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Sample records for alas tiit elenurm

  1. ALA Standards Manual.

    ERIC Educational Resources Information Center

    American Library Association, Chicago, IL. Committee on Standards.

    This American Library Association (ALA) policy statement and procedure manual is intended for use in the preparation of all standards issued by ALA and its component units to insure coordination of format and correlation of content of ALA standards. A brief discussion of the purpose of standards is offered, followed by definitions of four types of…

  2. ALA Standards Manual.

    ERIC Educational Resources Information Center

    American Library Association, Chicago, IL. Committee on Standards.

    This American Library Association (ALA) policy statement and procedure manual is intended for use in the preparation of all standards issued by ALA and its component units to insure coordination of format and correlation of content of ALA standards. A brief discussion of the purpose of standards is offered, followed by definitions of four types of…

  3. ALA Candidates: Presidential Timbre

    ERIC Educational Resources Information Center

    Berry, John N., III

    2010-01-01

    This article presents an interview with two effective spokespeople, notable school librarian Sara Kelly Johns and retired public library administrator Molly Raphael, who compete to be American Library Association (ALA) president. One of them will be elected president of ALA for a year's term beginning in July 2011. Each candidate comes from a…

  4. ALA Candidates: Presidential Timbre

    ERIC Educational Resources Information Center

    Berry, John N., III

    2010-01-01

    This article presents an interview with two effective spokespeople, notable school librarian Sara Kelly Johns and retired public library administrator Molly Raphael, who compete to be American Library Association (ALA) president. One of them will be elected president of ALA for a year's term beginning in July 2011. Each candidate comes from a…

  5. Delta-ALA urine test

    MedlinePlus

    ... be used to help diagnose a condition called porphyria . Normal Results Normal value range for adults is ... of urinary delta-ALA may indicate: Lead poisoning Porphyria (several types) A decreased level may occur with ...

  6. ALA Conference 2009: Chicago Hope

    ERIC Educational Resources Information Center

    Berry, John N., III

    2009-01-01

    There is joy among those who have the funds to go to Chicago for the American Library Association (ALA) annual conference, July 9-15. Every librarian knows there is nothing better than a Chicago gathering, with the city's wonderful haunts, museums, restaurants, and fine memories of past conferences. The conference program covers nearly every…

  7. ALA 2010: The Costly Cornucopia

    ERIC Educational Resources Information Center

    Berry, John N., III

    2010-01-01

    Every librarian wants to go to the American Library Association (ALA) annual conference in Washington, DC, June 24-29. Despite that, more than half of those asked informally said they can't afford it. The good news is a cornucopia of programs aimed at nearly every need of librarians of all types and including every best practice in libraries. Many…

  8. ALA Conference 2009: Chicago Hope

    ERIC Educational Resources Information Center

    Berry, John N., III

    2009-01-01

    There is joy among those who have the funds to go to Chicago for the American Library Association (ALA) annual conference, July 9-15. Every librarian knows there is nothing better than a Chicago gathering, with the city's wonderful haunts, museums, restaurants, and fine memories of past conferences. The conference program covers nearly every…

  9. Stick to the ALA Plan

    ERIC Educational Resources Information Center

    Berry, John N., III

    2007-01-01

    One candidate for president-elect of the American Library Association (ALA) is a woman, the other is a man. One can tell them apart by looking at them. But Nancy Davenport and James Rettig are not that far apart on the issues that confront the old association and the profession it serves. They have selected slightly different emphases for their…

  10. ALA 2010: The Costly Cornucopia

    ERIC Educational Resources Information Center

    Berry, John N., III

    2010-01-01

    Every librarian wants to go to the American Library Association (ALA) annual conference in Washington, DC, June 24-29. Despite that, more than half of those asked informally said they can't afford it. The good news is a cornucopia of programs aimed at nearly every need of librarians of all types and including every best practice in libraries. Many…

  11. Stick to the ALA Plan

    ERIC Educational Resources Information Center

    Berry, John N., III

    2007-01-01

    One candidate for president-elect of the American Library Association (ALA) is a woman, the other is a man. One can tell them apart by looking at them. But Nancy Davenport and James Rettig are not that far apart on the issues that confront the old association and the profession it serves. They have selected slightly different emphases for their…

  12. Sunset at the ALaMO

    NASA Image and Video Library

    A new color all-sky camera has opened its eyes at the ALaMO, or Automated Lunar and Meteor Observatory, at NASA's Marshall Space Flight Center in Huntsville, Ala. Watch its inaugural video below, s...

  13. Under Protest: ALA Midwinter in Denver.

    ERIC Educational Resources Information Center

    Berry, John; And Others

    1993-01-01

    Reviews the American Library Association (ALA) midwinter conference, including lobbying aims, plans for an organizational review, gay rights activities, high-tech conference exhibits and seminars, and ALA presidential candidates. ALA Executive Director Peggy Sullivan and the 1993 conference of the Association for Library and Information Science…

  14. ALA Midwinter 2011 Preview: A Better Place

    ERIC Educational Resources Information Center

    Berry, John N., III

    2010-01-01

    There has been an effort to make the American Library Association (ALA) Midwinter Meeting "member-friendly," so that more ALA members will attend. Held January 7-11 in beautiful San Diego, the conference program is loaded with interesting events that look suspiciously like entertainment, plus learning opportunities, and the usual parties and…

  15. Comparison between mALA- and ALA-PDT in the treatment of basal cell carcinomas

    NASA Astrophysics Data System (ADS)

    Schleier, Peter; Zenk, Witold; Hyckel, Peter; Berndt, Alexander

    2006-02-01

    Introduction: The external application of aminoleavulinic acid (ALA), which is a substrate of physiologic cell metabolism, represents a possible treatment option in superficial basal cell carcinomas (BCC). The development of new ALA-esters (mALA) with potential for higher penetration depths promises higher therapeutic success. This research aimed to prove the following hypothesis: The cytotoxic effect of the mALA- photodynamic therapy (mALA-PDT), when compared to the ALA-PDT, leads to a higher clinical success rate. Material and Methods: 24 patients with multiple facial tumors, after having received several local surgical excisions with known histology, were treated with either ALA- or mALA-PDT, during the past two years. In total, 89 basal cell carcinoma, 45 actinic keratoses, 6 keratoacanthoma, and 2 squamous cell carcinomas were treated. ALA-PDT: A thermo gel with 40 % mALA or ALA was applied from a cooled syringe. Three to five hours after gel application the skin was cleaned from any gel residues. Irradiation was done with a diode laser and was performed in two sessions, each 10 min long. After intervals of 2, 4 and 12 weeks, the patients were recalled to assess therapeutic efficacy. This was followed by photographic documentation. Results: More than 80% of the tumors treated primarily were resolved successfully. A recurrence rate of approximately 15% was observed. Three per cent of the tumors showed no reaction to therapy. There were no statistically significant differences between the two therapeutic groups. Discussion: The advantage of the use of ALA lies foremost in the fast metabolic use of the body's own photosensitizer PpIX. There are no known side effects of this therapy. Moreover, external application is superior to systemic application with regard to patient management. The method can be combined with other therapies. Although the mALA should have a better penetration in tumor tissue, the therapeutic outcome is similar to the use of ALA.

  16. PDT of the endometrium using ALA

    NASA Astrophysics Data System (ADS)

    Gannon, Michael J.; Vernon, David I.; Holroyd, J. Andrew; Stringer, Mark R.; Johnson, Nick; Brown, Stanley B.

    1997-05-01

    There is a widely recognized need for new approaches to effect endometrial ablation as an alternative to hysterectomy for treatment of menorrhagia. Photodynamic therapy (PDT) offers one such approach. We have investigated the use of 5-aminolaevulinic acid (ALA)-based PDT of the endometrium in model systems and in a series of patients. In all of this work, the ALA was administrated directly into the uterine cavity to reduce any possibility of systemic photosensitization. In a series of experiments in perfused ex vivo uteri, ALA was introduced into the cavity and protoporphyrin formation was measured in the endometrium, the underlying myometrium and the perfusate. ALA transfer into the perfusate was also measured. This work demonstrated that protoporphyrin formation in the endometrium was approximately ten fold that in the underlying myometrium and that systemic photosensitization would be unlikely to result form transfer of administered ALA from the uterus into the circulation. Similar results were found in studies carried out in vivo, where ALA was administered to patients scheduled for hysterectomy. Using a specially designed light source, the first patients have now been treated by giving intrauterine ALA followed by laser light. Two series of treatments - 10 in all - have been carried out. Eight patients have one year follow up. A reduction in measured menstrual blood loss was demonstrated in all but one patient. Complete symptomatic relief was obtained in tow women who did not require further treatment.

  17. Towards Understanding the Tandem Mass Spectra of Protonated Oligopeptides. 2: The Proline Effect in Collision-Induced Dissociation of Protonated Ala-Ala-Xxx-Pro-Ala (Xxx = Ala, Ser, Leu, Val, Phe, and Trp)

    NASA Astrophysics Data System (ADS)

    Bleiholder, Christian; Suhai, Sándor; Harrison, Alex G.; Paizs, Béla

    2011-06-01

    The product ion spectra of proline-containing peptides are commonly dominated by y n ions generated by cleavage at the N-terminal side of proline residues. This proline effect is investigated in the current work by collision-induced dissociation (CID) of protonated Ala-Ala-Xxx-Pro-Ala (Xxx includes Ala, Ser, Leu, Val, Phe, and Trp) in an electrospray/quadrupole/time-of-flight (QqTOF) mass spectrometer and by quantum chemical calculations on protonated Ala-Ala-Ala-Pro-Ala. The CID spectra of all investigated peptides show a dominant y 2 ion (Pro-Ala sequence). Our computational results show that the proline effect mainly arises from the particularly low threshold energy for the amide bond cleavage N-terminal to the proline residue, and from the high proton affinity of the proline-containing C-terminal fragment produced by this cleavage. These theoretical results are qualitatively supported by the experimentally observed y 2 / b 3 abundance ratios for protonated Ala-Ala-Xxx-Pro-Ala (Xxx = Ala, Ser, Leu, Val, Phe, and Trp). In the post-cleavage phase of fragmentation the N-terminal oxazolone fragment with the Ala-Ala-Xxx sequence and Pro-Ala compete for the ionizing proton for these peptides. As the proton affinity of the oxazolone fragment increases, the y 2 / b 3 abundance ratio decreases.

  18. Towards understanding the tandem mass spectra of protonated oligopeptides. 2: The proline effect in collision-induced dissociation of protonated Ala-Ala-Xxx-Pro-Ala (Xxx = Ala, Ser, Leu, Val, Phe, and Trp).

    PubMed

    Bleiholder, Christian; Suhai, Sándor; Harrison, Alex G; Paizs, Béla

    2011-06-01

    The product ion spectra of proline-containing peptides are commonly dominated by y(n) ions generated by cleavage at the N-terminal side of proline residues. This proline effect is investigated in the current work by collision-induced dissociation (CID) of protonated Ala-Ala-Xxx-Pro-Ala (Xxx includes Ala, Ser, Leu, Val, Phe, and Trp) in an electrospray/quadrupole/time-of-flight (QqTOF) mass spectrometer and by quantum chemical calculations on protonated Ala-Ala-Ala-Pro-Ala. The CID spectra of all investigated peptides show a dominant y(2) ion (Pro-Ala sequence). Our computational results show that the proline effect mainly arises from the particularly low threshold energy for the amide bond cleavage N-terminal to the proline residue, and from the high proton affinity of the proline-containing C-terminal fragment produced by this cleavage. These theoretical results are qualitatively supported by the experimentally observed y(2)/b(3) abundance ratios for protonated Ala-Ala-Xxx-Pro-Ala (Xxx = Ala, Ser, Leu, Val, Phe, and Trp). In the post-cleavage phase of fragmentation the N-terminal oxazolone fragment with the Ala-Ala-Xxx sequence and Pro-Ala compete for the ionizing proton for these peptides. As the proton affinity of the oxazolone fragment increases, the y(2)/b(3) abundance ratio decreases.

  19. ALA 2010: Where to Eat in DC

    ERIC Educational Resources Information Center

    Library Journal, 2010

    2010-01-01

    As host to visitors and transplants from around the world, Washington, DC, benefits from the constant infusion of different cultures. Although most neighborhoods lack a unified culinary flavor, make no mistake: DC is a city of distinctive areas, each with its own style, ensuring that hungry American Library Association (ALA) 2010 conference…

  20. Surviving the Tremors: ALA in San Francisco.

    ERIC Educational Resources Information Center

    Wilson Library Bulletin, 1992

    1992-01-01

    Reports on the American Library Association (ALA) 1992 Annual Conference. Highlights include awards given; libraries' futures; bibliographic instruction; NREN (National Research and Education Network); telecommunications; lack of status in librarianship; proposed guidelines for patron behavior; interlibrary loan; the Americans with Disabilities…

  1. ALA 2010: Where to Eat in DC

    ERIC Educational Resources Information Center

    Library Journal, 2010

    2010-01-01

    As host to visitors and transplants from around the world, Washington, DC, benefits from the constant infusion of different cultures. Although most neighborhoods lack a unified culinary flavor, make no mistake: DC is a city of distinctive areas, each with its own style, ensuring that hungry American Library Association (ALA) 2010 conference…

  2. School Librarian's Bill of Responsibilities and the ALA Core Competences

    ERIC Educational Resources Information Center

    Bogel, Gayle

    2009-01-01

    In January 2009, the American Library Association (ALA) completed a ten-year reexamination of the core competences needed by professional librarians graduating from ALA-accredited institutions. The ALA's "Core Competences of Librarianship" encompass the basic knowledge expected of all graduates in all specializations. The core beliefs and policies…

  3. A Redesigned Vancomycin Engineered for Dual D-Ala-D-Ala and D-Ala-D-Lac Binding Exhibits Potent Antimicrobial Activity Against Vancomycin-Resistant Bacteria

    PubMed Central

    Xie, Jian; Pierce, Joshua G.; James, Robert C.; Okano, Akinori; Boger, Dale L.

    2011-01-01

    The emergence of bacteria resistant to vancomycin, often the antibiotic of last resort, poses a major health problem. Vancomycin-resistant bacteria sense a glycopeptide antibiotic challenge and remodel their cell wall precursor peptidoglycan terminus from D-Ala-d-Ala to D-Ala-D-Lac, reducing the binding of vancomycin to its target 1000-fold and accounting for the loss in antimicrobial activity. Here, we report [Φ[C(=NH)NH]Tpg4]-vancomycin aglycon designed to exhibit the dual binding to D-Ala-D-Ala and D-Ala-D-Lac needed to reinstate activity against vancomycin-resistant bacteria. Its binding to a model D-Ala-D-Ala ligand was found to be only two-fold less than vancomycin aglycon and this affinity was maintained with a model D-Ala-D-Lac ligand, representing a 600-fold increase relative to vancomycin aglycon. Accurately reflecting these binding characteristics, it exhibits potent antimicrobial activity against vancomycin-resistant bacteria (MIC = 0.31 g/mL, VanA VRE). Thus, a complementary single atom exchange in the vancomycin core structure (O NH) to counter the single atom exchange in the cell wall precursors of resistant bacteria (NH O) reinstates potent antimicrobial activity and charts a rational path forward for the development of antibiotics for the treatment of vancomycin-resistant bacterial infections. PMID:21823662

  4. Morphological Versatility in the Self-Assembly of Val-Ala and Ala-Val Dipeptides.

    PubMed

    Erdogan, Hakan; Babur, Esra; Yilmaz, Mehmet; Candas, Elif; Gordesel, Merve; Dede, Yavuz; Oren, Ersin Emre; Demirel, Gokcen Birlik; Ozturk, Mustafa Kemal; Yavuz, Mustafa Selman; Demirel, Gokhan

    2015-07-07

    Since the discovery of dipeptide self-assembly, diphenylalanine (Phe-Phe)-based dipeptides have been widely investigated in a variety of fields. Although various supramolecular Phe-Phe-based structures including tubes, vesicles, fibrils, sheets, necklaces, flakes, ribbons, and wires have been demonstrated by manipulating the external physical or chemical conditions applied, studies of the morphological diversity of dipeptides other than Phe-Phe are still required to understand both how these small molecules respond to external conditions such as the type of solvent and how the peptide sequence affects self-assembly and the corresponding molecular structures. In this work, we investigated the self-assembly of valine-alanine (Val-Ala) and alanine-valine (Ala-Val) dipeptides by varying the solvent medium. It was observed that Val-Ala dipeptide molecules may generate unique self-assembly-based morphologies in response to the solvent medium used. Interestingly, when Ala-Val dipeptides were utilized as a peptide source instead of Val-Ala, we observed distinct differences in the final dipeptide structures. We believe that such manipulation may not only provide us with a better understanding of the fundamentals of the dipeptide self-assembly process but also may enable us to generate novel peptide-based materials for various applications.

  5. ALA Pretreatment Improves Waterlogging Tolerance of Fig Plants.

    PubMed

    An, Yuyan; Qi, Lin; Wang, Liangju

    2016-01-01

    5-aminolevulinic acid (ALA), a natural and environmentally friendly plant growth regulator, can improve plant tolerance to various environmental stresses. However, whether ALA can improve plant waterlogging tolerance is unknown. Here, we investigated the effects of ALA pretreatment on the waterlogging-induced damage of fig (Ficus carica Linn.) plants, which often suffer from waterlogging stress. ALA pretreatment significantly alleviated stress-induced morphological damage, increased leaf relative water content (RWC), and reduced leaf superoxide anion ([Formula: see text]) production rate and malonaldehyde (MDA) content in fig leaves, indicating ALA mitigates waterlogging stress of fig plants. We further demonstrated that ALA pretreatment largely promoted leaf chlorophyll content, photosynthetic electron transfer ability, and photosynthetic performance index, indicating ALA significantly improves plant photosynthetic efficiency under waterlogging stress. Moreover, ALA pretreatment significantly increased activities of leaf superoxide dismutase (SOD) and peroxidase (POD), root vigor, and activities of root alcohol dehydrogenase (ADH), and lactate dehydrogenase (LDH), indicating ALA also significantly improves antioxidant ability and root function of fig plants under waterlogging stress. Taken together, ALA pretreatment improves waterlogging tolerance of fig plants significantly, and the promoted root respiration, leaf photosynthesis, and antioxidant ability may contribute greatly to this improvement. Our data firstly shows that ALA can improve plant waterlogging tolerance.

  6. ALA Pretreatment Improves Waterlogging Tolerance of Fig Plants

    PubMed Central

    An, Yuyan; Qi, Lin; Wang, Liangju

    2016-01-01

    5-aminolevulinic acid (ALA), a natural and environmentally friendly plant growth regulator, can improve plant tolerance to various environmental stresses. However, whether ALA can improve plant waterlogging tolerance is unknown. Here, we investigated the effects of ALA pretreatment on the waterlogging-induced damage of fig (Ficus carica Linn.) plants, which often suffer from waterlogging stress. ALA pretreatment significantly alleviated stress-induced morphological damage, increased leaf relative water content (RWC), and reduced leaf superoxide anion (O2⋅¯) production rate and malonaldehyde (MDA) content in fig leaves, indicating ALA mitigates waterlogging stress of fig plants. We further demonstrated that ALA pretreatment largely promoted leaf chlorophyll content, photosynthetic electron transfer ability, and photosynthetic performance index, indicating ALA significantly improves plant photosynthetic efficiency under waterlogging stress. Moreover, ALA pretreatment significantly increased activities of leaf superoxide dismutase (SOD) and peroxidase (POD), root vigor, and activities of root alcohol dehydrogenase (ADH), and lactate dehydrogenase (LDH), indicating ALA also significantly improves antioxidant ability and root function of fig plants under waterlogging stress. Taken together, ALA pretreatment improves waterlogging tolerance of fig plants significantly, and the promoted root respiration, leaf photosynthesis, and antioxidant ability may contribute greatly to this improvement. Our data firstly shows that ALA can improve plant waterlogging tolerance. PMID:26789407

  7. Iontophoretic delivery of ALA provides a quantitative model for ALA pharmacokinetics and PpIX phototoxicity in human skin.

    PubMed

    Rhodes, L E; Tsoukas, M M; Anderson, R R; Kollias, N

    1997-01-01

    Photodynamic therapy (PDT) with topical 5-aminolevulinic acid (ALA) is increasingly employed for skin cancer, yet ALA dosing is crude. Using iontophoresis, we developed a rapid and quantifiable system for topical ALA delivery, with measurement of subsequent PpIX fluorescence and phototoxicity. ALA was iontophoresed from a 2% solution into upper inner arm skin of 13 healthy volunteers. Six doses of ALA were delivered with a series of charges varying from 3-120 milliCoulombs (mC); four additional doses were given with a charge of 60 mC. Five hours post-iontophoresis, sites were irradiated with broad-band yellow-red light, the series of six ALA doses receiving 100 J/cm2, while the four identical doses received 6.25, 12.5, 25, and 50 J/cm2, respectively. Resultant erythema was measured by reflectance spectroscopy. The time course of PpIX fluorescence was ALA-dose-dependent. With charge < or = 24 mC, PpIX fluorescence peaked at 3 h and returned to zero at 9-10 h, whereas charges > 24 mC had a sustained peak at 5-10 h, falling to zero by 24 h. Pre-irradiation, PpIX fluorescence correlated with ALA dose (r = 1.0). PpIX fluorescence fell immediately post-irradiation (p < 0.0001); recovery levels at 3 h correlated with ALA dose (p < 0.0001). Delayed erythema correlated with ALA dose and irradiation dose (p < 0.0001, p < 0.01, respectively). Both PpIX fluorescence intensity pre-irradiation and fall in PpIX fluorescence post-irradiation correlated with erythema (r = 0.98). Hence, PpIX synthesis is ALA-dose-dependent, and phototoxicity can be predicted from ALA dose, irradiation dose, and photobleaching of PpIX. This reproducible system allows accurate dosimetry in topical PDT and facilitates study of ALA metabolism.

  8. 5-ALA based photodynamic management of glioblastoma

    NASA Astrophysics Data System (ADS)

    Rühm, Adrian; Stepp, Herbert; Beyer, Wolfgang; Hennig, Georg; Pongratz, Thomas; Sroka, Ronald; Schnell, Oliver; Tonn, Jörg-Christian; Kreth, Friedrich-Wilhelm

    2014-03-01

    Objective: Improvement of the clinical outcome of glioblastoma (GBM) patients by employment of fluorescence and photosensitization on the basis of 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PpIX). Methods: In this report the focus is laid on the use of tumor selective PpIX fluorescence for stereotactic biopsy sampling and intra-operative treatment monitoring. In addition, our current concept for treatment planning is presented. For stereotactic interstitial photodynamic therapy (iPDT), radial diffusers were implanted into the contrast enhancing tumor volume. Spectroscopic measurements of laser light transmission and fluorescence between adjacent fibers were performed prior, during and post PDT. Results: PpIX concentrations in primary glioblastoma tissue show high intra- and inter-patient variability, but are usually sufficient for an effective PDT. During individual treatment attempts with 5-ALA based GBM-iPDT, transmission and fluorescence measurements between radial diffusers gave the following results: 1. In some cases, transmission after PDT is considerably reduced compared to the value before PDT, which may be attributable to a depletion of oxygenated hemoglobin and/or diffuse bleeding. 2. PpIX fluorescence is efficiently photobleached during PDT in all cases. Conclusion: iPDT with assessment of PpIX fluorescence and photobleaching is a promising treatment option. Individualization of treatment parameters appears to bear a potential to further improve clinical outcomes.

  9. Expression of the alaE gene is positively regulated by the global regulator Lrp in response to intracellular accumulation of l-alanine in Escherichia coli.

    PubMed

    Ihara, Kohei; Sato, Kazuki; Hori, Hatsuhiro; Makino, Yumiko; Shigenobu, Shuji; Ando, Tasuke; Isogai, Emiko; Yoneyama, Hiroshi

    2017-04-01

    The alaE gene in Escherichia coli encodes an l-alanine exporter that catalyzes the active export of l-alanine using proton electrochemical potential. In our previous study, alaE expression was shown to increase in the presence of l-alanyl-l-alanine (Ala-Ala). In this study, the global regulator leucine-responsive regulatory protein (Lrp) was identified as an activator of the alaE gene. A promoter less β-galactosidase gene was fused to an alaE upstream region (240 nucleotides). Cells that were lacZ-deficient and harbored this reporter plasmid showed significant induction of β-galactosidase activity (approximately 17-fold) in the presence of 6 mM l-alanine, l-leucine, and Ala-Ala. However, a reporter plasmid possessing a smaller alaE upstream region (180 nucleotides) yielded transformants with strikingly low enzyme activity under the same conditions. In contrast, lrp-deficient cells showed almost no β-galactosidase induction, indicating that Lrp positively regulates alaE expression. We next performed an electrophoretic mobility shift assay (EMSA) and a DNase I footprinting assay using purified hexahistidine-tagged Lrp (Lrp-His). Consequently, we found that Lrp-His binds to the alaE upstream region spanning nucleotide -161 to -83 with a physiologically relevant affinity (apparent KD, 288.7 ± 83.8 nM). Furthermore, the binding affinity of Lrp-His toward its cis-element was increased by l-alanine and l-leucine, but not by Ala-Ala and d-alanine. Based on these results, we concluded that the gene expression of the alaE is regulated by Lrp in response to intracellular levels of l-alanine, which eventually leads to intracellular homeostasis of l-alanine concentrations.

  10. John Ash, ALA., Photographer August 1997. VIEW OF LOS ANGELES ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    John Ash, ALA., Photographer August 1997. VIEW OF LOS ANGELES CITY HALL NINTH FLOOR NORTH OFFICE WING SHOWING PARTITIONS, WINDOWS AND RADIATOR, FACING SOUTHWEST - Los Angeles City Hall, 200 North Spring Street, Los Angeles, Los Angeles County, CA

  11. Structure of vancomycin and a vancomycin/D-Ala-D-Ala complex in solution

    SciTech Connect

    Molinari, H.; Pastore, A. ); Lian, Luyun ); Hawkes, G.E.; Sales, K. )

    1990-03-06

    Restrained molecular dynamics simulations were used to study the interactions between the glycopeptide antibiotic vancomycin and the dipeptide Ac-D-Ala-D-Ala. Restraints were obtained from a combination of homonuclear and heteronuclear two-dimensional NMR experiments (NOESY, ROESY, {sup 1}H-{sup 15}N inverse correlation). The comparison between the structures obtained for vancomycin alone and for the complex suggests a new hypothesis on the binding mode of this system. The numerical simulations were not straightforward because vancomycin is made of building blocks for which standard force-fields are not available. The representation of unusual chemical environments is also mandatory. The authors believe that the extension of the force-field parameters to their system could be of more general interest. Furthermore, they consider vancomycin and its complex a good example for exploring the more general problem of molecular recognition, a challenge that has been widely approached in the past few years but for which no unique and general methodology has, so far, been recognized.

  12. Synthesis, DNA recognition and cleavage studies of novel tetrapeptide complexes, Cu(II)/Zn(II)-Ala-Pro-Ala-Pro

    NASA Astrophysics Data System (ADS)

    Arjmand, Farukh; Jamsheera, A.; Mohapatra, D. K.

    2013-05-01

    New tetrapeptide complexes Cu(II)·Ala-Pro-Ala-Pro (1) and Zn(II)·Ala-Pro-Ala-Pro (2) were synthesized from the reaction of tetrapeptide, Ala-Pro-Ala-Pro and CuCl2/ZnCl2 and were thoroughly characterized by elemental analysis, IR,1H and 13C NMR (in case of 2), ESI-MS, UV and molar conductance measurements. The solution stability study was carried out employing UV-vis absorption titrations over a broad range of pH which suggested the stability of the complexes in solution. In vitro interaction of complexes 1 and 2 with CT-DNA was studied employing UV-vis, fluorescence, circular dichroic and viscometry studies. To throw insight into molecular binding event at the target site, UV-vis titrations of 1 and 2 with mononucleotides of interest viz.; 5'-GMP and 5'-TMP were carried out. Cleavage activity of the complexes with pBR322 plasmid DNA was evaluated by agarose gel electrophoresis and, the electrophoresis pattern demonstrated that both the complexes 1 and 2 are efficient cleavage agents. Further, the Cu(II) complex displayed efficient oxidative cleavage of supercoiled DNA while various reactive oxygen species are responsible for the cleavage in Zn(II) complex.

  13. Elevated urinary excretion of beta-aminoisobutyric acid and delta-aminolevulinic acid (ALA) and the inhibition of ALA-synthase and ALA-dehydratase activities in both liver and kidney in mice exposed to lead.

    PubMed

    Tomokuni, K; Ichiba, M; Hirai, Y

    1991-12-01

    Urinary excretion of beta-aminoisobutyric acid (ABA) and delta-aminolevulinic acid (ALA) was investigated in mice exposed to lead (500 p.p.m.) in drinking water for 14 days. Concentrations of both urinary ABA and urinary ALA increased significantly in the lead-exposed mice. However, the degree of increasing excretion was higher in urinary ALA (10-fold of the control) than in urinary ABA (2-fold of the control). On the other hand, it was demonstrated that ALA dehydratase in liver and kidney is inhibited by exposure to lead, while ALA synthase in these tissues has no inhibitory effect.

