is considered. Besides, such models do not take into account all substrates for each reaction during the search, leading to solutions that lack biological feasibility in many cases. This work proposes a new evolutionary algorithm that allows searching not only linear, but also branched metabolic pathways, formed by feasible reactions that relate multiple compounds simultaneously. Tests performed using several sets of reactions show that this algorithm is able to find feasible linear and branched metabolic pathways. PMID:27080162

  4. Pathways to deep decarbonization - 2015 report

    International Nuclear Information System (INIS)

    In September 2015, the Deep Decarbonization Pathways Project published the Executive Summary of the Pathways to Deep Decarbonization: 2015 Synthesis Report. The full 2015 Synthesis Report was launched in Paris on December 3, 2015, at a technical workshop with the Mitigation Action Plans and Scenarios (MAPS) program. The Deep Decarbonization Pathways Project (DDPP) is a collaborative initiative to understand and show how individual countries can transition to a low-carbon economy and how the world can meet the internationally agreed target of limiting the increase in global mean surface temperature to less than 2 degrees Celsius (deg. C). Achieving the 2 deg. C limit will require that global net emissions of greenhouse gases (GHG) approach zero by the second half of the century. In turn, this will require a profound transformation of energy systems by mid-century through steep declines in carbon intensity in all sectors of the economy, a transition we call 'deep decarbonization'

  5. Coinhibitory Pathways in Immunotherapy for Cancer.

    Science.gov (United States)

    Baumeister, Susanne H; Freeman, Gordon J; Dranoff, Glenn; Sharpe, Arlene H

    2016-05-20

    The immune system is capable of recognizing tumors and eliminates many early malignant cells. However, tumors evolve to evade immune attack, and the tumor microenvironment is immunosuppressive. Immune responses are regulated by a number of immunological checkpoints that promote protective immunity and maintain tolerance. T cell coinhibitory pathways restrict the strength and duration of immune responses, thereby limiting immune-mediated tissue damage, controlling resolution of inflammation, and maintaining tolerance to prevent autoimmunity. Tumors exploit these coinhibitory pathways to evade immune eradication. Blockade of the PD-1 and CTLA-4 checkpoints is proving to be an effective and durable cancer immunotherapy in a subset of patients with a variety of tumor types, and additional combinations are further improving response rates. In this review we discuss the immunoregulatory functions of coinhibitory pathways and their translation to effective immunotherapies for cancer. PMID:26927206

  6. Pathways to deep decarbonization - Interim 2014 Report

    International Nuclear Information System (INIS)

    The interim 2014 report by the Deep Decarbonization Pathways Project (DDPP), coordinated and published by IDDRI and the Sustainable Development Solutions Network (SDSN), presents preliminary findings of the pathways developed by the DDPP Country Research Teams with the objective of achieving emission reductions consistent with limiting global warming to less than 2 deg. C. The DDPP is a knowledge network comprising 15 Country Research Teams and several Partner Organizations who develop and share methods, assumptions, and findings related to deep decarbonization. Each DDPP Country Research Team has developed an illustrative road-map for the transition to a low-carbon economy, with the intent of taking into account national socio-economic conditions, development aspirations, infrastructure stocks, resource endowments, and other relevant factors. The interim 2014 report focuses on technically feasible pathways to deep decarbonization

  7. Policy Pathways: Energy Management Programmes for Industry

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2012-09-06

    The IEA Policy Pathway publications provide details on how to implement specific recommendations drawn from the IEA 25 Energy Efficiency Policy Recommendations. This Policy Pathway, jointly produced by the International Energy Agency and the Institute for Industrial Productivity, develops the critical steps for policy makers implementing energy management programmes for industry. Optimising energy use in industry is essential to improve industrial competitiveness and achieve wider societal goals such as energy security, economic recovery and development, climate change mitigation and environmental protection.While there is significant potential to decrease energy consumption in this sector, opportunities to improve energy efficiency are still under-exploited. Energy management programmes have shown to be instrumental in addressing many of the barriers that inhibit wide-scale uptake of energy management in industry. The Policy Pathway builds on lessons learned from country experiences and provides actionable guidance on how to plan and design, implement, evaluate and monitor energy management programmes for industry.

  8. Novel personalized pathway-based metabolomics models reveal key metabolic pathways for breast cancer diagnosis

    DEFF Research Database (Denmark)

    Huang, Sijia; Chong, Nicole; Lewis, Nathan;

    2016-01-01

    Background: More accurate diagnostic methods are pressingly needed to diagnose breast cancer, the most common malignant cancer in women worldwide. Blood-based metabolomics is a promising diagnostic method for breast cancer. However, many metabolic biomarkers are difficult to replicate among studies.......993. Moreover, important metabolic pathways, such as taurine and hypotaurine metabolism and the alanine, aspartate, and glutamate pathway, are revealed as critical biological pathways for early diagnosis of breast cancer. Conclusions: We have successfully developed a new type of pathway-based model to study...... metabolomics data for disease diagnosis. Applying this method to blood-based breast cancer metabolomics data, we have discovered crucial metabolic pathway signatures for breast cancer diagnosis, especially early diagnosis. Further, this modeling approach may be generalized to other omics data types for disease...

  9. Reciprocal regulation of metabolic and signaling pathways

    Directory of Open Access Journals (Sweden)

    Barth Andreas S

    2010-03-01

    Full Text Available Abstract Background By studying genome-wide expression patterns in healthy and diseased tissues across a wide range of pathophysiological conditions, DNA microarrays have revealed unique insights into complex diseases. However, the high-dimensionality of microarray data makes interpretation of heterogeneous gene expression studies inherently difficult. Results Using a large-scale analysis of more than 40 microarray studies encompassing ~2400 mammalian tissue samples, we identified a common theme across heterogeneous microarray studies evident by a robust genome-wide inverse regulation of metabolic and cell signaling pathways: We found that upregulation of cell signaling pathways was invariably accompanied by downregulation of cell metabolic transcriptional activity (and vice versa. Several findings suggest that this characteristic gene expression pattern represents a new principle of mammalian transcriptional regulation. First, this coordinated transcriptional pattern occurred in a wide variety of physiological and pathophysiological conditions and was identified across all 20 human and animal tissue types examined. Second, the differences in metabolic gene expression predicted the magnitude of differences for signaling and all other pathways, i.e. tissue samples with similar expression levels of metabolic transcripts did not show any differences in gene expression for all other pathways. Third, this transcriptional pattern predicted a profound effect on the proteome, evident by differences in structure, stability and post-translational modifications of proteins belonging to signaling and metabolic pathways, respectively. Conclusions Our data suggest that in a wide range of physiological and pathophysiological conditions, gene expression changes exhibit a recurring pattern along a transcriptional axis, characterized by an inverse regulation of major metabolic and cell signaling pathways. Given its widespread occurrence and its predicted effects

  10. Understanding trade pathways to target biosecurity surveillance

    Directory of Open Access Journals (Sweden)

    Manuel Colunga-Garcia

    2013-09-01

    Full Text Available Increasing trends in global trade make it extremely difficult to prevent the entry of all potential invasive species (IS. Establishing early detection strategies thus becomes an important part of the continuum used to reduce the introduction of invasive species. One part necessary to ensure the success of these strategies is the determination of priority survey areas based on invasion pressure. We used a pathway-centred conceptual model of pest invasion to address these questions: what role does global trade play in invasion pressure of plant ecosystems and how could an understanding of this role be used to enhance early detection strategies? We concluded that the relative level of invasion pressure for destination ecosystems can be influenced by the intensity of pathway usage (import volume and frequency, the number and type of pathways with a similar destination, and the number of different ecological regions that serve as the source for imports to the same destination. As these factors increase, pressure typically intensifies because of increasing a propagule pressure, b likelihood of transporting pests with higher intrinsic invasion potential, and c likelihood of transporting pests into ecosystems with higher invasibility. We used maritime containerized imports of live plants into the contiguous U.S. as a case study to illustrate the practical implications of the model to determine hotspot areas of relative invasion pressure for agricultural and forest ecosystems (two ecosystems with high potential invasibility. Our results illustrated the importance of how a pathway-centred model could be used to highlight potential target areas for early detection strategies for IS. Many of the hotspots in agricultural and forest ecosystems were within major U.S. metropolitan areas. Invasion ecologists can utilize pathway-centred conceptual models to a better understand the role of human-mediated pathways in pest establishment, b enhance current

  11. Interleukin 4 signals through two related pathways.

    OpenAIRE

    Pernis, A; Witthuhn, B.; Keegan, A D; Nelms, K; Garfein, E; Ihle, J N; Paul, W. E.; Pierce, J H; Rothman, P.

    1995-01-01

    The interleukin 4 (IL-4) signaling pathway involves activation, by tyrosine phosphorylation, of two distinct substrates, a signal-transducing factor (STF-IL4) and the IL-4-induced phosphotyrosine substrate (4PS). It is not known whether the IL-4-mediated activation of these substrates occurs via related or distinct signaling pathways. We report that 32D cells, an IL-3-dependent myeloid progenitor cell line in which no phosphorylated 4PS is found, activate high levels of STF-IL4 in response to...

  12. PI3K pathway in NSCLC

    Directory of Open Access Journals (Sweden)

    EnriquetaFelip

    2012-01-01

    Full Text Available The phosphatidylinositol 3-kinases (PI3Ks are members of a family of intracellular lipid kinases that phosphorylate the 3’-hydroxyl group of phosphatidylinositol and phosphoinositides. PI3K regulate signaling pathways for neoplasia, including cell proliferation, adhesion, survival and motility. Different classes of PI3K have distinct roles in cellular signal transduction. PI3K pathway is activated by several different mechanisms in cancers, including, somatic mutation and gene amplification. In this review, we examine the literature addressing PI3K mutation status and gene amplification, with an emphasis on non-small cell lung cancer (NSCLC.

  13. Intracranial pathology of the visual pathway

    Energy Technology Data Exchange (ETDEWEB)

    Mueller-Forell, W. E-mail: mueller-forell@neuroradio.klinik.uni-mainz.de

    2004-02-01

    Intracranial pathologies involving the visual pathway are manifold. Aligning to anatomy, the most frequent and/or most important extrinsic and intrinsic intracranial lesions are presented. Clinical symptoms and imaging characteristics of lesions of the sellar region are demonstrated in different imaging modalities. The extrinsic lesions mainly consist of pituitary adenomas, meningeomas, craniopharyngeomas and chordomas. In (asymptomatic and symptomatic) aneurysms, different neurological symptoms depend on the location of aneurysms of the circle of Willis. Intrinsic tumors as astrocytoma of any grade, ependymoma and primary CNS-lymphoma require the main pathology in the course of the visual pathway. Vascular and demyelinating diseases complete this overview of intracranial lesions.

  14. Simplified analysis for liquid pathway studies

    International Nuclear Information System (INIS)

    The analysis of the potential contamination of surface water via groundwater contamination from severe nuclear accidents is routinely calculated during licensing reviews. This analysis is facilitated by the methods described in this report, which is codified into a BASIC language computer program, SCREENLP. This program performs simplified calculations for groundwater and surface water transport and calculates population doses to potential users for the contaminated water irrespective of possible mitigation methods. The results are then compared to similar analyses performed using data for the generic sites in NUREG-0440, Liquid Pathway Generic Study, to determine if the site being investigated would pose any unusual liquid pathway hazards

  15. Análisis taxonómico y funcional del microbioma humano mediante aproximaciones clásicas, moleculares y metagenómicas

    OpenAIRE

    Cabrera Rubio, Raúl

    2014-01-01

    La presente tesis muestra distintas aproximaciones para el estudio del microbioma humano. Éstas han ido desde la secuenciación masiva de productos de PCR, la pirosecuenciación directa del ADN ambiental, la elaboración de librerías de fósmidos y por último el aislamiento de especies presentes en el microbioma mediante sembrado de la muestra. Todas estas técnicas tienen sus ventajas y desventajas, pero todas ellas son complementarias para el estudio de un determinado microbioma. Además la elabo...

  16. Caracterización metagenómica del moviloma plasmídico de la población bacteriana asociada a alfalfa

    OpenAIRE

    López, José Luis

    2016-01-01

    A través del tiempo las bacterias, como organismos unicelulares, han localizado eficientemente en sus pequeños genomas la información necesaria para afrontar el desafío de los cambios ambientales. En términos genéticos (informativos) las bacterias han concentrado la mayoría de las funciones basales (mantenimiento, housekeeping) en sus replicones más grandes (los cromosomas) dedicando compartimientos genéticos especiales y móviles (plásmidos, islas de ADN, transposones, integrones) para divers...

  17. MetaGen: a Promising Tool for Modeling Metabolic Networks From KEGG%MetaGen:从KEGG建模代谢网络的新工具

    Institute of Scientific and Technical Information of China (English)

    周婷婷; 容健锋; 陈振冲; 王正华; 朱云平; 贺福初

    2010-01-01

    为便于大规模代谢网络的计算,发展了一款方便实用的工具:MetaGen,对Kyoto Encyclopedia of Genes and Genomes(KEGG)中物种特异的各层次代谢系统进行建模,生成的代谢网络以酶图和通路图的方式表示.利用该工具,对人类代谢系统的bow-tie结构进行了初步研究,并以此为例展示了该工具广阔的应用前景.MetaGen利用KEGGweb服务保证建模数据的可靠性,依靠本地关系数据库加速网络建模过程并提供更多的数据管理和利用方式,并结合高级JAVA技术提高代码的可扩展性.MetaGen完全开源,可直接从http://bnct.sourceforge.net/下载.

  18. Pathways to Sexual Risk Taking Among Female Adolescent Detainees

    OpenAIRE

    Lopez, Vera; Kopak, Albert; Robillard, Alyssa; Gillmore, Mary Rogers; Holliday, Rhonda C.; Braithwaite, Ronald L.

    2010-01-01

    Sexual risk taking among female delinquents represents a significant public health problem. Research is needed to understand the pathways leading to sexual risk taking among this population. This study sought to address this issue by identifying and testing two pathways from child maltreatment to non-condom use among 329 White and 484 African American female adolescent detainees: a relational pathway and a substance use coping pathway. The relational pathway indicated that child maltreatment ...

  19. Multiple oxygen entry pathways in globin proteins revealed by intrinsic pathway identification method

    Science.gov (United States)

    Takayanagi, Masayoshi; Kurisaki, Ikuo; Nagaoka, Masataka

    2015-12-01

    Each subunit of human hemoglobin (HbA) stores an oxygen molecule (O2) in the binding site (BS) cavity near the heme group. The BS is buried in the interior of the subunit so that there is a debate over the O2 entry pathways from solvent to the BS; histidine gate or multiple pathways. To elucidate the O2 entry pathways, we executed ensemble molecular dynamics (MD) simulations of T-state tetramer HbA in high concentration O2 solvent to simulate spontaneous O2 entry from solvent into the BS. By analyzing 128 independent 8 ns MD trajectories by intrinsic pathway identification by clustering (IPIC) method, we found 141 and 425 O2 entry events into the BS of the α and β subunits, respectively. In both subunits, we found that multiple O2 entry pathways through inside cavities play a significant role for O2 entry process of HbA. The rate constants of O2 entry estimated from the MD trajectories correspond to the experimentally observed values. In addition, by analyzing monomer myoglobin, we verified that the high O2 concentration condition can reproduce the ratios of each multiple pathway in the one-tenth lower O2 concentration condition. These indicate the validity of the multiple pathways obtained in our MD simulations.

  20. Pathways to Relationship Aggression between Adult Partners

    Science.gov (United States)

    Busby, Dean M.; Holman, Thomas B.; Walker, Eric

    2008-01-01

    In this study, the pathways to adult aggression beginning in the family of origin (FOO) and continuing through adult relationships were investigated. With a sample of 30,600 individuals, a comprehensive model was evaluated that included the unique influences of violent victimization in the family, witnessing parental violence, perpetrating…

  1. Pathways to deep decarbonization in India

    DEFF Research Database (Denmark)

    Shukla, P.; Dhar, Subash; Pathak, Minal;

    This report is a part of the global Deep Decarbonisation Pathways (DDP) Project. The analysis consider two development scenarios for India and assess alternate roadmaps for transiting to a low carbon economy consistent with the globally agreed 2°C stabilization target. The report does not consider...

  2. Apoptosis signaling pathways and lymphocyte homeostasis

    Institute of Scientific and Technical Information of China (English)

    Guangwu Xu; Yufang Shi

    2007-01-01

    It has been almost three decades since the term "apoptosis" was first coined to describe a unique form of cell death that involves orderly, gene-dependent cell disintegration. It is now well accepted that apoptosis is an essential life process for metazoan animals and is critical for the formation and function of tissues and organs. In the adult mammalian body, apoptosis is especially important for proper functioning of the immune system. In recent years, along with the rapid advancement of molecular and cellular biology, great progress has been made in understanding the mechanisms leading to apoptosis. It is generally accepted that there are two major pathways of apoptotic cell death induction: extrinsic signaling through death receptors that leads to the formation of the death-inducing signaling complex (DISC), and intrinsic signaling mainly through mitochondria which leads to the formation of the apoptosome. Formation of the DISC or apoptosome, respectively, activates initiator and common effector caspases that execute the apoptosis process. In the immune system, both pathways operate; however, it is not known whether they are sufficient to maintain lymphocyte homeostasis. Recently, new apoptotic mechanisms including caspase-independent pathways and granzyme-initiated pathways have been shown to exist in lymphocytes. This review will summarize our understanding of the mechanisms that control the homeostasis of various lymphocyte populations.

  3. Regulatory pathways in the European Union.

    Science.gov (United States)

    Kohler, Manuela

    2011-01-01

    In principle, there are three defined procedures to obtain approval for a medicinal product in the European Union. As discussed in this overview of the procedures, the decision on which regulatory pathway to use will depend on the nature of the active substance, the target indication(s), the history of product and/or the marketing strategy. PMID:21487236

  4. Precursors of Young Women's Family Formation Pathways

    Science.gov (United States)

    Amato, Paul R.; Landale, Nancy S.; Havasevich-Brooks, Tara C.; Booth, Alan; Eggebeen, David J.; Schoen, Robert; McHale, Susan M.

    2008-01-01

    We used latent class analysis to create family formation pathways for women between the ages of 18 and 23. Input variables included cohabitation, marriage, parenthood, full-time employment, and attending school. Data (n = 2,290) came from Waves I and III of the National Longitudinal Study of Adolescent Health (Add Health). The analysis revealed…

  5. Final report on the Pathway Analysis Task

    Energy Technology Data Exchange (ETDEWEB)

    Whicker, F.W.; Kirchner, T.B. [Colorado State Univ., Fort Collins, CO (United States)

    1993-04-01

    The Pathway Analysis Task constituted one of several multi-laboratory efforts to estimate radiation doses to people, considering all important pathways of exposure, from the testing of nuclear devices at the Nevada Test Site (NTS). The primary goal of the Pathway Analysis Task was to predict radionuclide ingestion by residents of Utah, Nevada, and portions of seven other adjoining western states following radioactive fallout deposition from individual events at the NTS. This report provides comprehensive documentation of the activities and accomplishments of Colorado State University`s Pathway Analysis Task during the entire period of support (1979--91). The history of the project will be summarized, indicating the principal dates and milestones, personnel involved, subcontractors, and budget information. Accomplishments, both primary and auxiliary, will be summarized with general results rather than technical details being emphasized. This will also serve as a guide to the reports and open literature publications produced, where the methodological details and specific results are documented. Selected examples of results on internal dose estimates are provided in this report because the data have not been published elsewhere.

  6. Whole Algae Hydrothermal Liquefaction Technology Pathway

    Energy Technology Data Exchange (ETDEWEB)

    Biddy, M.; Davis, R.; Jones, S.

    2013-03-01

    This technology pathway case investigates the feasibility of using whole wet microalgae as a feedstock for conversion via hydrothermal liquefaction. Technical barriers and key research needs have been assessed in order for the hydrothermal liquefaction of microalgae to be competitive with petroleum-derived gasoline-, diesel-, and jet-range hydrocarbon blendstocks.

  7. Using biological pathway data with paxtools.

    Directory of Open Access Journals (Sweden)

    Emek Demir

    Full Text Available A rapidly growing corpus of formal, computable pathway information can be used to answer important biological questions including finding non-trivial connections between cellular processes, identifying significantly altered portions of the cellular network in a disease state and building predictive models that can be used for precision medicine. Due to its complexity and fragmented nature, however, working with pathway data is still difficult. We present Paxtools, a Java library that contains algorithms, software components and converters for biological pathways represented in the standard BioPAX language. Paxtools allows scientists to focus on their scientific problem by removing technical barriers to access and analyse pathway information. Paxtools can run on any platform that has a Java Runtime Environment and was tested on most modern operating systems. Paxtools is open source and is available under the Lesser GNU public license (LGPL, which allows users to freely use the code in their software systems with a requirement for attribution. Source code for the current release (4.2.0 can be found in Software S1. A detailed manual for obtaining and using Paxtools can be found in Protocol S1. The latest sources and release bundles can be obtained from biopax.org/paxtools.

  8. High salt recruits aversive taste pathways.

    Science.gov (United States)

    Oka, Yuki; Butnaru, Matthew; von Buchholtz, Lars; Ryba, Nicholas J P; Zuker, Charles S

    2013-02-28

    In the tongue, distinct classes of taste receptor cells detect the five basic tastes; sweet, sour, bitter, sodium salt and umami. Among these qualities, bitter and sour stimuli are innately aversive, whereas sweet and umami are appetitive and generally attractive to animals. By contrast, salty taste is unique in that increasing salt concentration fundamentally transforms an innately appetitive stimulus into a powerfully aversive one. This appetitive-aversive balance helps to maintain appropriate salt consumption, and represents an important part of fluid and electrolyte homeostasis. We have shown previously that the appetitive responses to NaCl are mediated by taste receptor cells expressing the epithelial sodium channel, ENaC, but the cellular substrate for salt aversion was unknown. Here we examine the cellular and molecular basis for the rejection of high concentrations of salts. We show that high salt recruits the two primary aversive taste pathways by activating the sour- and bitter-taste-sensing cells. We also demonstrate that genetic silencing of these pathways abolishes behavioural aversion to concentrated salt, without impairing salt attraction. Notably, mice devoid of salt-aversion pathways show unimpeded, continuous attraction even to very high concentrations of NaCl. We propose that the 'co-opting' of sour and bitter neural pathways evolved as a means to ensure that high levels of salt reliably trigger robust behavioural rejection, thus preventing its potentially detrimental effects on health. PMID:23407495

  9. Pathways from jobs to social cohesion

    OpenAIRE

    Wietzke, Frank-Borge

    2014-01-01

    There is growing recognition that access to good jobs is an important driver of social cohesion. While economic dimensions of labor market outcomes are relatively well documented, evidence on the link between social cohesion and jobs is still surprisingly scarce. This paper, based on an earlier background report for the WDR 2013, presents empirical evidence for pathways between labor marke...

  10. Air Research Program: Key Pathways research track

    Science.gov (United States)

    The pathways research track applies animal, cellular, and human studies to discern whether there is a common molecular mechanism (e.g. production of oxidative stress, phosphatase inhibition, disruption of iron homeostasis) through which air pollutants induce toxicity of air pollu...

  11. Policy Pathways: Energy Performance Certification of Buildings

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2010-07-01

    Improving energy efficiency is one of the most effective measures to address energy security, climate change and economic objectives. The Policy Pathways series can help countries capture this potential by assisting with the implementation of the 25 energy efficiency policy recommendations that were published by the International Energy Agency (IEA) in 2008. This policy pathway on energy performance certification of buildings is the second in the series. It aims to provide a 'how-to' guide to policy makers and relevant stakeholders on the essential elements in implementing energy performance certification of buildings programmes. Energy performance certification of buildings is a way to rate the energy efficiency of individual buildings -- whether they be residential, commercial or public. It is a key policy instrument that can assist governments in reducing energy consumption in buildings. This policy pathway showcases experiences from countries around the world to show examples of good practice and delivers a pathway of ten critical steps to implement energy performance certification of buildings programmes.

  12. Syngas Upgrading to Hydrocarbon Fuels Technology Pathway

    Energy Technology Data Exchange (ETDEWEB)

    Talmadge, M.; Biddy, Mary J.; Dutta, Abhijit; Jones, Susanne B.; Meyer, Pimphan A.

    2013-03-31

    In support of the Bioenergy Technologies Office, the National Renewable Energy Laboratory (NREL) and the Pacific Northwest National Laboratory (PNNL) are undertaking studies of biomass conversion technologies to hydrocarbon fuels to identify barriers and target research toward reducing conversion costs. Process designs and preliminary economic estimates for each of these pathway cases were developed using rigorous modeling tools (Aspen Plus and Chemcad). These analyses incorporated the best information available at the time of development, including data from recent pilot and bench-scale demonstrations, collaborative industrial and academic partners, and published literature and patents. This pathway case investigates the upgrading of biomass derived synthesis gas (‘syngas’) to hydrocarbon biofuels. While this specific discussion focuses on the conversion of syngas via a methanol intermediate to hydrocarbon blendstocks, there are a number of alternative conversion routes for production of hydrocarbons through a wide array of intermediates from syngas. Future work will also consider the variations to this pathway to determine the most economically viable and risk adverse conversion route. Technical barriers and key research needs have been identified that should be pursued for the syngas to hydrocarbon pathway to be competitive with petroleum-derived gasoline, diesel and jet range blendstocks.

  13. Teaching Courage: Service Learning at Pathway School.

    Science.gov (United States)

    Ioele, Michelle D.; Dolan, Anne L.

    1992-01-01

    Describes successful service club program serving adolescent boys with social, emotional, and learning problems who reside at Philadelphia's Pathway School. Considers strengths and weaknesses; power and helplessness; worthiness and worthlessness; and giving and dependency. Provides examples from programs and their participants. (NB)

  14. Dorsal and Ventral Pathways for Prosody.

    Science.gov (United States)

    Sammler, Daniela; Grosbras, Marie-Hélène; Anwander, Alfred; Bestelmeyer, Patricia E G; Belin, Pascal

    2015-12-01

    Our vocal tone--the prosody--contributes a lot to the meaning of speech beyond the actual words. Indeed, the hesitant tone of a "yes" may be more telling than its affirmative lexical meaning. The human brain contains dorsal and ventral processing streams in the left hemisphere that underlie core linguistic abilities such as phonology, syntax, and semantics. Whether or not prosody--a reportedly right-hemispheric faculty--involves analogous processing streams is a matter of debate. Functional connectivity studies on prosody leave no doubt about the existence of such streams, but opinions diverge on whether information travels along dorsal or ventral pathways. Here we show, with a novel paradigm using audio morphing combined with multimodal neuroimaging and brain stimulation, that prosody perception takes dual routes along dorsal and ventral pathways in the right hemisphere. In experiment 1, categorization of speech stimuli that gradually varied in their prosodic pitch contour (between statement and question) involved (1) an auditory ventral pathway along the superior temporal lobe and (2) auditory-motor dorsal pathways connecting posterior temporal and inferior frontal/premotor areas. In experiment 2, inhibitory stimulation of right premotor cortex as a key node of the dorsal stream decreased participants' performance in prosody categorization, arguing for a motor involvement in prosody perception. These data draw a dual-stream picture of prosodic processing that parallels the established left-hemispheric multi-stream architecture of language, but with relative rightward asymmetry. PMID:26549262

  15. Final report on the Pathway Analysis Task

    International Nuclear Information System (INIS)

    The Pathway Analysis Task constituted one of several multi-laboratory efforts to estimate radiation doses to people, considering all important pathways of exposure, from the testing of nuclear devices at the Nevada Test Site (NTS). The primary goal of the Pathway Analysis Task was to predict radionuclide ingestion by residents of Utah, Nevada, and portions of seven other adjoining western states following radioactive fallout deposition from individual events at the NTS. This report provides comprehensive documentation of the activities and accomplishments of Colorado State University's Pathway Analysis Task during the entire period of support (1979--91). The history of the project will be summarized, indicating the principal dates and milestones, personnel involved, subcontractors, and budget information. Accomplishments, both primary and auxiliary, will be summarized with general results rather than technical details being emphasized. This will also serve as a guide to the reports and open literature publications produced, where the methodological details and specific results are documented. Selected examples of results on internal dose estimates are provided in this report because the data have not been published elsewhere

  16. Salicylic acid-independent plant defence pathways

    NARCIS (Netherlands)

    Pieterse, C.M.J.; Loon, L.C. van

    1999-01-01

    Salicylic acid is an important signalling molecule involved in both locally and systemically induced disease resistance responses. Recent advances in our understanding of plant defence signalling have revealed that plants employ a network of signal transduction pathways, some of which are independen

  17. Regulatory pathways in the European Union

    OpenAIRE

    Kohler, Manuela

    2011-01-01

    In principle, there are three defined procedures to obtain approval for a medicinal product in the European Union. As discussed in this overview of the procedures, the decision on which regulatory pathway to use will depend on the nature of the active substance, the target indication(s), the history of product and/or the marketing strategy.