  14. Fluorescence-Guided Resection of Malignant Glioma with 5-ALA

    PubMed Central

    Kaneko, Sadahiro

    2016-01-01

    Malignant gliomas are extremely difficult to treat with no specific curative treatment. On the other hand, photodynamic medicine represents a promising technique for neurosurgeons in the treatment of malignant glioma. The resection rate of malignant glioma has increased from 40% to 80% owing to 5-aminolevulinic acid-photodynamic diagnosis (ALA-PDD). Furthermore, ALA is very useful because it has no serious complications. Based on previous research, it is apparent that protoporphyrin IX (PpIX) accumulates abundantly in malignant glioma tissues after ALA administration. Moreover, it is evident that the mechanism underlying PpIX accumulation in malignant glioma tissues involves an abnormality in porphyrin-heme metabolism, specifically decreased ferrochelatase enzyme activity. During resection surgery, the macroscopic fluorescence of PpIX to the naked eye is more sensitive than magnetic resonance imaging, and the alert real time spectrum of PpIX is the most sensitive method. In the future, chemotherapy with new anticancer agents, immunotherapy, and new methods of radiotherapy and gene therapy will be developed; however, ALA will play a key role in malignant glioma treatment before the development of these new treatments. In this paper, we provide an overview and present the results of our clinical research on ALA-PDD. PMID:27429612

  15. Ala/Ala Genotype of Pro12Ala Polymorphism in the Peroxisome Proliferator-Activated Receptor-γ2 Gene Is Associated with Obesity and Insulin Resistance in Asian Indians

    PubMed Central

    Bhatt, Surya Prakash; Misra, Anoop; Sharma, Mukti; Luthra, Kalpana; Guleria, Randeep; Pandey, Ravindra Mohan

    2012-01-01

    Abstract Aim We determined the association of the Pro12Ala polymorphism of the peroxisome proliferator activated receptor (PPAR)-γ2 gene with obesity, insulin resistance (IR), and lipids in Asian Indians without diabetes in north India. Subjects and Methods In this cross-sectional study (n=495; 279 males and 216 females, 18–60 years of age), anthropometric (body mass index, waist and hip circumferences, and skinfold thickness) and biochemical (fasting glucose, lipid profile, fasting insulin, leptin, and adiponectin) parameters were assessed. Polymerase chain reaction–restriction fragment length polymorphism analysis was used for identification of individual genotypes. Results Frequencies of the Pro and Ala alleles were 0.89 and 0.11, respectively. The genotype frequencies (%) of Pro/Pro, Pro/Ala, and Ala/Ala were 82.6, 14.7, and 2.7, respectively, without any gender differences. The frequency of the Ala/Ala genotype was higher in obese than in nonobese subjects (4.9% vs. 1.5%, P=0.06). The Ala/Ala genotype was associated with higher values of hip circumference, subscapular skinfold thickness, and sum of four skinfold thickness than the Pro/Pro and Pro/Ala genotypes (P<0.05). Using a multivariate logistic regression model after adjusting for age, sex, and insulin, subjects with the Ala/Ala genotype showed a high risk of obesity (odds ratio [OR], 3.2, 95% confidence interval [CI] 1.2–12.9) and IR (OR, 3.6, 95% CI: 1.04–12.4). Conclusion The Ala/Ala genotype of the PPAR-γ2 gene is associated with obesity and IR in Asian Indians without diabetes living in north India. PMID:22694222

  16. Application of 5-ALA for differential diagnostics of stomach diseases

    NASA Astrophysics Data System (ADS)

    Okhotnikova, Natalja L.; Dadvany, Sergey A.; Kuszin, Michail I.; Kharnas, Sergey S.; Zavodnov, Victor Y.; Sklyanskaya, Olga A.; Loschenov, Victor B.; Volkova, Anna I.; Agafonov, Valery V.

    2001-01-01

    59 patients with stomach diseases including gastric cancer or polyp, gastritis, esofagus disease were investigated. Before gastroscopy all patients were given 5-ALA in doses 5mg, 10mg and 20mg per 1kg of body weight orally. Fluorescence diagnostics which estimates concentration of ALA-induced PPIX in regular and alternated tissues of gastric mucosa were carried out in 2-4 hours. Using of 5-ALA has shown high diagnostic effectiveness for differential diagnostics of stomach diseases. This technique has proved 10 diagnosis of cancer and revealed 15 malignant stomach diseases including 4 cancer in situ for patients with preliminary diagnosis of gastric ulcer. It also revealed 5 patients with enhanced fluorescence for which aimed biopsy has shown high degree of inflammation process. The latter were assigned as a risk group.

  17. Chemical rescue of Asp237-->Ala and Lys358-->Ala mutants in the lactose permease of Escherichia coli.

    PubMed

    Frillingos, S; Kaback, H R

    1996-10-15

    Asp237 (helix VII) and Lys358 (helix XI) form a salt bridge in the lactose permease, and neutral replacement of either residue inactivates. Remarkably, noncovalent neutralization of the unpaired Asp or Lys residue, respectively, with n-alkylsulfonates or n-alkylamines of appropriate size restores active transport to high levels in the mutants. Saturation with respect to the concentration of the alkylamines and different size preferences suggest that the alkylamines bind sterically at position 358. Rescue of Asp237-->Ala by alkylsulfonates is apparently more indiscriminate, since methane-, ethane-, or propane-sulfonate have comparable effects. Sodium and chloride, respectively, are also effective in rescuing the Lys358-->Ala and Asp237-->Ala mutants, while various other compounds are ineffective. In marked contrast to Asp237-->Ala or Lys358-->Ala permease, alkylsulfonates or alkylamines have no effect whatsoever on the activity of mutants with neutral replacements for Asp240, Glu269, Arg302, Lys319, His322, or Glu325. The results support the conclusion that neutral replacement of one member of the charge pair between Asp237 and Lys358 leads to inactivation because of an unpaired charge in the low dielectric of the membrane. In addition, the findings are consistent with the idea that interactions between Arg302 and Glu325, His 322 and Glu269, and Asp240 and Lys319 play important roles in the mechanism of the permease, which is not the case for either Asp237 or Lys358 or the salt bridge between the two residues.

  18. In vitro evaluation of 5-aminolevulinic acid (ALA) loaded PLGA nanoparticles

    PubMed Central

    Shi, Lei; Wang, Xiuli; Zhao, Feng; Luan, Hansen; Tu, Qingfeng; Huang, Zheng; Wang, Hao; Wang, Hongwei

    2013-01-01

    Background 5-Aminolevulinic acid (ALA) is a prodrug for topical photodynamic therapy. The effectiveness of topical ALA can be limited by its bioavailability. The aim of this study was to develop a novel ALA delivery approach using poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs). Methods A modified double emulsion solvent evaporation method was used to prepare ALA loaded PLGA NPs (ALA PLGA NPs). The characteristics, uptake, protoporphyrin IX fluorescence kinetics, and cytotoxicity of ALA PLGA NPs toward a human skin squamous cell carcinoma cell line were examined. Results The mean particle size of spherical ALA PLGA NPs was 65.6 nm ± 26 nm with a polydispersity index of 0.62. The encapsulation efficiency was 65.8% ± 7.2% and ALA loading capacity was 0.62% ± 0.27%. When ALA was dispersed in PLGA NPs, it turned into an amorphous phase. ALA PLGA NPs could be taken up by squamous cell carcinoma cells and localized in the cytoplasm. The protoporphyrin IX fluorescence kinetics and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay showed that ALA PLGA NPs were more effective than free ALA of the same concentration. Conclusion PLGA NPs provide a promising ALA delivery strategy for topical ALA-photodynamic therapy of skin squamous cell carcinoma. PMID:23926429

  19. In vitro evaluation of 5-aminolevulinic acid (ALA) loaded PLGA nanoparticles.

    PubMed

    Shi, Lei; Wang, Xiuli; Zhao, Feng; Luan, Hansen; Tu, Qingfeng; Huang, Zheng; Wang, Hao; Wang, Hongwei

    2013-01-01

    5-Aminolevulinic acid (ALA) is a prodrug for topical photodynamic therapy. The effectiveness of topical ALA can be limited by its bioavailability. The aim of this study was to develop a novel ALA delivery approach using poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs). A modified double emulsion solvent evaporation method was used to prepare ALA loaded PLGA NPs (ALA PLGA NPs). The characteristics, uptake, protoporphyrin IX fluorescence kinetics, and cytotoxicity of ALA PLGA NPs toward a human skin squamous cell carcinoma cell line were examined. The mean particle size of spherical ALA PLGA NPs was 65.6 nm±26 nm with a polydispersity index of 0.62. The encapsulation efficiency was 65.8%±7.2% and ALA loading capacity was 0.62%±0.27%. When ALA was dispersed in PLGA NPs, it turned into an amorphous phase. ALA PLGA NPs could be taken up by squamous cell carcinoma cells and localized in the cytoplasm. The protoporphyrin IX fluorescence kinetics and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay showed that ALA PLGA NPs were more effective than free ALA of the same concentration. PLGA NPs provide a promising ALA delivery strategy for topical ALA-photodynamic therapy of skin squamous cell carcinoma.

  20. Identification and expression analyses of the alanine aminotransferase (AlaAT) gene family in poplar seedlings

    PubMed Central

    Xu, Zhiru; Ma, Jing; Qu, Chunpu; Hu, Yanbo; Hao, Bingqing; Sun, Yan; Liu, Zhongye; Yang, Han; Yang, Chengjun; Wang, Hongwei; Li, Ying; Liu, Guanjun

    2017-01-01

    Alanine aminotransferase (AlaAT, E.C.2.6.1.2) catalyzes the reversible conversion of pyruvate and glutamate to alanine and α-oxoglutarate. The AlaAT gene family has been well studied in some herbaceous plants, but has not been well characterized in woody plants. In this study, we identified four alanine aminotransferase homologues in Populus trichocarpa, which could be classified into two subgroups, A and B. AlaAT3 and AlaAT4 in subgroup A encode AlaAT, while AlaAT1 and AlaAT2 in subgroup B encode glutamate:glyoxylate aminotransferase (GGAT), which catalyzes the reaction of glutamate and glyoxylate to α-oxoglutarate and glycine. Four AlaAT genes were cloned from P. simonii × P. nigra. PnAlaAT1 and PnAlaAT2 were expressed predominantly in leaves and induced by exogenous nitrogen and exhibited a diurnal fluctuation in leaves, but was inhibited in roots. PnAlaAT3 and PnAlaAT4 were mainly expressed in roots, stems and leaves, and was induced by exogenous nitrogen. The expression of PnAlaAT3 gene could be regulated by glutamine or its related metabolites in roots. Our results suggest that PnAlaAT3 gene may play an important role in nitrogen metabolism and is regulated by glutamine or its related metabolites in the roots of P. simonii × P. nigra. PMID:28378825

  1. Identification and expression analyses of the alanine aminotransferase (AlaAT) gene family in poplar seedlings.

    PubMed

    Xu, Zhiru; Ma, Jing; Qu, Chunpu; Hu, Yanbo; Hao, Bingqing; Sun, Yan; Liu, Zhongye; Yang, Han; Yang, Chengjun; Wang, Hongwei; Li, Ying; Liu, Guanjun

    2017-04-05

    Alanine aminotransferase (AlaAT, E.C.2.6.1.2) catalyzes the reversible conversion of pyruvate and glutamate to alanine and α-oxoglutarate. The AlaAT gene family has been well studied in some herbaceous plants, but has not been well characterized in woody plants. In this study, we identified four alanine aminotransferase homologues in Populus trichocarpa, which could be classified into two subgroups, A and B. AlaAT3 and AlaAT4 in subgroup A encode AlaAT, while AlaAT1 and AlaAT2 in subgroup B encode glutamate:glyoxylate aminotransferase (GGAT), which catalyzes the reaction of glutamate and glyoxylate to α-oxoglutarate and glycine. Four AlaAT genes were cloned from P. simonii × P. nigra. PnAlaAT1 and PnAlaAT2 were expressed predominantly in leaves and induced by exogenous nitrogen and exhibited a diurnal fluctuation in leaves, but was inhibited in roots. PnAlaAT3 and PnAlaAT4 were mainly expressed in roots, stems and leaves, and was induced by exogenous nitrogen. The expression of PnAlaAT3 gene could be regulated by glutamine or its related metabolites in roots. Our results suggest that PnAlaAT3 gene may play an important role in nitrogen metabolism and is regulated by glutamine or its related metabolites in the roots of P. simonii × P. nigra.

  2. ALA and ALA hexyl ester-induced porphyrin synthesis in chemically induced skin tumours: the role of different vehicles on improving photosensitization

    PubMed Central

    Casas, A; Perotti, C; Fukuda, H; Rogers, L; Butler, A R; Batlle, A

    2001-01-01

    Exogenous administration of 5-aminolevulinic acid (ALA) is becoming widely used to enhance the endogenous synthesis of Protoporphyrin IX (PpIX) in photodynamic therapy. We analysed porphyrin formation in chemically induced squamous papillomas, after topical application of ALA and ALA hexyl ester (He-ALA) administered in different formulations, as well as the pattern of distribution in the internal organs, and the synthesis of porphyrins in distant tumoural and normal skins. A lotion formulation containing DMSO and ethanol was the best vehicle for topical ALA delivery to papillomas, whereas cream was the most efficient formulation for He-ALA application. Similar porphyrin concentration can be accumulated in the skin tumours employing either ALA or He-ALA delivered in their optimal formulations. The use of cream as a vehicle of both ALA and He-ALA, induces highest porphyrin tumour/normal skin ratios. The main advantage of using He-ALA is that porphyrins synthesized from the ester are more confined to the site of application, thus inducing low porphyrin levels in normal skin, liver, blood and spleen, as well as in papillomas distant from the point of application, independently on the vehicle employed, so reducing potential side effects of photodynamic therapy. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11742504

  3. A spectroscopic and calorimetric investigation on the thermal stability of the Cys3Ala/Cys26Ala azurin mutant.

    PubMed Central

    Guzzi, R; Sportelli, L; La Rosa, C; Milardi, D; Grasso, D; Verbeet, M P; Canters, G W

    1999-01-01

    The disulfide bond connecting Cys-3 and Cys-26 in wild type azurin has been removed to study the contribution of the -SS- bond to the high thermal resistance previously registered for this protein (. J. Phys. Chem. 99:14864-14870). Site-directed mutagenesis was used to replace both cysteines for alanines. The characterization of the Cys-3Ala/Cys-26Ala azurin mutant has been carried out by means of electron paramagnetic resonance spectroscopy at 77 K, UV-VIS optical absorption, fluorescence emission and circular dichroism at room temperature. The results show that the spectral features of the Cys-3Ala/Cys-26Ala azurin resemble those of the wild type azurin, indicating that the double mutation does not affect either the formation of the protein's overall structure or the assembly of the metal-binding site. The thermal unfolding of the Cys-3Ala/Cys-26Ala azurin has been followed by differential scanning calorimetry, optical absorption variation at lambda(max) = 625 nm, and fluorescence emission using 295 nm as excitation wavelength. The analysis of the data shows that the thermal transition from the native to the denaturated state of the modified azurin follows the same multistep unfolding pathway as observed in wild type azurin. However, the removal of the disulfide bridge results in a dramatic reduction of the thermodynamic stability of the protein. In fact, the transition temperatures registered by the different techniques are down-shifted by about 20 degrees C with respect to wild type azurin. Moreover, the Gibbs free energy value is about half of that found for the native azurin. These results suggest that the disulfide bridge is a structural element that significantly contributes to the high stability of wild type azurin. PMID:10423449

  4. The Dipeptide Ala-Gly in the Gas Phase

    NASA Astrophysics Data System (ADS)

    Bermúdez, Celina; Varela, Marcelino; Cabezas, Carlos; Peña, Isabel; Alonso, José L.

    2014-06-01

    The dipeptide Ala-Gly has been examined in gas phase by laser ablation molecular beam Fourier transform microwave (LA-MB-FTMW) spectroscopy in the frequency region 3-12 GHz. Three rotamers have been detected in the supersonic expansion. The quadrupole hyperfine structure of two 14N (I=1) nuclei has been totally resolved allowing the conclusive identification of one conformer.

  5. ALA 2010 Midwinter Meeting: The Price to Participate

    ERIC Educational Resources Information Center

    Berry, John N., III

    2009-01-01

    While the library economy continues its downward slide, the cost of attending the American Library Association (ALA) Midwinter Meeting seems as high as ever. That is the price of professional participation. These days it seems a bit too high and tends to limit involvement in the old association to librarians in the higher echelons of the field.…

  6. Leading by Example? ALA Division Publications, Open Access, and Sustainability

    ERIC Educational Resources Information Center

    Hall, Nathan; Arnold-Garza, Sara; Gong, Regina; Shorish, Yasmeen

    2016-01-01

    This investigation explores scholarly communication business models in American Library Association (ALA) division peer-reviewed academic journals. Previous studies reveal the numerous issues organizations and publishers face in the academic publishing environment. Through an analysis of documented procedures, policies, and finances of five ALA…

  7. Leading by Example? ALA Division Publications, Open Access, and Sustainability

    ERIC Educational Resources Information Center

    Hall, Nathan; Arnold-Garza, Sara; Gong, Regina; Shorish, Yasmeen

    2016-01-01

    This investigation explores scholarly communication business models in American Library Association (ALA) division peer-reviewed academic journals. Previous studies reveal the numerous issues organizations and publishers face in the academic publishing environment. Through an analysis of documented procedures, policies, and finances of five ALA…

  8. The 1997 AIA/ALA Library Buildings Award Recipients.

    ERIC Educational Resources Information Center

    Dreazen, Elizabeth

    1997-01-01

    Describes the seven library buildings named as winners by the American Institute of Architects (AIA) and the American Library Association (ALA) that include four new facilities, one conversion of a warehouse building to library use, and two renovations. Public, school, and university libraries are included. (LRW)

  9. 33 CFR 110.194 - Mobile Bay, Ala., at entrance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... ANCHORAGES ANCHORAGE REGULATIONS Anchorage Grounds § 110.194 Mobile Bay, Ala., at entrance. (a) The anchorage grounds. The waters within a radius of 750 yards from a point located 1,000 yards true north from Fort... an anchorage. It may be used for a general anchorage when not required for vessels...

  10. ALA-induced PpIX fluorescence in epileptogenic tissue

    NASA Astrophysics Data System (ADS)

    Kleen, Jonathan K.; Valdes, Pablo A.; Harris, Brent T.; Holmes, Gregory L.; Paulsen, Keith D.; Roberts, David W.

    2011-03-01

    Astrogliotic tissue displays markedly increased levels of ALA-induced PpIX fluorescence, making it useful for fluorescence-guided resection in glioma surgery. In patients with temporal lobe epilepsy (TLE) and corresponding animal models, there are areas of astrogliosis that often co-localize with the epileptic focus, which can be resected to eliminate seizures in the majority of treated patients. If this epileptogenic tissue can exhibit PpIX fluorescence that is sufficiently localized, it could potentially help identify margins in epilepsy surgery. We tested the hypothesis that ALA-induced PpIX fluorescence could visually accentuate epileptogenic tissue, using an established animal model of chronic TLE. An acute dose of pilocarpine was used to induce chronic seizure activity in a rat. This rat and a normal control were given ALA, euthanized, and brains examined post-mortem for PpIX fluorescence and neuropathology. Preliminary evidence indicates increased PpIX fluorescence in areas associated with chronic epileptic changes and seizure generation in TLE, including the hippocampus and parahippocampal areas. In addition, strong PpIX fluorescence was clearly observed in layer II of the piriform cortex, a region known for epileptic reorganization and involvement in the generation of seizures in animal studies. We are further investigating whether ALA-induced PpIX fluorescence can consistently identify epileptogenic zones, which could warrant the extension of this technique to clinical studies for use as an adjuvant guidance technology in the resection of epileptic tissue.

  11. ALA 2010 Midwinter Meeting: The Price to Participate

    ERIC Educational Resources Information Center

    Berry, John N., III

    2009-01-01

    While the library economy continues its downward slide, the cost of attending the American Library Association (ALA) Midwinter Meeting seems as high as ever. That is the price of professional participation. These days it seems a bit too high and tends to limit involvement in the old association to librarians in the higher echelons of the field.…

  12. LJ Q&A "ALA Candidates": Library Advocacy x 2

    ERIC Educational Resources Information Center

    Berry, John N., III

    2008-01-01

    Library advocacy in one of two directions is the top priority of both Camila Alire and J. Linda Williams, the candidates campaigning to capture the 2009-10 term as president of the American Library Association (ALA). Alire, dean emeritus of the libraries of both the University of New Mexico and Colorado State University, will push for enhancements…

  13. Librarians in Winter: Bullish on ALA, Bearish on Chicago.

    ERIC Educational Resources Information Center

    Wilson Library Bulletin, 1986

    1986-01-01

    Summary of American Library Association's (ALA) 1986 Midwinter Meeting highlights administrative reports, legislative update, government publishing update, finances and operations (the long range outlook), the Oxford Project, library education, standards, issues and ideas, accreditation project, toward a White House conference, aspiring ALA…

  14. Librarians in Winter: Bullish on ALA, Bearish on Chicago.

    ERIC Educational Resources Information Center

    Wilson Library Bulletin, 1986

    1986-01-01

    Summary of American Library Association's (ALA) 1986 Midwinter Meeting highlights administrative reports, legislative update, government publishing update, finances and operations (the long range outlook), the Oxford Project, library education, standards, issues and ideas, accreditation project, toward a White House conference, aspiring ALA…

  15. LJ Q&A "ALA Candidates": Library Advocacy x 2

    ERIC Educational Resources Information Center

    Berry, John N., III

    2008-01-01

    Library advocacy in one of two directions is the top priority of both Camila Alire and J. Linda Williams, the candidates campaigning to capture the 2009-10 term as president of the American Library Association (ALA). Alire, dean emeritus of the libraries of both the University of New Mexico and Colorado State University, will push for enhancements…

  16. Quantitative Determination of Ala-Ala Conformer Ratios in Solution by Decomposition of Raman Optical Activity Spectra.

    PubMed

    Jungwirth, Jakub; Šebestík, Jaroslav; Šafařík, Martin; Kapitán, Josef; Bouř, Petr

    2017-09-18

    Raman optical activity (ROA) spectroscopy combined with quantum-chemical simulations is a sensitive method to determine the absolute configuration and conformation of chiral molecules in solutions. However, the precision of this approach varies for different systems. In the present study, the reliability and numerical stability of decomposing experimental spectra into calculated subspectra is tested on the Ala-Ala dipeptide. Molecular dynamics (MD) snapshots of Ala-Ala/water clusters are averaged to account for solvent effects and molecular flexibility. Multiple experiments with protonated, zwitterionic, and deprotonated dipeptide forms and natural and d2- and d8-isotopically labeled dipeptides are used to verify the results and estimate the overall accuracy. Although the precision is still limited by experimental noise and computational error, a very close match between the observed and theoretical spectral shapes has been achieved. This enabled quantitative determination of conformer populations with a typical dispersion of 10%. The spectroscopy also demonstrated how the conformation depends on pH. The ROA results were more consistent than the Raman ones. Typically, the ROA analysis was more resistant to artifacts in the experiment, such as incomplete baseline subtraction. Conformer ratios predicted by MD agree fairly but not fully with the experimental ones. This indicates minor deficiencies in the Amber force field, particularly for the protonated dipeptide. Overall, the combination of ROA experiment and computational chemistry appears to be a robust tool providing deep insight into molecular structure.

  17. Metabolism of oral ALA combined small dose HPD in the small rat glioma

    NASA Astrophysics Data System (ADS)

    Wang, Yu; Zhu, Jing; Zhang, Hui-Guo; Yan, Ming; Lu, Liping

    2005-07-01

    Objective: Research on the metabolism of oral ALA combined small dose HPD in the small rat glioma to find the optimal oral dose and diagnostic time for the ALA-photodynamic diagnosis and therapy of brain glioma. Methods: Measure the fluorescence spectra of tumor in the treatment groups and control group and of brain tissue of no-tumor group with different doses of ALA taken orally combined injectd small dose HPD and different time before and after take ALA when irradiated by laser. We analyzed the spectrum of fluorescence of every groups with optical multichannel analyzer (OMA) and compared it each other. Result: The maximum ratio (Itumor/Inomal ) of fluorescence was obtained at 60mg/kg of ALA taken orally and 6-8h after ALA taken. Conclusion: The optimal oral dose is 60mg/kg of ALA and the optimal measure time is 6-8 hours after ALA taken.

  18. ALA, the MLS, and Professional Employment: An Observer's Field Guide to the Issues.

    ERIC Educational Resources Information Center

    Wilson, Pauline

    1984-01-01

    Examines issues arising from recent controversy associated with American Library Association's (ALA) support of MLS degree as minimum requirement for professional employment. Highlights include ALA involvement in legal cases and viewpoints of ALA groups focusing on goals, constituency and handling of conflict versus nature of librarianship and its…

  19. Basic principles of fluorescence detection with use of 5-ALA

    NASA Astrophysics Data System (ADS)

    Baumgartner, Reinhold; Stepp, Herbert G.

    2000-06-01

    5-Aminolevulinic acid (5-ALA) has been proven to induce selective accumulation of flourescent Protoporphyrin IX (PPIX) in many types of malignant tissue. According to the target to treatment different routes of topical and systemical application of 5-ALA can be chosen. They include techniques like inhalation, installation and rinsing. For fluorescence detection a lamp based system have been developed in the laser-Forschungslabor in Munich together with Storz company. By skillful balancing of excitation filter centered around 400 nm and the observation filter with transmission above 450 nm images with high color contrast can be obtained. The universal application of the D-LIGHT could be demonstrated in different clinical disciplines like urology, neurosurgery, ENT clinic, gynecology and others.

  20. Pro12Ala polymorphism in PPARgamma2 associated with depression in Chinese nonagenarians/centenarians.

    PubMed

    Ji-Rong, Yue; Bi-Rong, Dong; Chang-Quan, Huang; Zhen-Chan, Lu; Hong-Mei, Wu; Yan-Ling, Zhang; Mattis, Tod A

    2009-07-01

    The Pro12Ala polymorphism of peroxisome proliferator-activated receptor-gamma (PPARgamma) has been associated with decreased obesity, insulin resistance, type 2 diabetes and other age-associated diseases such as cognitive impairment, hypertension, cancer, osteoarthritis. Each one of these diseases had been linked to depression. Moreover, there is also an association between Pro12 Ala polymorphism in PPAR gamma2 and longevity. The aim of the study was to evaluate the association between Pro12 Ala polymorphism and depression in Chinese nonagenarians and centenarians. The sample included 697 unrelated Chinese nonagenarians/centenarians (aged between 90-108 years, mean age: 93.5+/-3.35 years; 67.2% women). The Pro12Ala variant was examined using polymerase chain reaction-restriction fragment length polymorphism. Depression was measured with brief 23-item Geriatrics Depression Scale Chinese-edition (GDS-CD). In this sample, the genotype frequencies of the Pro12Ala polymorphism were 0% Ala12Ala, 9.2% Pro12Ala, 90.8% Pro12Pro and the prevalence of depression was 25.3%. Subjects who were 12Ala carriers had significantly lower prevalence of depression than those who were not 12Ala carriers (14.06 vs. 26.38%, p=0.034). Subjects without depression also had a higher frequency of 12Ala gene than those with depression (5.28 vs. 2.56%, p=0.031). Adjusting for certain clinical factors that may be associated with depression or with 12Ala carriers, multiple logistic regressions showed the 12Ala gene was associated with decreased incidence of depression. In summary, we found that among Chinese nonagenarians and centenarians, the Pro12Ala polymorphism in PPARgamma2 was associated with depression and that the 12Ala gene may be a factor for decreased depression.

  1. Ala-His Mediated Peptide Bond Formation Revisited

    NASA Astrophysics Data System (ADS)

    Larkin, Deana C.; Martinis, Susan A.; Roberts, Deborah J.; Fox, George E.

    2001-12-01

    The historical origin of the translation machinery remains unresolved. Although the large 23S ribosomal RNA (rRNA) is almost certainly the catalytic component of the peptidyl transferase center in the modern ribosome, it is likely that greatly simplified systems were initially employed in the late stages of the prebiotic world. In particular, it has been suggested that small RNAs carrying amino acids were important for the genesis of protein synthesis. Consistent with this, a dipeptide, Ala-His, was previously claimed to be a prebiotically feasible catalyst mediating peptide bond formation in the presence of aminoacylated tRNA and cognate mRNA template, in the absence of other ribosomal components (Shimizu, 1996). We herein report a detailed study of putative dipeptide formation by Ala-His and RNAs carrying leucine. Based on the results presented here, it is unlikely that the dipeptide, Ala-His, catalyzes significant levels of Leu-Leu dipeptide formation in solution. A product is produced which can be readily mistaken for a dipeptide in the TLC separation systems employed in earlier work. We offer explanations for the formation of this product as well as another unexpected product. The results presented here are consistent with the notion that the translation machinery was likely based on catalytic RNA from its very inception.

  2. The complex filling of alae crater, Kilauea Volcano, Hawaii

    USGS Publications Warehouse

    Swanson, D.A.; Duffield, W.A.; Jackson, D.B.; Peterson, D.W.

    1972-01-01

    Since February 1969 Alae Crater, a 165-m-deep pit crater on the east rift of Kilauea Volcano, has been completely filled with about 18 million m3 of lava. The filling was episodic and complex. It involved 13 major periods of addition of lava to the crater, including spectacular lava falls as high as 100 m, and three major periods of draining of lava from the crater. Alae was nearly filled by August 3, 1969, largely drained during a violent ground-cracking event on August 4, 1969, and then filled to the low point on its rim on October 10, 1969. From August 1970 to May 1971, the crater acted as a reservoir for lava that entered through subsurface tubes leading from the vent fissure 150 m away. Another tube system drained the crater and carried lava as far as the sea, 11 km to the south. Much of the lava entered Alae by invading the lava lake beneath its crust and buoying the crust upward. This process, together with the overall complexity of the filling, results in a highly complicated lava lake that would doubtless be misinterpreted if found in the fossil record. ?? 1972 Stabilimento Tipografico Francesco Giannini & Figli.