  18. e-Science and biological pathway semantics

    Directory of Open Access Journals (Sweden)

    Luciano Joanne S

    2007-05-01

    Full Text Available Abstract Background The development of e-Science presents a major set of opportunities and challenges for the future progress of biological and life scientific research. Major new tools are required and corresponding demands are placed on the high-throughput data generated and used in these processes. Nowhere is the demand greater than in the semantic integration of these data. Semantic Web tools and technologies afford the chance to achieve this semantic integration. Since pathway knowledge is central to much of the scientific research today it is a good test-bed for semantic integration. Within the context of biological pathways, the BioPAX initiative, part of a broader movement towards the standardization and integration of life science databases, forms a necessary prerequisite for its successful application of e-Science in health care and life science research. This paper examines whether BioPAX, an effort to overcome the barrier of disparate and heterogeneous pathway data sources, addresses the needs of e-Science. Results We demonstrate how BioPAX pathway data can be used to ask and answer some useful biological questions. We find that BioPAX comes close to meeting a broad range of e-Science needs, but certain semantic weaknesses mean that these goals are missed. We make a series of recommendations for re-modeling some aspects of BioPAX to better meet these needs. Conclusion Once these semantic weaknesses are addressed, it will be possible to integrate pathway information in a manner that would be useful in e-Science.

  19. Origin and evolution of metabolic pathways

    Science.gov (United States)

    Fani, Renato; Fondi, Marco

    2009-03-01

    The emergence and evolution of metabolic pathways represented a crucial step in molecular and cellular evolution. In fact, the exhaustion of the prebiotic supply of amino acids and other compounds that were likely present in the ancestral environment, imposed an important selective pressure, favoring those primordial heterotrophic cells which became capable of synthesizing those molecules. Thus, the emergence of metabolic pathways allowed primitive organisms to become increasingly less-dependent on exogenous sources of organic compounds. Comparative analyses of genes and genomes from organisms belonging to Archaea, Bacteria and Eukarya revealed that, during evolution, different forces and molecular mechanisms might have driven the shaping of genomes and the arisal of new metabolic abilities. Among these gene elongations, gene and operon duplications undoubtedly played a major role since they can lead to the (immediate) appearance of new genetic material that, in turn, might undergo evolutionary divergence giving rise to new genes coding for new metabolic abilities. Gene duplication has been invoked in the different schemes proposed to explain why and how the extant metabolic pathways have arisen and shaped. Both the analysis of completely sequenced genomes and directed evolution experiments strongly support one of them, i.e. the patchwork hypothesis, according to which metabolic pathways have been assembled through the recruitment of primitive enzymes that could react with a wide range of chemically related substrates. However, the analysis of the structure and organization of genes belonging to ancient metabolic pathways, such as histidine biosynthesis and nitrogen fixation, suggested that other different hypothesis, i.e. the retrograde hypothesis or the semi-enzymatic theory, may account for the arisal of some metabolic routes.

  20. Evaluation of skin and ingestion exposure pathways

    International Nuclear Information System (INIS)

    After a nuclear accident when there has been a release of radionuclides into the atmosphere with consequential deposition on the ground, decisions are necessary on whether protective action guides should be implemented. In order to do this, several pathways for radiation exposure must be evaluated to determine the projected dose to individuals. The objective of this study, conducted by Pacific Northwest Laboratories for the U.S. Environmental Protection Agency, is to provide background information on exposure pathways for use in the development of Protective Action Guides. The relative importance of three exposure pathways that are usually considered to be unimportant compared to other pathways expected to control relocation decisions following a nuclear power plant accident is evaluated. The three pathways are the skin dose from contact with radionuclides transferred from the ground, the skin dose from radionuclides on the ground surface, and ingestion of radionuclides transferred directly to the mouth from the hands or other contaminated surfaces. Ingestion of contaminated food is not included in this evaluation, except for situations where the food is contaminated as a result of actions by the person who consumes the food (e.g., transfer of contamination from hands to food). Estimates of skin and ingestion doses are based on a source term with a radionuclide mix predicted for an SST2-type nuclear accident in an area where the first year reference whole-body dose equivalent from whole body external exposure to gamma radiation plus the committed effective dose equivalent from inhalation of resuspended radionuclides is 1 rem. Appendixes have been included to allow the reader to examine dose factor calculations, source-term data, and quantification of contact and ingestion parameters in more detail

  1. Minimal metabolic pathway structure is consistent with associated biomolecular interactions.

    Science.gov (United States)

    Bordbar, Aarash; Nagarajan, Harish; Lewis, Nathan E; Latif, Haythem; Ebrahim, Ali; Federowicz, Stephen; Schellenberger, Jan; Palsson, Bernhard O

    2014-01-01

    Pathways are a universal paradigm for functionally describing cellular processes. Even though advances in high-throughput data generation have transformed biology, the core of our biological understanding, and hence data interpretation, is still predicated on human-defined pathways. Here, we introduce an unbiased, pathway structure for genome-scale metabolic networks defined based on principles of parsimony that do not mimic canonical human-defined textbook pathways. Instead, these minimal pathways better describe multiple independent pathway-associated biomolecular interaction datasets suggesting a functional organization for metabolism based on parsimonious use of cellular components. We use the inherent predictive capability of these pathways to experimentally discover novel transcriptional regulatory interactions in Escherichia coli metabolism for three transcription factors, effectively doubling the known regulatory roles for Nac and MntR. This study suggests an underlying and fundamental principle in the evolutionary selection of pathway structures; namely, that pathways may be minimal, independent, and segregated. PMID:24987116

  2. Targeting the Fanconi Anemia Pathway to Identify Tailored Anticancer Therapeutics

    Directory of Open Access Journals (Sweden)

    Chelsea Jenkins

    2012-01-01

    Full Text Available The Fanconi Anemia (FA pathway consists of proteins involved in repairing DNA damage, including interstrand cross-links (ICLs. The pathway contains an upstream multiprotein core complex that mediates the monoubiquitylation of the FANCD2 and FANCI heterodimer, and a downstream pathway that converges with a larger network of proteins with roles in homologous recombination and other DNA repair pathways. Selective killing of cancer cells with an intact FA pathway but deficient in certain other DNA repair pathways is an emerging approach to tailored cancer therapy. Inhibiting the FA pathway becomes selectively lethal when certain repair genes are defective, such as the checkpoint kinase ATM. Inhibiting the FA pathway in ATM deficient cells can be achieved with small molecule inhibitors, suggesting that new cancer therapeutics could be developed by identifying FA pathway inhibitors to treat cancers that contain defects that are synthetic lethal with FA.

  3. Phosphoketolase Pathway Dominates in Lactobacillus reuteri ATCC 55730 Containing Dual Pathways for Glycolysis▿

    OpenAIRE

    Årsköld, Emma; Lohmeier-Vogel, Elke; Cao, Rong; Roos, Stefan; Rådström, Peter; van Niel, Ed W. J.

    2007-01-01

    Metabolic flux analysis indicated that the heterofermentative Lactobacillus reuteri strain ATCC 55730 uses both the Embden-Meyerhof pathway (EMP) and phosphoketolase pathway (PKP) when glucose or sucrose is converted into the three-carbon intermediate stage of glycolysis. In all cases studied, the main flux is through the PKP, while the EMP is used as a shunt. In the exponential growth phase, 70%, 73%, and 84% of the flux goes through the PKP in cells metabolizing (i) glucose plus fructose, (...

  4. Phosphoketolase pathway dominates in Lactobacillus reuteri ATCC 55730 containing dual pathways for glycolysis

    OpenAIRE

    Årsköld, Emma; Lohmeier-Vogel, Elke; Cao, Rong; Roos, Stefan; Rådström, Peter; van Niel, Ed

    2008-01-01

    Metabolic flux analysis indicated that the heterofermentative Lactobacillus reuteri strain ATCC 55730 uses both the Embden-Meyerhof pathway (EMP) and phosphoketolase pathway (PKP) when glucose or sucrose is converted into the three-carbon intermediate stage of glycolysis. In all cases studied, the main flux is through the PKP, while the EMP is used as a shunt. In the exponential growth phase, 70%, 73%, and 84% of the flux goes through the PKP in cells metabolizing (i) glucose plus fructose, (...

  5. KeyPathwayMiner: Detecting Case-Specific Biological Pathways Using Expression Data

    OpenAIRE

    Alcaraz, Nicolas; Kücük, Hande; Weile, Jochen; Wipat, Anil; Baumbach, Jan

    2011-01-01

    Recent advances in systems biology have provided us with massive amounts of pathway data that describe the interplay of genes and their products. The resulting biological networks can be modeled as graphs. By means of "omics" technologies, such as microarrays, the activity of genes and proteins can be measured. Here, data from microarray experiments is integrated with the network data to gain deeper insights into gene expression. We introduce KeyPathwayMiner, a method that enab...

  6. The cardiopulmonary effects of ambient air pollution and mechanistic pathways: a comparative hierarchical pathway analysis.

    Directory of Open Access Journals (Sweden)

    Ananya Roy

    Full Text Available Previous studies have investigated the associations between exposure to ambient air pollution and biomarkers of physiological pathways, yet little has been done on the comparison across biomarkers of different pathways to establish the temporal pattern of biological response. In the current study, we aim to compare the relative temporal patterns in responses of candidate pathways to different pollutants. Four biomarkers of pulmonary inflammation and oxidative stress, five biomarkers of systemic inflammation and oxidative stress, ten parameters of autonomic function, and three biomarkers of hemostasis were repeatedly measured in 125 young adults, along with daily concentrations of ambient CO, PM2.5, NO2, SO2, EC, OC, and sulfate, before, during, and after the Beijing Olympics. We used a two-stage modeling approach, including Stage I models to estimate the association between each biomarker and pollutant over each of 7 lags, and Stage II mixed-effect models to describe temporal patterns in the associations when grouping the biomarkers into the four physiological pathways. Our results show that candidate pathway groupings of biomarkers explained a significant amount of variation in the associations for each pollutant, and the temporal patterns of the biomarker-pollutant-lag associations varied across candidate pathways (p<0.0001 and were not linear (from lag 0 to lag 3: p = 0.0629, from lag 3 to lag 6: p = 0.0005. These findings suggest that, among this healthy young adult population, the pulmonary inflammation and oxidative stress pathway is the first to respond to ambient air pollution exposure (within 24 hours and the hemostasis pathway responds gradually over a 2-3 day period. The initial pulmonary response may contribute to the more gradual systemic changes that likely ultimately involve the cardiovascular system.

  7. Genome-Wide Pathway Analysis Identifies Genetic Pathways Associated with Psoriasis.

    Science.gov (United States)

    Aterido, Adrià; Julià, Antonio; Ferrándiz, Carlos; Puig, Lluís; Fonseca, Eduardo; Fernández-López, Emilia; Dauden, Esteban; Sánchez-Carazo, José Luís; López-Estebaranz, José Luís; Moreno-Ramírez, David; Vanaclocha, Francisco; Herrera, Enrique; de la Cueva, Pablo; Dand, Nick; Palau, Núria; Alonso, Arnald; López-Lasanta, María; Tortosa, Raül; García-Montero, Andrés; Codó, Laia; Gelpí, Josep Lluís; Bertranpetit, Jaume; Absher, Devin; Capon, Francesca; Myers, Richard M; Barker, Jonathan N; Marsal, Sara

    2016-03-01

    Psoriasis is a chronic inflammatory disease with a complex genetic architecture. To date, the psoriasis heritability is only partially explained. However, there is increasing evidence that the missing heritability in psoriasis could be explained by multiple genetic variants of low effect size from common genetic pathways. The objective of this study was to identify new genetic variation associated with psoriasis risk at the pathway level. We genotyped 598,258 single nucleotide polymorphisms in a discovery cohort of 2,281 case-control individuals from Spain. We performed a genome-wide pathway analysis using 1,053 reference biological pathways. A total of 14 genetic pathways (PFDR ≤ 2.55 × 10(-2)) were found to be significantly associated with psoriasis risk. Using an independent validation cohort of 7,353 individuals from the UK, a total of 6 genetic pathways were significantly replicated (PFDR ≤ 3.46 × 10(-2)). We found genetic pathways that had not been previously associated with psoriasis risk such as retinol metabolism (Pcombined = 1.84 × 10(-4)), the transport of inorganic ions and amino acids (Pcombined = 1.57 × 10(-7)), and post-translational protein modification (Pcombined = 1.57 × 10(-7)). In the latter pathway, MGAT5 showed a strong network centrality, and its association with psoriasis risk was further validated in an additional case-control cohort of 3,429 individuals (P < 0.05). These findings provide insights into the biological mechanisms associated with psoriasis susceptibility. PMID:26743605

  8. Alternative miRNA biogenesis pathways and the interpretation of core miRNA pathway mutants

    OpenAIRE

    Yang, Shiuan; Lai, Eric C.

    2011-01-01

    Since the establishment of a canonical animal microRNA biogenesis pathway driven by the RNase III enzymes Drosha and Dicer, an unexpected variety of alternative mechanisms that generate functional microRNAs have emerged. We review here the many Drosha-independent and Dicer-independent microRNA biogenesis strategies characterized over the past few years. Beyond reflecting the flexibility of small RNA machineries, the existence of non-canonical pathways has consequences for interpreting mutants...