  3. PPARγ2Pro12Ala Polymorphism and Human Health

    PubMed Central

    He, Weimin

    2009-01-01

    The nuclear hormone receptor peroxisome proliferator activated receptor gamma (PPARγ) is an important transcription factor regulating adipocyte differentiation, lipid and glucose homeostasis, and insulin sensitivity. Numerous genetic mutations of PPARγ have been identified and these mutations positively or negatively regulate insulin sensitivity. Among these, a relatively common polymorphism of PPARγ, Pro12Ala of PPARγ2, the isoform expressed only in adipose tissue has been shown to be associated with lower body mass index, enhanced insulin sensitivity, and resistance to the risk of type 2 diabetes in human subjects carrying this mutation. Subsequent studies in different ethnic populations, however, have revealed conflicting results, suggesting a complex interaction between the PPARγ2 Pro12Ala polymorphism and environmental factors such as the ratio of dietary unsaturated fatty acids to saturated fatty acids and/or between the PPARγ2 Pro12Ala polymorphism and genetic factors such as polymorphic mutations in other genes. In addition, this polymorphic mutation in PPARγ2 is associated with other aspects of human diseases, including cancers, polycystic ovary syndrome, Alzheimer disease and aging. This review will highlight findings from recent studies. PMID:19390629

  4. Characterization of the l-alanine exporter AlaE of Escherichia coli and its potential role in protecting cells from a toxic-level accumulation of l-alanine and its derivatives.

    PubMed

    Kim, Seryoung; Ihara, Kohei; Katsube, Satoshi; Hori, Hatsuhiro; Ando, Tasuke; Isogai, Emiko; Yoneyama, Hiroshi

    2015-08-01

    We previously reported that the alaE gene of Escherichia coli encodes the l-alanine exporter AlaE. The objective of this study was to elucidate the mechanism of the AlaE exporter. The minimum inhibitory concentration of l-alanine and l-alanyl-l-alanine in alaE-deficient l-alanine-nonmetabolizing cells MLA301ΔalaE was 4- and >4000-fold lower, respectively, than in the alaE-positive parent cells MLA301, suggesting that AlaE functions as an efflux pump to avoid a toxic-level accumulation of intracellular l-alanine and its derivatives. Furthermore, the growth of the alaE-deficient mutant derived from the l-alanine-metabolizing strain was strongly inhibited in the presence of a physiological level of l-alanyl-l-alanine. Intact MLA301ΔalaE and MLA301ΔalaE/pAlaE cells producing plasmid-borne AlaE, accumulated approximately 200% and 50%, respectively, of the [(3) H]l-alanine detected in MLA301 cells, suggesting that AlaE exports l-alanine. When 200 mmol/L l-alanine-loaded inverted membrane vesicles prepared from MLA301ΔalaE/pAlaE were placed in a solution containing 200 mmol/L or 0.34 μmol/L l-alanine, energy-dependent [(3) H]l-alanine accumulation occurred under either condition. This energy-dependent uphill accumulation of [(3) H]l-alanine was strongly inhibited in the presence of carbonyl cyanide m-chlorophenylhydrazone but not by dicyclohexylcarbodiimide, suggesting that the AlaE-mediated l-alanine extrusion was driven by proton motive force. Based on these results, physiological roles of the l-alanine exporter are discussed.

  5. Characterization of the l-alanine exporter AlaE of Escherichia coli and its potential role in protecting cells from a toxic-level accumulation of l-alanine and its derivatives

    PubMed Central

    Kim, Seryoung; Ihara, Kohei; Katsube, Satoshi; Hori, Hatsuhiro; Ando, Tasuke; Isogai, Emiko; Yoneyama, Hiroshi

    2015-01-01

    We previously reported that the alaE gene of Escherichia coli encodes the l-alanine exporter AlaE. The objective of this study was to elucidate the mechanism of the AlaE exporter. The minimum inhibitory concentration of l-alanine and l-alanyl-l-alanine in alaE-deficient l-alanine-nonmetabolizing cells MLA301ΔalaE was 4- and >4000-fold lower, respectively, than in the alaE-positive parent cells MLA301, suggesting that AlaE functions as an efflux pump to avoid a toxic-level accumulation of intracellular l-alanine and its derivatives. Furthermore, the growth of the alaE-deficient mutant derived from the l-alanine-metabolizing strain was strongly inhibited in the presence of a physiological level of l-alanyl-l-alanine. Intact MLA301ΔalaE and MLA301ΔalaE/pAlaE cells producing plasmid-borne AlaE, accumulated approximately 200% and 50%, respectively, of the [3H]l-alanine detected in MLA301 cells, suggesting that AlaE exports l-alanine. When 200 mmol/L l-alanine-loaded inverted membrane vesicles prepared from MLA301ΔalaE/pAlaE were placed in a solution containing 200 mmol/L or 0.34 μmol/L l-alanine, energy-dependent [3H]l-alanine accumulation occurred under either condition. This energy-dependent uphill accumulation of [3H]l-alanine was strongly inhibited in the presence of carbonyl cyanide m-chlorophenylhydrazone but not by dicyclohexylcarbodiimide, suggesting that the AlaE-mediated l-alanine extrusion was driven by proton motive force. Based on these results, physiological roles of the l-alanine exporter are discussed. PMID:26073055

  6. [Radiosensitizing effect of 5-aminolevulinic acid (5-ALA ) in Colon cancer].

    PubMed

    Kamada, Yosuke; Murayama, Yasutoshi; Harada, Kyoichi; Nishimura, Masumi; Kondo, Yutaka; Konishi, Hirotaka; Morimura, Ryo; Komatsu, Shuhei; Shiozaki, Atsushi; Kuriu, Yoshiaki; Ikoma, Hisashi; Nakanishi, Masayoshi; Ichikawa, Daisuke; Fujiwara, Hitoshi; Okamoto, Kazuma; Sakakura, Chouhei; Otsuji, Eigo

    2014-11-01

    5-aminolevulinic acid (5-ALA) is widely used in clinical practice because it shows tumor-selective accumulation of protoporphyrin IX, a fluorescent substance and a metabolite of 5-ALA. In addition, some studies have reported that 5-ALA increases the radiation sensitivity of glioma and melanoma. In this study, we investigated the radiosensitization effect of 5-ALA on colon cancer. Mice implanted with the human colon cancer cell line HT29 were administered 5-ALA and subsequently X-ray irradiated. These mice were compared with those not administered 5-ALA. Following multiple irradiations, the tumor volume of the 5-ALA group was significantly lower than that of the non-5-ALA group (day 5: p value=0.0489, day 8: p value= 0.0318, day 12: p value=0.0394). Tumor growth was inhibited by multiple irradiations in the 5-ALA group compared with the non-5-ALA group. These results suggest that 5-ALA also exhibits a radiosensitization effect on colon cancer.

  7. Assessment of whole body ALA-D concentrations in juvenile rainbow trout: Methods development

    SciTech Connect

    Burden, V.; Sandheinrich, M.; Caldwell, C.

    1995-12-31

    Activity of delta-aminolevulinic acid dehydratase (ALA-D) is an important biomarker of environmental lead contamination of fish. ALA-D may predict lead exposure more accurately than analysis of lead concentrations in water because current methods cannot differentiate between total and biologically-available lead. Measurements of fish ALA-D activity have typically been made on blood but decreased ALA-D activity also occurs in the liver, kidney, and spleen. Juvenile fish are typically more sensitive to lead than adult fish, but ALA-D analysis of blood and individual organs is difficult due to their small size. The authors developed a method to measure ALA-D activity on the supernatant of a tissue homogenate from whole fish (rainbow trout, Oncorhynchus mykiss). ALA-D activity was standardized to protein concentration of the supernatant from the homogenate. Protein concentration was determined by a spectrophotometric dye-binding procedure with bovine serum albumin as a standard.

  8. Impact of charged amino acid substitution in the transmembrane domain of L-alanine exporter, AlaE, of Escherichia coli on the L-alanine export.

    PubMed

    Kim, Seryoung; Ihara, Kohei; Katsube, Satoshi; Ando, Tasuke; Isogai, Emiko; Yoneyama, Hiroshi

    2017-01-01

    The Escherichia coli alaE gene encodes the L-alanine exporter, AlaE, that catalyzes active export of L-alanine using proton electrochemical potential. The transporter comprises only 149 amino acid residues and four predicted transmembrane domains (TMs), which contain three charged amino acid residues. The AlaE-deficient L-alanine non-metabolizing cells (ΔalaE cells) appeared hypersusceptible to L-alanyl-L-alanine showing a minimum inhibitory concentration (MIC) of 2.5 µg/ml for the dipeptide due to a toxic accumulation of L-alanine. To elucidate the mechanism by which AlaE exports L-alanine, we replaced charged amino acid residues in the TMs, glutamic acid-30 (TM-I), arginine-45 (TM-II), and aspartic acid-84 (TM-III) with their respective charge-conserved amino acid or a net neutral cysteine. The ΔalaE cells producing R45K or R45C appeared hypersusceptible to the dipeptide, indicating that arginine-45 is essential for AlaE activity. MIC of the dipeptide in the ΔalaE cells expressing E30D and E30C was 156 µg/ml and >10,000 µg/ml, respectively, thereby suggesting that a negative charge at this position is not essential. The ΔalaE cells expressing D84E or D84C showed an MIC >10,000 and 78 µg/ml, respectively, implying that a negative charge is required at this position. These results were generally consistent with that of the L-alanine accumulation experiments in intact cells. We therefore concluded that charged amino acid residues (R45 and D84) in the AlaE transmembrane domain play a pivotal role in L-alanine export. Replacement of three cysteine residues at C22, C28 (both in TM-I), and C135 (C-terminal region) with alanine showed only a marginal effect on L-alanine export.

  9. Multi-chelation approach towards natural product-like skeletons: one-pot access to a nitrogen-containing tetracyclic framework from AlaAla dipeptide.

    PubMed

    Vellaisamy, Kasipandi; Napoleon, John Victor; Venkatachalam, Ramkumar; Manheri, Muraleedharan Kannoth

    2010-12-28

    Reductive transformation of the dipeptide BocAlaAlaOMe to a complex, internally charge-stabilized, natural product-like skeleton in one synthetic step is discussed. Stepwise replacement of the B-H bonds in borane by B-N or B-O resulted in incorporation of three boron atoms in a tetracyclic framework whereby one is stereogenic!

  10. Fluorescence spectroscopy of gastrointestinal tumors using δ-ALA

    NASA Astrophysics Data System (ADS)

    Borisova, E. G.; Vladimirov, B. G.; Angelov, I. G.; Avramov, L. A.

    2007-03-01

    In the recent study delta-aminolevulinic acid/Protoporphyrin IX (δ-ALA/PpIX) is used as fluorescent marker for dysplasia and tumor detection in esophagus and stomach. The δ-ALA is administered per os six hours before measurements at dose 20mg/kg weight. High-power light-emitting diode at 405 nm is used as an excitation source. Special opto-mechanical device is built to use the light guide of standard video-endoscopic system (Olimpus Corp.). Through endoscopic instrumental channel a fiber is applied to return information about fluorescence to microspectrometer (USB4000, OceanOptics Inc.). The fluorescence detected from tumor sites has very complex spectral origins. It consists of autofluorescence, fluorescence from exogenous fluorophores and re-absorption from the chromophores accumulated in the tissue investigated. Mucosa autofluorescence lies at 450-600 nm region. The fluorescence of PpIX is clearly pronounced at the 630-710 nm region. Deep minima in the tumor fluorescence signals are observed in the region 540-575 nm, related to hemoglobin re-absorption. Such high hemoglobin content is an indication of the tumors neovascularisation and it is clearly pronounced in all dysplastic and tumor sites investigated. The lack of fluorescence peaks in the red spectral area for normal mucosa is an indication for selective accumulation of δ-ALA/PpIX only in abnormal sites and gives high contrast when lesion borders are determined from clinicians during video observation in the process of diagnostic procedure. Very good correlation between fluorescence signals and histology examination results of the lesions investigated is achieved.

  11. Pro12Ala polymorphism in PPAR-γ2 and dementia in Chinese nonagenarians/centenarians

    PubMed Central

    Ji-Rong, Yue; Chang-Quan, Huang; Zhen-Chan, Lu; Hong-Mei, Wu; Yan-Ling, Zhang

    2010-01-01

    We examined the existence of a relationship between polymorphism and dementia in subjects aged 90 years and above. The sample included 732 unrelated Chinese nonagenarians/centenarians (aged 90–108 years, mean age 93.68 years; 67.5% women). The Pro12Ala variant was examined using polymerase chain reaction restriction fragment length polymorphism. Cognitive function was measured with 30-item mini-mental state examination. The genotype frequencies of the Pro12Ala polymorphism were 0% Ala12Ala, 9.1% Pro12Ala, and 90.9% Pro12Pro. The prevalence rates of dementia were 64.9% in the whole sample (45.0% for men and 74.5% for women). In both men and women, between subjects with and without 12Ala carriers, there was no significant difference in cognitive function scores and also no significant difference in prevalence of dementia; there was no significant difference in frequency of 12Ala carriers between subjects with and without dementia. Multiple logistic regression was performed by adjusting clinical factors that are thought to be associated with cognitive function or with 12Ala carriers. We found that 12Ala is not a risk factor for dementia. We found that Pro12Ala polymorphism in PPAR-γ2 was not directly correlated with dementia among Chinese nonagenarians and centenarians. PMID:20640553

  12. Pro12Ala polymorphism in PPAR-gamma2 and dementia in Chinese nonagenarians/centenarians.

    PubMed

    Yue, Ji-Rong; Dong, Bi-Rong; Huang, Chang-Quan; Lu, Zhen-Chan; Wu, Hong-Mei; Zhang, Yan-Ling

    2010-09-01

    We examined the existence of a relationship between polymorphism and dementia in subjects aged 90 years and above. The sample included 732 unrelated Chinese nonagenarians/centenarians (aged 90-108 years, mean age 93.68 years; 67.5% women). The Pro12Ala variant was examined using polymerase chain reaction restriction fragment length polymorphism. Cognitive function was measured with 30-item mini-mental state examination. The genotype frequencies of the Pro12Ala polymorphism were 0% Ala12Ala, 9.1% Pro12Ala, and 90.9% Pro12Pro. The prevalence rates of dementia were 64.9% in the whole sample (45.0% for men and 74.5% for women). In both men and women, between subjects with and without 12Ala carriers, there was no significant difference in cognitive function scores and also no significant difference in prevalence of dementia; there was no significant difference in frequency of 12Ala carriers between subjects with and without dementia. Multiple logistic regression was performed by adjusting clinical factors that are thought to be associated with cognitive function or with 12Ala carriers. We found that 12Ala is not a risk factor for dementia. We found that Pro12Ala polymorphism in PPAR-gamma2 was not directly correlated with dementia among Chinese nonagenarians and centenarians.

  13. Evidence for a Contribution of ALA Synthesis to Plastid-To-Nucleus Signaling

    SciTech Connect

    Czarnecki, Olaf; Gläßer, Christine; Chen, Jin-Gui; Mayer, Klaus F. X.; Grimm, Bernhard

    2012-01-01

    The formation of 5-aminolevulinic acid (ALA) in tetrapyrrole biosynthesis is widely controlled by environmental and metabolic feedback cues that determine the influx into the entire metabolic path. Because of its central role as the rate-limiting step, we hypothesized a potential role of ALA biosynthesis in tetrapyrrole-mediated retrograde signaling and exploited the direct impact of ALA biosynthesis on nuclear gene expression (NGE) by using two different approaches. Firstly, the Arabidopsis gun1, hy1 (gun2), hy2 (gun3), gun4 mutants showing uncoupled NGE from the physiological state of chloroplasts were thoroughly examined for regulatory modifications of ALA synthesis and transcriptional control in the nucleus. We found that reduced ALA-synthesizing capacity is common to analyzed gun mutants. Inhibition of ALA synthesis by gabaculine (GAB) that inactivates glutamate-1-semialdehyde aminotransferase and ALA feeding of wild-type and mutant seedlings corroborate the expression data of gun mutants. Transcript level of photosynthetic marker genes were enhanced in norflurazon (NF)-treated seedlings upon additional GAB treatment, while enhanced ALA amounts diminish these RNA levels in NF-treated wild-type in comparison to the solely NF-treated seedlings. Secondly, the impact of posttranslationally down-regulated ALA synthesis on NGE was investigated by global transcriptome analysis of GAB-treated Arabidopsis seedlings and the gun4-1 mutant, which is also characterized by reduced ALA formation. A common set of significantly modulated genes was identified indicating ALA synthesis as a potential signal emitter. The over-represented gene ontology categories of genes with decreased or increased transcript abundance highlight a few biological processes and cellular functions, which are remarkably affected in response to plastid-localized ALA biosynthesis. These results support the hypothesis that ALA biosynthesis correlates with retrograde signaling-mediated control of NGE.

  14. CD24 Ala/Val polymorphism and multiple sclerosis.

    PubMed

    Goris, An; Maranian, Melanie; Walton, Amie; Yeo, Tai Wai; Ban, Maria; Gray, Julia; Dubois, Bénédicte; Compston, Alastair; Sawcer, Stephen

    2006-06-01

    CD24 is expressed on a broad range of cells in the immune and central nervous systems and appears to be required for development of experimental autoimmune encephalomyelitis in mice. Association of a CD24 Ala/Val coding polymorphism with susceptibility to and progression of multiple sclerosis was recently reported. We typed this coding polymorphism in a combined cohort of 1,180 cases and 1,168 unrelated and family-based controls from Belgium and the UK, but were unable to confirm either association. Since the CD24 gene is part of a segmental duplication, special care is required for the identification and genotyping of single nucleotide polymorphisms.

  15. Introducing ALAS: A Novel Agent-Oriented Programming Language

    NASA Astrophysics Data System (ADS)

    Mitrović, Dejan; Ivanović, Mirjana; Vidaković, Milan

    2011-09-01

    Agent-oriented programming languages represent a family of programming languages that provide developers with high-level abstractions and constructs necessary for implementing and using agent-related concepts. In this paper a novel agent-oriented programming language for rapid and efficient development of reactive agents, named ALAS, is presented. The simple, but powerful set of language constructs is designed to support the execution of agents in heterogenous environments, and to enable easy employment of advanced agent features, such as mobility and web service integration.

  16. 5-ALA/PpIX fluorescence detection of gastrointestinal neoplasia

    NASA Astrophysics Data System (ADS)

    Borisova, Ekaterina G.; Vladimirov, Borislav; Terziev, Ivan; Ivanova, Radina; Avramov, Latchezar

    2009-07-01

    In the recent study delta-ALA/PpIX is used as fluorescent marker for dysplasia and tumor detection in esophagus, stomach and colon. ALA is administered per os six to eight (depending on the lesion location) hours before measurements at dose 20mg/kg weight. High-power light-emitting diode at 405 nm is used as an excitation source. Special opto-mechanical device is built for the LED to use the light guide of standard video-endoscopic system. Through endoscopic instrumental channel a fiber is applied to return information about fluorescence to microspectrometer. The fluorescence detected from tumor sites has very complex spectral origins. It consists of autofluorescence, fluorescence from exogenous fluorophores and re-absorption from the chromophores accumulated in the tissue investigated. Spectral features observed during endoscopic investigations could be distinct as the next regions: 450-630 nm region, where tissue autofluorescence is observed; 630-710 nm region, where fluorescence of PpIX is clearly pronounced; 530-580 nm region, where minima in the autofluorescence signal are observed, related to re-absorption of oxy-hemoglobin in this spectral area. Endogenous and exogenous fluorescence spectra are used to develop simple but effective algorithm, based on dimensionless ratio of the signals at 560 and 635 nm, for differentiation of normal/abnormal gastrointestinal tissues. Very good correlation between fluorescence signals and histology examination of the lesions investigated is achieved.

  17. Monitoring blood flow and photobleaching during topical ALA PDT treatment

    NASA Astrophysics Data System (ADS)

    Sands, Theresa L.; Sunar, Ulas; Foster, Thomas H.; Oseroff, Allan R.

    2009-02-01

    Photodynamic therapy (PDT) using topical aminolevulinic acid (ALA) is currently used as a clinical treatment for nonmelanoma skin cancers. In order to optimize PDT treatment, vascular shutdown early in treatment must be identified and prevented. This is especially important for topical ALA PDT where vascular shutdown is only temporary and is not a primary method of cell death. Shutdown in vasculature would limit the delivery of oxygen which is necessary for effective PDT treatment. Diffuse correlation spectroscopy (DCS) was used to monitor relative blood flow changes in Balb/C mice undergoing PDT at fluence rates of 10mW/cm2 and 75mW/cm2 for colon-26 tumors implanted intradermally. DCS is a preferable method to monitor the blood flow during PDT of lesions due to its ability to be used noninvasively throughout treatment, returning data from differing depths of tissue. Photobleaching of the photosensitizer was also monitored during treatment as an indirect manner of monitoring singlet oxygen production. In this paper, we show the conditions that cause vascular shutdown in our tumor model and its effects on the photobleaching rate.

  18. Fluorescence microscopy studies on ALA-sensitized tissues

    NASA Astrophysics Data System (ADS)

    Huettmann, Gereon; Achtelik, Wolfgang; Loening, Martin; Sommer, Konrad; Diddens, Heyke C.

    1996-12-01

    Fluorescence microscopy has the potential to study the spatial distribution of photosensitizers in tissue samples with cellular or subcellular resolution. A fluorescence microscope was developed to study the distribution of photosensitizer in tissue samples by acquiring fluorescence images in various spectral ranges and spatially resolved fluorescence spectra both from identical samples. Both methods provide complementary information, since the fluorescence images show the distribution of the sensitizers with a high spatial resolution whereas spatially resolved fluorescence spectra can identify the sensitizers and separate their fluorescence from background light emission by the spectral shape of the fluorescence. Protoporphyrin IX (PPIX) distribution induced by 5-aminolevulinic acid (ALA) was studied by fluorescence microscopy in basal cell carcinoma (BCC) and in cervical intraepithelial neoplasia (CIN). In an attempt to understand the varying success in treating BCC with topically applied ALA the PPIX distribution was studied in BCC samples of 10 patients. A strong fluorescence was observed in tumor cells as well as in epidermis, sebaceous glands, and hair follicles. The depth of PPIX sensitization of the BCCs ranged from 0.4 to 3 mm and the ratio of tumor versus epidermal fluorescence of uninvolved skin was near one. In the BCCs an uneven sensitization with a lower fluorescence in the center of the tumor was often observed. Samples of the cervical mucosa also showed PPIX fluorescence in the endothelial layer, the malignant tissues and the glands. No increased fluorescence of the dysplastic lesions compared to the epithelium was observed.

  19. Fluorescence diagnosis of bladder cancer: a novel in vivo approach using 5-aminolevulinic acid (ALA) dendrimers.

    PubMed

    François, Aurélie; Battah, Sinan; MacRobert, Alexander J; Bezdetnaya, Lina; Guillemin, François; D'Hallewin, Marie-Ange

    2012-12-01

    What's known on the subject? and What does the study add? Fluorescence cystoscopy with hexylaminolevulinate (h-ALA, Hexvix®) is known to improve tumour detection in non-muscle-invasive bladder cancer. However, specificity is relatively low and the intensity of the observed fluorescence signal decreases over time due to protoporphyrin IX (PpIX) efflux. This study evaluates in an in vivo model the use of a dendritic 5-aminolevulinic acid compound for fluorescence diagnosis. Fluorescence ratios between tumour and urothelium as well as muscle were significantly better as compared with h-ALA. Sustained synthesis of PpIX accounts for preservation of fluorescence for >24 h. • To overcome the relative lack of tumour selectivity of fluorescence-guided cystoscopy using 5-aminolevulinic acid (ALA) or its ester derivative (e.g. hexylaminolevulinate, h-ALA; Hexvix®), we evaluated the use of dendrimers bearing different ALA loads in rats bearing orthotopic bladder tumours. • Rat bladders were instilled with h-ALA or ALA dendrimers and fluorescence ratio between tumour and normal urothelium, as well as tumour and muscle and depth of fluorescence were determined with Image J software. • Quantification of ALA and/or esters systemic reabsorption was evaluated by high-performance liquid chromatography. • Slow hydrolysis of ALA from dendrimers as observed in vitro implies a higher initial ALA load and longer resting times in vivo. Sustained synthesis of protoporphyrin IX (PpIX) explains persistence of fluorescence for >24 h. • There were significantly better fluorescence ratios with dendrimers, as well as higher penetration depths and absence of systemic reabsorption. • The prolonged and sustained PpIX synthesis, the improved tumour selectivity with a deeper penetration and the absence of systemic reabsorption are primary indicators that ALA dendrimers could be an alternative to h-ALA in fluorescence-guided cystoscopy. © 2012 THE AUTHORS. BJU INTERNATIONAL © 2012 BJU

  20. In vivo study of ALA PLGA nanoparticles-mediated PDT for treating cutaneous squamous cell carcinoma

    NASA Astrophysics Data System (ADS)

    Wang, Xiaojie; Shi, Lei; Huang, Zheng; Wang, Xiuli

    2014-09-01

    Background: Squamous cell carcinoma (SCC) is a common skin cancer and its treatment is still a challenge. Although topical photodynamic therapy (PDT) is effective for treating in situ and superficial SCC, the effectiveness of topical ALA delivery to thick SCC can be limited by its bioavailability. Polylactic-co-glycolic acid nanopartieles (PLGA NPs) might provide a promising ALA delivery strategy. The aim of this study was to evaluate the efficacy of ALA PLGA NPs PDT for the treatment of cutaneous SCC in a mouse model. Methods: ALA loaded PLGA NPs were prepared and characterized. The therapeutic efficacy of ALA PLGA NP mediated PDT in treating UV-induced cutaneous SCC in the mice model were examined. Results: In vivo study showed that ALA PLGA NPs PDT were more effective than free ALA of the same concentration in treating mouse cutaneous SCC. Conclusion: ALA PLGA NPs provides a promising strategy for delivering ALA and treating cutaneous SCC.

  1. Tissue distribution and kinetics of endogenous porphyrins synthesized after topical application of ALA in different vehicles

    PubMed Central

    Casas, A; Fukuda, H; Batlle, A M del C

    1999-01-01

    The use of 5-aminolaevulinic acid (ALA) is gaining increasing attention for photosensitization in photodynamic therapy of superficially localized tumours. The aim of this work was to determine the kinetics of porphyrin generation in tissues after topical application of ALA delivered in different vehicles on the skin overlying the tumour and normal skin of mice. Maximal accumulation was found in tumour 3 h after ALA application in both cream and lotion preparations. Normal and overlying tumour skin tissues showed different kinetic patterns, reflecting histological changes when the latter is invaded by tumour cells. Liver, kidney, spleen and blood porphyrins also raised from basal levels, showing that ALA and/or ALA-induced porphyrins reach all tissues after topical application. During the first 24 h of ALA topical application, precursors and porphyrins are excreted by both urine and faeces. ALA lotion applied on the skin overlying the tumour induced higher accumulation of tumoural porphyrins than cream, and lotion applied on normal skin appeared to be the most efficient upon inducing total body porphyrins. This work has demonstrated the great influence of the formulation of ALA vehicle on penetration through the skin. Knowledge of the kinetics of porphyrin generation after different conditions of ALA application is needed for the optimization of diagnosis and phototherapy in human tumours. © 1999 Cancer Research Campaign PMID:10487606

  2. Role of ALA sensitivity in HepG2 cell in the presence of diode laser

    NASA Astrophysics Data System (ADS)

    Fakhar-E-Alam, M.; Atif, M.; Alsalhi, M. S.; Siddique, M.; Kishwar, S.; Qadir, M. I.; Willander, M.

    2011-05-01

    5-aminolevulinic acid (ALA) being an amazing second generation photosensitizer was studied as photodamaging drug on hepatocellular carcinoma (HepG2) cells. The mentioned photosensitizer is converted to PpIX in HepG2 cells in vitro, inducing haem in the cell causing generation of singlet oxygen leading to cell apoptosis. Cell uptake of 5-ALA was evaluated with different concentrations (ranging from 0-800 μg/ml) for 0-49 h incubation period. ALA administered in HepG2 cells is converted into Protoporphyrin IX (PpIX) which has a short half life and constitute a good hematoporphyrin derivative (HPD). Cytotoxicity of ALA in dark and cellular viability without ALA in the presence of light was studied, showing minimal toxic effects in dark with no photodamaging effect on mentioned cells in absence of ALA were observed. The optimal uptake of photosensitizer (5-ALA) in HepG2 cells was investigated by means of spectrophotometeric measurements, cellular viability was determined by means of neutral red assay (NRA). It was observed that with different concentrations (0-800 μg/ml) of ALA or light doses (0-160 J/cm2), there were no significant effect on cellular viability when studied independently. The novel of photocytotoxic study indicates that light dose of 120 J/cm2 produces convincing Photodynamic therapy (PDT) results for HepG2 cells incubated with 262 μg/ml of 5-ALA deducting that HepG2 cell line is sensitive to ALA mediated PDT. Finally morphological changes in HePG2 cells were determined before and after ALA-mediated PDT by confocal microscopy.