  9. The metabolic pathway collection from EMP: the enzymes and metabolic pathways database.

    OpenAIRE

    Basmanova, S; Gaasterland, T.; Goryanin, I; Gretchkin, Y; Maltsev, N.; Nenashev, V; Overbeek, R; Panyushkina, E; Pronevitch, L; Selkov, E; Yunus, I

    1996-01-01

    The Enzymes and Metabolic Pathways database (EMP) is an encoding of the contents of over 10 000 original publications on the topics of enzymology and metabolism. This large body of information has been transformed into a queryable database. An extraction of over 1800 pictorial representations of metabolic pathways from this collection is freely available on the World Wide Web. We believe that this collection will play an important role in the interpretation of genetic sequence data, as well a...

  10. Impact of MAPK Cascade Pathway and P53 Pathway upon Liver Transplant

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    The change and the role of MAPK cascade pathway and P53 pathway after liver transplantation were explored. Thirty-four punctured donor liver specimens and 10 normal liver specimens were classified as group A (no rejection, n= 10), group B (mild/moderate acute rejection, n = 10), group C (serious acute rejection, n = 8), group D (chronic rejection/fibrosis, n = 6) and group E (control, n= 10). By using tmmunohistochemistry, the expression levels of mitogen activated protein kinase (MAPK), Ras and P53 proteins, and by in situ hybridization, MAPK and ras mRNA expression levels were detected. The results showed that the expression levels of MAPK and Ras proteins were increased by turns in groups A, B and C, and decreased by turns in groups D and E. The protein expression of P53 was higher in the treated groups. The expression of Ras,HSP70 mRNA was identical as that of protein. It is suggested that the MAPK cascade pathway and P53 pathway can protect the hepatocytes by different mechanisms after liver transplantation.MAPKs cascade pathway repairs hepatocyte injury or accelerates hepatocytes into proliferation or differentiation. P53 pathway blocks cell cycle within G1 phase to make hepatocyte repair or apoptosis to reduce disorder differentiation.

  11. A gene expression signature of RAS pathway dependence predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated tumors

    Directory of Open Access Journals (Sweden)

    Paweletz Cloud

    2010-06-01

    Full Text Available Abstract Background Hyperactivation of the Ras signaling pathway is a driver of many cancers, and RAS pathway activation can predict response to targeted therapies. Therefore, optimal methods for measuring Ras pathway activation are critical. The main focus of our work was to develop a gene expression signature that is predictive of RAS pathway dependence. Methods We used the coherent expression of RAS pathway-related genes across multiple datasets to derive a RAS pathway gene expression signature and generate RAS pathway activation scores in pre-clinical cancer models and human tumors. We then related this signature to KRAS mutation status and drug response data in pre-clinical and clinical datasets. Results The RAS signature score is predictive of KRAS mutation status in lung tumors and cell lines with high (> 90% sensitivity but relatively low (50% specificity due to samples that have apparent RAS pathway activation in the absence of a KRAS mutation. In lung and breast cancer cell line panels, the RAS pathway signature score correlates with pMEK and pERK expression, and predicts resistance to AKT inhibition and sensitivity to MEK inhibition within both KRAS mutant and KRAS wild-type groups. The RAS pathway signature is upregulated in breast cancer cell lines that have acquired resistance to AKT inhibition, and is downregulated by inhibition of MEK. In lung cancer cell lines knockdown of KRAS using siRNA demonstrates that the RAS pathway signature is a better measure of dependence on RAS compared to KRAS mutation status. In human tumors, the RAS pathway signature is elevated in ER negative breast tumors and lung adenocarcinomas, and predicts resistance to cetuximab in metastatic colorectal cancer. Conclusions These data demonstrate that the RAS pathway signature is superior to KRAS mutation status for the prediction of dependence on RAS signaling, can predict response to PI3K and RAS pathway inhibitors, and is likely to have the most clinical

  12. Lung carcinoma signaling pathways activated by smoking

    Institute of Scientific and Technical Information of China (English)

    Jing Wen; Jian-Hua Fu; Wei Zhang; Ming Guo

    2011-01-01

    Lung cancer is the leading cause of cancer death in men and women worldwide, with over a million deaths annually. Tobacco smoke is the major etiologic risk factor for lung cancer in current or previous smokers and has been strongly related to certain types of lung cancer, such as small cell lung carcinoma and squamous cell lung carcinoma. In recent years, there has been an increased incidence of lung adenocarcinoma. This change is strongly associated with changes in smoking behavior and cigarette design. Carcinogens present in tobacco products and their intermediate metabolites can activate multiple signaling pathways that contribute to lung cancer carcinogenesis. In this review, we summarize the smoking-activated signaling pathways involved in lung cancer.

  13. Whole Algae Hydrothermal Liquefaction Technology Pathway

    Energy Technology Data Exchange (ETDEWEB)

    Biddy, Mary J.; Davis, Ryan; Jones, Susanne B.; Zhu, Yunhua

    2013-03-31

    In support of the Bioenergy Technologies Office, the National Renewable Energy Laboratory (NREL) and the Pacific Northwest National Laboratory (PNNL) are undertaking studies of biomass conversion technologies to hydrocarbon fuels to identify barriers and target research toward reducing conversion costs. Process designs and preliminary economic estimates for each of these pathway cases were developed using rigorous modeling tools (Aspen Plus and Chemcad). These analyses incorporated the best information available at the time of development, including data from recent pilot and bench-scale demonstrations, collaborative industrial and academic partners, and published literature and patents. This pathway case investigates the feasibility of using whole wet microalgae as a feedstock for conversion via hydrothermal liquefaction. Technical barriers and key research needs have been assessed in order for the hydrothermal liquefaction of microalgae to be competitive with petroleum-derived gasoline, diesel and jet range blendstocks.

  14. Obesity-Induced Hypertension: Brain Signaling Pathways.

    Science.gov (United States)

    do Carmo, Jussara M; da Silva, Alexandre A; Wang, Zhen; Fang, Taolin; Aberdein, Nicola; de Lara Rodriguez, Cecilia E P; Hall, John E

    2016-07-01

    Obesity greatly increases the risk for cardiovascular, metabolic, and renal diseases and is one of the most significant and preventable causes of increased blood pressure (BP) in patients with essential hypertension. This review highlights recent advances in our understanding of central nervous system (CNS) signaling pathways that contribute to the etiology and pathogenesis of obesity-induced hypertension. We discuss the role of excess adiposity and activation of the brain leptin-melanocortin system in causing increased sympathetic activity in obesity. In addition, we highlight other potential brain mechanisms by which increased weight gain modulates metabolic and cardiovascular functions. Unraveling the CNS mechanisms responsible for increased sympathetic activation and hypertension and how circulating hormones activate brain signaling pathways to control BP offer potentially important therapeutic targets for obesity and hypertension. PMID:27262997

  15. Biocatalytic Pathway Selection in Transient Tripeptide Nanostructures.

    Science.gov (United States)

    Pappas, Charalampos G; Sasselli, Ivan R; Ulijn, Rein V

    2015-07-01

    Structural adaption in living systems is achieved by competing catalytic pathways that drive assembly and disassembly of molecular components under the influence of chemical fuels. We report on a simple mimic of such a system that displays transient, sequence-dependent formation of supramolecular nanostructures based on biocatalytic formation and hydrolysis of self-assembling tripeptides. The systems are catalyzed by α-chymotrypsin and driven by hydrolysis of dipeptide aspartyl-phenylalanine-methyl ester (the sweetener aspartame, DF-OMe). We observed switch-like pathway selection, with the kinetics and consequent lifetime of transient nanostructures controlled by the peptide sequence. In direct competition, kinetic (rather than thermodynamic) component selection is observed. PMID:26014441

  16. Stochastic Processes via the Pathway Model

    Directory of Open Access Journals (Sweden)

    Arak M. Mathai

    2015-04-01

    Full Text Available After collecting data from observations or experiments, the next step is to analyze the data to build an appropriate mathematical or stochastic model to describe the data so that further studies can be done with the help of the model. In this article, the input-output type mechanism is considered first, where reaction, diffusion, reaction-diffusion, and production-destruction type physical situations can fit in. Then techniques are described to produce thicker or thinner tails (power law behavior in stochastic models. Then the pathway idea is described where one can switch to different functional forms of the probability density function through a parameter called the pathway parameter. The paper is a continuation of related solar neutrino research published previously in this journal.

  17. Studying lipids involved in the endosomal pathway.

    Science.gov (United States)

    Bissig, Christin; Johnson, Shem; Gruenberg, Jean

    2012-01-01

    Endosomes along the degradation pathway exhibit a multivesicular appearance and differ in their lipid compositions. Association of proteins to specific membrane lipids and presumably also lipid-lipid interactions contribute to the formation of functional membrane platforms that regulate endosome biogenesis and function. This chapter provides a brief review of the functions of endosomal lipids in the degradation pathway, a discussion of techniques that allow studying lipid-based mechanisms and a selection of step-by-step protocols for in vivo and in vitro methods commonly used to study lipid roles in endocytosis. The techniques described here have been used to elucidate the function of the late endosomal lipid lysobisphosphatidic acid and allow the monitoring of lipid distribution, levels and dynamics, as well as the characterization of lipid-binding partners. PMID:22325596

  18. Finding pathways between distant local minima

    Science.gov (United States)

    Carr, Joanne M.; Trygubenko, Semen A.; Wales, David J.

    2005-06-01

    We report a new algorithm for constructing pathways between local minima that involve a large number of intervening transition states on the potential energy surface. A significant improvement in efficiency has been achieved by changing the strategy for choosing successive pairs of local minima that serve as endpoints for the next search. We employ Dijkstra's algorithm [E. W. Dijkstra, Numer. Math. 1, 269 (1959)] to identify the "shortest" path corresponding to missing connections within an evolving database of local minima and the transition states that connect them. The metric employed to determine the shortest missing connection is a function of the minimized Euclidean distance. We present applications to the formation of buckminsterfullerene and to the folding of various biomolecules: the B1 domain of protein G, tryptophan zippers, and the villin headpiece subdomain. The corresponding pathways contain up to 163 transition states and will be used in future discrete path sampling calculations.

  19. Mathematics of the NFAT signalling pathway

    OpenAIRE

    Rendall, A.

    2012-01-01

    This paper is a mathematical study of some aspects of the signalling pathway leading to the activation of the transcription factor NFAT (nuclear factor of activated T cells). Activation takes place by dephosphorylation at multiple sites. This has been modelled by Salazar and H\\"ofer using a large system of ordinary differential equations depending on many parameters. With the help of chemical reaction network theory we show that for any choice of the parameters this system has a unique statio...

  20. Insulin signaling pathways in lepidopteran steroidogenesis

    Directory of Open Access Journals (Sweden)

    WendySmith

    2014-02-01

    Full Text Available Molting and metamorphosis are stimulated by the secretion of ecdysteroid hormones from the prothoracic glands. Insulin-like hormones have been found to enhance prothoracic gland activity, providing a mechanism to link molting to nutritional state. In silk moths (Bombyx mori, the prothoracic glands are directly stimulated by insulin and the insulin-like hormone bombyxin. Further, in Bombyx , the neuropeptide prothoracicotropic hormone (PTTH appears to act at least in part through the insulin-signaling pathway. In the prothoracic glands of Manduca sexta, while insulin stimulates the phosphorylation of the insulin receptor and Akt, neither insulin nor bombyxin II stimulate ecdysone secretion. Involvement of the insulin-signaling pathway in Manduca prothoracic glands was explored using two inhibitors of phosphatidylinositol-3-kinase (PI3K, LY294002 and wortmannin. PI3K inhibitors block the phosphorylation of Akt and 4EBP but have no effect on ecdysone secretion, or on the phosphorylation of the MAPkinase, ERK. Inhibitors that block phosphorylation of ERK, including the MEK inhibitor U0126, and high doses of the RSK inhibitor SL0101, effectively inhibit ecdysone secretion. The results highlight differences between the two lepidopteran insects most commonly used to directly study ecdysteroid secretion. In Bombyx, the PTTH and insulin-signaling pathways intersect; both insulin and PTTH enhance the phosphorylation of Akt and stimulate ecdysteroid secretion, and inhibition of PI3K reduces ecdysteroid secretion. By contrast, in Manduca, the action of PTTH is distinct from insulin. The results highlight species differences in the roles of translational regulators such as 4EBP, and members of the MAPkinase pathway such as ERK and RSK, in the effects of nutritionally-sensitive hormones such as insulin on ecdysone secretion and molting.

  1. Conservation of small RNA pathways in platypus

    OpenAIRE

    Murchison, Elizabeth P.; Kheradpour, Pouya; Sachidanandam, Ravi; Smith, Carly; Hodges, Emily; Xuan, Zhenyu; Kellis, Manolis; Grützner, Frank; Stark, Alexander; Hannon, Gregory J.

    2008-01-01

    Small RNA pathways play evolutionarily conserved roles in gene regulation and defense from parasitic nucleic acids. The character and expression patterns of small RNAs show conservation throughout animal lineages, but specific animal clades also show variations on these recurring themes, including species-specific small RNAs. The monotremes, with only platypus and four species of echidna as extant members, represent the basal branch of the mammalian lineage. Here, we examine the small RNA pat...

  2. Rabies Virus-Induced Membrane Fusion Pathway

    OpenAIRE

    Gaudin, Yves

    2000-01-01

    Fusion of rabies virus with membranes is triggered at low pH and is mediated by the viral glycoprotein (G). The rabies virus-induced fusion pathway was studied by investigating the effects of exogenous lipids having various dynamic molecular shapes on the fusion process. Inverted cone-shaped lysophosphatidylcholines (LPCs) blocked fusion at a stage subsequent to fusion peptide insertion into the target membrane. Consistent with the stalk-hypothesis, LPC with shorter alkyl chains inhibited fus...

  3. Stroke patients’ pathways to rehabilitation in Portugal

    OpenAIRE

    Silvina Santana; Patrícia Redondo; Conceição Neves; José Rente; Marta Viana; Mariana Ribeiro; Nina Szczygiel

    2011-01-01

    Purpose To report on stroke patients’ pathways to rehabilitation in Portugal, in light of an ongoing EHSD procedure. Theory and methods The Portuguese government has created the National Network of Continuous Integrated Care (RNCCI) to reduce costly acute care and length of stay in hospitals by substituting less costly care closer to the community. The network is based on establishing protocols with existing institutions, designated according to the kind of services they provide as convalesce...

  4. Online treatment compliance checking for clinical pathways.

    Science.gov (United States)

    Huang, Zhengxing; Bao, Yurong; Dong, Wei; Lu, Xudong; Duan, Huilong

    2014-10-01

    Compliance checking for clinical pathways (CPs) is getting increasing attention in health-care organizations due to stricter requirements for cost control and treatment excellence. Many compliance measures have been proposed for treatment behavior inspection in CPs. However, most of them look at aggregated data seen from an external perspective, e.g. length of stay, cost, infection rate, etc., which may provide only a posterior impression of the overall conformance with the established CPs such that in-depth and in near real time checking on the compliance of the essential/critical treatment behaviors of CPs is limited. To provide clinicians real time insights into violations of the established CP specification and support online compliance checking, this article presents a semantic rule-based CP compliance checking system. In detail, we construct a CP ontology (CPO) model to provide a formal grounding of CP compliance checking. Using the proposed CPO, domain treatment constraints are modeled into Semantic Web Rule Language (SWRL) rules to specify the underlying treatment behaviors and their quantified temporal structure in a CP. The established SWRL rules are integrated with the CP workflow such that a series of applicable compliance checking and evaluation can be reminded and recommended during the pathway execution. The proposed approach can, therefore, provides a comprehensive compliance checking service as a paralleling activity to the patient treatment journey of a CP rather than an afterthought. The proposed approach is illustrated with a case study on the unstable angina clinical pathway implemented in the Cardiology Department of a Chinese hospital. The results demonstrate that the approach, as a feasible solution to provide near real time conformance checking of CPs, not only enables clinicians to uncover non-compliant treatment behaviors, but also empowers clinicians with the capability to make informed decisions when dealing with treatment compliance

  5. Wnt Signalling Pathway Parameters for Mammalian Cells

    OpenAIRE

    Tan, Chin Wee; Gardiner, Bruce S.; Hirokawa, Yumiko; Layton, Meredith J.; Smith, David W.; Burgess, Antony W.

    2012-01-01

    Wnt/β-catenin signalling regulates cell fate, survival, proliferation and differentiation at many stages of mammalian development and pathology. Mutations of two key proteins in the pathway, APC and β-catenin, have been implicated in a range of cancers, including colorectal cancer. Activation of Wnt signalling has been associated with the stabilization and nuclear accumulation of β-catenin and consequential up-regulation of β-catenin/TCF gene transcription. In 2003, Lee et al. constructed a c...

  6. Loss of vision: imaging the visual pathways

    International Nuclear Information System (INIS)

    This is an overview of diseases presenting with visual impairment, which aims to provide an understanding of the anatomy and pathology of the visual pathways. It discusses the relevant clinical background and neuroimaging findings on CT and standard and advanced MRI of diseases affecting the globe; optic nerve/sheath complex; optic chiasm, tract and radiation; and visual cortex. The overview covers common tumours, trauma, inflammatory and vascular pathology, and conditions such as benign intracranial hypertension and posterior reversible leukoencephalopathy syndrome. (orig.)

  7. Remixing as a Pathway to Computational Thinking

    OpenAIRE

    Dasgupta, Sayamindu; Hale, William; Monroy-Hernández, Andrés; Hill, Benjamin Mako

    2016-01-01

    Theorists and advocates of "remixing" have suggested that appropriation can act as a pathway for learning. We test this theory quantitatively using data from more than 2.4 million multimedia programming projects shared by more than 1 million users in the Scratch online community. First, we show that users who remix more often have larger repertoires of programming commands even after controlling for the numbers of projects and amount of code shared. Second, we show that exposure to computatio...

  8. The sensory transduction pathways in bacterial chemotaxis

    Science.gov (United States)

    Taylor, Barry L.

    1989-01-01

    Bacterial chemotaxis is a useful model for investigating in molecular detail the behavioral response of cells to changes in their environment. Peritrichously flagellated bacteria such as coli and typhimurium swim by rotating helical flagella in a counterclockwise direction. If flagellar rotation is briefly reversed, the bacteria tumble and change the direction of swimming. The bacteria continuously sample the environment and use a temporal sensing mechanism to compare the present and immediate past environments. Bacteria respond to a broad range of stimuli including changes in temperature, oxygen concentration, pH and osmotic strength. Bacteria are attracted to potential sources of nutrition such as sugars and amino acids and are repelled by other chemicals. In the methylation-dependent pathways for sensory transduction and adaptation in E. coli and S. typhimurium, chemoeffectors bind to transducing proteins that span the plasma membrane. The transducing proteins are postulated to control the rate of autophosphorylation of the CheA protein, which in turn phosphorylates the CheY protein. The phospho-CheY protein binds to the switch on the flagellar motor and is the signal for clockwise rotation of the motor. Adaptation to an attractant is achieved by increasing methylation of the transducing protein until the attractant stimulus is cancelled. Responses to oxygen and certain sugars involve methylation-independent pathways in which adaption occurs without methylation of a transducing protein. Taxis toward oxygen is mediated by the electron transport system and changes in the proton motive force. Recent studies have shown that the methylation-independent pathway converges with the methylation-dependent pathway at or before the CheA protein.

  9. Mathematical modeling of the Phoenix Rising pathway.

    Directory of Open Access Journals (Sweden)

    Chad Liu

    2014-02-01

    Full Text Available Apoptosis is a tightly controlled process in mammalian cells. It is important for embryogenesis, tissue homoeostasis, and cancer treatment. Apoptosis not only induces cell death, but also leads to the release of signals that promote rapid proliferation of surrounding cells through the Phoenix Rising (PR pathway. To quantitatively understand the kinetics of interactions of different molecules in this pathway, we developed a mathematical model to simulate the effects of various changes in the PR pathway on the secretion of prostaglandin E2 (PGE2, a key factor for promoting cell proliferation. These changes include activation of caspase 3 (C3, caspase 7 (C7, and nuclear factor κB (NFκB. In addition, we simulated the effects of cyclooxygenase-2 (COX2 inhibition and C3 knockout on the level of secreted PGE2. The model predictions on PGE2 in MEF and 4T1 cells at 48 hours after 10-Gray radiation were quantitatively consistent with the experimental data in the literature. Compared to C7, the model predicted that C3 activation was more critical for PGE2 production. The model also predicted that PGE2 production could be significantly reduced when COX2 expression was blocked via either NFκB inactivation or treatment of cells with exogenous COX2 inhibitors, which led to a decrease in the rate of conversion from arachidonic acid to prostaglandin H2 in the PR pathway. In conclusion, the mathematical model developed in this study yielded new insights into the process of tissue regrowth stimulated by signals from apoptotic cells. In future studies, the model can be used for experimental data analysis and assisting development of novel strategies/drugs for improving cancer treatment or normal tissue regeneration.

  10. Signaling Pathways Involved in Cardiac Hypertrophy

    Institute of Scientific and Technical Information of China (English)

    Tao Zewei; Li Longgui

    2006-01-01

    Cardiac hypertrophy is the heart's response to a variety of extrinsic and intrinsic stimuli that impose increased biomechanical stress.Traditionally, it has been considered a beneficial mechanism; however, sustained hypertrophy has been associated with a significant increase in the risk of cardiovascular disease and mortality. Delineating intracellular signaling pathways involved in the different aspects of cardiac hypertrophy will permit future improvements in potential targets for therapeutic intervention. Generally, there are two types of cardiac hypertrophies, adaptive hypertrophy, including eutrophy (normal growth) and physiological hypertrophy (growth induced by physical conditioning), and maladaptive hypertrophy, including pathologic or reactive hypertrophy (growth induced by pathologic stimuli) and hypertrophic growth caused by genetic mutations affecting sarcomeric or cytoskeletal proteins. Accumulating observations from animal models and human patients have identified a number of intracellular signaling pathways that characterized as important transducers of the hypertrophic response,including calcineurin/nuclear factor of activated Tcells, phosphoinositide 3-kinases/Akt (PI3Ks/Akt),G protein-coupled receptors, small G proteins,MAPK, PKCs, Gp130/STAT'3, Na+/H+ exchanger,peroxisome proliferator-activated receptors, myocyte enhancer factor 2/histone deacetylases, and many others. Furthermore, recent evidence suggests that adaptive cardiac hypertrophy is regulated in large part by the growth hormone/insulin-like growth factors axis via signaling through the PI3K/Akt pathway. In contrast, pathological or reactive hypertrophy is triggered by autocrine and paracrine neurohormonal factors released during biomechanical stress that signal through the Gq/phosphorlipase C pathway, leading to an increase in cytosolic calcium and activation of PKC.

  11. Isoprenoid Pathway And Neurological And Psychiatric Disorders

    Directory of Open Access Journals (Sweden)

    Ravikumar A

    1999-01-01

    Full Text Available The coexistence of neuronal degeneration, psychiatric manifestation, immune activation and malignant transformation has been documented in literature, suggesting a central dysfunction in the pathophysiology of these disorders. The isoprenoid pathway may be candidate in this respect, in view of the changes in the concentration of some products of this pathway in many of these disorders, however, no detailed study has been carried out in this respect. In view of this, a study was undertaken on the isoprenoid pathway in some of these disorders - primary generalized epilepsy, Parkinson’s disease (PD, schizophrenia, manic depressive psychosis (MDP, CNS glioma, multiple sclerosis, subacute sclerosing panencephalitis (SSPEand a familial group with familial coexistence of schizophrenia, PD, primary generalized epilepsy, malignant neoplasia, rheumatoid arthritis and syndrome-X over three generations. The following parameters were studied in the patients of these disorders as compared to age and sex matched control subjects - ubiquinone dolichol, digoxin, activity of HMG CoA reductase in the plasma and erthyorcyte membrane Na -K--ATpase. Increase in the activity of HMG CoA reductase and in the concentration of plasma digoxin and dolichol was observed in most of these cases. On the other hand, there was decrease in the concentration of plasma ubiquinone. Decrease in the activity of erythrocyte membrane Na-K- ATpase activity for which digoxin is an inhibitor was also observed in all the cases studied. These results indicate an upregulation of the isoprenoid pathway in the neurological and psychiatric disorders studied. The implications of this change is discussed in details.

  12. Multiple Pathways Linking Racism to Health Outcomes

    OpenAIRE

    Harrell, Camara Jules P.; Burford, Tanisha I.; Cage, Brandi N.; Nelson, Travette McNair; Shearon, Sheronda; Thompson, Adrian; Green, Steven

    2011-01-01

    This commentary discusses advances in the conceptual understanding of racism and selected research findings in the social neurosciences. The traditional stress and coping model holds that racism constitutes a source of aversive experiences that, when perceived by the individual, eventually lead to poor health outcomes. Current evidence points to additional psychophysiological pathways linking facets of racist environments with physiological reactions that contribute to disease. The alternativ...

  13. Brain evolution by brain pathway duplication

    OpenAIRE

    Chakraborty, Mukta; Jarvis, Erich D

    2015-01-01

    Understanding the mechanisms of evolution of brain pathways for complex behaviours is still in its infancy. Making further advances requires a deeper understanding of brain homologies, novelties and analogies. It also requires an understanding of how adaptive genetic modifications lead to restructuring of the brain. Recent advances in genomic and molecular biology techniques applied to brain research have provided exciting insights into how complex behaviours are shaped by selection of novel ...

  14. Targeting the Hedgehog Pathway in Pediatric Medulloblastoma

    OpenAIRE

    Sherri Y. Huang; Jer-Yen Yang

    2015-01-01

    Medulloblastoma (MB), a primitive neuroectomal tumor of the cerebellum, is the most common malignant pediatric brain tumor. The cause of MB is largely unknown, but aberrant activation of Hedgehog (Hh) pathway is responsible for ~30% of MB. Despite aggressive treatment with surgical resection, radiation and chemotherapy, 70%–80% of pediatric medulloblastoma cases can be controlled, but most treated patients suffer devastating side effects. Therefore, developing a new effective treatment strate...

  15. BMP pathway regulation of and by macrophages.

    Directory of Open Access Journals (Sweden)

    Megha Talati

    Full Text Available Pulmonary arterial hypertension (PAH is a disease of progressively increasing pulmonary vascular resistance, associated with mutations of the type 2 receptor for the BMP pathway, BMPR2. The canonical signaling pathway for BMPR2 is through the SMAD family of transcription factors. BMPR2 is expressed in every cell type, but the impact of BMPR2 mutations affecting SMAD signaling, such as Bmpr2delx4+, had only previously been investigated in smooth muscle and endothelium. In the present study, we created a mouse with universal doxycycline-inducible expression of Bmpr2delx4+ in order to determine if broader expression had an impact relevant to the development of PAH. We found that the most obvious phenotype was a dramatic, but patchy, increase in pulmonary inflammation. We crossed these double transgenic mice onto an NF-κB reporter strain, and by luciferase assays on live mice, individual organs and isolated macrophages, we narrowed down the origin of the inflammatory phenotype to constitutive activation of tissue macrophages. Study of bone marrow-derived macrophages from mutant and wild-type mice suggested a baseline difference in differentiation state in Bmpr2 mutants. When activated with LPS, both mutant and wild-type macrophages secrete BMP pathway inhibitors sufficient to suppress BMP pathway activity in smooth muscle cells (SMC treated with conditioned media. Functionally, co-culture with macrophages results in a BMP signaling-dependent increase in scratch closure in cultured SMC. We conclude that SMAD signaling through BMP is responsible, in part, for preventing macrophage activation in both live animals and in cells in culture, and that activated macrophages secrete BMP inhibitors in sufficient quantity to cause paracrine effect on vascular smooth muscle.

  16. Biochemical research elucidating metabolic pathways in Pneumocystis*

    Directory of Open Access Journals (Sweden)

    Kaneshiro E.S.

    2010-12-01

    Full Text Available Advances in sequencing the Pneumocystis carinii genome have helped identify potential metabolic pathways operative in the organism. Also, data from characterizing the biochemical and physiological nature of these organisms now allow elucidation of metabolic pathways as well as pose new challenges and questions that require additional experiments. These experiments are being performed despite the difficulty in doing experiments directly on this pathogen that has yet to be subcultured indefinitely and produce mass numbers of cells in vitro. This article reviews biochemical approaches that have provided insights into several Pneumocystis metabolic pathways. It focuses on 1 S-adenosyl-L-methionine (AdoMet; SAM, which is a ubiquitous participant in numerous cellular reactions; 2 sterols: focusing on oxidosqualene cyclase that forms lanosterol in P. carinii; SAM:sterol C-24 methyltransferase that adds methyl groups at the C-24 position of the sterol side chain; and sterol 14α-demethylase that removes a methyl group at the C-14 position of the sterol nucleus; and 3 synthesis of ubiquinone homologs, which play a pivotal role in mitochondrial inner membrane and other cellular membrane electron transport.