  3. Photodynamic Detection of Peritoneal Metastases Using 5-Aminolevulinic Acid (ALA)

    PubMed Central

    Yonemura, Yutaka; Endo, Yoshio; Canbay, Emel; Liu, Yang; Ishibashi, Haruaki; Mizumoto, Akiyoshi; Hirano, Masamitu; Imazato, Yuuki; Takao, Nobuyuki; Ichinose, Masumi; Noguchi, Kousuke; Li, Yan; Wakama, Satoshi; Yamada, Kazuhiro; Hatano, Koutarou; Shintani, Hiroshi; Yoshitake, Hiroyuki; Ogura, Shun-ichiro

    2017-01-01

    In the past, peritoneal metastasis (PM) was considered as a terminal stage of cancer. From the early 1990s, however, a new comprehensive treatment consisting of cytoreductive surgery and perioperative chemotherapy has been established to improve long-term survival for selected patients with PM. Among prognostic indicators after the treatment, completeness of cytoreduction is the most independent predictors of survival. However, peritoneal recurrence is a main cause of recurrence, even after complete cytoreduction. As a cause of peritoneal recurrence, small PM may be overlooked at the time of cytoreductive surgery (CRS), therefore, development of a new method to detect small PM is desired. Recently, photodynamic diagnosis (PDD) was developed for detection of PM. The objectives of this review were to evaluate whether PDD using 5-aminolevulinic acid (ALA) could improve detection of small PM. PMID:28257041

  4. 5-ALA-assisted photodynamic therapy in canine prostates

    NASA Astrophysics Data System (ADS)

    Sroka, Ronald; Muschter, Rolf; Knuechel, Ruth; Steinbach, Pia; Perlmutter, Aaron P.; Martin, Thomas; Baumgartner, Reinhold

    1996-05-01

    Photodynamic therapy (PDT) and interstitial thermotherapy are well known treatment modalities in urology. The approach of this study is to combine both to achieve a selective treatment procedure for benign prostatic hyperplasia (BPH) and prostate carcinoma. Measurements of thy in-vivo pharmacokinetics of 5-ALA induced porphyrins by means of fiber assisted ratiofluorometry showed a maximum fluorescence intensity at time intervals of 3 - 4 h post administration. Fluorescence microscopy at that time showed bright fluorescence in epithelial cells while in the stroma fluorescence could not be observed. Interstitial PDT using a 635-nm dye laser with an irradiation of 50 J/cm2 resulted in a nonthermic hemorrhagic lesion. The lesion size did not change significantly when an irradiation of 100 J/cm2 was used. The usefulness of PDT for treating BPH as well as prostate carcinoma has to be proven in further studies.

  5. Photodynamic Detection of Peritoneal Metastases Using 5-Aminolevulinic Acid (ALA).

    PubMed

    Yonemura, Yutaka; Endo, Yoshio; Canbay, Emel; Liu, Yang; Ishibashi, Haruaki; Mizumoto, Akiyoshi; Hirano, Masamitu; Imazato, Yuuki; Takao, Nobuyuki; Ichinose, Masumi; Noguchi, Kousuke; Li, Yan; Wakama, Satoshi; Yamada, Kazuhiro; Hatano, Koutarou; Shintani, Hiroshi; Yoshitake, Hiroyuki; Ogura, Shun-Ichiro

    2017-03-01

    In the past, peritoneal metastasis (PM) was considered as a terminal stage of cancer. From the early 1990s, however, a new comprehensive treatment consisting of cytoreductive surgery and perioperative chemotherapy has been established to improve long-term survival for selected patients with PM. Among prognostic indicators after the treatment, completeness of cytoreduction is the most independent predictors of survival. However, peritoneal recurrence is a main cause of recurrence, even after complete cytoreduction. As a cause of peritoneal recurrence, small PM may be overlooked at the time of cytoreductive surgery (CRS), therefore, development of a new method to detect small PM is desired. Recently, photodynamic diagnosis (PDD) was developed for detection of PM. The objectives of this review were to evaluate whether PDD using 5-aminolevulinic acid (ALA) could improve detection of small PM.

  6. Mechanism of atomic layer epitaxy of AlAs

    NASA Astrophysics Data System (ADS)

    Hirose, S.; Yamaura, M.; Yoshida, A.; Ibuka, H.; Hara, K.; Munekata, H.

    1998-11-01

    A systematic study on atomic layer epitaxy (ALE) of AlAs thin films has been carried out by using ethyldimethylamine alane as an Al source. Self-limiting growth modes accompanied by one, two and three monolayers per ALE cycle have been clearly presented. Each growth mode shows unique dependence of growth temperature on carbon contents. We discuss that one monolayer self-limiting growth proceeds with the conventional adsorbate inhibition model, whereas the self-limiting growth with two and three monolayers can only be explained by the formation of metallic Al layers. We also point out that atomic configuration of the layer may depend on the substrate temperature. Kinetic consideration is also given to examine these models.

  7. Multiphoton tomography of skin tumors after ALA application

    NASA Astrophysics Data System (ADS)

    Riemann, Iris; Ehlers, Alexander; Dill-Müller, Dorothee; Martin, Sven; König, Karsten

    2007-02-01

    In skin, the most common form of cancer is the basal cell carcinoma, affecting about 800.000 people in US each year. One of the treatments is photodynamic therapy (PDT) with a topical application of 5-aminolevulinic acid (ALA) derivates. These photosensitizers accumulate mainly in cancerous cells and can be activated by light resulting in a destruction of the cells. We performed multiphoton tomography based on near-infrared (NIR) femtosecond laser pulses on skin biopsies in order to study the biosynthesis of protoporphyrine IX and the effect of treatment with submicron resolution. The fluorescence of the photosensitizer was excited using two-photon processes and monitored through the epidermis towards the basal layer. In comparison with normal skin the cancerous cells showed different morphology and fluorescence behavior. Multiphoton tomography might become a useful tool for high resolution imaging of cancerous tissue and to evaluate the therapeutical effects.

  8. Alpha linolenic acid (ALA) from Rosa canina, sacha inchi and chia oils may increase ALA accretion and its conversion into n-3 LCPUFA in diverse tissues of the rat.

    PubMed

    Valenzuela B, Rodrigo; Barrera R, Cynthia; González-Astorga, Marcela; Sanhueza C, Julio; Valenzuela B, Alfonso

    2014-07-25

    Alpha-linolenic acid (ALA) is an essential n-3 PUFA; its n-3 LCPUFA derivatives EPA and DHA, which have diverse beneficial effects, are scarce in the human diet. In recent years nontraditional vegetable oils rich in ALA (up to 45%) have been developed as new alternatives to increase ALA consumption. This work evaluated the accretion of ALA, EPA and DHA into the phospholipids extracted from erythrocytes, liver, kidney, small intestine, heart, quadriceps and the brain in rats fed sunflower (SFO), canola (CO), Rosa canina (RCO), sacha inchi (Plukenetia volubilis, SIO) and chia (Salvia hispánica, ChO) oils. Five experimental groups (n = 12 per group) were fed for 21 days with SFO (1% ALA), CO (10% ALA), RCO (33% ALA), SIO (49% ALA), and ChO (64% ALA). SIO and ChO allowed higher ALA accretion in all tissues, except the brain, and a reduction in the content of arachidonic acid in all tissues except the brain. EPA was increased in erythrocytes, liver, kidney, small intestine, heart and quadriceps, but not in the brain. DHA was increased in the liver, small intestine and brain tissues. Our results demonstrate that ALA, when provided in significant amounts, can be converted into n-3 LCPUFA, mostly DHA in the liver and brain. It is suggested that oils rich in ALA, such as SIO and ChO, are good sources for obtaining higher tissue levels of ALA, also allowing its selective conversion into n-3 LCPUFA in some tissues of the rat.

  9. A Fifty-Five Year Partnership: ALA and the AFL-CIO.

    ERIC Educational Resources Information Center

    Meyers, Arthur S.

    2002-01-01

    Provides a history of the establishment of the AFL-CIO/ALA (American Federation of Labor (AFL)-Congress of Industrial Organizations (CIO)/American Library Association (ALA)) Joint Committee on Library Service to Labor Groups. Topics include public learning, labor, and libraries; services to labor; problems and issues, including conflicts between…

  10. ALAS2 acts as a modifier gene in patients with congenital erythropoietic porphyria.

    PubMed

    To-Figueras, Jordi; Ducamp, Sarah; Clayton, Jerome; Badenas, Celia; Delaby, Constance; Ged, Cecile; Lyoumi, Said; Gouya, Laurent; de Verneuil, Hubert; Beaumont, Carole; Ferreira, Gloria C; Deybach, Jean-Charles; Herrero, Carmen; Puy, Herve

    2011-08-11

    Mutations in the uroporphyrinogen III synthase (UROS) gene cause congenital erythropoietic porphyria (CEP), an autosomal-recessive inborn error of erythroid heme biosynthesis. Clinical features of CEP include dermatologic and hematologic abnormalities of variable severity. The discovery of a new type of erythroid porphyria, X-linked dominant protoporphyria (XLDPP), which results from increased activity of 5-aminolevulinate synthase 2 (ALAS2), the rate-controlling enzyme of erythroid heme synthesis, led us to hypothesize that the CEP phenotype may be modulated by sequence variations in the ALAS2 gene. We genotyped ALAS2 in 4 unrelated CEP patients exhibiting the same C73R/P248Q UROS genotype. The most severe of the CEP patients, a young girl, proved to be heterozygous for a novel ALAS2 mutation: c.1757 A > T in exon 11. This mutation is predicted to affect the highly conserved and penultimate C-terminal amino acid of ALAS2 (Y586). The rate of 5-aminolevulinate release from Y586F was significantly increased over that of wild-type ALAS2. The contribution of the ALAS2 gain-of-function mutation to the CEP phenotype underscores the importance of modifier genes underlying CEP. We propose that ALAS2 gene mutations should be considered not only as causative of X-linked sideroblastic anemia (XLSA) and XLDPP but may also modulate gene function in other erythropoietic disorders.

  11. Enhanced photodynamic efficacy of PLGA-encapsulated 5-ALA nanoparticles in mice bearing Ehrlich ascites carcinoma

    NASA Astrophysics Data System (ADS)

    Shaker, Maryam N.; Ramadan, Heba S.; Mohamed, Moustafa M.; El khatib, Ahmed M.; Roston, Gamal D.

    2014-10-01

    Nanoparticles (NPs) fabricated from the biodegradable copolymer poly(lactic- co-glycolic acid) (PLGA) were investigated as a drug delivery system to enhance the photodynamic efficacy of 5-aminolevulinic acid (5-ALA) in mice bearing Ehrlich ascites carcinoma. The PLGA-encapsulated 5-ALA NPs were prepared using binary organic solvent diffusion method and characterized in terms of shape and particle size. The in vivo photodynamic efficiency in Ehrlich ascites-bearing mice was studied. The obtained particles were uniform in size with spherical shape of mean size of 249.5 nm as obtained by particle size analyzer and the in vitro release studies demonstrated a controlled release profile of 5-ALA. Tumor-bearing mice injected with PLGA-encapsulated 5-ALA NPs exhibited significantly smaller mean tumor volume, increased tumor growth delay compared with the control group and the group injected with free 5-ALA during the time course of the experiment. Histopathological examination of tumor from mice treated with PLGA-encapsulated 5-ALA NPs showed regression of tumor cells, in contrast to those obtained from mice treated with free 5-ALA. The results indicate that PLGA-encapsulated 5-ALA NPs are a successful delivery system for improving photodynamic activity in the target tissue.

  12. Paradox of mistranslation of serine for alanine caused by AlaRS recognition dilemma.

    PubMed

    Guo, Min; Chong, Yeeting E; Shapiro, Ryan; Beebe, Kirk; Yang, Xiang-Lei; Schimmel, Paul

    2009-12-10

    Mistranslation arising from confusion of serine for alanine by alanyl-tRNA synthetases (AlaRSs) has profound functional consequences. Throughout evolution, two editing checkpoints prevent disease-causing mistranslation from confusing glycine or serine for alanine at the active site of AlaRS. In both bacteria and mice, Ser poses a bigger challenge than Gly. One checkpoint is the AlaRS editing centre, and the other is from widely distributed AlaXps-free-standing, genome-encoded editing proteins that clear Ser-tRNA(Ala). The paradox of misincorporating both a smaller (glycine) and a larger (serine) amino acid suggests a deep conflict for nature-designed AlaRS. Here we show the chemical basis for this conflict. Nine crystal structures, together with kinetic and mutational analysis, provided snapshots of adenylate formation for each amino acid. An inherent dilemma is posed by constraints of a structural design that pins down the alpha-amino group of the bound amino acid by using an acidic residue. This design, dating back more than 3 billion years, creates a serendipitous interaction with the serine OH that is difficult to avoid. Apparently because no better architecture for the recognition of alanine could be found, the serine misactivation problem was solved through free-standing AlaXps, which appeared contemporaneously with early AlaRSs. The results reveal unconventional problems and solutions arising from the historical design of the protein synthesis machinery.

  13. Inducible L-alanine exporter encoded by the novel gene ygaW (alaE) in Escherichia coli.

    PubMed

    Hori, Hatsuhiro; Yoneyama, Hiroshi; Tobe, Ryuta; Ando, Tasuke; Isogai, Emiko; Katsumata, Ryoichi

    2011-06-01

    We previously isolated a mutant hypersensitive to L-alanyl-L-alanine from a non-L-alanine-metabolizing Escherichia coli strain and found that it lacked an inducible l-alanine export system. Consequently, this mutant showed a significant accumulation of intracellular L-alanine and a reduction in the L-alanine export rate compared to the parent strain. When the mutant was used as a host to clone a gene(s) that complements the dipeptide-hypersensitive phenotype, two uncharacterized genes, ygaW and ytfF, and two characterized genes, yddG and yeaS, were identified. Overexpression of each gene in the mutant resulted in a decrease in the intracellular l-alanine level and enhancement of the L-alanine export rate in the presence of the dipeptide, suggesting that their products function as exporters of L-alanine. Since ygaW exhibited the most striking impact on both the intra- and the extracellular L-alanine levels among the four genes identified, we disrupted the ygaW gene in the non-L-alanine-metabolizing strain. The resulting isogenic mutant showed the same intra- and extracellular L-alanine levels as observed in the dipeptide-hypersensitive mutant obtained by chemical mutagenesis. When each gene was overexpressed in the wild-type strain, which does not intrinsically excrete alanine, only the ygaW gene conferred on the cells the ability to excrete alanine. In addition, expression of the ygaW gene was induced in the presence of the dipeptide. On the basis of these results, we concluded that YgaW is likely to be the physiologically most relevant exporter for L-alanine in E. coli and proposed that the gene be redesignated alaE for alanine export.

  14. Inducible l-Alanine Exporter Encoded by the Novel Gene ygaW (alaE) in Escherichia coli ▿

    PubMed Central

    Hori, Hatsuhiro; Yoneyama, Hiroshi; Tobe, Ryuta; Ando, Tasuke; Isogai, Emiko; Katsumata, Ryoichi

    2011-01-01

    We previously isolated a mutant hypersensitive to l-alanyl-l-alanine from a non-l-alanine-metabolizing Escherichia coli strain and found that it lacked an inducible l-alanine export system. Consequently, this mutant showed a significant accumulation of intracellular l-alanine and a reduction in the l-alanine export rate compared to the parent strain. When the mutant was used as a host to clone a gene(s) that complements the dipeptide-hypersensitive phenotype, two uncharacterized genes, ygaW and ytfF, and two characterized genes, yddG and yeaS, were identified. Overexpression of each gene in the mutant resulted in a decrease in the intracellular l-alanine level and enhancement of the l-alanine export rate in the presence of the dipeptide, suggesting that their products function as exporters of l-alanine. Since ygaW exhibited the most striking impact on both the intra- and the extracellular l-alanine levels among the four genes identified, we disrupted the ygaW gene in the non-l-alanine-metabolizing strain. The resulting isogenic mutant showed the same intra- and extracellular l-alanine levels as observed in the dipeptide-hypersensitive mutant obtained by chemical mutagenesis. When each gene was overexpressed in the wild-type strain, which does not intrinsically excrete alanine, only the ygaW gene conferred on the cells the ability to excrete alanine. In addition, expression of the ygaW gene was induced in the presence of the dipeptide. On the basis of these results, we concluded that YgaW is likely to be the physiologically most relevant exporter for l-alanine in E. coli and proposed that the gene be redesignated alaE for alanine export. PMID:21531828

  15. 5-ALA fluorescence of cerebral metastases and its impact for the local-in-brain progression

    PubMed Central

    Kamp, Marcel A.; Fischer, Igor; Bühner, Julia; Turowski, Bernd; Cornelius, Jan Frederick; Steiger, Hans-Jakob; Rapp, Marion; Slotty, Philipp J.; Sabel, Michael

    2016-01-01

    Aim of the present study was to analyze the oncological impact of 5-ALA fluorescence of cerebral metastases. A retrospective analysis was performed for 84 patients who underwent 5-ALA fluorescence-guided surgery of a cerebral metastasis. Dichotomized fluorescence behavior was correlated to the histopathological subtype and primary site of the metastases, the degree of surgical resection on an early postoperative MRI within 72 hours after surgery, the local in-brain-progression rate and the overall survival. 34/84 metastases (40.5%) showed either strong or faint and 50 metastases (59.5%) no 5-ALA derived fluorescence. Neither the primary site of the cerebral metastases nor their subtype correlated with fluorescence behavior. The dichotomized 5-ALA fluorescence (yes vs. no) had no statistical influence on the degree of surgical resection. Local in-brain progression within or at the border of the resection cavity was observed in 26 patients (30.9%). A significant correlation between 5-ALA fluorescence and local in-brain-progression rate was observed and patients with 5-ALA-negative metastases had a significant higher risk of local recurrence compared to patients with 5-ALA positive metastases. After exclusion of the 20 patients without any form of adjuvant radiation therapy, there was a trend towards a relation of the 5-ALA behavior on the local recurrence rate and the time to local recurrence, although results did not reach significance anymore. Absence of 5-ALA-induced fluorescence may be a risk factor for local in-brain-progression but did not influence the mean overall survival. Therefore, the dichotomized 5-ALA fluorescence pattern might be an indicator for a more aggressive tumor. PMID:27564260

  16. Cognitive deficits and ALA-D-inhibition in children exposed to multiple metals.

    PubMed

    do Nascimento, Sabrina N; Barth, Anelise; Göethel, Gabriela; Baierle, Marília; Charão, Mariele F; Brucker, Natália; Moro, Angela M; Bubols, Guilherme B; Sobreira, Johanna S; Sauer, Elisa; Rocha, Rafael; Gioda, Adriana; Dias, Ana Cristina; Salles, Jerusa F; Garcia, Solange C

    2015-01-01

    Children are especially vulnerable to adverse effects of multiple metals exposure. The aim of this study was to assess some metals concentrations such as lead (Pb), arsenic (As), chromium (Cr), manganese (Mn) and iron (Fe) in whole blood, serum, hair and drinking water samples using inductively coupled plasma-mass spectrometry (ICP-MS) in rural and urban children. In addition, evaluate the adverse effects of multiple metals exposure on cognitive function and δ-aminolevulinate dehydratase (ALA-D) activity. The cognitive ability assessment was performed by the Raven's Colored Progressive Matrices (RCPM) test. The ALA-D activity and ALA-D reactivation index (ALA-RE) activity with DTT and ZnCl2 also were determined. Forty-six rural children and 23 urban children were enrolled in this study. Rural children showed percentile IQ scores in the RCPM test significantly decreased in relation to urban children. According to multiple linear regression analysis, the Mn and Fe in hair may account for the cognitive deficits of children. Manganese and Fe in hair also were positively correlated with Mn and Fe in drinking water, respectively. These results suggest that drinking water is possibly a source of metals exposure in children. ALA-D activity was decreased and ALA-RE with DTT and ZnCl2 was increased in rural children in comparison to urban children. Moreover, ALA-D inhibition was correlated with Cr blood levels and ALA-RE/DDT and ALA-RE/ZnCl2 were correlated with levels of Cr and Hg in blood. Thus, our results indicated some adverse effects of children's exposure to multiple metals, such as cognitive deficits and ALA-D inhibition, mainly associated to Mn, Fe, Cr and Hg. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. Evaluation of ALA-induced PpIX as a photosensitizer for PDT in cats

    NASA Astrophysics Data System (ADS)

    Lucroy, Michael D.; Edwards, Benjamin F.; Peavy, George M.; Krasieva, Tatiana B.; Griffey, Stephen M.; Madewell, Bruce R.

    1998-07-01

    Given exogenously, ALA defeats intrinsic regulatory feedback mechanisms allowing intracellular accumulation of protoporphyrin IX (PpIX), a highly efficient photosensitizer. In vivo, PpIX synthesis in neoplastic mammary tissues averages 20-fold higher than in normal mammary tissues. PpIX is retained intracellularly, unlike perivascular localization of other photosensitizers, and it is then cleared quickly from the body. In vitro, ALA induced PpIX production in our laboratory in 6 cell lines tested, including an established feline kidney cell line and dermal fibroblasts from primary skin biopsy explant, resulting in photosensitization. Fluorescent microscopy confirmed PpIX production in skin adnexae following ALA administration in a normal cat. To evaluate toxicity, three cats were treated with a single i.v. dose of ALA (either 100, 200, of 400 mg/kg) and followed for 7 days. Cats receiving 100 or 200 mg/kg ALA i.v. had elevated liver enzymes and bilirubin within 24 hours. Histopathology revealed hydropic changes in the liver and renal fibrosis. The cat receiving 400 mg/kg ALA intravenously had cutaneous flush, bradycardia and apnea associated with ALA administration; within 24 hours the cat was lethargic, anorectic and icteric. ALT, AST and bilirubin concentrations had increased significantly. At necropsy the liver had a prominent lobular pattern; histopathology revealed severe periportal hepatitis and splenic necrosis. Systemically administered ALA induces PpIX production, but toxicity may preclude its clinical application in the cat. PpIX levels seem to be more time dependent than those dependent at these three ALA doses and they are well beyond the saturation point for adequate PpIX conversion. The literature is scant regarding toxicity associated with parenteral administration of ALA.

  18. Fibrinogen residue γAla341 is necessary for calcium binding and 'A-a' interactions.

    PubMed

    Park, Rojin; Ping, Lifang; Song, Jaewoo; Hong, Sung-Yu; Choi, Tae-Youn; Choi, Jong-Rak; Gorkun, Oleg V; Lord, Susan T

    2012-05-01

    The fibrinogen γ-module has several important sites relating to fibrinogen function, which include the high affinity calcium binding site, hole 'a' that binds with knob 'A', and the D:D interface. Residue γAla341, which is located in the vicinity of these sites, is altered in three variant fibrinogens: fibrinogen Seoul (γAla341Asp), Tolaga Bay (γAla341Val), and Lyon III (γAla341Thr). In order to investigate the impaired polymerisation of fibrinogens γAla341Asp and γAla341Val to understand the role of γAla341 in fibrin polymerisation and fibrinogen synthesis, we have expressed γAla341Asp and γAla341Val in Chinese hamster ovary (CHO) cells, purified these fibrinogens from the culture media and performed biochemical tests to elucidate their function. Expression in CHO cells was similar for these variants. For both variants the kinetics of thrombin-catalysed FpA release was not different from normal fibrinogen, while FpB release was slower than that of normal. Thrombin-catalysed polymerisation of both variants was dependent on the calcium concentration. At physiologic calcium (1 mM) the variants showed impaired polymerisation with a longer lag period and a slower Vmax than normal fibrinogen. Scanning electron micrographs showed the clots were less organised than normal, having thicker and more twisted fibers, and larger pores. Analysis by SDS-PAGE showed that factor XIIIa-catalysed γ and α chain cross-linking was delayed, and plasmin-catalysed lysis was not reduced by the presence of 5 mM calcium or 5 mM GPRP (Gly-Pro-Arg-Pro). Our data indicate that fibrinogen residue γAla341 is important for the proper conformation of the γ-module, maintaining calcium-binding site and 'A-a' interactions.

  19. PPARg2 Ala¹² variant protects against Graves' orbitopathy and modulates the course of the disease.

    PubMed

    Pawlak-Adamska, Edyta; Daroszewski, Jacek; Bolanowski, Marek; Oficjalska, Jolanta; Janusz, Przemyslaw; Szalinski, Marek; Frydecka, Irena

    2013-07-01

    Orbital fibroblast differentiation to adipocytes is a peroxisome proliferator-activated receptor g (PPARg)-dependent process essential for pathogenic tissue remodeling in Graves' orbitopathy (GO). PPARg2 Pro¹²Ala polymorphism modulates expression and/or function of the molecule encoded by this gene and is a promising locus of GO. Here, we analyzed associations of PPARg2 Pro¹²Ala with clinical manifestation of GO in 742 Polish Caucasians including 276 Graves' disease (GD) patients. In our study, the Ala¹² allele and Ala¹² variant (Ala¹²Ala and/or Pro¹²Ala genotype) decreased the risk of GO (p = 0.000012 and p = 0.00013). Moreover, Ala¹²Ala genotype was observed only in patients without GO (p = 0.002). GD patients with Ala¹² variant had less active and less severe eye symptoms. Female carriers of the Ala¹² allele rarely developed GO, but the marker was not related to symptoms of GO. The opposite finding was recorded in males, in whom the studied polymorphism was related to activity, but not to the development, of GO. In Ala¹² variant carriers without familial history of thyroid disease, risk of GO was lower than in persons with a familial background. The Ala¹² allele seemed to protect smokers from GO, but in nonsmokers, such a relation was not obvious. A multivariate analysis indicated the Pro¹²Ala marker as an independent risk factor of eye symptoms (p = 0.0001) and lack of Ala increases the risk of GO 3.24-fold. In conclusion, the gain-of-function Ala¹² variant protects against GO and modulates the course of the disease.

  20. 5-ALA induced fluorescent image analysis of actinic keratosis

    NASA Astrophysics Data System (ADS)

    Cho, Yong-Jin; Bae, Youngwoo; Choi, Eung-Ho; Jung, Byungjo

    2010-02-01

    In this study, we quantitatively analyzed 5-ALA induced fluorescent images of actinic keratosis using digital fluorescent color and hyperspectral imaging modalities. UV-A was utilized to induce fluorescent images and actinic keratosis (AK) lesions were demarcated from surrounding the normal region with different methods. Eight subjects with AK lesion were participated in this study. In the hyperspectral imaging modality, spectral analysis method was utilized for hyperspectral cube image and AK lesions were demarcated from the normal region. Before image acquisition, we designated biopsy position for histopathology of AK lesion and surrounding normal region. Erythema index (E.I.) values on both regions were calculated from the spectral cube data. Image analysis of subjects resulted in two different groups: the first group with the higher fluorescence signal and E.I. on AK lesion than the normal region; the second group with lower fluorescence signal and without big difference in E.I. between two regions. In fluorescent color image analysis of facial AK, E.I. images were calculated on both normal and AK lesions and compared with the results of hyperspectral imaging modality. The results might indicate that the different intensity of fluorescence and E.I. among the subjects with AK might be interpreted as different phases of morphological and metabolic changes of AK lesions.

  1. Stability of Ala 125 recombinant human interleukin-2 in solution.

    PubMed

    Reyes, Nuria; Ruiz, Llamil; Aroche, Kethia; Gerónimo, Haydee; Brito, Olga; Hardy, Eugenio

    2005-01-01

    Herein, we describe the preformulation study of Ala 125- recombinant human interleukin-2 (rhIL-2A(125)) in solution. This modified form of the natural human IL-2 is obtained by the replacement of cysteine with alanine at position 125. The compatibility of this rhIL-2A(125) with type I borosilicate glass vials showed no significant adsorption at liquid-vial interface. The effect of single excipients on the stability of this lymphokine was evaluated through RP-HPLC, SDS-PAGE and biological activity assay. Polysorbate 80 at high concentrations decreased the stability of rhIL-2A(125) in solution. On the other hand, the use of antioxidants (methionine and EDTA Na(2)) diminished the oxidation rate of the active ingredient. Additionally, a group of amino acids (glutamine, alanine, glycine and histidine) stabilized rhIL-2A(125) in different grades, and glycine at 5 mg mL(-1) allowed for the best stability behaviour. Taken together, these preformulation results can be used to design an adequate liquid vehicle for rhIL-2A(125) to be manufactured for human use.

  2. Quantitative evaluation of PPAR-γ2 Pro12Ala polymorphism with hypertension.

    PubMed

    Yang, W; Wang, J; Ye, W; Li, X

    2017-09-18

    The peroxisome proliferator-activated receptor γ2 (PPARγ2)Pro12Ala polymorphism has been reported to be associated with hypertension. However, relevant studies have shown inconsistent results. To quantitatively evaluate the relationship between the PPARγ2Pro12Ala polymorphism and hypertension risk, we conducted a meta-analysis based on all available studies selected from Scopus, Web of Science, PubMed, Chinese National Knowledge Infrastructure, and Wanfang databases. In all, 13 studies were finally included in this meta-analysis. In the allelic model (Ala vs. Pro), the Ala allele of PPARγ2 Pro12Ala polymorphism was associated with hypertension (Odds Ratio [OR] = 0.723, 95% confidence interval [CI] = 0.607-0.861). Sensitivity analysis and exclusion of studies with poor quality scores or controls complicated by other diseases confirmed the validity of this association. Moreover, the PPARγ2Pro12Ala polymorphism was associated with hypertension in the codominant (OR = 0.710, 95% CI = 0.626-0.806), recessive (OR = 0.561, 95% CI = 0.418-0.754), and dominant (OR = 0.693, 95% CI = 0.577-0.833) models. The Ala allele appears to have a protective effect against hypertension and a dominant function.

  3. Design rules for modulation-doped AlAs quantum wells

    NASA Astrophysics Data System (ADS)

    Chung, Yoon Jang; Baldwin, K. W.; West, K. W.; Kamburov, D.; Shayegan, M.; Pfeiffer, L. N.

    2017-07-01

    Owing to their multivalley, anisotropic, energy band structure, two-dimensional electron systems (2DESs) in modulation-doped AlAs quantum wells (QWs) provide a unique platform to investigate electron interaction physics and ballistic transport. Indeed, a plethora of phenomena unseen in other 2DESs have been observed over the past decade. However, a foundation for sample design is still lacking for AlAs 2DESs, limiting the means to achieve optimal quality samples. Here, we present a systematic study on the fabrication of modulation-doped AlAs and GaAs QWs over a wide range of AlxGa1 -xAs barrier alloy compositions. Our data indicate clear similarities in modulation doping mechanisms for AlAs and GaAs, and provide guidelines for the fabrication of very high quality AlAs 2DESs. We highlight the unprecedented quality of the fabricated AlAs samples by presenting the magnetotransport data for low-density (≃1 ×1011cm-2 ) AlAs 2DESs that exhibit high-order fractional quantum Hall signatures.

  4. Molecular mechanisms associated with ALA-PDT of brain tumor cells

    NASA Astrophysics Data System (ADS)

    Alqawi, Omar; Espiritu, Myrna; Singh, Gurmit

    2009-06-01

    Previous studies have shown that low-dose PDT using 5-aminolevulinic acid (ALA)-induced photoporphyrin IX (PpIX) can induce apoptosis in tumor cells without causing necrosis. In this study we investigated the molecular mechanisms associated with apoptosis after ALA-PDT treatment in two brain glioma cell lines: human U87, and rat CNS-1cells. We used high energy light at a short time (acute PDT) and low energy light at a long time of exposure (metronomic PDT) to treat both cell lines. The cells were treated with 0.25 mM ALA at 5 joules for energy. We found that CNS-1 cells were more resistant to ALA-PDT than U87 cells when treated by both acute and metronomic PDT. To screen possible apoptosis mechanisms associated with acute and metronomic PDT, microarray analysis of gene expression was performed on RNA from glioblastoma cells treated with either acute or metronomic ALA-PDT. Within the set of genes that were negatively or positively regulated by both treatments are tumor necrosis factor receptors. The expression of TNF receptors was investigated further by RT-PCR and western blotting. The apoptosis mechanism of the cell death occurred through different pathways including BCL-2 and TNF receptors, and in part caused by cleaving caspase 3. Interestingly, metronomic ALA-PDT inhibited the expression of LTβR and the transcription factor NFκB. This inhibition was ALA concentration dependent at low concentrations.

  5. The role of DAMPS in ALA-PDT for skin squamous cell carcinoma (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Wang, Xiuli; Wang, Xiaojie; Ji, Jie; Zhang, Haiyan; Shi, Lei

    2016-03-01

    5-Aminolevulinic acid mediated photodynamic therapy (ALA-PDT) is an established local approach for skin squamous cell carcinoma. It is believed that dangerous signals damage-associated molecular patterns (DAMPs) play an important role in ALA-PDT. In this study, we evaluated in vitro and in vivo expressions of major DAMPs, calreticulin (CRT), heat shock proteins 70 (HSP70), and high mobility group box 1 (HMGB1), induced by ALA-PDT using immunohistochemistry, western blot, and ELISA in a squamous cell carcinoma (SCC) mouse model. The role of DAMPs in the maturation of DCs potentiated by ALA-PDT-treated tumor cells was detected by FACS and ELISA. Our results showed that ALA-PDT enhanced the expression of CRT, HSP70, and HMGB1. These induced DAMPs played an important role in activating DCs by PDT-treated tumor cells, including phenotypic maturation (upregulation of surface expression of MHC-II, CD80, and CD86) and functional maturation (enhanced capability to secrete IFN-γ and IL-12). Furthermore, injecting ALA-PDT-treated tumor cells into naïve mice resulted in complete protection against cancer cells of the same origin. Our findings indicate that ALA-PDT can upregulate DAMPs and enhance tumor immunogenicity, providing a promising strategy for inducing a systemic anticancer immune response.

  6. The neuroprotective benefit from pioglitazone (PIO) addition on the alpha lipoic acid (ALA)-based treatment in experimental diabetic rats.

    PubMed

    Jin, Heung Yong; Lee, Kyung Ae; Wu, Jin Zu; Baek, Hong Sun; Park, Tae Sun

    2014-12-01

    In this study, we investigated the combined effect of pioglitazone (PIO) with alpha lipoic acid (ALA) on the peripheral nerves of diabetic rats. Animals were divided into 8 groups (N = 6-8) and designated according to ALA (100 mg/kg/day) and PIO (10 mg/kg/day) treatment: Normal, Normal + ALA, Normal + PIO, Normal + ALA + PIO, DM, DM + ALA, DM + PIO, and DM + ALA + PIO. After 24 weeks, current perception threshold, mechanical allodynia, oxidative stresses, intraepidermal nerve fiber density (IENFD), and axonal morphology in the sciatic nerve were compared among groups. IENFD in the DM + ALA + PIO group was significantly less reduced than in other DM groups (7.61 ± 0.52 vs. 5.62 ± 0.96, 5.56 ± 0.60, and 7.10 ± 0.70 for DM, DM + ALA, and DM + PIO, respectively P < 0.05). The mean myelinated axonal area in the sciatic nerves was significantly higher in the DM + ALA + PIO group compared with non-treated DM group (70.2 ± 3.46 vs. 61.1 ± 2.91, P < 0.05) although significant differences were not present between combination therapy and monotherapy independent of ALA or PIO. Our results demonstrated that combination therapy using PIO based on ALA can give an additional benefit in peripheral nerve preservation in diabetes. Moreover, PIO can be preferentially considered when additional glucose-lowering agent is required in DPN patients treated with ALA.

  7. Association between Manganese Superoxide Dismutase (MnSOD Val-9Ala) genotypes with the risk of generalized aggressive periodontitis disease.

    PubMed

    Kazemi, E; Moradi, M-T; Yari, K; Mousavi, S A R; Kahrizi, D

    2015-12-19

    Generalized aggressive periodontitis (GAP) is a subtype of periodontal diseases that characterized by rapid destruction of periodontal supporting tissues. The MnSOD Val-9Ala mutation of manganese superoxide dismutase gene (MnSOD Val-9Ala) and its correlation with periodontal diseases has been studied in different populations. The purpose of this study was to investigate the possible association of MnSODVal-9Ala polymorphism with periodontitis disease in sample of GAP patients in Iran for the first time. Following a GAP examination, 50 GAP patients and 100 healthy individuals were recruited. Genomic DNA was extracted from peripheral blood leukocytes and the MnSODVal-9Ala polymorphismwas detected using PCR-RFLP method. The frequency of Ala/Ala, Ala/Val and Val/Val genotypes in healthy individuals were 25, 66 and 9%, respectively. In periodontitis patients, frequencies were as Ala/Ala (12%), Ala/Val (50%) and Val/Val (38%) genotypes. There was a significant positive association between distribution of MnSOD Val-9Ala genotypes and the risk of periodontitis disease (p<0.05). Our results indicated that MnSOD Val-9Ala gene polymorphism has a positive association with the risk of periodontitis disease.

  8. Association between PPAR-γ2 Pro12Ala polymorphism and obesity: a meta-analysis.

    PubMed

    Yao, Ying-Shui; Li, Jie; Jin, Yue-Long; Chen, Yan; He, Lian-Ping

    2015-06-01

    The peroxisome proliferator-activated receptor-γ2 (PPAR-γ2) gene has been reported in the pathogeny of obesity. However, the results have been inconsistent. The purpose of this meta-analysis was to acquire a more accurate assessment of the association between PPAR-γ2 Pro12Ala polymorphism and obesity. PubMed, Wan Fang (Chinese) databases, Chinese Biomedical Medical databases, and Chinese National Knowledge Infrastructure were searched to identify eligible studies. Finally, 25 studies (6491 cases and 8242 controls) were enrolled in this meta-analysis. The effect summary odds ratio (OR) with 95 % confidence interval (CI) was applied. Random-effects or fixed-effects model was performed based on the heterogeneity. STATA 12.0 was applied for this meta-analysis. The combined results showed that PPAR-γ Pro12Ala polymorphism was associated with the obesity risk (Ala vs. Pro: OR = 1.55, 95 % CI 1.34-1.80; Pro/Ala vs. Pro/Pro: OR = 1.54, 95 % CI 1.31-1.82; Ala/Ala + Pro/Ala vs. Pro/Pro: OR = 1.61, 95 % CI 1.36-1.90). Subgroup analysis by ethnicity showed that there were significant associations between PPAR-γ Pro12Ala polymorphism and obesity risk in Caucasians, Asians, and Mixed population. Subgroup analysis by obesity's cutoff points showed that the associations were found among the patients with the cutoff point of BMI ≥24 and BMI ≥30 but not among the patients with the cutoff point of BMI ≥95th percentile. These results suggested that PPAR-γ Pro12Ala polymorphism might be a risk factor for obesity susceptibility.

  9. Conversion of the agent-oriented domain-specific language ALAS into JavaScript

    NASA Astrophysics Data System (ADS)

    Sredojević, Dejan; Vidaković, Milan; Okanović, Dušan; Mitrović, Dejan; Ivanović, Mirjana

    2016-06-01

    This paper shows generation of JavaScript code from code written in agent-oriented domain-specific language ALAS. ALAS is an agent-oriented domain-specific language for writing software agents that are executed within XJAF middleware. Since the agents can be executed on various platforms, they must be converted into a language of the target platform. We also try to utilize existing tools and technologies to make the whole conversion process as simple as possible, as well as faster and more efficient. We use the Xtext framework that is compatible with Java to implement ALAS infrastructure - editor and code generator. Since Xtext supports Java, generation of Java code from ALAS code is straightforward. To generate a JavaScript code that will be executed within the target JavaScript XJAF implementation, Google Web Toolkit (GWT) is used.

  10. InAs/GaAs quantum dot solar cell with an AlAs cap layer

    NASA Astrophysics Data System (ADS)

    Tutu, F. K.; Lam, P.; Wu, J.; Miyashita, N.; Okada, Y.; Lee, K.-H.; Ekins-Daukes, N. J.; Wilson, J.; Liu, H.

    2013-04-01

    We report the effects of the deposition of an AlAs cap layer (CL) over InAs quantum dots (QDs) on the performance of QD solar cells (QDSCs). The growth of AlAs CL over InAs QDs led to the elimination of the wetting layer absorption and hence the enhancement of the open-current voltage, Voc, of a 20-layer InAs/GaAs QDSC from 0.69 V to 0.79 V. Despite a slight reduction in short-circuit current, Jsc, for the QDSC with AlAs CL, the enhancement of the Voc is enough to ensure that its efficiency is higher than the QDSC without AlAs CL.

  11. New developments in fluorescence detection of ALA-induced protoporphyrin IX for cancer localization

    NASA Astrophysics Data System (ADS)

    Stepp, Herbert G.; Baumgartner, Reinhold; Betz, Christian; Bise, Karl; Brand, P.; Gamarra, Fernando; Haeussinger, Karl; Hillemanns, Peter; Huber, Rudolf M.; Knuechel, Ruth; Kriegmair, M.; Leunig, Andreas; Pichler, J.; Rick, Kai; Schulz, H.; Stanzel, F.; Stocker, Susanne; Wagner, Simon; Weigandt, H.

    1997-12-01

    After the very promising clinical results for the detection of bladder cancer in urology, preclinical and clinical studies on aminolevulinic acid (5-ALA) induced protoporphyrin IX (PPIX) are preformed in various disciplines now. This paper provides a brief overview of the progress on 5-ALA assisted fluorescence diagnosis in urology, pulmonology, neurosurgery, gynecology and ENT performed in collaboration with the Laser Research Laboratory at the Department of Urology of the Ludwig-Maximilians-University in Munich. Five-ALA can be applied either topically or systemically to induce an intracellular accumulation of fluorescing PPIX. With appropriate dosage of 5-ALA, malignant tissue can be stained selectively, and irradiation with violet light excites a bright red fluorescence of the tumor. Optical properties of the tissue tend to hamper the precise identification and demarcation of suspect areas in fluorescence images. Multicolor remission and fluorescence imaging, therefore, seems to be indispensable for a reliable tumor localization.

  12. Latest results of 5-ALA-based fluorescence diagnosis and other medical disciplines

    NASA Astrophysics Data System (ADS)

    Baumgartner, Reinhold

    1999-02-01

    Preclinical and clinical studies on 5-aminolevulinic acid (5- ALA) induced Protoporphyrin IX (PPIX) are performed in various departments now following promising clinical results for the detection of bladder cancer in urology. This paper provides an overview on the progress of 5-ALA assisted fluorescence diagnosis in urology, pulmonology, neurosurgery, gynecology and ENT coordinated by the Laser Research Laboratory of the Ludwig-Maximilians-University in Munich. 5-ALA can be applied either topically or systematically to induce an intracellular accumulation of fluorescing PPIX. With appropriate dosage of 5-ALA, malignant tissue can be stained selectively, and irradiation with violet light excites a bright red fluorescence of the tumor visible with naked eyes. Optical properties of the tissue tend to hamper the precise identification and demarcation of suspect areas in fluorescence images. Multicolor remission and fluorescence imaging, therefore, should improve tumor localization in future.

  13. Novel development of 5-aminolevurinic acid (ALA) in cancer diagnoses and therapy.

    PubMed

    Ishizuka, Masahiro; Abe, Fuminori; Sano, Yuki; Takahashi, Kiwamu; Inoue, Katsushi; Nakajima, Motowo; Kohda, Takeo; Komatsu, Naoki; Ogura, Shun-ichiro; Tanaka, Tohru

    2011-03-01

    Early detection and intervention are needed for optimal outcomes in cancer therapy. Improvements in diagnostic technology, including endoscopy, photodynamic diagnosis (PDD), and photodynamic therapy (PDT), have allowed substantial progress in the treatment of cancer. 5-Aminolevulinic acid (ALA) is a natural, delta amino acid biosynthesized by animal and plant mitochondria. ALA is a precursor of porphyrin, heme, and bile pigments, and it is metabolized into protoporphyrin IX (PpIX) in the course of heme synthesis. PpIX preferentially accumulates in tumor cells resulting in a red fluorescence following irradiation with violet light and the formation of singlet oxygen. This reaction, utilized to diagnose and treat cancer, is termed ALA-induced PDD and PDT. In this review, the biological significance of heme metabolites, the mechanism of PpIX accumulation in tumor cells, and the therapeutic potential of ALA-induced PDT alone and combined with hyperthermia and immunotherapy are discussed.

  14. Tight-binding analysis of the electronic states in AlAs with N isoelectronic impurities

    SciTech Connect

    Jo, M.; Mano, T.; Sakuma, Y.; Sakoda, K.

    2014-03-28

    Incorporation of nitrogen (N) atoms into III–V semiconductors significantly changes their electronic structures. The aim of this study was to assess the electronic states in AlAs that contained N impurities. An sp{sup 3}s{sup *} tight-binding model along with valence-force-field strain calculations were used to obtain the energy levels in N-doped AlAs. The calculations showed that an isolated N atom formed a resonant state above the conduction band edge in AlAs. In contrast, NN{sub 1}[110] and NN{sub 4}[220] pairs formed bound states inside the band gap. The formation of two bound states was consistent with the photoluminescence spectrum of N δ-doped AlAs.

  15. Treating cutaneous squamous cell carcinoma using ALA PLGA nanoparticle-mediated photodynamic therapy in a mouse model

    NASA Astrophysics Data System (ADS)

    Wang, Xiaojie; Shi, Lei; Tu, Qingfeng; Wang, Hongwei; Zhang, Haiyan; Wang, Peiru; Zhang, Linglin; Huang, Zheng; Wang, Xiuli; Zhao, Feng; Luan, Hansen

    2015-03-01

    Background: Squamous cell carcinoma (SCC) is a common skin cancer and its treatment is still difficult. The aim of this study was to evaluate the effectiveness of nanoparticle (NP)-assisted ALA delivery for topical photodynamic therapy (PDT) of cutaneous SCC. Methods: UV-induced cutaneous SCCs were established in hairless mice. ALA loaded polylactic-co-glycolic acid (PLGA) NPs were prepared and characterized. The kinetics of ALA PLGA NPs-induced protoporphyrin IX (PpIX) fluorescence in SCCs, therapeutic efficacy of ALA NP-mediated PDT, and immune responses were examined. Results: PLGA NPs could enhance PpIX production in SCC. ALA PLGA NP mediated topical PDT was more effective than free ALA of the same concentration in treating cutaneous SCC. Conclusion: PLGA NPs provide a promising strategy for delivering ALA in topical PDT of cutaneous SCC.

  16. Cognitive decline and the PPAR-γ Pro12Ala genotype: variation by sex and ethnicity.

    PubMed

    A West, Nancy; Baxter, Judith; L Bryant, Lucinda; L Nelson, Tracy

    2017-01-06

    We investigated the association between the peroxisome proliferator-activated receptor (PPAR)-gamma Pro12Ala polymorphism and cognitive decline in older adults. Participants from a population-based cohort of older Hispanic and non-Hispanic white adults (n = 492) were administered the Mini Mental State Examination (MMSE), a multi-domain cognitive screening tool, and the Behavioral Dyscontrol Scale (BDS), a measure of executive cognitive function, at baseline and at follow-up, an average of 22 months later. Multiple linear regression was used to investigate the association between the two cognitive test scores and the Pro12Ala polymorphism. At baseline, presence of the Ala12 allele was not significantly associated with MMSE score (P = 0.62) nor with BDS score (P = 0.85). Heterogeneity was present for cognitive decline as measured by the MMSE among ethnic, sex and Ala12 allele status (P = 0.04 for three-way interaction term). Stratification by the cross-classification of sex and ethnicity revealed significantly greater declines in MMSE score among male Hispanic carriers of the Ala12 allele compared to male Hispanic non-carriers (decline = 4.0 versus 1.6 points; P = 0.02). A significant difference in decline between Ala12 carriers and non-carriers was not present among the other sex/ethnic groups. Carriers of the PPAR-γ Ala12 allele showed greater cognitive decline compared to non-carriers as detected by the MMSE but the risk varied across sex and ethnic groups. Male Ala12 carriers of Hispanic origin may be a high-risk group for cognitive decline.

  17. Lack of association between serum adiponectin levels and the Pro12Ala polymorphism in Asian Indians.

    PubMed

    Radha, V; Vimaleswaran, K S; Babu, S; Deepa, R; Anjana, M; Ghosh, S; Majumder, P P; Rao, M R S; Mohan, V

    2007-04-01

    The aim of the study was to investigate the association of serum adiponectin levels with the Pro12Ala polymorphism of the peroxisome proliferator activated receptor-gamma (PPARG) gene in Asian Indians. We selected 400 diabetic subjects, 200 with the Pro12Pro genotype (100 male and 100 female) and 200 with the Pro12Ala genotype (100 male and 100 female) and 400 age- and sex-matched normal glucose tolerance subjects with similar genotype profiles from the Chennai Urban Rural Epidemiology Study. Fasting serum adiponection levels were measured using radioimmunoassay. The Pro12Ala polymorphism was genotyped by PCR-restriction fragment length polymorphism using BstUI. All clinical and biochemical parameters were similar in the subjects with the Pro12Pro and Pro12Ala genotypes. There was no significant difference in serum adiponectin values between subjects with the Pro12Pro and Pro12Ala genotypes (males 5.4 vs. 5.8 microg/ml, P = 0.546; females 6.9 vs. 7.2 microg/ml, P = 0.748). Adiponectin values did not differ among these two genotypes even when categorized based on their diabetes status (normal glucose tolerance Pro12Pro 7.9 vs. Pro12Ala 7.7 microg/ml, P = 0.994; diabetes Pro12Pro 4.7 vs. Pro12Ala 5.4 microg/ml, P = 0.622). The Pro12Ala polymorphism of the PPARG gene is not associated with serum adiponectin levels in Asian Indians.

  18. Using a modified nasotracheal tube to prevent nasal ala pressure sore during prolonged nasotracheal intubation.

    PubMed

    Cherng, Chen-Hwan; Chen, Yuan-Wu

    2010-12-01

    Nasotracheal tube induced nasal ala pressure sores or necrosis during prolonged nasotracheal intubation have been reported, and it is a serious but preventable complication. Here we introduce a modified nasotracheal tube to prevent this complication. This modified nasotracheal tube is composed of two parts, an oral endotracheal tube and a proximal part of a preformed nasotracheal tube, which are linked by a connector. The use of this modified nasotracheal tube can prevent nasal ala pressure sores during prolonged nasotracheal intubation.

  19. ALA-PDT of glioma cell micro-clusters in BD-IX rat brain

    NASA Astrophysics Data System (ADS)

    Madsen, Steen J.; Angell-Petersen, Even; Spetalen, Signe; Carper, Stephen W.; Ziegler, Sarah A.; Hirschberg, Henry

    2006-02-01

    A significant contributory factor to the poor prognosis of patients with glioblastoma multiforme is the inability of conventional treatments to eradicate infiltrating glioma cells. A syngeneic rat brain tumor model is used to investigate the effects of aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT) on small clusters of tumor cells sequestered in normal brain. The intrinsic sensitivity of rat glioma cells to PDT was investigated by exposing ALA-incubated cells to a range of radiant exposures and irradiances using 635 nm light. Biodistribution studies were undertaken on tumor-bearing animals in order to determine the tumor selectivity of the photosensitizer following systemic administration (i.p.) of ALA. Effects of ALA-PDT on normal brain and gross tumor were evaluated using histopathology. Effects of PDT on isolated glioma cells in normal brain were investigated by treating animals 48 h after tumor cell implantation: a time when the micro-clusters of cells are protected by an intact blood-brain-barrier (BBB). Rat glioma cells in monolayer are susceptible to ALA-PDT - lower irradiances are more effective than higher ones. Fluorescence microscopy of frozen tissue sections showed that photosensitizer is produced with better than 200:1 tumor-to-normal tissue selectivity following i.p. ALA administration. ALA-PDT resulted in significant damage to both gross tumor and normal brain, however, the treatment failed to prolong survival of animals with newly implanted glioma cells compared to non-treated controls if the drug was delivered either i.p. or directly into the brain. In contrast, animals inoculated with tumor cells pre-incubated in vitro with ALA showed a significant survival advantage in response to PDT.

  20. Paired and LIM class homeodomain proteins coordinate differentiation of the C. elegans ALA neuron.

    PubMed

    Van Buskirk, Cheryl; Sternberg, Paul W

    2010-06-01

    The ancient origin of sleep is evidenced by deeply conserved signaling pathways regulating sleep-like behavior, such as signaling through the Epidermal growth factor receptor (EGFR). In Caenorhabditis elegans, a sleep-like state can be induced at any time during development or adulthood through conditional expression of LIN-3/EGF. The behavioral response to EGF is mediated by EGFR activity within a single cell, the ALA neuron, and mutations that impair ALA differentiation are expected to confer EGF-resistance. Here we describe three such EGF-resistant mutants. One of these corresponds to the LIM class homeodomain (HD) protein CEH-14/Lhx3, and the other two correspond to Paired-like HD proteins CEH-10/Chx10 and CEH-17/Phox2. Whereas CEH-14 is required for ALA-specific gene expression throughout development, the Prd-like proteins display complementary temporal contributions to gene expression, with the requirement for CEH-10 decreasing as that of CEH-17 increases. We present evidence that CEH-17 participates in a positive autoregulatory loop with CEH-14 in ALA, and that CEH-10, in addition to its role in ALA differentiation, functions in the generation of the ALA neuron. Similarly to CEH-17, CEH-10 is required for the posterior migration of the ALA axons, but CEH-14 appears to regulate an aspect of ALA axon outgrowth that is distinct from that of the Prd-like proteins. Our findings reveal partial modularity among the features of a neuronal differentiation program and their coordination by Prd and LIM class HD proteins.

  1. First principles predictions of intrinsic defects in aluminum arsenide, AlAs : numerical supplement.

    SciTech Connect

    Schultz, Peter Andrew

    2012-04-01

    This Report presents numerical tables summarizing properties of intrinsic defects in aluminum arsenide, AlAs, as computed by density functional theory. This Report serves as a numerical supplement to the results published in: P.A. Schultz, 'First principles predictions of intrinsic defects in Aluminum Arsenide, AlAs', Materials Research Society Symposia Proceedings 1370 (2011; SAND2011-2436C), and intended for use as reference tables for a defect physics package in device models.

  2. Increased risk of advanced prostate cancer associated with MnSOD Ala-9-Val gene polymorphism.

    PubMed

    Kucukgergin, Canan; Sanli, Oner; Tefik, Tzevat; Aydın, Makbule; Ozcan, Faruk; Seckin, Sule

    2012-01-01

    We aimed to investigate the association between manganese superoxide dismutase (MnSOD) Ala-9-Val gene polymorphism and the initiation and/or progression of prostate cancer (PCa) as well as to evaluate its potential interactions with advanced age and smoking status. MnSOD Ala-9-Val gene polymorphism was carried out in 134 (mean age 64.1±7.48) PCa patients and 159 (mean age 62.5±7.53) healthy controls with serum prostate specific antigen (PSA) levels (<4 ng/ml) and normal digital rectal examination (DRE) findings in this prospectively designed study. PCa patients were classified as low stage disease (T1 or T2 and N0M0 stages) and high stage disease (T3 or T4 and N0M0 or N1 or M1 stages). Genotypes for MnSOD Ala-9-Val gene polymorphism were identified by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFPL). Despite lack of association between different genotypes of MnSOD Ala-9-Val gene polymorphism and the presence of PCa, patients with Ala/Ala genotype were at an increased risk of high stage disease compared with those with the Val/Val genotype [odds ratio (OR), 3.77; 95% CI, 1.30-10.94; P=0.012]. However, no significant difference was observed in the distribution of each genotype among PCa patients, with respect to tumor grade. On the other hand, smoking status and aging did not seem to change the association between genotypes and PCa risk. Ala/Ala genotype of MnSOD polymorphism may have an effect on adverse features of PCa such as high stage disease.

  3. [Association of PPARgamma2 Pro12Ala polymorphism and cognitive dysfunction in hypertension patients].

    PubMed

    Peng, Yong; Luo, Xiao-jia; Chen, Xiao-ping; Li, Long-xin; Wan, Li-yan; He, Sen; Chen, Xiao-ni; Wu, Kai

    2010-11-01

    To study the relationship between PPARgamma2 Pro12Ala polymorphism and cognitive function in patients with primary hypertension. This study enrolled 502 hypertensive patients of Chinese Han population from Jan 2008 to Feb 2009 in West China Hospital of Sichuan University. We collected the general data and applied the mini mental state examination (MMSE) to test the cognitive function and computed score. Total cholesterol (TC), triglyeride (TG), fasting plasma glucose (FPG) and postprandial blood sugar (PPBS), fasting insulin (FINS) and postprandial plasma insulin (PINS) were measured. PCR-RELP method was used to analysis the PPARgamma2 Pro12Ala gene polymorphism. Pro12Pro genotype was present in 88.6% of the patients and Prol2Ala genotype was present in 11.4% of the population. Allele frequencies were 94.3% for Pro allele and 5.7% for Ala allele. In cognitive normal group, the frequencies of PP and PA genotype were 328 (87.2%) and 48 (12.8%), while the frequencies of PP and PA genotypes in the cognitive dysfunction group were 126 (92.9%), 9 (7.1%) respectively. Analyzed by chi2 test, both the genotype frequency and the allele frequency of PPARy2 Pro12Ala polymorphism did not display statistical variability between the cognitive normal group and the cognitive dysfunction group, even eliminating the influence of age and sexuality. Pro12Ala polymorphism in PPARgamma2 with primary hypertension may not associate with cognitive impairment.

  4. Whole bladder wall photodynamic therapy using 5-ALA: an experimental study in pigs

    NASA Astrophysics Data System (ADS)

    van Staveren, Hugo J.; Beek, Johan F.; Verlaan, Cess W.; Edixhoven, Annie; Saarnak, Anne E.; Sterenborg, Dick; de Reijke, Theo M.; de la Riviere, Guy B.; Thomsen, Sharon L.; van Gemert, Martin J. C.; Star, Willem M.

    1996-01-01

    The agent 5-aminolevulinic acid (5-ALA) can be an alternative drug in whole bladder wall (WBW) photodynamic therapy (PDT), as its good tumor selectivity and the short time skin photosensitivity after systemic administration are advantageous for clinical use. To determine the maximum drug and light doses for reversible normal tissue damage, a pre-clinical study was performed using an in vivo normal piglet bladder model. First, the kinetics of PpIX production in 2 pigs was determined in vitro after oral administration of 75 and 150 mg/kg ALA respectively. The concentration of PpIX in plasma, and erythrocytes was determined by reversed phase high-performance liquid chromatography (HPLC) and the maximum was reached at approximately equals 5 hours after the administration of ALA. This provided a guideline for the optimum interval between ALA administration and light application. Next, various ALA doses were either administered orally or instilled in the bladder and different light doses were applied. Bladder biopsies were taken at regular intervals and normal tissue damage was investigated histologically. Reversible tissue damage was obtained using 60 mg/kg of 5-ALA in combination with a light dose of 100 J cm-2 (non-scattered plus scattered 630 nm wavelength light) in the case of oral administration. In the case of intravesical instillation, a drug dose of 2.5 gram and a light dose of 100 J cm-2 are still too high to obtain reversible tissue damage.

  5. ALA-based photodynamic therapy in epithelial tumors: in vivo and in vitro models

    NASA Astrophysics Data System (ADS)

    Casas, Adriana; Fukuda, Haydee; Batlle, Alcira

    2000-03-01

    PDT shows considerable potential as a treatment modality for superficial tumors. PDT is based on the accumulation of a photosensitizer in the target tissue. Subsequent illumination with light of an appropriate wavelength provokes a photochemical reaction that results in tumor destruction. Aminolevulinic acid (ALA) is a porphyrin precursor, and its administration result in the endogenous production of phototoxic porphyrins, which has been exploited for PDT. We assessed PDT efficacy employing both in vivo and in vitro models. We used papillomas, keratoacanthomas and in situ carcinomas chemically induced in the skin of SENCAR mice. Using ALA lotion and cream formulations, the maximal amount of porphyrin accumulation in papillomas was 5.52 (mu) g/g tissue. An energy of 150 of J/cm2 was delivered by a copper-dye laser tuned at 630 nm. Microscopically, we found several signs of tissue destruction, more markedly in the upper strata of the in situ carcinomas. Papillomas, characterized by hyperkeratinization, were resistant to PDT. In our in vitro studies, we used an epithelial adenocarcinoma cell line. We tested ALA and its hexyl and methyl derivatives with the aim of increasing porphyrin synthesis. We found that hexyl-ALA was the best compound. When cultures incubated 3 hours in 0.6 mM ALA and 0.1 mM hexyl-ALA respectively were irradiated with 3 J/cm2 only 5 percent of cells survived.