  17. Nonlinear fitness landscape of a molecular pathway.

    Directory of Open Access Journals (Sweden)

    Lilia Perfeito

    2011-07-01

    Full Text Available Genes are regulated because their expression involves a fitness cost to the organism. The production of proteins by transcription and translation is a well-known cost factor, but the enzymatic activity of the proteins produced can also reduce fitness, depending on the internal state and the environment of the cell. Here, we map the fitness costs of a key metabolic network, the lactose utilization pathway in Escherichia coli. We measure the growth of several regulatory lac operon mutants in different environments inducing expression of the lac genes. We find a strikingly nonlinear fitness landscape, which depends on the production rate and on the activity rate of the lac proteins. A simple fitness model of the lac pathway, based on elementary biophysical processes, predicts the growth rate of all observed strains. The nonlinearity of fitness is explained by a feedback loop: production and activity of the lac proteins reduce growth, but growth also affects the density of these molecules. This nonlinearity has important consequences for molecular function and evolution. It generates a cliff in the fitness landscape, beyond which populations cannot maintain growth. In viable populations, there is an expression barrier of the lac genes, which cannot be exceeded in any stationary growth process. Furthermore, the nonlinearity determines how the fitness of operon mutants depends on the inducer environment. We argue that fitness nonlinearities, expression barriers, and gene-environment interactions are generic features of fitness landscapes for metabolic pathways, and we discuss their implications for the evolution of regulation.

  18. Environmental pathways of radioactivity to man

    International Nuclear Information System (INIS)

    The report reviews and discusses the environmental pathways by which radioactive materials can lead to the irradiation of man, in a way that should be understood by non-specialists who have neither the time nor the knowledge to study all of the relevant literature on this subject. The role of these environmental pathways in the general structure of radiological protection is considered, and the various mechanisms which lead to the dispersion or re-concentration of radioactive materials are discussed at some length. Particular groups of radionuclides from the nuclear power industry are considered in some detail. Similarly the question of the corresponding pathways from naturally-occurring radioactive materials is covered. The doses to animals and plants resulting from the nuclear industry are examined, and it is concluded that there is no reason to expect that these doses will lead to significant harm. Finally a summary is presented, and it is noted that it has been possible to obtain a very extensive knowledge of the behaviour of radionuclides in the environment only because of the extreme sensitivity of the techniques available for their detection, identification and assay. As a result a fund of knowledge has been built up about the behaviour of radioactive materials in the environment which is far more extensive than our knowledge of the behaviour of many highly toxic chemicals which are also discharged into the environment. (UK)

  19. H/CNG pathway to hydrogen

    International Nuclear Information System (INIS)

    'Full text:' The addition of hydrogen to natural gas to produce a 'premium' fuel offers an ideal bridge to the hydrogen and fuel cell era. This pathway provides many of the expected benefits of hydrogen and fuel cells, reduces cost and risk, and facilitates the transition to hydrogen incrementally through existing infrastructure, technologies and channels. The H/CNG pathway is evaluated qualitatively and quantitatively in the context of: barriers to introducing hydrogen infrastructure and how they can be addressed; potential benefits (emissions, energy security) and drawbacks (range, technical compatibility) of H/CNG blended fuels; economics; and, comparative analysis to the use of ethanol in gasoline. Leveraging the NGV industry eases the transition to fuel cells by taking advantage of existing infrastructure, technologies, skills, codes and standards, and provides for incremental change that may be more acceptable to consumers, regulators and incumbent technology providers. The greatest benefits can be achieved through a two-track pathway. One would utilize small amounts of hydrogen in existing NGVs and installed power systems - much as ethanol is added to gasoline. The second introduce products designed specifically to operate on higher levels of H/CNG, like buses, in concentrations where the greatest emission benefits can be achieved. (author)

  20. Role of Hedgehog Signaling Pathway in NASH

    Directory of Open Access Journals (Sweden)

    Mariana Verdelho Machado

    2016-06-01

    Full Text Available Non-alcoholic fatty liver disease (NAFLD is the number one cause of chronic liver disease in the Western world. Although only a minority of patients will ultimately develop end-stage liver disease, it is not yet possible to efficiently predict who will progress and, most importantly, effective treatments are still unavailable. Better understanding of the pathophysiology of this disease is necessary to improve the clinical management of NAFLD patients. Epidemiological data indicate that NAFLD prognosis is determined by an individual’s response to lipotoxic injury, rather than either the severity of exposure to lipotoxins, or the intensity of liver injury. The liver responds to injury with a synchronized wound-healing response. When this response is abnormal, it leads to pathological scarring, resulting in progressive fibrosis and cirrhosis, rather than repair. The hedgehog pathway is a crucial player in the wound-healing response. In this review, we summarize the pre-clinical and clinical evidence, which demonstrate the role of hedgehog pathway dysregulation in NAFLD pathogenesis, and the preliminary data that place the hedgehog pathway as a potential target for the treatment of this disease.

  1. Molecular Pathways: Targeting ATR in Cancer Therapy.

    Science.gov (United States)

    Karnitz, Larry M; Zou, Lee

    2015-11-01

    The human ATR gene encodes a kinase that is activated by DNA damage and replication stress as a central transducer of a checkpoint signaling pathway. Once activated, ATR phosphorylates multiple substrates, including the kinase Chk1, to regulate cell-cycle progression, replication fork stability, and DNA repair. These events promote cell survival during replication stress and in cells with DNA damage. Accordingly, there has been the tantalizing possibility that ATR inhibitors would be therapeutically useful, especially if they were more effective in tumor versus normal cells. Indeed, multiple studies have demonstrated that alterations that promote tumorigenesis, such as defects in the ATM-p53 pathway, constitutive oncogene activation, and acquisition of the alternative lengthening of telomeres pathway, render tumor cells sensitive to ATR inhibitor monotherapy and/or increase the synergy between ATR inhibitors and genotoxic chemotherapies. Now, nearly two decades after the discovery of ATR, two highly selective and potent ATR inhibitors, AZD6738 and VX-970, are in early-phase clinical trials either as monotherapies or paired with a variety of genotoxic chemotherapies. These trials will generate important insights into the effects of ATR inhibition in humans and the potential role of inhibiting this kinase in the treatment of human malignancies. PMID:26362996

  2. Role of Hedgehog Signaling Pathway in NASH.

    Science.gov (United States)

    Verdelho Machado, Mariana; Diehl, Anna Mae

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease in the Western world. Although only a minority of patients will ultimately develop end-stage liver disease, it is not yet possible to efficiently predict who will progress and, most importantly, effective treatments are still unavailable. Better understanding of the pathophysiology of this disease is necessary to improve the clinical management of NAFLD patients. Epidemiological data indicate that NAFLD prognosis is determined by an individual's response to lipotoxic injury, rather than either the severity of exposure to lipotoxins, or the intensity of liver injury. The liver responds to injury with a synchronized wound-healing response. When this response is abnormal, it leads to pathological scarring, resulting in progressive fibrosis and cirrhosis, rather than repair. The hedgehog pathway is a crucial player in the wound-healing response. In this review, we summarize the pre-clinical and clinical evidence, which demonstrate the role of hedgehog pathway dysregulation in NAFLD pathogenesis, and the preliminary data that place the hedgehog pathway as a potential target for the treatment of this disease. PMID:27258259

  3. Pathways, Networks and Systems Medicine Conferences

    Energy Technology Data Exchange (ETDEWEB)

    Nadeau, Joseph H. [Pacific Northwest Research Institute

    2013-11-25

    The 6th Pathways, Networks and Systems Medicine Conference was held at the Minoa Palace Conference Center, Chania, Crete, Greece (16-21 June 2008). The Organizing Committee was composed of Joe Nadeau (CWRU, Cleveland), Rudi Balling (German Research Centre, Brauschweig), David Galas (Institute for Systems Biology, Seattle), Lee Hood (Institute for Systems Biology, Seattle), Diane Isonaka (Seattle), Fotis Kafatos (Imperial College, London), John Lambris (Univ. Pennsylvania, Philadelphia),Harris Lewin (Univ. of Indiana, Urbana-Champaign), Edison Liu (Genome Institute of Singapore, Singapore), and Shankar Subramaniam (Univ. California, San Diego). A total of 101 individuals from 21 countries participated in the conference: USA (48), Canada (5), France (5), Austria (4), Germany (3), Italy (3), UK (3), Greece (2), New Zealand (2), Singapore (2), Argentina (1), Australia (1), Cuba (1), Denmark (1), Japan (1), Mexico (1), Netherlands (1), Spain (1), Sweden (1), Switzerland (1). With respect to speakers, 29 were established faculty members and 13 were graduate students or postdoctoral fellows. With respect to gender representation, among speakers, 13 were female and 28 were male, and among all participants 43 were female and 58 were male. Program these included the following topics: Cancer Pathways and Networks (Day 1), Metabolic Disease Networks (Day 2), Day 3 ? Organs, Pathways and Stem Cells (Day 3), and Day 4 ? Inflammation, Immunity, Microbes and the Environment (Day 4). Proceedings of the Conference were not published.

  4. Sonic hedgehog-Gli1 pathway in colorectal adenocarcinomas

    OpenAIRE

    Bian, Yue-Hong; Huang, Shu-Hong; Yang, Ling; Ma, Xiao-Li; Xie, Jing-Wu; Zhang, Hong-Wei

    2007-01-01

    AIM: To determine the role of Sonic hedgehog (Shh) pathway in colorectal adenocarcinomas through analysis of the expression of Shh pathway-related molecules, Shh, Ptch1, hedgehog-interacting protein (Hip), Gli1, Gli3 and PDGFRα.

  5. Evaluating pathway enumeration algorithms in metabolic engineering case studies

    OpenAIRE

    Liu, Filipe; Vilaça, Paulo; Rocha, I; Rocha, Miguel

    2014-01-01

    The design of cell factories for the production of compounds involves the search for suitable heterologous pathways. Different strategies have been proposed to infer such pathways, but most are optimization approaches with specific objective functions, not suited to enumerate multiple pathways. In this work, we analyze two pathway enumeration algorithms based on graph representations: the Solution Structure Generation and the Find Path algorithms. Both are capable of enumerating exhaustively ...

  6. Minimal metabolic pathway structure is consistent with associated biomolecular interactions

    OpenAIRE

    Bordbar, Aarash; Nagarajan, Harish; Lewis, Nathan E.; Latif, Haythem; Ebrahim, Ali; Federowicz, Stephen; Schellenberger, Jan; Palsson, Bernhard

    2014-01-01

    Pathways are a universal paradigm for functionally describing cellular processes. Even though advances in high-throughput data generation have transformed biology, the core of our biological understanding, and hence data interpretation, is still predicated on human-defined pathways. Here, we introduce an unbiased, pathway structure for genome-scale metabolic networks defined based on principles of parsimony that do not mimic canonical human-defined textbook pathways. Instead, these minimal pa...

  7. Inherited variation in immune genes and pathways and glioblastoma risk

    OpenAIRE

    Schwartzbaum, Judith A.; Xiao, Yuanyuan; Liu, Yanhong; Tsavachidis, Spyros; Berger, Mitchel S.; Bondy, Melissa L,; Chang, Jeffrey S.; Chang, Susan M.; Decker, Paul A.; Ding, Bo; Hepworth, Sarah J; Richard S. Houlston; Hosking, Fay J; Jenkins, Robert B.; Kosel, Matthew L.

    2010-01-01

    To determine whether inherited variations in immune function single-nucleotide polymorphisms (SNPs), genes or pathways affect glioblastoma risk, we analyzed data from recent genome-wide association studies in conjunction with predefined immune function genes and pathways. Gene and pathway analyses were conducted on two independent data sets using 6629 SNPs in 911 genes on 17 immune pathways from 525 glioblastoma cases and 602 controls from the University of California, San Francisco (UCSF) an...

  8. Lethal Mutations in the Isoprenoid Pathway of Salmonella enterica

    OpenAIRE

    Cornish, Rita M.; Roth, John R.; Poulter, C. Dale

    2006-01-01

    Essential isoprenoid compounds are synthesized using the 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway in many gram-negative bacteria, some gram-positive bacteria, some apicomplexan parasites, and plant chloroplasts. The alternative mevalonate pathway is found in archaea and eukaryotes, including cytosolic biosynthesis in plants. The existence of orthogonal essential pathways in eukaryotes and bacteria makes the MEP pathway an attractive target for the development of antimicrobial agents....

  9. A Study of the PDGF Signaling Pathway with PRISM

    OpenAIRE

    Qixia Yuan; Jun Pang; Sjouke Mauw; Panuwat Trairatphisan; Monique Wiesinger; Thomas Sauter

    2011-01-01

    In this paper, we apply the probabilistic model checker PRISM to the analysis of a biological system -- the Platelet-Derived Growth Factor (PDGF) signaling pathway, demonstrating in detail how this pathway can be analyzed in PRISM. We show that quantitative verification can yield a better understanding of the PDGF signaling pathway.

  10. Roles of Pathways in Self-Access Centres.

    Science.gov (United States)

    Kell, James; Newton, Clive

    1997-01-01

    Discusses possible roles for self-access pathways to guide second-language learners, particularly in cultures that have no tradition of self-study. Suggests how pathways might influence the design and running of self-access centers and gives an illustration of how pathways were designed and employed in a center in China. Feedback is based on a…

  11. Development of Network Analysis and Visualization System for KEGG Pathways

    Directory of Open Access Journals (Sweden)

    Dongmin Seo

    2015-07-01

    Full Text Available Big data refers to informationalization technology for extracting valuable information through the use and analysis of large-scale data and, based on that data, deriving plans for response or predicting changes. With the development of software and devices for next generation sequencing, a vast amount of bioinformatics data has been generated recently. Also, bioinformatics data based big-data technology is rising rapidly as a core technology by the bioinformatician, biologist and big-data scientist. KEGG pathway is bioinformatics data for understanding high-level functions and utilities of the biological system. However, KEGG pathway analysis requires a lot of time and effort because KEGG pathways are high volume and very diverse. In this paper, we proposed a network analysis and visualization system that crawl user interest KEGG pathways, construct a pathway network based on a hierarchy structure of pathways and visualize relations and interactions of pathways by clustering and selecting core pathways from the network. Finally, we construct a pathway network collected by starting with an Alzheimer’s disease pathway and show the results on clustering and selecting core pathways from the pathway network.