  6. Topical application of ALA PDT for the treatment of moderate to severe acne vulgaris

    NASA Astrophysics Data System (ADS)

    Wang, Xiu-Li; Wang, Hong-Wei; Zhang, Ling-Lin; Su, Lina; Guo, Ming-Xia; Huang, Zheng

    2009-06-01

    Objectives: To evaluate the effectiveness of topical 5-aminolevulinic acid (ALA)- medicated photodynamic therapy (ALA PDT) for the treatment of moderate to severe acne vulgaris. Methods: Sixteen Chinese patients with moderate to severe facial acne were treated with 1-3 courses of ALA PDT. ALA cream (3%) was freshly prepared and applied to acne lesions for 3-4 h. The lesions were irradiated by a 635 nm diode laser at dose levels of 60 - 80 J/cm2 at 100 mW/cm2. Clinical assessments were conducted before and after treatment up to 3 months. Results: All patents showed response to ALA PDT. Complete clearance was seen in 10 patients (62.5%) and partial clearance in 6 patients (37.5%). One case showed recurrence after complete clearance at 2 months and another two showed recurrence after complete clearance at 3 months. However, the number of new lesions were significantly reduced. Adverse effects were minimal. Conclusions: The results of this preliminary clinical study is encouraging. ALA PDT is a simple, safe and useful therapeutic option for the treatment of moderate to severe acne. Further studies to evaluate the treatment with a larger number of patients and for a longer period of follow-up are needed.

  7. Antiproliferative effect of T/Tn specific Artocarpus lakoocha agglutinin (ALA) on human leukemic cells (Jurkat, U937, K562) and their imaging by QD-ALA nanoconjugate.

    PubMed

    Chatterjee, Urmimala; Bose, Partha Pratim; Dey, Sharmistha; Singh, Tej P; Chatterjee, Bishnu P

    2008-11-01

    T/Tn specificity of Artocarpus lakoocha agglutinin (ALA), isolated from the seeds of A. lakoocha (Moraceae) fruit and a heterodimer (16 kD and 12 kD) of molecular mass 28 kD, was further confirmed by SPR analysis using T/Tn glycan containing mammalian glycoproteins. N-terminal amino acid sequence analysis of ALA showed homology at 15, 19-21, 24-27, and 29 residues with other lectin members of Moraceae family viz., Artocarpus integrifolia (jacalin) lectin, Artocarpus hirsuta lectin, and Maclura pomifera agglutinin. It is mitogenic to human PBMC and the maximum proliferation was observed at 1 ng/ml. It showed an antiproliferative effect on leukemic cells, with the highest effect toward Jurkat cells (IC(50) 13.15 ng/ml). Synthesized CdS quantum dot-ALA nanoconjugate was employed to detect the expression of T/Tn glycans on Jurkat, U937, and K562 leukemic cells surfaces as well as normal lymphocytes by fluorescence microscopy. No green fluorescence was observed with normal lymphocytes indicating that T/Tn determinants, which are recognized as human tumor associated structures were cryptic on normal lymphocyte surfaces, whereas intense green fluorescent dots appeared during imaging of leukemic cells, where such determinants were present in unmasked form. The above results indicated that QD-ALA nanoconjugate is an efficient fluorescent marker for identification of leukemic cell lines that gives rise to high quality images.

  8. The enzymology of alanine aminotransferase (AlaAT) isoforms from Hordeum vulgare and other organisms, and the HvAlaAT crystal structure.

    PubMed

    Duff, Stephen M G; Rydel, Timothy J; McClerren, Amanda L; Zhang, Wenlan; Li, Jimmy Y; Sturman, Eric J; Halls, Coralie; Chen, Songyang; Zeng, Jiamin; Peng, Jiexin; Kretzler, Crystal N; Evdokimov, Artem

    2012-12-01

    In this paper we describe the expression, purification, kinetics and biophysical characterization of alanine aminotransferase (AlaAT) from the barley plant (Hordeum vulgare). This dimeric PLP-dependent enzyme is a pivotal element of several key metabolic pathways from nitrogen assimilation to carbon metabolism, and its introduction into transgenic plants results in increased yield. The enzyme exhibits a bi-bi ping-pong reaction mechanism with a K(m) for alanine, 2-oxoglutarate, glutamate and pyruvate of 3.8, 0.3, 0.8 and 0.2 mM, respectively. Barley AlaAT catalyzes the forward (alanine-forming) reaction with a k(cat) of 25.6 s(-1), the reverse (glutamate-forming) reaction with k(cat) of 12.1 s(-1) and an equilibrium constant of ~0.5. The enzyme is also able to utilize aspartate and oxaloacetate with ~10% efficiency as compared to the native substrates, which makes it much more specific than related bacterial/archaeal enzymes (that also have lower K(m) values). We have crystallized barley AlaAT in complex with PLP and l-cycloserine and solved the structure of this complex at 2.7 Å resolution. This is the first example of a plant AlaAT structure, and it reveals a canonical aminotransferase fold similar to structures of the Thermotoga maritima, Pyrococcus furiosus, and human enzymes. This structure bridges our structural understanding of AlaAT mechanism between three kingdoms of life and allows us to shed some light on the specifics of the catalysis performed by these proteins.

  9. Combination therapies in adjuvant with topical ALA-mediated photodynamic therapy for DMBA-induced hamster buccal pouch premalignant lesions

    NASA Astrophysics Data System (ADS)

    Yang, Deng-Fu; Hsu, Yih-Chih

    2012-03-01

    In Taiwan, oral cancer has becomes the fastest growth male cancer disease due to the betel nut chewing habit combing with smoking and alcohol-drinking lifestyle of people. In order to eliminate the systemic phototoxic effect of 5-aminolevulinic acid (ALA), this study was designed to use a topical ALA-mediated PDT for treatment of DMBA-induced hamster buccal pouch precancerous lesions. DMBA was applied to one of the buccal pouches of hamsters thrice a week for 10 to 12 weeks. Cancerous lesions were induced and proven by histological examination. These DMBA-induced cancerous lesions were used for testing the efficacy of topical ALA-mediated PDT. Before PDT, fluorescence spectroscopy was used to determine when ALA reached its peak level in the lesional epithelial cells after topical application of ALA gel. We found that ALA reached its peak level in precancerous lesions about 2.5 hrs after topical application of ALA gel. The cancerous lesions in hamsters were then treated with topical ALA -mediated PDT with light exposure dose of 150 J/cm2 using LED 635 nm fiber-guided light device. Visual examination demonstrated that adjuvant topical ALA -mediated PDT group has shown better therapeutic results in compared to those of non-adjuvant topical ALA-mediated PDT group for DMBA-induced hamster buccal pouch precancerous lesions.

  10. PPARgamma Pro12Ala polymorphism in HIV-1-infected patients with HAART-related lipodystrophy.

    PubMed

    Saumoy, Maria; Veloso, Sergi; Alonso-Villaverde, Carlos; Domingo, Pere; Chacón, Matilde R; Miranda, Merce; Aragonès, Gerard; Gutiérrez, Maria Mar; Viladés, Consuelo; Peraire, Joaquim; Sirvent, Joan-Josep; López-Dupla, Miguel; Aguilar, Carmen; Richart, Cristóbal; Vidal, Francesc

    2009-09-01

    Peroxisome proliferator-activated receptor gamma (PPARgamma) is involved in obesity and in some components of the metabolic syndrome in unselected population. To determine whether PPARgamma genetic variants are associated with the risk of developing lipodystrophy and its associated metabolic disturbances in HIV-1-infected patients treated with HAART and to assess PPARgamma mRNA expression in subcutaneous adipose tissue (SAT). The study group comprised 278 patients infected with HIV-1 and treated with antiretroviral drugs (139 with lipodystrophy and 139 without) and 105 uninfected controls (UC). The PPARgamma Pro12Ala (C%>G) single nucleotide polymorphism (SNP) was assessed using PCR-RFLPs on white cell DNA. PPARgamma mRNA expression in SAT was assessed in 38 patients (25 with lipodystrophy and 13 without) and in 21 UC by real-time PCR. Statistical analysis was based on Student's T tests, Chi(2) tests, Spearman's correlations tests and logistic regression tests. PPARgamma Pro12Ala genotype distribution and allele frequencies were non-significantly different between both HIV-1-infected categories, lipodystrophy vs non-lipodystrophy (p=0.9 and p=0.87, respectively). Lipodystrophic patients harbouring the rare X/Ala genotype (Ala/Ala plus Pro/Ala) had significantly greater plasma total and LDL cholesterol levels compared with carriers of the common Pro/Pro genotype (p=0.029 and p=0.016, respectively) at univariate analyses. At multivariate analyses these associations were no longer significant. There was a near-significant decreased SAT PPARgamma mRNA expression in patients with lipodystrophy compared to UC (p=0.054). PPARgamma Pro12Ala SNP has no effect on the risk of developing lipodystrophy in HIV-1-infected patients treated with HAART. PPARgamma mRNA SAT expression appears decreased in lipodystrophy.

  11. Study of the efficacy of 5-ALA mediated photodynamic therapy on human rhabdomyosarcoma cell line (RD)

    NASA Astrophysics Data System (ADS)

    Atif, M.; Fakhar-e-Alam, M.; Firdous, S.; Zaidi, S. S. Z.; Suleman, R.; Ikram, M.

    2010-10-01

    The aim of this study was to investigate the mechanism of cell death by photodynamic therapy (PDT) in the Rhabdomyosarcoma (RD) cell line. The present study evaluates the effects of photodynamic therapy (PDT) with 5-ALA as photosensitizer using human muscle cancer cells as experimental model. We study the photosensitizer uptake, cytotoxicity, phototoxicity, and cellular viability of the RD cells which was estimated by means of neutral-red spectrophotometric assay. The given experiment was consisted of two steps. For the first one, RD cells were exposed to 5-ALA at concentrations of 0 up to 1000 μg of ALA/ml in minimum essential medium (MEM). The optimal uptake of photosensitizer (5-ALA) in RD cells was investigated by means of spectrometric measurements. Cells viability was determined by means of neutral red assay (NRA). In the second step, 5-ALA exposed RD cells were irradiated with red light (a diode laser, λ = 635 nm) at total light dose of 80 J/cm2. The influence of different incubation times and concentrations of 5-ALA, different irradiation doses and various combinations of photosensitizer and light doses on the viability of RD cells were investigated. It was observed that sensitizer concentration or light doses have no significant effect on cells viability when studied independently. The maximal cellular uptake occurred after 47 hours in vitro incubation. The phototoxic assay showed that ALA-PDT induced killing of 76% of the cells at 250 μg/ml drug dose and 80 J/cm2 light dose.

  12. Combination of 5-ALA and iMRI in re-resection of recurrent glioblastoma.

    PubMed

    Quick-Weller, Johanna; Lescher, Stephanie; Forster, Marie-Therese; Konczalla, Jürgen; Seifert, Volker; Senft, Christian

    2016-06-01

    Background Tumour resection plays a role in the initial treatment but also in the setting of recurrent glioblastoma (rGBM). To achieve maximum resection, 5-aminolevulinic acid (5-ALA) and intraoperative MRI (iMRI) are used as surgical tools. Aiming at complete tumour re-resection, we started combining iMRI with 5-ALA to find out if this leads to better surgical results. Methods We performed tumour resections in seven patients with rGBM, combining 5-ALA (20 mg/kg bodyweight) with iMRI (0.15 T). Radiologically complete resections were intended in all seven patients. We assessed intraoperative fluorescence findings and compared these with intraoperative imaging. All patients had early postoperative MRI (3 T) to verify final iMRI scans and received adjuvant treatment according to interdisciplinary tumour board decision. Results Median patient age was 63 years. Median KPS score was 90, and median tumour volume was 8.2 cm(3). In six of seven patients (85%), 5-ALA induced fluorescence of tumour-tissue was detected intraoperatively. All tumours were good to visualise with iMRI and contrast media. One patient received additional resection of residual contrast enhancing tissue on intraoperative imaging, which did not show fluorescence. Radiologically complete resections according to early postoperative MRI were achieved in all patients. Median survival since second surgery was 7.6 months and overall survival since diagnosis was 27.8 months. Conclusions 5-ALA and iMRI are important surgical tools to maximise tumour resection also in rGBM. However, not all rGBMs exhibit fluorescence after 5-ALA administration. We propose the combined use of 5-ALA and iMRI in the surgery of rGBM.

  13. Harnessing cellular differentiation to improve ALA-based photodynamic therapy in an artificial skin model

    NASA Astrophysics Data System (ADS)

    Maytin, Edward; Anand, Sanjay; Sato, Nobuyuki; Mack, Judith; Ortel, Bernhard

    2005-04-01

    During ALA-based photodynamic therapy (PDT), a pro-drug (aminolevulinic acid; ALA) is taken up by tumor cells and metabolically converted to a photosensitizing intermediate (protoporphyrin IX; PpIX). ALA-based PDT, while an emerging treatment modality, remains suboptimal for most cancers (e.g. squamous cell carcinoma of the skin). Many treatment failures may be largely due to insufficient conversion of ALA to PpIX within cells. We discovered a novel way to increase the conversion of ALA to PpIX, by administering agents that can drive terminal differentiation (i.e., accelerate cellular maturation). Terminally-differentiated epithelial cells show higher levels of intracellular PpIX, apparently via increased levels of a rate-limiting enzyme, coproporphyrinogen oxidase (CPO). To study these mechanisms in a three-dimensional tissue, we developed an organotypic model that mimics true epidermal physiology in a majority of respects. A line of rat epidermal keratinocytes (REKs), when grown in raft cultures, displays all the features of a fully-differentiated epidermis. Addition of ALA to the culture medium results in ALA uptake and PpIX synthesis, with subsequent death of keratinocytes upon exposure to blue light. Using this model, we can manipulate cellular differentiation via three different approaches. (1) Vitamin D, a hormone that enhances keratinocyte differentiation; (2) Hoxb13, a nuclear transcription factor that affects the genetically-controlled differentiation program of stratifying cells (3) Hyaluronan, an abundant extracellular matrix molecule that regulates epidermal differentiation. Because the raft cultures contain only a single cell type (no blood, fibroblasts, etc.) the effects of terminal differentiation upon CPO, PpIX, and keratinocyte cell death can be specifically defined.

  14. Crystallization of tholeiitic basalt in Alae Lava Lake, Hawaii

    USGS Publications Warehouse

    Peck, D.L.; Wright, T.L.; Moore, J.G.

    1966-01-01

    The eruption of Kilauea Volcano August 21-23, 1963, left 600,000 cubic meters of basaltic lava in a lava lake as much as 15 meters deep in Alae pit crater. Field studies of the lake began August 27 and include repeated core drilling, measurements of temperature in the crust and melt, and precise level surveys of the lake surface. The last interstitial melt in the lake solidified late in September 1964; by mid August 1965 the maximum temperature was 690??C at a depth of 11.5 meters. Pumice air-quenched from about 1140??C contains only 5 percent crystals - clinopyroxene, cuhedral olivine (Fo 80), and a trace of plagioclase, (An 70). Drill cores taken from the zone of crystallization in the lake show that olivine continued crystallizing to about 1070??C; below that it reacts with the melt, becoming corroded and mantled by pyroxene and plagioclase. Below 1070??C, pyroxene and plagioclase crystallized at a constant ratio. Ilmenite first appeared at about 1070??C and was joined by magnetite at about 1050??C; both increased rapidly in abundance to 1000??C. Apatite first appeared as minute needles in interstitial glass at 1000??C. Both the abundance and index of refraction of glass quenched from melt decreased nearly linearly with falling temperature. At 1070??C the quenched lava contains about 65 percent dark-brown glass with an index of 1.61; at 980??C it contains about 8 percent colorless glass with an index of 1.49. Below 980??C, the percentage of glass remained constant. Progressive crystallization forced exsolution of gases from the melt fraction; these formed vesicles and angular pores, causing expansion of the crystallizing lava and lifting the surface of the central part of the lake an average of 19.5 cm. The solidified basalt underwent pneumatolitic alteration, including deposition of cristobalite at 800??C, reddish alteration of olivine at 700??C, tarnishing of ilmenite at 550??C, deposition of anhydrite at 250??C, and deposition of native sulfur at 100??C

  15. Influence of ALA54THR polymorphism of fatty acid-binding protein 2 on obesity and cardiovascular risk factors.

    PubMed

    de Luis, D A; Sagrado, M G; Aller, R; Izaola, O; Conde, R

    2007-11-01

    A transition of G to A at codon 54 of FABP2 results in an amino acid substitution (Ala54 to Thr54). This polymorphism was associated with some cardiovascular risk factors. The aim of our study was to investigate the influence of Thr54 polymorphism in the FABP2 gene on obesity anthropometric parameters and cardiovascular risk factors. A population of 226 obesity (body mass index >30) nondiabetic outpatients were analyzed. An indirect calorimetry, tetrapolar electrical bioimpedance, blood pressure, a serial assessment of nutritional intake with 3 days of written food records, and biochemical analysis (lipid profile, adipocytokines, insulin, CRP, and lipoprotein-a) were performed. The statistical analysis was performed for the combined ALA54/THR54 and THR54/THR54 as a mutant group and wild type ALA54/ALA54 as a second group. Two-hundred and twenty-six patients gave informed consent and were enrolled in the study. The mean age was 44.2+/-16 years and the mean BMI 35.1+/-5.1, with 63 males (28.3%) and 163 females (71.7%). One-hundred and thirteen patients (50%) had the genotype ALA54/ALA54 (wild group) and 113 (50%) patients had the genotype ALA54/THR54 (91 patients, 40.2%) or THR54/THR54 (22 patients, 9.8%) (mutant group). The ANOVA analysis of the three groups ( ALA54/THR54, THR54/THR54 and ALA54/ALA54) shows a higher levels of fat mass in Thr54/Thr54 group (45.6+/-14.6 kg) than Ala54/Ala54 (37.5+/-11.2 kg: p<0.05), without differences with Ala54/Thr54 group (41.2+/-13.5 kg). CRP, IL-6, and lipoprotein-a were higher in mutant group ( ALA54/THR54, THR54/THR54) than in wild group ( ALA54/ALA54). The novel finding of this study is the association of the Thr54/Ala54 and Thr54/Thr54 FABP2 phenotypes with higher levels of C reactive protein, IL6, and lipoprotein-a. Further studies are needed to explain the role of this polymorphism in different populations.

  16. Protective Effect of ALA in Crushed Optic Nerve Cat Retinal Ganglion Cells Using a New Marker RBPMS

    PubMed Central

    Wang, Yanling; Wang, Wenyao; Liu, Jessica; Huang, Xin; Liu, Ruixing; Xia, Huika; Brecha, Nicholas C.; Pu, Mingliang; Gao, Jie

    2016-01-01

    In this study we first sought to determine whether RNA-binding protein with multiple splicing (RBPMS) can serve as a specific marker for cat retina ganglion cells (RGCs) using retrograde labeling and immunohistochemistry staining. RBPM was then used as an RGC marker to study RGC survival after optic nerve crush (ONC) and alpha-lipoic acid (ALA) treatment in cats. ALA treatment yielded a peak density of RBPMS-alpha cells within the peak isodensity zone (>60/mm2) which did not differ from ONC retinas. The area within the zone was significantly enlarged (control: 2.3%, ONC: 0.06%, ONC+ALA: 0.1%). As for the 10-21/mm2 zone, ALA treatment resulted in a significant increase in area (control: 34.5%, ONC: 12.1%, ONC+ALA: 35.9%). ALA can alleviate crush-induced RGC injury. PMID:27504635

  17. D2-Thr92Ala, thyroid hormone levels and biochemical hypothyroidism in preeclampsia.

    PubMed

    Procopciuc, Lucia Maria; Caracostea, Gabriela; Hazi, Georgeta; Nemeti, Georgiana; Stamatian, Florin

    2017-02-01

    To identify if there is a relationship between the deiodinase D2-Thr92Ala genetic variant, thyroid hormone levels and biochemical hypothyroidism in preeclampsia. We genotyped 125 women with preeclampsia and 131 normal pregnant women using PCR-RFLP. Serum thyroid hormone levels were determined using ELISA. Our study showed higher TSH and FT4 levels and lower FT3 levels in women with preeclampsia compared to normal pregnant women, with statistical significance for women with mild and severe preeclampsia. The risk to develop pregnancy-induced hypertension (PIH), mild or severe preeclampsia was increased in carriers of at least one D2-Ala92 allele. TSH and FT4 levels were significantly higher and FT3 levels were significantly lower in preeclamptic women with severe preeclampsia if they carried the D2-Ala92 allele compared to non-carriers. Pregnant women with PIH and mild preeclampsia, carriers of at least one D2-Ala92 allele, delivered at lower gestational age neonates with a lower birth weight compared to non-carriers, but the results were statistically significant only in severe preeclampsia. The D2-Thr92Ala genetic variant is associated with the severity and the obstetric outcome of preeclampsia, and it also influences thyroid hormone levels. The study demonstrates non-thyroidal biochemical hypothyroidism - as a result of deiodination effects due to D2 genotypes.

  18. Pro12Ala PPAR gamma2 gene polymorphism in women with polycystic ovary syndrome.

    PubMed

    Bidzińska-Speichert, Bozena; Lenarcik, Agnieszka; Tworowska-Bardzińska, Urszula; Slezak, Ryszard; Bednarek-Tupikowska, Grazyna; Milewicz, Andrzej; Krepuła, Katarzyna

    2011-06-01

    The pathogenesis of PCOS has not been definitively determined and includes a number of genes linked with steroidogenesis, regulation of gonadotropin secretion, actions of insulin, obesity as well as chronic inflammatory processes. Some authors indicate that PPARgamma play a role in insulin sensitivity and are probably involved in hyperandrogenism in PCOS. The aim of the study was to assess the frequency of the Pro12Ala and Pro115Gln PPARgamma2 gene polymorphisms in women with PCOS. 54 PCOS women and 51 healthy women were recruited. Genetic studies to detect Pro12Ala and Pro115Gln PPARgamma2 gene polymorphism were performed. In the whole studied group the Pro115Gln polymorphism of the PPARgamma2 gene was not found. The frequency of the Pro12Ala polymorphism was estimated at 26.47% in the controls and at 23.15% in the PCOS patients. Women from the control and PCOS groups with BMI > or = 30 had statistically higher occurrence of the Ala allele than women with BMI <30 (38.80% versus 12.50% and 38.23% versus 18.75%). The frequency of the Pro12Ala polymorphism observed in the sample of women from the Lower Silesian population was significantly higher than in the majority of European populations.

  19. Does Pro12Ala Polymorphism Enhance the Physiological Role of PPARγ2?

    PubMed Central

    Pereira, A. C.; Oliveira, R.; Castro, A. C.; Fernandes, R.

    2013-01-01

    Obesity and type 2 diabetes mellitus (T2D) are two major public health problems that have motivated the scientific community to investigate the high contribution of genetic factors to these disorders. The peroxisome proliferator activated by gamma 2 (PPARγ2) plays an important role in the lipid metabolism. Since PPARγ2 is expressed mainly in adipose tissue, a moderate reduction of its activity influences the sensitivity to insulin, diabetes, and other metabolic parameters. The present study aims to contribute to the elucidation of the impact of the Pro12Ala polymorphism associated with T2D and obesity through a meta-analysis study of the literature that included approximately 11500 individuals, from which 3870 were obese and 7625 were diabetic. Statistical evidence supports protective effect in T2D of polymorphism Pro12Ala of PPARγ2 (OR = 0.702 with 95% CI: 0.622; 0.791, P < 0.01). Conversely the same polymorphism Pro12Ala of PPARγ2 seems to favor obesity since 1.196 more chance than nonobese was found (OR = 1.196 with 95% CI: 1.009; 1.417, P < 0.004). Our results suggest that Pro12Ala polymorphism enhances both adipogenic and antidiabetogenic physiological role of PPARγ. Does Pro12Ala polymorphism represent an evolutionary step towards the stabilization of the molecular function of PPARγ transcription factor signaling pathway? PMID:23983677

  20. Flourescence analysis of ALA-induced Protoporphyrin IX in psoriatic plaque

    NASA Astrophysics Data System (ADS)

    Stringer, Mark R.; Robinson, Dominic J.; Collins, P.

    1996-01-01

    The success reported for the treatment of superficial skin carcinomas by photodynamic therapy (PDT), following topical application of 5-aminolaevulinic acid (ALA), has therapeutic implications for the treatment of other skin disorders. This presentation describes the accumulation of the photosensitizing agent protoporphyrin IX (PpIX) in areas of psoriatic plaque, by monitoring the fluorescence emission induced by low-intensity laser excitation at 488 nm. We present the results from 15 patients, with a total of 42 plaques. These results show that PpIX fluorescence increases in intensity within the 6 hour period following application of ALA, which implies there is a potential for PDT. The emission is localized to the area of ALA application and the effect of occlusion appears insignificant. Also, the rate of increase, and maximum intensity of fluorescence emission, is not directly related to the applied quantity of ALA. The variability of the fluorescence intensity is as great between plaques at different sites on the same patient as between different patients. We also present measurements of the depletion in intensity of fluorescence emission during PDT treatment, using white light, at an irradiance of 25 mW cm-2, that is a consequence of the molecular photo-oxidation of PpIX. The use of fluorescence measurements in predicting the therapeutic effect of treating plaque psoriasis by ALA-PDT is discussed.

  1. Intron 1 GATA site enhances ALAS2 expression indispensably during erythroid differentiation

    PubMed Central

    Zhang, Yingchi; Zhang, Jingliao; An, Wenbin; Wan, Yang; Ma, Shihui; Yin, Jie; Li, Xichuan; Gao, Jie; Yuan, Weiping; Guo, Ye; Engel, James Douglas; Shi, Lihong; Cheng, Tao; Zhu, Xiaofan

    2017-01-01

    The first intronic mutations in the intron 1 GATA site (int-1-GATA) of 5-aminolevulinate synthase 2 (ALAS2) have been identified in X-linked sideroblastic anemia (XLSA) pedigrees, strongly suggesting it could be causal mutations of XLSA. However, the function of this int-1-GATA site during in vivo development remains largely unknown. Here, we generated mice lacking a 13 bp fragment, including this int-1-GATA site (TAGATAAAGCCCC) and found that hemizygous deletion led to an embryonic lethal phenotype due to severe anemia resulting from a lack of ALAS2 expression, indicating that this non-coding sequence is indispensable for ALAS2 expression in vivo. Further analyses revealed that this int-1-GATA site anchored the GATA site in intron 8 (int-8-GATA) and the proximal promoter, forming a long-range loop to enhance ALAS2 expression by an enhancer complex including GATA1, TAL1, LMO2, LDB1 and Pol II at least, in erythroid cells. However, compared with the int-8-GATA site, the int-1-GATA site is more essential for regulating ALAS2 expression through CRISPR/Cas9-mediated site-specific deletion. Therefore, the int-1-GATA site could serve as a valuable site for diagnosing XLSA in cases with unknown mutations. PMID:28123038

  2. Is the Ala12 variant of the PPARG gene an "unthrifty allele"?

    PubMed Central

    Ruiz-Narvaez, E

    2005-01-01

    Background: The thrifty genotype hypothesis proposes that genetic susceptibility to type 2 diabetes results from the positive selection of "thrifty" alleles in the past. A corollary of this hypothesis is that genetic variants protecting against the development of diabetes are "unthrifty" and thus subject to negative selection during human evolution. Methods: It was assessed whether age estimates of the diabetes protective PPARG Ala12 allele indicate effects of natural selection. Based on published data from four populations, the date of origin of the diabetes protective PPARG Ala12 variant was estimated using both allele frequency and linkage disequilibrium (LD) with the C1431T single nucleotide polymorphism in exon 6 of the PPARG gene. Results: The best LD based estimate of the age of the Ala12 allele gave an average of ∼32 000 years with a maximum upper bound of ∼58 000 years. Assuming a population with a growth rate of r = 0.01 per generation, the frequency based estimate of the age of the Ala12 variant gave an average of ∼27 000 years with a maximum upper bound of ∼42 000 years. Discussion: The similarity of both time estimates is consistent with selective equivalence of the diabetes protective PPARG Ala12 allele and the diabetes susceptible PPARG Pro12 allele. PMID:15994875

  3. Simplified and optimized multispectral imaging for 5-ALA-based fluorescence diagnosis of malignant lesions

    PubMed Central

    Minamikawa, Takeo; Matsuo, Hisataka; Kato, Yoshiyuki; Harada, Yoshinori; Otsuji, Eigo; Yanagisawa, Akio; Tanaka, Hideo; Takamatsu, Tetsuro

    2016-01-01

    5-aminolevulinic acid (5-ALA)-based fluorescence diagnosis is now clinically applied for accurate and ultrarapid diagnosis of malignant lesions such as lymph node metastasis during surgery. 5-ALA-based diagnosis evaluates fluorescence intensity of a fluorescent metabolite of 5-ALA, protoporphyrin IX (PPIX); however, the fluorescence of PPIX is often affected by autofluorescence of tissue chromophores, such as collagen and flavins. In this study, we demonstrated PPIX fluorescence estimation with autofluorescence elimination for 5-ALA-based fluorescence diagnosis of malignant lesions by simplified and optimized multispectral imaging. We computationally optimized observation wavelength regions for the estimation of PPIX fluorescence in terms of minimizing prediction error of PPIX fluorescence intensity in the presence of typical chromophores, collagen and flavins. By using the fluorescence intensities of the optimized wavelength regions, we verified quantitative detection of PPIX fluorescence by using chemical mixtures of PPIX, flavins, and collagen. Furthermore, we demonstrated detection capability by using metastatic and non-metastatic lymph nodes of colorectal cancer patients. These results suggest the potential and usefulness of the background-free estimation method of PPIX fluorescence for 5-ALA-based fluorescence diagnosis of malignant lesions, and we expect this method to be beneficial for intraoperative and rapid cancer diagnosis. PMID:27149301

  4. Supplementation of milled chia seeds increases plasma ALA and EPA in postmenopausal women.

    PubMed

    Jin, Fuxia; Nieman, David C; Sha, Wei; Xie, Guoxiang; Qiu, Yunping; Jia, Wei

    2012-06-01

    Ten postmenopausal women (age 55.6 ± 0.8 years, BMI 24.6 ± 1.1 kg/m²) ingested 25 g/day milled chia seed during a 7-week period, with six plasma samples collected for measurement of α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA). Subjects operated as their own controls with overnight fasted blood samples taken at baseline (average of two samples), and then after 1, 2, 3, 5, and 7 weeks supplementation. Plasma ALA increased significantly after one week supplementation and was 138 % above baseline levels by the end of the study (overall time effect, P < 0.001). EPA increased 30 % above baseline (overall time effect, P = 0.019) and was correlated across time with ALA (r = 0.84, P = 0.02). No significant change in plasma DPA levels was measured (overall time effect, P = 0.067). Plasma DHA decreased slightly by the end of the study (overall time effect, P = 0.030) and was not correlated with change in ALA. In conclusion, ingestion of 25 g/day milled chia seeds for seven weeks by postmenopausal women resulted in significant increases in plasma ALA and EPA but not DPA and DHA.

  5. 5-ALA fluorescence-guided endoscopic surgery for mixed germ cell tumors.

    PubMed

    Takeda, Junichi; Nonaka, Masahiro; Li, Yi; Komori, Yumiko; Kamei, Takamasa; Iwata, Ryoichi; Hashiba, Tetsuo; Yoshimura, Kunikazu; Asai, Akio

    2017-08-01

    5-Aminolevulinic acid (5-ALA) fluorescence-guided surgery is widely used for detection and planning of resection of malignant gliomas and other brain tumors. However, no reports have described 5-ALA fluorescence-guided surgery or direct visualization of germ cell tumors. Here, we report two cases of germ cell tumors in which a positive 5-ALA fluorescent signal was visualized with a neuroendoscope. Both cases had a tumor in the pineal region that was associated with hydrocephalus. The patients underwent surgery after administration of 5-ALA. After ventricular puncture of the anterior horn, we could observe the ventricular wall and tumor using the Karl Storz Photodynamic diagnosis system endoscope. Then, biopsy of the pineal tumor and endoscopic third ventriculostomy were performed in both cases. In case 1, a 22-year-old man, part of the ventricular wall and tumor tissue showed red fluorescence. In case 2, a 16-year-old man, part of the fornix and infundibular recess showed red fluorescence, and the tumor showed relatively weak red fluorescence. The histopathological diagnosis of both cases was pure germinoma. This is the first report of direct visualization of mixed germinomas with 5-ALA fluorescence-guided endoscopic surgery. This method not only allows visualization of the tumor mass, but may also be useful for detailed observation in the ventricular wall.

  6. Light Fractionation Significantly Increases the Efficacy of Photodynamic Therapy Using BF-200 ALA in Normal Mouse Skin.

    PubMed

    de Bruijn, Henriëtte S; Brooks, Sander; van der Ploeg-van den Heuvel, Angélique; Ten Hagen, Timo L M; de Haas, Ellen R M; Robinson, Dominic J

    2016-01-01

    Light fractionation significantly increases the efficacy of 5-aminolevulinic acid (ALA) based photodynamic therapy (PDT) using the nano-emulsion based gel formulation BF-200. PDT using BF-200 ALA has recently been clinically approved and is under investigation in several phase III trials for the treatment of actinic keratosis. This study is the first to compare BF-200 ALA with ALA in preclinical models. In hairless mouse skin there is no difference in the temporal and spatial distribution of protoporphyrin IX determined by superficial imaging and fluorescence microscopy in frozen sections. In the skin-fold chamber model, BF-200 ALA leads to more PpIX fluorescence at depth in the skin compared to ALA suggesting an enhanced penetration of BF-200 ALA. Light fractionated PDT after BF-200 ALA application results in significantly more visual skin damage following PDT compared to a single illumination. Both ALA formulations show the same visual skin damage, rate of photobleaching and change in vascular volume immediately after PDT. Fluorescence immunohistochemical imaging shows loss of VE-cadherin in the vasculature at day 1 post PDT which is greater after BF-200 ALA compared to ALA and more profound after light fractionation compared to a single illumination. The present study illustrates the clinical potential of light fractionated PDT using BF-200 ALA for enhancing PDT efficacy in (pre-) malignant skin conditions such as basal cell carcinoma and vulval intraepithelial neoplasia and its application in other lesion such as cervical intraepithelial neoplasia and oral squamous cell carcinoma where current approaches have limited efficacy.

  7. Aminolevulinic acid (ALA)-protoporphyrin IX fluorescence guided tumour resection. Part 2: theoretical, biochemical and practical aspects.

    PubMed

    Colditz, Michael J; Leyen, Karin van; Jeffree, Rosalind L

    2012-12-01

    The importance of the extent of resection for gliomas, and the utility of aminolevulinic acid (ALA) and protoporphyrin IX fluorescence in increasing the extent of resection, has become increasingly evident over the past decade. This review continues from Part 1 and focuses on the biochemical mechanisms by which ALA ingestion leads to tumour fluorescence, and discusses practicalities of the equipment and techniques needed to introduce ALA and fluorescence guided resection into neurosurgical practice.

  8. Light Fractionation Significantly Increases the Efficacy of Photodynamic Therapy Using BF-200 ALA in Normal Mouse Skin

    PubMed Central

    de Bruijn, Henriëtte S.; Brooks, Sander; van der Ploeg-van den Heuvel, Angélique; ten Hagen, Timo L. M.; de Haas, Ellen R. M.; Robinson, Dominic J.

    2016-01-01

    Background Light fractionation significantly increases the efficacy of 5-aminolevulinic acid (ALA) based photodynamic therapy (PDT) using the nano-emulsion based gel formulation BF-200. PDT using BF-200 ALA has recently been clinically approved and is under investigation in several phase III trials for the treatment of actinic keratosis. This study is the first to compare BF-200 ALA with ALA in preclinical models. Results In hairless mouse skin there is no difference in the temporal and spatial distribution of protoporphyrin IX determined by superficial imaging and fluorescence microscopy in frozen sections. In the skin-fold chamber model, BF-200 ALA leads to more PpIX fluorescence at depth in the skin compared to ALA suggesting an enhanced penetration of BF-200 ALA. Light fractionated PDT after BF-200 ALA application results in significantly more visual skin damage following PDT compared to a single illumination. Both ALA formulations show the same visual skin damage, rate of photobleaching and change in vascular volume immediately after PDT. Fluorescence immunohistochemical imaging shows loss of VE-cadherin in the vasculature at day 1 post PDT which is greater after BF-200 ALA compared to ALA and more profound after light fractionation compared to a single illumination. Discussion The present study illustrates the clinical potential of light fractionated PDT using BF-200 ALA for enhancing PDT efficacy in (pre-) malignant skin conditions such as basal cell carcinoma and vulval intraepithelial neoplasia and its application in other lesion such as cervical intraepithelial neoplasia and oral squamous cell carcinoma where current approaches have limited efficacy. PMID:26872051

  9. Pro12Ala polymorphism in PPAR gamma 2 associated with essential hypertension in Chinese nonagenarians/centenarians.

    PubMed

    Lu, Zhenchan; Dong, Birong; Mo, Xianming; Chen, Tie; Wu, Hongmei; Zhang, Yanling; Xiao, Hengyi

    2008-12-01

    The Pro12Ala polymorphism of PPAR gamma 2 has been shown to influence hypertension and the benefit of longevity in previous studies. We examined whether the polymorphism was related to essential hypertension among long-lived subjects (is greater than 90 years). The Pro12Ala variant was examined using polymerase chain reaction restriction fragment length polymorphism in a population-based sample of 839 long-lived subjects (mean 94 years SD 4 years, aged 90-108 years). The genotype frequencies of the Pro12Ala polymorphism were 0.2% Ala12Ala, 9.4% Pro12Ala and 90.4% Pro12Pro in all participants. The frequency of the Ala12 allele was 3.45% in the hypertension group and 6.92% among the normotension group (P=0.001). Moreover, in the total study population, Ala12 allele carriers had lower levels of triglycerides (1.03+/-0.5 mmol/L (means+/-SD) vs. 1.25+/-0.61 mmol/L; P<0.001). In conclusion, these results suggest that the Pro12Ala polymorphism of the PPAR gamma 2 gene is associated with hypertension and triglycerides levels in Chinese nonagenarians/centenarians.

  10. Chilling Tolerance in Arabidopsis Involves ALA1, a Member of a New Family of Putative Aminophospholipid Translocases

    PubMed Central

    Gomès, Eric; Jakobsen, Mia Kyed; Axelsen, Kristian B.; Geisler, Markus; Palmgren, Michael Gjedde

    2000-01-01

    The lipid composition of membranes is a key determinant for cold tolerance, and enzymes that modify membrane structure seem to be important for low-temperature acclimation. We have characterized ALA1 (for aminophospholipid ATPase1), a novel P-type ATPase in Arabidopsis that belongs to the gene family ALA1 to ALA11. The deduced amino acid sequence of ALA1 is homologous with those of yeast DRS2 and bovine ATPase II, both of which are putative aminophospholipid translocases. ALA1 complements the deficiency in phosphatidylserine internalization into intact cells that is exhibited by the drs2 yeast mutant, and expression of ALA1 results in increased translocation of aminophospholipids in reconstituted yeast membrane vesicles. These lines of evidence suggest that ALA1 is involved in generating membrane lipid asymmetry and probably encodes an aminophospholipid translocase. ALA1 complements the cold sensitivity of the drs2 yeast mutant. Downregulation of ALA1 in Arabidopsis results in cold-affected plants that are much smaller than those of the wild type. These data suggest a link between regulation of transmembrane bilayer lipid asymmetry and the adaptation of plants to cold. PMID:11148289

  11. Photodynamic therapy (PDT) and photodiagnosis (PD) using endogenous photosensitization induced by 5-aminolevulinic acid (ALA): current clinical and development status

    NASA Astrophysics Data System (ADS)

    Marcus, Stuart L.; Sobel, Russel S.; Golub, Allyn L.; Carroll, Ronald L.; Lundahl, Scott L.; Shulman, D. Geoffrey

    1996-04-01

    Exogenous provision of ALA to many tissues results in the accumulation of sufficient quantities of the endogenous photosensitizer protoporphyrin IX, (PpIX), to produce a photodynamic effect. Therefore, ALA may be considered the only current PDT agent in clinical development which is a biochemical precursor of a photosensitizer. Topical ALA application, followed by exposure to activating light (ALA PDT), has been reported effective for the treatment of a variety of dermatologic diseases including cutaneous T-cell lymphoma, superficial basal cell carcinoma, Bowen's disease, and actinic (solar) keratoses, and is also being examined for treatment of acne and hirsutism. PpIX induced by ALA application also may serve as a fluorescence detection marker for photodiagnosis (PD) of malignant and pre- malignant conditions of the urinary bladder and other organs. Local internal application of ALA has also been used for selective endometrial ablation in animal model systems and is beginning to be examined in human clinical studies. Systemic, oral administration of ALA has been used for ALA PDT of superficial head and neck cancer, various gastrointestinal cancers, and the condition known as Barrett's esophagus. This brief paper reviews the current clinical and development status of ALA PDT.

  12. Desleucyl-Oritavancin with a Damaged d-Ala-d-Ala Binding Site Inhibits the Transpeptidation Step of Cell-Wall Biosynthesis in Whole Cells of Staphylococcus aureus.

    PubMed

    Kim, Sung Joon; Singh, Manmilan; Sharif, Shasad; Schaefer, Jacob

    2017-03-14

    We have used solid-state nuclear magnetic resonance to characterize the exact nature of the dual mode of action of oritavancin in preventing cell-wall assembly in Staphylococcus aureus. Measurements performed on whole cells labeled selectively in vivo have established that des-N-methylleucyl-N-4-(4-fluorophenyl)benzyl-chloroeremomycin, an Edman degradation product of [(19)F]oritavancin, which has a damaged d-Ala-d-Ala binding aglycon, is a potent inhibitor of the transpeptidase activity of cell-wall biosynthesis. The desleucyl drug binds to partially cross-linked peptidoglycan by a cleft formed between the drug aglycon and its biphenyl hydrophobic side chain. This type of binding site is present in other oritavancin-like glycopeptides, which suggests that for these drugs a similar transpeptidase inhibition occurs.

  13. Intracellular Targeting Signals and Lipid Specificity Determinants of the ALA/ALIS P4-ATPase Complex Reside in the Catalytic ALA α-Subunit

    PubMed Central

    Poulsen, Lisbeth R.; Hanisch, Susanne; Meffert, Katharina; Buch-Pedersen, Morten J.; Jakobsen, Mia K.; Pomorski, Thomas Günther; Palmgren, Michael G.

    2010-01-01

    Members of the P4 subfamily of P-type ATPases are believed to catalyze flipping of phospholipids across cellular membranes, in this way contributing to vesicle biogenesis in the secretory and endocytic pathways. P4-ATPases form heteromeric complexes with Cdc50-like proteins, and it has been suggested that these act as β-subunits in the P4-ATPase transport machinery. In this work, we investigated the role of Cdc50-like β-subunits of P4-ATPases for targeting and function of P4-ATPase catalytic α-subunits. We show that the Arabidopsis P4-ATPases ALA2 and ALA3 gain functionality when coexpressed with any of three different ALIS Cdc50-like β-subunits. However, the final cellular destination of P4-ATPases as well as their lipid substrate specificity are independent of the nature of the ALIS β-subunit they were allowed to interact with. PMID:20053675

  14. Conformations of Gly(n)H+ and Ala(n)H+ peptides in the gas phase.

    PubMed Central

    Hudgins, R R; Mao, Y; Ratner, M A; Jarrold, M F

    1999-01-01

    High-resolution ion mobility measurements and molecular dynamics simulations have been used to probe the conformations of protonated polyglycine and polyalanine (Gly(n)H and Ala(n)H+, n = 3-20) in the gas phase. The measured collision integrals for both the polyglycine and the polyalanine peptides are consistent with a self-solvated globule conformation, where the peptide chain wraps around and solvates the charge located on the terminal amine. The conformations of the small peptides are governed entirely by self-solvation, whereas the larger ones have additional backbone hydrogen bonds. Helical conformations, which are stable for neutral Alan peptides, were not observed in the experiments. Molecular dynamics simulations for Ala(n)H+ peptides suggest that the charge destabilizes the helix, although several of the low energy conformations found in the simulations for the larger Ala(n)H+ peptides have small helical regions. PMID:10049339

  15. Assessment of ALA-induced PpIX production in porcine skin pretreated with microneedles.

    PubMed

    Rodrigues, Phamilla Gracielli Sousa; Campos de Menezes, Priscila Fernanda; Fujita, Alessandra Keiko Lima; Escobar, André; Barboza de Nardi, Andrigo; Kurachi, Cristina; Bagnato, Vanderlei S

    2015-09-01

    Photodynamic therapy (PDT) is used for skin treatments of premalignant and cancer lesions and recognized as a non-invasive technique that combines tissue photosensitization and subsequent exposure to light to induce cell death. However, it is limited to the treatment of superficial lesions, mainly due to the low cream penetration. Therefore, the improvement of transdermal distribution of aminolevulinic acid (ALA) is needed. In this study, the kinetics and homogeneity of production of ALA-induced PpIX after the skin pre-treatment with microneedles rollers of 0.5, 1.0 and 1.5 mm length were investigated. An improvement in homogeneity and production of PpIX was shown in a porcine model. Widefield fluorescence imaging three hours after the topical application of ALA-cream in the combined treatment with microeedles rollers.

  16. Kinetic study of delta-Ala induced porphyrins in mice using photoacoustic and fluorescence spectroscopies.

    PubMed

    Stolik, Suren; Tomás, Sergio A; Ramón-Gallegos, Eva; Sánchez, Feliciano

    2002-11-01

    The production of delta-aminolevulinic acid (ALA)-induced porphyrins in mice skin and blood was studied by photoacoustic and fluorescence spectroscopies. Mice were intraperitoneally administered with 30 mg/kg of ALA. The abdominal skin was subsequently excised at specific times within an 8-h interval and its absorption spectrum obtained by photoacoustics. The highest porphyrins concentration in skin, determined from the optical absorption of the Soret band at 410 nm, was found to occur nearly 2 h after ALA administration, but a first peak was also observed at approximately 15 min. Our hypothesis that the first peak represents the porphyrins content in blood vessels within the skin, whereas the second peak corresponds to porphyrins production in skin tissue, was confirmed by analysing the evolution of protoporphyrin IX content in plasma extracted intracardiacally. By finally applying phase resolved photoacoustic spectroscopy, we were able to evaluate the mean depth at which porphyrins are generated.

  17. Mature bovine articular cartilage contains abundant aggrecan that is C-terminally truncated at Ala719-Ala720, a site which is readily cleaved by m-calpain

    PubMed Central

    2004-01-01

    Extracts of normal mature articular cartilage contain aggrecan molecules which bear the G1 domain (the N-terminal globular domain of aggrecan) and are C-terminally truncated by proteolysis at a number of sites. A proportion of these molecules are generated by an aggrecanase and/or matrix-metalloproteinase-mediated cleavage in the IGD (interglobular domain between the G1 and G2 domains of aggrecan). However, the proteinase(s) responsible for formation of the majority of the larger G1-G2 and glycosaminoglycan-bearing truncated species is (are) unknown. N-terminal sequencing of aggrecan core fragments generated by m-calpain digestion of bovine aggrecan has identified four novel cleavage sites: one within the CS (chondroitin sulphate)-1 domain (at one or more of the bonds Ser1229–Val1230, Ser1249–Val1250, Ser1287–Val1288, Gly1307–Val1308 and Ser1346–Val1347), two within the IGD (at bonds Ala474–Ala475 and Gly365–Gly366) and one within the KS (keratan sulphate) domain (at Ala719–Ala720). A new monoclonal antibody (SK-28) to the C-terminal neoepitope at M710VTQVGPGVA719 showed that aggrecan products generated by this cleavage are present in high abundance in mature bovine articular cartilage extracts. We conclude that m-calpain, or an unidentified proteinase with the capacity to cleave at the same site, is active during aggrecan biosynthesis/secretion by mature chondrocytes or in the matrix of mature bovine articular cartilage in vivo. PMID:15175011

  18. Association of the PPARγ2 Pro12Ala polymorphism with increased risk of cardiovascular diseases.

    PubMed

    Li, Y; Zhu, J; Ding, J Q

    2015-12-29

    This meta-analysis investigated the correlation between the PPARγ2 Pro12Ala polymorphism and cardiovascular disease (CVD). Electronic database and manual searches were conducted to retrieve studies published relevant to the PPARγ2 Pro12Ala polymorphism and CVD. Rigorous inclusion and exclusion criteria were employed for selection of high-quality patients-control studies. Statistical data analyses on allelic, dominant, homozygous, heterozygous, and recessive inheritance models were performed using the R 3.1.0 and Stata 12.0 software. We enrolled 12 case-control studies consisting of 10,189 patients with CVD [1070 with myocardial infarction (MI), 7849 with coronary artery disease (CAD), and 1270 with acute coronary syndromes (ACS)] and 17,899 controls. The results of meta-analyses revealed that the PPARγ2 Pro12Ala (rs1801282) polymorphism was correlated with a higher risk of CVD under both allelic and dominant models, while no statistical significance was found under homozygous, heterozygous, or recessive models. Subgroup analysis based on disease showed that the PPARγ2 Pro12Ala (rs1801282) polymorphism was correlated with a higher risk of MI under both allelic and dominant models, while no statistical significance was found for association with CAD or ACS under allele or dominant models. Furthermore, under homozygous, heterozygous, and recessive models, the PPARγ2 Pro12Ala (rs1801282) polymorphism had no statistically significant association with MI, CAD, or ACS. The results of this meta-analysis suggest that the PPARγ2 Pro12Ala (rs1801282) polymorphism might be correlated with a higher risk of CVD, particularly MI, and could serve as an important early indicator for CVD.

  19. Photodynamic damage study of HeLa cell line using ALA

    NASA Astrophysics Data System (ADS)

    AlSalhi, M. S.; Atif, M.; AlObiadi, A. A.; Aldwayyan, A. S.

    2011-04-01

    The present study evaluates the photodynamic damage with 5-aminolevulinic acid (5-ALA) using HeLa as experimental model. HeLa cell line was irradiated with red light (He-Ne laser, λ = 632.8 CW nm). The influence of different incubation times and concentrations of 5-ALA, different irradiation doses and various combinations of photosensitizer and light doses on the cellular viability of HeLa cells were studied. The optimal uptake of photosensitizer ALA in HeLa cells was investigated by means of PpIX fluorescence intensity by exciting the HeLa cell suspension at 450 nm and a detection wavelength set at 690 nm. Cells viability was determined by means of trypan blue solution. The spectrometric measurements showed that the maximal cellular uptake of 5-ALA occurred after 4 h in vitro incubation. We found that the combination with 5-ALA and laser irradiation leads to time/concentration-dependent increase of cells death and also energy doses-dependent enlarge the cells death. The fluorescence intensity after PDD of carcinoma cells reduce when compared with the control group. The fluorescence emission spectral profiles after PDD of carcinoma cells showed a dip around 425-525 nm when compared with the control group. This may be due to the damage of mitochondria component of cells. The percentage of HeLa cells after PDD shows that the percentage of cells survival rate as function of laser dose (power). Hence it is clear that at 200 μg/ml ALA and 20 mW laser irradiation, more than 70% of HeLa cells were dead after 15 min.

  20. Distribution of ALA metabolic products in esophageal carcinoma cells using spectrally resolved confocal laser microscopy

    NASA Astrophysics Data System (ADS)

    Smolka, Jozef; Mateasik, Anton

    2006-08-01

    Aminolevulinic acid (ALA) is an efficient substance used in photodynamic therapy (PDT). It is a precursor of light-sensitive products that can selectively accumulate in malignant cells following the altered activity of the heme biosynthetic pathway enzymes in such cells. These products are synthesized in mitochondria and distributed to various cellular structures [1]. The localization of ALA products in subcellular structures depends on their chemical characteristics as well as on the properties of the intracellular environment [2]. Characterization of such properties is possible by means of fluorescent probes like JC-1 and carboxy SNARF-1. However, the emission spectra of these probes are overlapped with spectral pattern of typical ALA product -protoporphyrin IX (PpIX). Spectral overlap of fluorescence signals prevents to clearly separate a distribution of probes from PpIX distribution what can completely mess the applicability of these probes in characterization of cell properties. The spectrally resolved confocal laser microscopy can be used to overcome this problem. In this study, a distribution of ALA metabolic products in relation to the mitochondrial membrane potential and intracellular pH was examined. Human cell lines (KYSE-450, KYSE-70) from esophageal squamous cell carcinoma were used. Cells were incubated with 1mM solution of ALA for four hours. Two fluorescent probes, carboxy SNARF-1 and JC-1 , were used to monitor intracellular pH levels and to determine membrane potential changes, respectively. The samples were scanned by spectrally resolved laser scanning microscope. Spectral linear unmixing method was used to discriminate and separate regions of accumulation of ALA metabolic products of JC-1 and carboxy SNARF-1.

  1. ALA PDT for high grade dysplasia in Barrett's oesophagus: review of a decade's experience

    NASA Astrophysics Data System (ADS)

    Bown, Stephen G.; Mackenzie, Gary D.; Dunn, Jason M.; Thorpe, Sally M.; Lovat, Laurence B.

    2009-06-01

    We have been investigating PDT with 5 aminolaevulinic acid (ALA) for the treatment of high grade dysplasia (HGD) in Barrett's oesophagus (BO) for over a decade. This drug has inherent advantages over porfimer sodium (Photofrin), the current approved photosensitiser in the UK and USA, which causes strictures in 18-50% and light sensitivity for up to three months. ALA has a lower rate of oesophageal strictures due to its preferential activity in the mucosa, sparing the underlying muscle, and patients are only light sensitive for 1-2 days. Within a randomised controlled trial, we demonstrated that an ALA dose of 60mg/kg activated by 1000J/cm red laser light is the most effective. Using these values we achieved complete reversal of HGD at 1 year in 89% of 27 patients. A randomised controlled trial of ALA vs porfimer sodium PDT for HGD is currently under way with end points of efficacy and safety. 50 of 66 patients have been recruited. Preliminary data suggest ALA PDT is safer with a trend to higher efficacy. Late relapse can occur in 20% of patients. New prognostic markers, in particular aneuploidy, are helping us to identify and target patients at risk of late relapse. Furthermore optical biopsy techniques such as elastic scattering spectroscopy (ESS) may allow detection of nuclear abnormalities in vivo and enable us to target areas of interest whilst reducing sampling error. PDT faces new challenges for the treatment of HGD in BO, with the recent introduction of balloon based radiofrequency ablation. This technique appears simpler and as effective as PDT, but follow up is currently short and long term safety data is lacking. In our experience ALA PDT is currently the most effective minimally invasive treatment for HGD in BO. This work was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme.

  2. OPN gene polymorphism (Ala250) and lower serum OPN levels are associated with urolithiasis.

    PubMed

    Tugcu, Volkan; Simsek, Abdulmuttalip; Tarhan, Tugba; Atalar, Fatmahan; Bitkin, Alper; Tasci, Ali Ihsan; Kural, Ali Riza; Altug, Tuncay

    2013-07-01

    Osteopontin (OPN) is one of the urinary proteins with an important role in stone formation. Recently, OPN Ala250 (rs1126616) polymorphism and other single nucleotide polymorphisms (SNPs) have been studied to define their role in urolithiasis. This study was conducted to examine the impact of OPN Ala250 polymorphism on the risk of stone formation and their association with serum OPN levels. OPN Ala250 polymorphism was investigated in 127 urolithiasis patients and 92 healthy controls. Stones were analyzed for their chemical composition by using X-Ray diffraction method. Genomic DNA was isolated from peripheral blood leucocytes. The study groups were genotyped by PCR-RFLP and serum OPN levels were measured by ELISA. There was a significant difference between urolithiasis patients and controls concerning genotype and allele frequencies of OPN Ala250 (p < 0.05). Separate analysis by BMI greater or less than 25 kg/m(2) showed that the presence of one mutant T-allele was more frequent in patients with higher BMI than patients with BMI less than 25 kg/m(2) (p < 0.05). Serum OPN concentrations were two-fold higher in the control group compared to urolithiasis patients (p < 0.05). But the mean serum levels did not show any significant difference between OPN Ala250 genotypes in both groups. Moreover, we found an association between higher BMI and stone formation. Our findings suggest that OPN Ala250 polymorphism is associated with the correlation between weight gain and urolithiasis. However, the correlation between urolithiasis and obesity needs to be further studied in larger cohorts.

  3. Neurotransmitter transporter family including SLC6A6 and SLC6A13 contributes to the 5-aminolevulinic acid (ALA)-induced accumulation of protoporphyrin IX and photodamage, through uptake of ALA by cancerous cells.

    PubMed

    Tran, Tai Tien; Mu, Anfeng; Adachi, Yuka; Adachi, Yasushi; Taketani, Shigeru

    2014-01-01

    δ-Aminolevulinic acid (ALA)-induced protoporphyrin accumulation is widely used in the treatment of cancer, as photodynamic therapy (PDT). To clarify the mechanisms of ALA uptake by tumor cells, we have examined the ALA-induced accumulation of protoporphyrin by the treatment of colon cancer DLD-1 and epithelial cancer HeLa cells with γ-aminobutyric acid (GABA)-related compounds. When the cells were treated with GABA, taurine and β-alanine, the level of protoporphyrin was decreased, suggesting that plasma membrane transporters involved in the transport of neurotransmitters contribute to the uptake of ALA. By transfection with neurotransmitter transporters SLC6A6, SLC6A8 and SLC6A13 cDNA, the ALA- and ALA methylester-dependent accumulation of protoporphyrin markedly increased in HEK293T cells, dependent on an increase in the uptake of ALA. When ALA-treated cells were exposed to white light, the extent of photodamage increased in SLC6A6- and SLC6A13-expressing cells. Conversely, knockdown of SLC6A6 or SLC6A13 with siRNAs in DLD-1 and HeLa cells decreased the ALA-induced accumulation. The expression of SLC6A6 and SLC6A13 was found in some cancer cell lines. Immunohistochemical studies revealed that the presence of these transporters was elevated in colon cancerous cells. These results indicated that neurotransmitter transporters including SLC6A6 and SLC6A13 mediate the uptake of ALA and can play roles in the enhancement of ALA-induced accumulation of protoporphyrin in cancerous cells.