  12. Pathways to nuclear disarmament:delegitimising nuclear violence

    OpenAIRE

    Ritchie, Nicholas Edward

    2016-01-01

    This paper explores pathways for diplomatic responses to the continuing threat of nuclear violence. It differentiates between pathways focussed on the devaluing of nuclear weapons by the nuclear-armed states and pathways focussed on delegitimising nuclear weapons by a wider community of states.

  13. The carotenoid biosynthetic pathway: thinking in all dimensions.

    Science.gov (United States)

    Shumskaya, Maria; Wurtzel, Eleanore T

    2013-07-01

    The carotenoid biosynthetic pathway serves manifold roles in plants related to photosynthesis, photoprotection, development, stress hormones, and various volatiles and signaling apocarotenoids. The pathway also produces compounds that impact human nutrition and metabolic products that contribute to fragrance and flavor of food and non-food crops. It is no surprise that the pathway has been a target of metabolic engineering, most prominently in the case of Golden Rice. The future success and predictability of metabolic engineering of carotenoids rests in the ability to target carotenoids for specific physiological purposes as well as to simultaneously modify carotenoids along with other desired traits. Here, we ask whether predictive metabolic engineering of the carotenoid pathway is indeed possible. Despite a long history of research on the pathway, at this point in time we can only describe the pathway as a parts list and have almost no knowledge of the location of the complete pathway, how it is assembled, and whether there exists any trafficking of the enzymes or the carotenoids themselves. We discuss the current state of knowledge regarding the "complete" pathway and make the argument that predictive metabolic engineering of the carotenoid pathway (and other pathways) will require investigation of the three dimensional state of the pathway as it may exist in plastids of different ultrastructures. Along with this message we point out the need to develop new types of visualization tools and resources that better reflect the dynamic nature of biosynthetic pathways. PMID:23683930

  14. Phosphoketolase pathway dominates in Lactobacillus reuteri ATCC 55730 containing dual pathways for glycolysis.

    Science.gov (United States)

    Arsköld, Emma; Lohmeier-Vogel, Elke; Cao, Rong; Roos, Stefan; Rådström, Peter; van Niel, Ed W J

    2008-01-01

    Metabolic flux analysis indicated that the heterofermentative Lactobacillus reuteri strain ATCC 55730 uses both the Embden-Meyerhof pathway (EMP) and phosphoketolase pathway (PKP) when glucose or sucrose is converted into the three-carbon intermediate stage of glycolysis. In all cases studied, the main flux is through the PKP, while the EMP is used as a shunt. In the exponential growth phase, 70%, 73%, and 84% of the flux goes through the PKP in cells metabolizing (i) glucose plus fructose, (ii) glucose alone, and (iii) sucrose alone, respectively. Analysis of the genome of L. reuteri ATCC 55730 confirmed the presence of the genes for both pathways. Further evidence for the simultaneous operation of two central carbon metabolic pathways was found through the detection of fructose-1,6-bisphosphate aldolase, phosphofructokinase, and phosphoglucoisomerase activities and the presence of phosphorylated EMP and PKP intermediates using in vitro 31P NMR. The maximum specific growth rate and biomass yield obtained on glucose were twice as low as on sucrose. This was the result of low ATP levels being present in glucose-metabolizing cells, although the ATP production flux was as high as in sucrose-metabolizing cells due to a twofold increase of enzyme activities in both glycolytic pathways. Growth performance on glucose could be improved by adding fructose as an external electron acceptor, suggesting that the observed behavior is due to a redox imbalance causing energy starvation. PMID:17965151

  15. Hypoxia Inducible Factor Pathway and Physiological Adaptation: A Cell Survival Pathway?

    Science.gov (United States)

    Kumar, Hemant; Choi, Dong-Kug

    2015-01-01

    Oxygen homeostasis reflects the constant body requirement to generate energy. Hypoxia (0.1-1% O2), physioxia or physoxia (∼1-13%), and normoxia (∼20%) are terms used to define oxygen concentration in the cellular environment. A decrease in oxygen (hypoxia) or excess oxygen (hyperoxia) could be deleterious for cellular adaptation and survival. Hypoxia can occur under both physiological (e.g., exercise, embryonic development, underwater diving, or high altitude) and pathological conditions (e.g., inflammation, solid tumor formation, lung disease, or myocardial infarction). Hypoxia plays a key role in the pathophysiology of heart disease, cancers, stroke, and other causes of mortality. Hypoxia inducible factor(s) (HIFs) are key oxygen sensors that mediate the ability of the cell to cope with decreased oxygen tension. These transcription factors regulate cellular adaptation to hypoxia and protect cells by responding acutely and inducing production of endogenous metabolites and proteins to promptly regulate metabolic pathways. Here, we review the role of the HIF pathway as a metabolic adaptation pathway and how this pathway plays a role in cell survival. We emphasize the roles of the HIF pathway in physiological adaptation, cell death, pH regulation, and adaptation during exercise. PMID:26491231

  16. Development and Implementation of Oncology Care Pathways in an Integrated Care Network: The Via Oncology Pathways Experience

    OpenAIRE

    Ellis, Peter G.

    2013-01-01

    The Via Pathways model used at the UPMC CancerCenter, in which the oncologists developing the clinical content are ultimately those who use the pathways portal, has proven to be successful in ensuring physician participation.

  17. Comparative classification of species and the study of pathway evolution based on the alignment of metabolic pathways

    OpenAIRE

    2010-01-01

    Background Pathways provide topical descriptions of cellular circuitry. Comparing analogous pathways reveals intricate insights into individual functional differences among species. While previous works in the field performed genomic comparisons and evolutionary studies that were based on specific genes or proteins, whole genomic sequence, or even single pathways, none of them described a genomic system level comparative analysis of metabolic pathways. In order to properly implement such an a...

  18. Estudo da variação do pH da pele humana exposta à formulação cosmética acrescida ou não das vitaminas A, E ou de ceramida, por metodologia não invasiva Study of pH variation on the skin using cosmetic formulation s with and without vitamins A, E or ceramide: by a non-invasive method

    Directory of Open Access Journals (Sweden)

    Gislaine Ricci Leonardi

    2002-10-01

    Full Text Available FUNDAMENTOS: Os cosméticos hidratantes melhoram a pele, aproximando-a de suas condições ideais, pois aumentam a quantidade de água no estrato córneo. As vitaminas A e E, bem como as ceramidas, são substâncias ativas que vêm sendo muito empregadas em hidratantes, os quais constituem uma das mais importantes classes de produtos cosméticos e de higiene corporal. OBJETIVO: - O objetivo deste trabalho foi avaliar o efeito no pH cutâneo da pele humana de uma emulsão O/A (constituída de base auto-emulsionante não iônica acrescida, ou não, de vitamina A palmitato ou vitamina E acetato ou ceramida III, por metodologia não invasiva MÉTODOS:O estudo foi realizado em 40 mulheres com idade entre 30 e 45 anos, empregando-se o equipamento Skin Phmeter PH 900 PC. As medidas foram efetuadas no antebraço das voluntárias nos tempos de sete e 30 dias após auto-aplicação diária (duas vezes ao dia, dos produtos envolvidos no estudo RESULTADOS E CONCLUSÃO: A presença das vitaminas A ou E, ou da ceramida não alterou de maneira significativa o pH da pele, o que mostra que as formulações estudadas são adequadas para o uso cosmético.BACKGROUND: Moisturizers are believed to improve the skin's condition by increasing the water content of the stratum corneum. Vitamins A and E and ceramides have been widely used in cosmetic moisturizing products, and these are one of the most important cosmetic and body care products. OBJECTIVE: The aim of this research was to evaluate the effects on the pH of human skin of an O/W emulsion (non ionic self-emulsifying base with and without vitamin A palmitate, or vitamin E acetate, or ceramide III, using a non-invasive method. METHOD: The investigations were carried out on a group of 40 healthy female test subjects aged between 30 and 45 years old, using the Skin pH meter PH 900 PC. The measurements were performed on the forearm of volunteers at 7 and 30 days after daily use (twice a day of the products used in

  19. pathways to deep decarbonization - 2014 report

    International Nuclear Information System (INIS)

    The Deep Decarbonization Pathways Project (DDPP) is a collaborative initiative to understand and show how individual countries can transition to a low-carbon economy and how the world can meet the internationally agreed target of limiting the increase in global mean surface temperature to less than 2 degrees Celsius (deg. C). Achieving the 2 deg. C limit will require that global net emissions of greenhouse gases (GHG) approach zero by the second half of the century. This will require a profound transformation of energy systems by mid-century through steep declines in carbon intensity in all sectors of the economy, a transition we call 'deep decarbonization.' Successfully transition to a low-carbon economy will require unprecedented global cooperation, including a global cooperative effort to accelerate the development and diffusion of some key low carbon technologies. As underscored throughout this report, the results of the DDPP analyses remain preliminary and incomplete. The DDPP proceeds in two phases. This 2014 report describes the DDPP's approach to deep decarbonization at the country level and presents preliminary findings on technically feasible pathways to deep decarbonization, utilizing technology assumptions and timelines provided by the DDPP Secretariat. At this stage we have not yet considered the economic and social costs and benefits of deep decarbonization, which will be the topic for the next report. The DDPP is issuing this 2014 report to the UN Secretary-General Ban Ki-moon in support of the Climate Leaders' Summit at the United Nations on September 23, 2014. This 2014 report by the Deep Decarbonization Pathway Project (DDPP) summarizes preliminary findings of the technical pathways developed by the DDPP Country Research Partners with the objective of achieving emission reductions consistent with limiting global warming to less than 2 deg. C., without, at this stage, consideration of economic and social costs and benefits. The DDPP is a knowledge

  20. Notch, Wnt, and Hedgehog Pathways in Rhabdomyosarcoma: From Single Pathways to an Integrated Network

    Directory of Open Access Journals (Sweden)

    Josep Roma

    2012-01-01

    Full Text Available Rhabdomyosarcoma (RMS is the most common type of soft tissue sarcoma in children. Regarding histopathological criteria, RMS can be divided into 2 main subtypes: embryonal and alveolar. These subtypes differ considerably in their clinical phenotype and molecular features. Abnormal regulation or mutation of signalling pathways that regulate normal embryonic development such as Notch, Hedgehog, and Wnt is a recurrent feature in tumorigenesis. Herein, the general features of each of the three pathways, their implication in cancer and particularly in RMS are reviewed. Finally, the cross-talking among these three pathways and the possibility of better understanding of the horizontal communication among them, leading to the development of more potent therapeutic approaches, are discussed.

  1. DMPD: TLR pathways and IFN-regulatory factors: to each its own. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17273997 TLR pathways and IFN-regulatory factors: to each its own. Colonna M. Eur J... Immunol. 2007 Feb;37(2):306-9. (.png) (.svg) (.html) (.csml) Show TLR pathways and IFN-regulatory factors: ...to each its own. PubmedID 17273997 Title TLR pathways and IFN-regulatory factors: to each its own. Authors C

  2. DMPD: Multiple signaling pathways leading to the activation of interferon regulatoryfactor 3. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 12213596 Multiple signaling pathways leading to the activation of interferon regulatoryfactor...(.html) (.csml) Show Multiple signaling pathways leading to the activation of interferon regulatoryfactor 3.... PubmedID 12213596 Title Multiple signaling pathways leading to the activation of... interferon regulatoryfactor 3. Authors Servant MJ, Grandvaux N, Hiscott J. Publication Biochem Pharmacol. 2

  3. Policy Pathways: Modernising Building Energy Codes

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2013-08-01

    Buildings are the largest consumers of energy worldwide and will continue to be a source of increasing energy demand in the future. Globally, the sector’s final energy consumption doubled between 1971 and 2010 to reach 2 794 million tonnes of oil equivalent (Mtoe), driven primarily by population increase and economic growth. Under current policies, the global energy demand of buildings is projected by the IEA experts to grow by an additional 838 Mtoe by 2035 compared to 2010. The challenges of the projected increase of energy consumption due to the built environment vary by country. In IEA member countries, much of the future buildings stock is already in place, and so the main challenge is to renovate existing buildings stock. In non-IEA countries, more than half of the buildings stock needed by 2050 has yet to be built. The IEA and the UNDP partnered to analyse current practices in the design and implementation of building energy codes. The aim is to consolidate existing efforts and to encourage more attention to the role of the built environment in a low-carbon and climate-resilient world. This joint IEA-UNDP Policy Pathway aims to share lessons learned between IEA member countries and non-IEA countries. The objective is to spread best practices, limit pressures on global energy supply, improve energy security, and contribute to environmental sustainability. Part of the IEA Policy Pathway series, Modernising building energy codes to secure our global energy future sets out key steps in planning, implementation, monitoring and evaluation. The Policy Pathway series aims to help policy makers implement the IEA 25 Energy Efficiency Policy Recommendations endorsed by IEA Ministers (2011).

  4. Curation and Computational Design of Bioenergy-Related Metabolic Pathways

    Energy Technology Data Exchange (ETDEWEB)

    Karp, Peter D. [SRI International, Menlo Park, CA (United States)

    2014-09-12

    Pathway Tools is a systems-biology software package written by SRI International (SRI) that produces Pathway/Genome Databases (PGDBs) for organisms with a sequenced genome. Pathway Tools also provides a wide range of capabilities for analyzing predicted metabolic networks and user-generated omics data. More than 5,000 academic, industrial, and government groups have licensed Pathway Tools. This user community includes researchers at all three DOE bioenergy centers, as well as academic and industrial metabolic engineering (ME) groups. An integral part of the Pathway Tools software is MetaCyc, a large, multiorganism database of metabolic pathways and enzymes that SRI and its academic collaborators manually curate. This project included two main goals: I. Enhance the MetaCyc content of bioenergy-related enzymes and pathways. II. Develop computational tools for engineering metabolic pathways that satisfy specified design goals, in particular for bioenergy-related pathways. In part I, SRI proposed to significantly expand the coverage of bioenergy-related metabolic information in MetaCyc, followed by the generation of organism-specific PGDBs for all energy-relevant organisms sequenced at the DOE Joint Genome Institute (JGI). Part I objectives included: 1: Expand the content of MetaCyc to include bioenergy-related enzymes and pathways. 2: Enhance the Pathway Tools software to enable display of complex polymer degradation processes. 3: Create new PGDBs for the energy-related organisms sequenced by JGI, update existing PGDBs with new MetaCyc content, and make these data available to JBEI via the BioCyc website. In part II, SRI proposed to develop an efficient computational tool for the engineering of metabolic pathways. Part II objectives included: 4: Develop computational tools for generating metabolic pathways that satisfy specified design goals, enabling users to specify parameters such as starting and ending compounds, and preferred or disallowed intermediate compounds

  5. Freshwater exposure pathways in the Nordic countries

    International Nuclear Information System (INIS)

    The report relates to a subproject under a Nordic project called ''Large reactor accidents - consequences and mitigating actions''. The report summarizes information available, primarily in the Nordic countries, on freshwater exposure pathways. Experimental and theoretical data concerning the deposition and run-off of the nuclides *sp90*Sr and*Sp137*Cs is presented. Internal exposure via drinking water and freshwater fish is dealt with, as well as external exposure due to swimming, boating, contact with fishing utensils and use of beach areas. In addition is exposure via irrigated agricultural products considered. (RF)

  6. Minimum Energy Pathways for Chemical Reactions

    Science.gov (United States)

    Walch, S. P.; Langhoff, S. R. (Technical Monitor)

    1995-01-01

    Computed potential energy surfaces are often required for computation of such parameters as rate constants as a function of temperature, product branching ratios, and other detailed properties. We have found that computation of the stationary points/reaction pathways using CASSCF/derivative methods, followed by use of the internally contracted CI method to obtain accurate energetics, gives useful results for a number of chemically important systems. The talk will focus on a number of applications to reactions leading to NOx and soot formation in hydrocarbon combustion.

  7. Policy Pathways: Monitoring, Verification and Enforcement

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2010-07-01

    The IEA estimates that, if implemented globally without delay, the 25 IEA Energy Efficiency recommendations could save 8.2 Gt CO2 per year by 2030. Yet many governments struggle with their implementation and thus miss a great part of the energy efficiency potential. The new IEA series Policy Pathways: Showing the way to energy efficiency implementation now aims to assist countries with improving energy efficiency policies. It features practical 'how-to' guides for designing, implementing and evaluating energy efficiency policies and achieving greater improvement.

  8. A new pathway for lower limb ulceration

    OpenAIRE

    Atkin, Leanne; Tickle, Joy

    2016-01-01

    Leg ulceration is a common cause of suffering for patients, additionally it places a significant burden on the NHS. As the NHS continues to face times of austerity, services need to find other ways of working to reduce cost and release nursing time whilst maintaining standards of care. The implementation of a pathway for the treatment of leg ulceration, which aids diagnosis and uses compression hosiery kits as a first-line management for venous leg ulceration, can form part of the solution by...

  9. On the interconversion pathway of HBOBOH

    Science.gov (United States)

    Peng, Qian; Wang, Yubin; Suo, Bing; Shi, Qizhen; Wen, Zhenyi

    2004-07-01

    The potential energy surfaces have been constructed for the 1A', 3A', and 3A″ states of HBO by using the multireference perturbation theory with the basis set cc-pVTZ (6d,10f ). Two stationary points and a transition state have been characterized on all the three surfaces, which are in good agreement with available experiments and previous calculations. The interconversion pathways from metastable boron hydroxide BOH to the considerably more stable HBO are expounded based on the nature of the surfaces.

  10. Ontology modeling for generation of clinical pathways

    Directory of Open Access Journals (Sweden)

    Jasmine Tehrani

    2012-12-01

    Full Text Available Purpose: Increasing costs of health care, fuelled by demand for high quality, cost-effective healthcare has drove hospitals to streamline their patient care delivery systems. One such systematic approach is the adaptation of Clinical Pathways (CP as a tool to increase the quality of healthcare delivery. However, most organizations still rely on are paper-based pathway guidelines or specifications, which have limitations in process management and as a result can influence patient safety outcomes. In this paper, we present a method for generating clinical pathways based on organizational semiotics by capturing knowledge from syntactic, semantic and pragmatic to social level. Design/methodology/approach: The proposed modeling approach to generation of CPs adopts organizational semiotics and enables the generation of semantically rich representation of CP knowledge. Semantic Analysis Method (SAM is applied to explicitly represent the semantics of the concepts, their relationships and patterns of behavior in terms of an ontology chart. Norm Analysis Method (NAM is adopted to identify and formally specify patterns of behavior and rules that govern the actions identified on the ontology chart. Information collected during semantic and norm analysis is integrated to guide the generation of CPs using best practice represented in BPMN thus enabling the automation of CP. Findings: This research confirms the necessity of taking into consideration social aspects in designing information systems and automating CP. The complexity of healthcare processes can be best tackled by analyzing stakeholders, which we treat as social agents, their goals and patterns of action within the agent network. Originality/value: The current modeling methods describe CPs from a structural aspect comprising activities, properties and interrelationships. However, these methods lack a mechanism to describe possible patterns of human behavior and the conditions under which the

  11. Exposure pathways and environmental dose assessment

    International Nuclear Information System (INIS)

    Radionuclides released into the environment from various nuclear facilities during normal operating conditions and under accident conditions eventually reach man through various pathways of exposure. It is required to assess the dose received by members of the public at various stages of nuclear facility. At the design stage of the nuclear facility such assessment is necessary for determining the adequacy of design provisions. During the operational phase, the assessment is needed to establish compliance with the standards and limits laid down for the facility and site

  12. Synthetic pathways to make nanoparticles fluorescent

    Science.gov (United States)

    Sokolova, Viktoriya; Epple, Matthias

    2011-05-01

    In biosciences, it is often necessary to follow the pathway of nanoparticles within cells or tissues. The nanoparticles can be used as labeled sensors which may, e.g., address functionalities within a cell, carry other specific agents like drugs or be magnetic for tumor thermotherapy. In the context of nanotoxicology, the fate of a given nanoparticle is of interest. As many methods in cell biology are based on fluorescence detection, there is a strong demand to make nanoparticles fluorescent. Different ways to introduce fluorescence are reviewed and exemplified with typical kinds of nanoparticles, i.e. polymers, silica and calcium phosphate.

  13. Life cycle analysis of transportation fuel pathways

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2012-02-24

    The purpose of this work is to improve the understanding of the concept of life cycle analysis (LCA) of transportation fuels and some of its pertinent issues among non-technical people, senior managers, and policy makers. This work should provide some guidance to nations considering LCA-based policies and to people who are affected by existing policies or those being developed. While the concept of employing LCA to evaluate fuel options is simple and straightforward, the act of putting the concept into practice is complex and fraught with issues. Policy makers need to understand the limitations inherent in carrying out LCA work for transportation fuel systems. For many systems, even those that have been employed for a 100 years, there is a lack of sound data on the performance of those systems. Comparisons between systems should ideally be made using the same tool, so that differences caused by system boundaries, allocation processes, and temporal issues can be minimized (although probably not eliminated). Comparing the results for fuel pathway 1 from tool A to those of fuel system 2 from tool B introduces significant uncertainty into the results. There is also the question of the scale of system changes. LCA will give more reliable estimates when it is used to examine small changes in transportation fuel pathways than when used to estimate large scale changes that replace current pathways with completely new pathways. Some LCA tools have been developed recently primarily for regulatory purposes. These tools may deviate from ISO principles in order to facilitate simplicity and ease of use. In a regulatory environment, simplicity and ease of use are worthy objectives and in most cases there is nothing inherently wrong with this approach, particularly for assessing relative performance. However, the results of these tools should not be confused with, or compared to, the results that are obtained from a more complex and rigorous ISO compliant LCA. It should be

  14. Complement pathways and meningococcal disease : diagnostic aspects

    DEFF Research Database (Denmark)

    Sjöholm, A G; Truedsson, L; Jensenius, Jens Christian

    2001-01-01

    activation on the bacterial surface (6,7). The newly discovered mannan-binding lectin (MBL) pathway of complement activation appears to be protective against many types of infection (8) and adds previously unsuspected aspects of innate immunity to complement-mediated defense. Interestingly, immune responses...... are influenced by complement (9), and it could be that acquisition of protective antibodies is impaired in some types of complement deficiency. A further aspect of interactions between Neisseria and complement is the potential role of membrane-bound complement regulators as cellular receptors for the...

  15. Small fusion reactors: problems, promise, and pathways

    International Nuclear Information System (INIS)

    The prevalent vision of magnetic fusion as a central-station power plant projects a high-technology, low-power-density nuclear boiler that may require high energy costs to be economic. Smaller, higher-power-density approaches can reduce the impact of the fusion power core and associated support equipment on the overall cost equation for fusion. In the course of attaining sizes, power capacity, and costs that are more in line with alternative energy sources, a range of problems, promise, and pathways can be identified. The issues related to these more compact systems are addressed on the basis of generic reactor models

  16. KeyPathwayMiner 4.0

    DEFF Research Database (Denmark)

    Alcaraz, Nicolas; Pauling, Josch; Batra, Richa;

    2014-01-01

    BACKGROUND: Over the last decade network enrichment analysis has become popular in computational systems biology to elucidate aberrant network modules. Traditionally, these approaches focus on combining gene expression data with protein-protein interaction (PPI) networks. Nowadays, the so...... release of KeyPathwayMiner (version 4.0) that is not limited to analyses of single omics data sets, e.g. gene expression, but is able to directly combine several different omics data types. Version 4.0 can further integrate existing knowledge by adding a search bias towards sub-networks that contain...

  17. The metabolic pathway collection from EMP: the enzymes and metabolic pathways database.

    Science.gov (United States)

    Selkov, E; Basmanova, S; Gaasterland, T; Goryanin, I; Gretchkin, Y; Maltsev, N; Nenashev, V; Overbeek, R; Panyushkina, E; Pronevitch, L; Selkov, E; Yunus, I

    1996-01-01

    The Enzymes and Metabolic Pathways database (EMP) is an encoding of the contents of over 10 000 original publications on the topics of enzymology and metabolism. This large body of information has been transformed into a queryable database. An extraction of over 1800 pictorial representations of metabolic pathways from this collection is freely available on the World Wide Web. We believe that this collection will play an important role in the interpretation of genetic sequence data, as well as offering a meaningful framework for the integration of many other forms of biological data. PMID:8594593

  18. Parental and adolescent health behaviors and pathways to adulthood.

    Science.gov (United States)

    Bauldry, Shawn; Shanahan, Michael J; Macmillan, Ross; Miech, Richard A; Boardman, Jason D; O Dean, Danielle; Cole, Veronica

    2016-07-01

    This paper examines associations among parental and adolescent health behaviors and pathways to adulthood. Using data from the National Longitudinal Study of Adolescent to Adult Health, we identify a set of latent classes describing pathways into adulthood and examine health-related predictors of these pathways. The identified pathways are consistent with prior research using other sources of data. Results also show that both adolescent and parental health behaviors differentiate pathways. Parental and adolescent smoking are associated with lowered probability of the higher education pathway and higher likelihood of the work and the work & family pathways (entry into the workforce soon after high school completion). Adolescent drinking is positively associated with the work pathway and the higher education pathway, but decreases the likelihood of the work & family pathway. Neither parental nor adolescent obesity are associated with any of the pathways to adulthood. When combined, parental/adolescent smoking and adolescent drinking are associated with displacement from the basic institutions of school, work, and family. PMID:27194662

  19. BowTieBuilder: modeling signal transduction pathways

    Directory of Open Access Journals (Sweden)

    Schröder Adrian

    2009-06-01

    Full Text Available Abstract Background Sensory proteins react to changing environmental conditions by transducing signals into the cell. These signals are integrated into core proteins that activate downstream target proteins such as transcription factors (TFs. This structure is referred to as a bow tie, and allows cells to respond appropriately to complex environmental conditions. Understanding this cellular processing of information, from sensory proteins (e.g., cell-surface proteins to target proteins (e.g., TFs is important, yet for many processes the signaling pathways remain unknown. Results Here, we present BowTieBuilder for inferring signal transduction pathways from multiple source and target proteins. Given protein-protein interaction (PPI data signaling pathways are assembled without knowledge of the intermediate signaling proteins while maximizing the overall probability of the pathway. To assess the inference quality, BowTieBuilder and three alternative heuristics are applied to several pathways, and the resulting pathways are compared to reference pathways taken from KEGG. In addition, BowTieBuilder is used to infer a signaling pathway of the innate immune response in humans and a signaling pathway that potentially regulates an underlying gene regulatory network. Conclusion We show that BowTieBuilder, given multiple source and/or target proteins, infers pathways with satisfactory recall and precision rates and detects the core proteins of each pathway.

  20. Pathway-Specific Striatal Substrates for Habitual Behavior.

    Science.gov (United States)

    O'Hare, Justin K; Ade, Kristen K; Sukharnikova, Tatyana; Van Hooser, Stephen D; Palmeri, Mark L; Yin, Henry H; Calakos, Nicole

    2016-02-01

    The dorsolateral striatum (DLS) is implicated in habit formation. However, the DLS circuit mechanisms underlying habit remain unclear. A key role for DLS is to transform sensorimotor cortical input into firing of output neurons that project to the mutually antagonistic direct and indirect basal ganglia pathways. Here we examine whether habit alters this input-output function. By imaging cortically evoked firing in large populations of pathway-defined striatal projection neurons (SPNs), we identify features that strongly correlate with habitual behavior on a subject-by-subject basis. Habitual behavior correlated with strengthened DLS output to both pathways as well as a tendency for action-promoting direct pathway SPNs to fire before indirect pathway SPNs. In contrast, habit suppression correlated solely with a weakened direct pathway output. Surprisingly, all effects were broadly distributed in space. Together, these findings indicate that the striatum imposes broad, pathway-specific modulations of incoming activity to render learned motor behaviors habitual. PMID:26804995