  4. Pro-oxidant effect of ALA is implicated in mitochondrial dysfunction of HepG2 cells.

    PubMed

    Laafi, Jihane; Homedan, Chadi; Jacques, Caroline; Gueguen, Naig; Schmitt, Caroline; Puy, Hervé; Reynier, Pascal; Carmen Martinez, Maria; Malthièry, Yves

    2014-11-01

    Heme biosynthesis begins in the mitochondrion with the formation of delta-aminolevulinic acid (ALA). In acute intermittent porphyria, hereditary tyrosinemia type I and lead poisoning patients, ALA is accumulated in plasma and in organs, especially the liver. These diseases are also associated with neuromuscular dysfunction and increased incidence of hepatocellular carcinoma. Many studies suggest that this damage may originate from ALA-induced oxidative stress following its accumulation. Using the MnSOD as an oxidative stress marker, we showed here that ALA treatment of cultured cells induced ROS production, increasing with ALA concentration. The mitochondrial energetic function of ALA-treated HepG2 cells was further explored. Mitochondrial respiration and ATP content were reduced compared to control cells. For the 300 μM treatment, ALA induced a mitochondrial mass decrease and a mitochondrial network imbalance although neither necrosis nor apoptosis were observed. The up regulation of PGC-1, Tfam and ND5 genes was also found; these genes encode mitochondrial proteins involved in mitochondrial biogenesis activation and OXPHOS function. We propose that ALA may constitute an internal bioenergetic signal, which initiates a coordinated upregulation of respiratory genes, which ultimately drives mitochondrial metabolic adaptation within cells. The addition of an antioxidant, Manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP), resulted in improvement of maximal respiratory chain capacity with 300 μM ALA. Our results suggest that mitochondria, an ALA-production site, are more sensitive to pro-oxidant effect of ALA, and may be directly involved in pathophysiology of patients with inherited or acquired porphyria. Copyright © 2014 Elsevier B.V. and Société française de biochimie et biologie Moléculaire (SFBBM). All rights reserved.

  5. Hexyl aminolevulinate: 5-ALA hexylester, 5-ALA hexylesther, aminolevulinic acid hexyl ester, hexaminolevulinate, hexyl 5-aminolevulinate, P 1206.

    PubMed

    2005-01-01

    Hexyl aminolevulinate [aminolevulinic acid hexyl ester, hexyl 5-aminolevulinate, 5-ALA hexylester, hexaminolevulinate, Hexvix, Hexvix PD, Hexvix PDT, P 1206] is being developed by PhotoCure, a Norwegian company, for the diagnosis and treatment of bladder cancer. The current standard diagnosis of bladder cancer involves cystoscopic examination of urine and bladder washings and is combined with biopsy for better detection of low-grade malignancies. However, the method largely relies on the experience of the surgeon and often results in false negatives especially for low-grade malignancies and pre-cancerous tissues. Photocure believes that imaging with hexyl aminolevulinate (Hexvix) offers significant advantages over standard diagnostic methods for detection of bladder cancer and also can be used in combination with those to ensure the optimal diagnostic accuracy. PhotoCure's procedure for diagnosis of bladder cancer involves filling of the patient's bladder with hexyl aminolevulinate solution and allowing the active agent to accumulate in the cancerous tissue. Following bladder emptying, blue light illumination is applied to the bladder causing red fluorescence that is clearly visible, thus identifying the cancerous tissue. Imaging with hexyl aminolevulinate improves detection of bladder tumours and also can be used together with transurethral resection to check the completeness of tumour removal. PhotoCure is looking for the opportunity to out-license hexaminolevulinate for all regions except the Nordic regions. PhotoCure has proprietary rights for hexyl aminolevulinate from the Norwegian Radium Hospital. Under the terms of the agreement with the Norwegian Radium Hospital, PhotoCure gains an access to, and an option to acquire, all of the new photodynamic therapy technologies developed by the Norwegian Radium Hospital. For its part, PhotoCure provides research and development funding to the Norwegian Radium Hospital. This 3-year agreement was extended in February

  6. Association of serum uric acid with Pro12Ala polymorphism in PPAR-γ2 among Chinese nonagenarians/centenarians.

    PubMed

    Zhou, Yan; Huang, Chang-Quan; Lu, Zhen-Chan; Dong, Bi-Rong

    2012-04-01

    In previous studies, Pro12Ala polymorphism in peroxisome proliferator- activated receptors gamma 2 (PPAR-γ2) was shown to be associated with both longevity and metabolic syndrome, which was closely related with hyperuricemia. We examined long-lived subjects (≥90 years), to ascertain whether the polymorphism is associated with the level of serum uric acid (SUA). The present study analysed data from a survey conducted in 2005 on all residents aged 90 years or more in a district with 2,311,709 inhabitants. The sample comprised 669 unrelated Chinese participants (aged 90-108 years, mean: 93.54±3.53 years; 67.2% women). The genotype frequencies of the Pro12Ala polymorphism were 0% Ala12Ala and 9.0% Pro12Ala, 91.0% Pro12Pro. Between men or women, and between subjects who were or were not 12Ala carriers, neither in SUA levels nor the prevalence of hyperuricemia were significant. Between subjects with and without hyperuricemia, the difference in prevalence of 12Ala carriers was also non-significant. Unadjusted and adjusted multiple logistic regressions showed that the odds ratios (OR) for hyperuricemia were not associated with Pro12Ala polymorphism in PPAR-γ2. In Chinese nonagenarians and centenarians, SUA levels are not associated with polymorphism in PPAR-γ2.

  7. Association between the Pro12Ala Polymorphism of the Peroxisome Proliferator-Activated Receptor Gamma Gene and Strength Athlete Status

    PubMed Central

    Maciejewska-Karlowska, Agnieszka; Sawczuk, Marek; Cieszczyk, Pawel; Zarebska, Aleksandra; Sawczyn, Stanislaw

    2013-01-01

    Background The 12Ala allele of the Peroxisome Proliferator-Activated Receptor gamma gene (PPARG) Pro12Ala polymorphism produces a decreased binding affinity of the PPARγ2 protein, resulting in low activation of the target genes. The 12Ala allele carriers display a significantly improved insulin sensitivity that may result in better glucose utilisation in working skeletal muscles. We hypothesise that the PPARG 12Ala allele could be associated with strength athlete status in Polish athletes. Methodology The genotype distribution of PPARG Pro12Ala was examined in 660 Polish athletes. The athletes were stratified into four subgroups: endurance, strength-endurance, sprint-strength and strength. Control samples were prepared from 684 unrelated sedentary volunteers. A χ2 test was used to compare the PPARG Pro12Ala allele and genotype frequencies between the different groups of athletes and control subjects. Bonferroni’s correction for multiple testing was applied. Results A statistically significant higher frequency of PPARG 12Ala alleles was observed in the subgroup of strength athletes performing short-term and very intense exertion characterised by predominant anaerobic energy production (13.2% vs. 7.5% in controls; P = 0.0007). Conclusion The PPARG 12Ala allele may be a relevant genetic factor favouring strength abilities in professional athletes, especially in terms of insulin-dependent metabolism, a shift of the energy balance towards glucose utilisation and the development of a favourable weight-to-strength ratio. PMID:23799144

  8. Association between the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma gene and strength athlete status.

    PubMed

    Maciejewska-Karlowska, Agnieszka; Sawczuk, Marek; Cieszczyk, Pawel; Zarebska, Aleksandra; Sawczyn, Stanislaw

    2013-01-01

    The 12Ala allele of the Peroxisome Proliferator-Activated Receptor gamma gene (PPARG) Pro12Ala polymorphism produces a decreased binding affinity of the PPARγ2 protein, resulting in low activation of the target genes. The 12Ala allele carriers display a significantly improved insulin sensitivity that may result in better glucose utilisation in working skeletal muscles. We hypothesise that the PPARG 12Ala allele could be associated with strength athlete status in Polish athletes. The genotype distribution of PPARG Pro12Ala was examined in 660 Polish athletes. The athletes were stratified into four subgroups: endurance, strength-endurance, sprint-strength and strength. Control samples were prepared from 684 unrelated sedentary volunteers. A χ(2) test was used to compare the PPARG Pro12Ala allele and genotype frequencies between the different groups of athletes and control subjects. Bonferroni's correction for multiple testing was applied. A statistically significant higher frequency of PPARG 12Ala alleles was observed in the subgroup of strength athletes performing short-term and very intense exertion characterised by predominant anaerobic energy production (13.2% vs. 7.5% in controls; P = 0.0007). The PPARG 12Ala allele may be a relevant genetic factor favouring strength abilities in professional athletes, especially in terms of insulin-dependent metabolism, a shift of the energy balance towards glucose utilisation and the development of a favourable weight-to-strength ratio.

  9. 5-ALA fluorescence-assisted surgery in pediatric brain tumors: report of three cases and review of the literature.

    PubMed

    Barbagallo, Giuseppe M V; Certo, Francesco; Heiss, Kathrin; Albanese, Vincenzo

    2014-12-01

    5-aminolevulinic acid (5-ALA) has been used for the last 5 years to increase the extent of resection in adult brain tumors, mostly glioblastomas, but it is not approved yet as standard adjuvant treatment in the pediatric population. We report three different cases of pediatric brain tumors (two glioblastomas and one medulloblastoma) recently operated using 5-ALA fluorescence guidance, highlighting how useful it is in pediatric high-grade glioma (but not in medulloblastoma) also and confirming the lack of 5-ALA-related side effects. The first glioma was a recurrent GBM, whilst the second was a primary tumor. In all children, 5-ALA was administrated after discussing its use, including pros and cons, with the parents. 5-ALA fluorescence was a very useful tool to better identify tumor tissue and achieve gross-total tumor resection in GBMs, as confirmed by postoperative magnetic resonance imaging (MRI). In the medulloblastoma case no useful 5-ALA fluorescence was identified. No hematological or dermatological complications nor other side effects related to use of 5-ALA were observed. We submit that 5-ALA fluorescence guided surgery can be safe and useful in pediatric high-grade glioma, although its use in children still remains an off-label indication and requires validation through larger studies.

  10. Substitution of the Lys linker with the β-Ala linker dramatically decreased the renal uptake of 99mTc-labeled Arg-X-Asp-conjugated and X-Ala-Asp-conjugated α-melanocyte stimulating hormone peptides.

    PubMed

    Flook, Adam M; Yang, Jianquan; Miao, Yubin

    2014-11-13

    The purpose of this study was to examine whether the substitution of the Lys linker with the β-Ala could reduce the renal uptake of (99m)Tc-labeled Arg-X-Asp-conjugated and X-Ala-Asp-conjugated α-melanocyte stimulating hormone (α-MSH) peptides. RSD-β-Ala-(Arg(11))CCMSH (1) {c[Arg-Ser-Asp-dTyr-Asp]-β-Ala-Cys-Cys-Glu-His-dPhe-Arg-Trp-Cys-Arg-Pro-Val-NH2}, RTD-β-Ala-(Arg(11))CCMSH (2), RVD-β-Ala-(Arg(11))CCMSH (3), RAD-β-Ala-(Arg(11))CCMSH (4), NAD-β-Ala-(Arg(11))CCMSH (5), and EAD-β-Ala-(Arg(11))CCMSH (6) peptides were synthesized and evaluated for their melanocortin 1 (MC1) receptor binding affinities in B16/F1 melanoma cells. The biodistribution of their (99m)Tc-conjugates were determined in B16/F1 melanoma-bearing C57 mice. The substitution of the Lys linker with β-Ala linker dramatically reduced the renal uptake of all six (99m)Tc-peptides. (99m)Tc-4 exhibited the highest melanoma uptake (15.66 ± 6.19% ID/g) and the lowest kidney uptake (20.18 ± 3.86% ID/g) among these (99m)Tc-peptides at 2 h postinjection. The B16/F1 melanoma lesions could be clearly visualized by single photon emission computed tomography (SPECT)/CT using (99m)Tc-4 as an imaging probe.

  11. Shifting with the Paradigm: LJ's Picks & Pans for ALA in Disneyland

    ERIC Educational Resources Information Center

    Berry, John N., III

    2008-01-01

    The feelings of librarians planning for the American Library Association (ALA) conference at Disneyland (aka Anaheim, California, June 26-July 2) range from moderate pleasure to dread. Some remember the joys and difficulties of Orlando, especially the exorbitant cab fares and mediocre restaurants. Others quail at screaming kids and tourists in…

  12. "LJ" Report "Anaheim, ALA 2008": Amid the Fantasy, Doses of Reality

    ERIC Educational Resources Information Center

    Blumenstein, Lynn; Berry, John; Fialkoff, Francine; Fox, Bette-Lee; Hadro, Josh; Horrocks, Norman; Oder, Norman; Roncevic, Mirela

    2008-01-01

    If the resort city of Anaheim, California, home of Disneyland and its "imagineers," marked a departure from the urban reality of the typical American Library Association (ALA) annual conference, it was impossible, at this 2008 meeting, to avoid urgent library issues. How do libraries maintain their value and cultural presence as users…

  13. ALAS: Achievement for Latinos through Academic Success. What Works Clearinghouse Intervention Report

    ERIC Educational Resources Information Center

    What Works Clearinghouse, 2006

    2006-01-01

    "ALAS," an acronym for "Achievement for Latinos through Academic Success" that means "wings" in Spanish, is a middle school (or junior high school) intervention designed to address student, school, family, and community factors that affect dropping out. Each student is assigned a counselor who monitors attendance,…

  14. Impact of various emulsifiers on ALA bioavailability and chylomicron synthesis through changes in gastrointestinal lipolysis.

    PubMed

    Couëdelo, L; Amara, S; Lecomte, M; Meugnier, E; Monteil, J; Fonseca, L; Pineau, G; Cansell, M; Carrière, F; Michalski, M C; Vaysse, C

    2015-05-01

    Formulating healthy food rich in omega 3 fatty acids requires prior knowledge of the parameters influencing their bioavailability and their metabolic fate. In this context, we studied the effects of various emulsifiers widely used in the food industry, on the gastrointestinal lipolysis of flaxseed oil emulsions in an in vitro model and on the intestinal absorption and lymphatic secretion of alpha-linolenic acid (ALA) in rats. In vitro data showed that the emulsification of flaxseed oil with soya lecithin improved the gastric lipolysis of the oil (+30%), while the presence of Tween 80 or of sodium caseinate decreased it (-80% and -40%, respectively). The in vivo data demonstrated that the intestinal absorption and the lymphatic secretion of ALA were improved with soya lecithin (Cmax = 24 mg mL(-1)) and reduced in the presence of sodium caseinate (Cmax = 7 mg mL(-1)) compared to unemulsified flaxseed oil (Cmax = 16 mg mL(-1)); Tween 80 had no effect. In addition, the synthesized chylomicrons were notably larger and more numerous with soya lecithin whereas they were smaller in the presence of sodium caseinate (p < 0.05). This study shows that the intestinal bioavailability of ALA was increased by the emulsification of flaxseed oil with soya lecithin via an improved lipolysis, favouring the intestinal absorption of ALA and the secretion of many large chylomicrons in lymph.

  15. Association of Pro12Ala polymorphism in peroxisome proliferator activated receptor gamma with proliferative diabetic retinopathy

    PubMed Central

    Tariq, Khadija; Malik, Saira Bano; Ali, Syeda Hafiza Benish; Maqsood, Sundas Ejaz; Azam, Aisha; Muslim, Irfan; Khan, Muhammad Shakil; Azam, Maleeha; Waheed, Nadia Khalida

    2013-01-01

    Purpose The association of non-synonymous substitution polymorphism rs1801282 (c.34C>G, p.Pro12Ala) in exon 4 of the peroxisome proliferator activated receptor gamma gene with diabetic retinopathy (DR) has been reported inconsistently. Therefore, the purpose of the present study was to understand the population-specific role of the Pro12Ala polymorphism in DR susceptibility in Pakistani subjects. Methods A total of 180 subjects with DR, 193 subjects with type 2 diabetes mellitus (T2DM) with no diabetic retinopathy, and 200 healthy normoglycemic non-retinopathic Pakistani individuals were genotyped for the rs1801282 (c.34C>G) polymorphism using polymerase chain reaction-restriction fragment length polymorphism. Results We found the individuals with T2DM carrying 12Ala were at a reduced risk of developing DR (odds ratio [OR]=0.53; 95% confidence interval [CI]=0.33–0.87). Upon stratified analysis regarding disease severity, we observed this protective effect was confined to proliferative DR (OR=0.4; 95% CI=0.2–0.8) with non-significant effects on the susceptibility of non-proliferative DR (OR=0.67; 95% CI=0.37–1.19). Conclusions We report a protective role of the 12Ala polymorphism against proliferative DR in individuals with T2DM in Pakistan. PMID:23559865

  16. Holcim, Inc. Receives Gulf Guardian Award for Eliminating Stormwater Discharges from Theodore, Ala.

    EPA Pesticide Factsheets

    ATLANTA - The U.S. Environmental Protection Agency's (EPA) Gulf of Mexico Program recognized Holcim Inc., which operates a cement plant in Theodore, Ala., with the First Place 2015 Gulf Guardian Award in the Business and Industry Category. The awards cerem

  17. X-linked macrocytic dyserythropoietic anemia in females with an ALAS2 mutation

    PubMed Central

    Sankaran, Vijay G.; Ulirsch, Jacob C.; Tchaikovskii, Vassili; Ludwig, Leif S.; Wakabayashi, Aoi; Kadirvel, Senkottuvelan; Lindsley, R. Coleman; Bejar, Rafael; Shi, Jiahai; Lovitch, Scott B.; Bishop, David F.; Steensma, David P.

    2015-01-01

    Macrocytic anemia with abnormal erythropoiesis is a common feature of megaloblastic anemias, congenital dyserythropoietic anemias, and myelodysplastic syndromes. Here, we characterized a family with multiple female individuals who have macrocytic anemia. The proband was noted to have dyserythropoiesis and iron overload. After an extensive diagnostic evaluation that did not provide insight into the cause of the disease, whole-exome sequencing of multiple family members revealed the presence of a mutation in the X chromosomal gene ALAS2, which encodes 5′-aminolevulinate synthase 2, in the affected females. We determined that this mutation (Y365C) impairs binding of the essential cofactor pyridoxal 5′-phosphate to ALAS2, resulting in destabilization of the enzyme and consequent loss of function. X inactivation was not highly skewed in wbc from the affected individuals. In contrast, and consistent with the severity of the ALAS2 mutation, there was a complete skewing toward expression of the WT allele in mRNA from reticulocytes that could be recapitulated in primary erythroid cultures. Together, the results of the X inactivation and mRNA studies illustrate how this X-linked dominant mutation in ALAS2 can perturb normal erythropoiesis through cell-nonautonomous effects. Moreover, our findings highlight the value of whole-exome sequencing in diagnostically challenging cases for the identification of disease etiology and extension of the known phenotypic spectrum of disease. PMID:25705881

  18. Preservice Legal Education for Academic Librarians within ALA-Accredited Degree Programs

    ERIC Educational Resources Information Center

    Cross, William M.; Edwards, Phillip M.

    2011-01-01

    In order to explore the current state of legal education for graduates of LIS programs, we present the results of an examination of the curricula and faculty composition at all 57 institutions that offer ALA-accredited graduate degrees. Concluding that, even under the best circumstances, many students graduate with a limited understanding of legal…

  19. Hey, Small Spender: An Insider's Guide to Navigating ALA's Chicago Conference on the Cheap

    ERIC Educational Resources Information Center

    School Library Journal, 2009

    2009-01-01

    This article presents an insider's guide to navigating the American Library Association's (ALA) annual conference in Chicago on July 9-15. As for the extracurricular activities, Chicago has a lot to offer. This article provides tips from the arts and entertainment bible "Time Out Chicago" on where to go and what to do (on a limited…

  20. CDC64 Encodes Cytoplasmic Alanyl-tRNA Synthetase, Ala1p, of Saccharomyces cerevisiae

    PubMed Central

    Wrobel, Carolyn; Schmidt, Emmett V.; Polymenis, Michael

    1999-01-01

    The cdc64-1 mutation causes G1 arrest in Saccharomyces cerevisiae corresponding to a type II Start phenotype. We report that CDC64 encodes Ala1p, an alanyl-tRNA synthetase. Thus, cdc64-1 might affect charging of tRNAAla and thereby initiation of cell division. PMID:10601222

  1. Studying Online: Student Motivations and Experiences in ALA-Accredited LIS Programs

    ERIC Educational Resources Information Center

    Oguz, Fatih; Chu, Clara M.; Chow, Anthony S.

    2015-01-01

    This paper presents a large scale study of online MLIS students (n = 910), who completed at least one online course and were enrolled in 36 of the 58 ALA-accredited MLIS programs in Canada and the United States. The results indicate that the typical student is female, White, lives in an urban setting, and is in her mid-30s. Online students were…

  2. Targeted opening of the blood brain barrier by ALA-mediated photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Hirschberg, Henry; Peng, Qian; Uzal, Francisco A.; Chighvinadze, David; Zhang, Michelle J.; Madsen, Steen J.

    2009-06-01

    Background and Objective: We have evaluated the ability of ALA-mediated PDT to selectivly open the BBB in rats. This will permit access of chemotherapeutic agents to brain tumor cells remaining in the resection cavity wall, but limit their penetration into normal brain remote from the site of illumination. Study Design/Materials and Methods: ALA-PDT was performed on non-tumor bearing inbred Fischer rats at increasing fluence levels. Contrast T1-weighted high field (3 T) magnetic resonance imaging (MRI) scans were used to monitor the degree of BBB disruption. Results: PDT at increasing fluence levels between 9 and 17 J demonstrated an increasing contrast flow rate. The BBB was found to be disrupted 2 h following PDT and 80 - 100 % restored 72 h later at the lowest fluence level. No effect on the BBB was observed if 26 J of light was given in the absence of ALA. Conclusion: ALA-PDT was highly effective in opening the BBB in a localized region of the brain. The degradation of the BBB was temporary in nature at fluence levels of 9 J, opening rapidly following treatment and significantly restored during the next 72 h. No signs of permanent tissue damage were seen on histological sections at this fluence level.

  3. Effect of Surfactant on Production of Oxygenated Unsaturated Fatty Acids by Bacillus megaterium ALA2

    USDA-ARS?s Scientific Manuscript database

    Bacillus megaterium ALA2 NRRL B-21660 was well studied to produce many oxygenated unsaturated fatty acids from linoleic acid. Its major product, 12,13,17-trihydroxy-9(Z)-octadecenoic acid (12,13,17-THOA) inhibited the growth of many plant pathogenic fungi [1]. We were not able to demonstrate 12,13...

  4. Effect of surfactants on production of oxygenated unsaturated fatty acids by Bacillus megaterium ALA2

    USDA-ARS?s Scientific Manuscript database

    Bacillus megaterium ALA2 produces many oxygenated unsaturated fatty acids from linoleic acid. Its major product, 12,13,17-trihydroxy-9(Z)-octadecenoic acid (12,13,17-THOA) inhibits the growth of some plant pathogenic fungi. Because hydrophobic fatty acids need to be evenly dispersed in culture for...

  5. Effect of Surfactants on Production of Oxygenated Unsaturated Fatty Acids by Bacillus megaterium ALA2

    USDA-ARS?s Scientific Manuscript database

    Bacillus megaterium ALA2 (NRRL B-21660) produces many oxygenated unsaturated fatty acids from linoleic acid. Its major product, 12,13,17-trihydroxy-9(Z)-octadecenoic acid (12,13,17-THOA), inhibits the growth of some plant pathogenic fungi. Because hydrophobic fatty acids need to be evenly disperse...

  6. ALA-PDT mediated DC vaccine for skin squamous cell carcinoma

    NASA Astrophysics Data System (ADS)

    Ji, Jie; Fan, Zhixia; Zhou, Feifan; Wang, Xiaojie; Shi, Lei; Zhang, Haiyan; Wang, Peiru; Yang, Degang; Zhang, Linglin; Wang, Xiuli; Chen, Wei R.

    2015-03-01

    Dendritic cell (DC) based vaccine has emerged as a promising immunotherapy for cancers. However, most DC vaccines so far have only achieved limited success in cancer treatment. Photodynamic therapy (PDT), an established cancer treatment strategy, can cause immunogenic apoptosis to induce an effective antitumor immune response. In this study, we developed a DC-based cancer vaccine using immunogenic apoptotic tumor cells induced by 5-aminolevulinic acid (ALA) mediated PDT. The maturation of DCs induced by PDT-treated apoptotic cells was evaluated. The anti-tumor immunity of ALA-PDT-DC vaccine was tested with mouse model. We observed the maturations of DCs potentiated by ALA-PDT treated tumor cells, including phenotypic maturation (upregulation of surface expression of MHC-II, DC80, and CD86), and functional maturation (enhanced capability to secret INF-Υ and IL-12). ALA-PDT-DC vaccine mediated by apoptotic cells provided protection against tumor in mice, far stronger than that of DC vaccine obtained from freeze/thaw treated tumor cells. Our results indicate that immunogenic apoptotic tumor cells can be more effective in enhancing DC-based cancer vaccine, which could improve the clinical application of PDT- DC vaccines.

  7. [Two-photon excitation fluorescence of 5-ALA induced PpIX in DHL cells].

    PubMed

    Huang, Zu-Fang; Chen, Rong; Li, Yong-Zeng; Chen, Guan-Nan; Chen, Xian-Ling; Feng, Shang-Yuan; Jia, Pei-Min

    2008-11-01

    Two-photon fluorescence microscopy is a novel imaging technique, which is primarily sensitive to a specimen's response coming from an in-focus plane, thus has low photo-bleaching and photo-damage to biological samples. 5-ALA induced production of PpIX in DHL cells was excited by 820 nm femtosecond laser; two-photon excitation fluorescence of single cell was obtained in Lambda mode of laser scanning confocal microscope. The specific fluorescence intensity of PpIX which accumulated in DHL cells was measured at 2, 4 and 10 mmol x L(-1) concentration of 5-ALA with different incubation time, which reflected the kinetics of 5-ALA accumulated in DHL cells. Accumulation of PpIX in DHL cells was a dynamic change process. Biphasic alterations of PpIX accumulation were noted: PpIX content enhanced with the increasing time and reached the maximal value around 3 h, however PpIX content decreased in the subsequent incubation time. Results indicate that two-photon fluorescence based on laser scanning microscope can be a useful technology for studying the kinetics of 5-ALA induced PpIX production in DHL cells and other leukemia cells.

  8. "LJ" Report "Anaheim, ALA 2008": Amid the Fantasy, Doses of Reality

    ERIC Educational Resources Information Center

    Blumenstein, Lynn; Berry, John; Fialkoff, Francine; Fox, Bette-Lee; Hadro, Josh; Horrocks, Norman; Oder, Norman; Roncevic, Mirela

    2008-01-01

    If the resort city of Anaheim, California, home of Disneyland and its "imagineers," marked a departure from the urban reality of the typical American Library Association (ALA) annual conference, it was impossible, at this 2008 meeting, to avoid urgent library issues. How do libraries maintain their value and cultural presence as users…

  9. Hey, Small Spender: An Insider's Guide to Navigating ALA's Chicago Conference on the Cheap

    ERIC Educational Resources Information Center

    School Library Journal, 2009

    2009-01-01

    This article presents an insider's guide to navigating the American Library Association's (ALA) annual conference in Chicago on July 9-15. As for the extracurricular activities, Chicago has a lot to offer. This article provides tips from the arts and entertainment bible "Time Out Chicago" on where to go and what to do (on a limited…

  10. Potentiation of ALA-PDT antitumor activity in mice using topical DMXAA

    NASA Astrophysics Data System (ADS)

    Marrero, Allison; Sunar, Ulas; Sands, Theresa; Oseroff, Allan; Bellnier, David

    2009-06-01

    Photodynamic treatment of subcutaneously implanted Colon 26 tumors in BALB/c mice using the aminolevulinic acid (ALA)-induced photosensitizer protoporphyrin IX (PpIX) was shown to be enhanced by the addition of the vascular disrupting agent 5,6-Dimethylxanthenone-4-acetic-acid (DMXAA; Novartis ASA404). DMXAA increases vascular permeability and decreases blood flow in both murine and human tumors. Sufficiently high parenteral DMXAA doses can lead to tumor collapse and necrosis. We have previously reported marked enhancement of antitumor activity when PDT, using either Photofrin or HPPH, is combined with low-dose intraperitoneal DMXAA. We now describe the first attempt to combine topically-applied DMXAA with PDT. For this, DMXAA was applied two hours before PpIX-activating light delivery. PDT with ALA-PDT alone (ALA 20%; 80 J/cm2 delivered at 75 mW/cm2) caused a 39% decrease in tumor volume compared to unirradiated controls. Addition of topical DMXAA to ALA-PDT resulted in a 74% reduction in tumor volume. Diffuse correlation spectroscopy (DCS), a non-invasive blood flow imaging method, is being used to understand the mechanism of this effect and to aid in the proper design of the therapy. For instance, our most recent DCS data suggests that the 2-hour interval between the DMXAA and light applications may not be optimum. This preliminary study suggests a potential role for topical DMXAA in combination with PDT for dermatologic tumors.

  11. Studying Online: Student Motivations and Experiences in ALA-Accredited LIS Programs

    ERIC Educational Resources Information Center

    Oguz, Fatih; Chu, Clara M.; Chow, Anthony S.

    2015-01-01

    This paper presents a large scale study of online MLIS students (n = 910), who completed at least one online course and were enrolled in 36 of the 58 ALA-accredited MLIS programs in Canada and the United States. The results indicate that the typical student is female, White, lives in an urban setting, and is in her mid-30s. Online students were…

  12. ALA Office for Intellectual Freedom: Who We Are and How We Help Librarians

    ERIC Educational Resources Information Center

    Pekoll, Kristin

    2015-01-01

    The American Library Association's (ALA's) Office for Intellectual Freedom (OIF) strives to educate librarians and the public about the nature and importance of intellectual freedom in libraries, and it will celebrate its fiftieth anniversary in 2017. Libraries are a forum for information and ideas (under the First Amendment), and librarians are…

  13. ALA Office for Intellectual Freedom: Who We Are and How We Help Librarians

    ERIC Educational Resources Information Center

    Pekoll, Kristin

    2015-01-01

    The American Library Association's (ALA's) Office for Intellectual Freedom (OIF) strives to educate librarians and the public about the nature and importance of intellectual freedom in libraries, and it will celebrate its fiftieth anniversary in 2017. Libraries are a forum for information and ideas (under the First Amendment), and librarians are…

  14. Pathogenic mitochondrial mt-tRNA(Ala) variants are uniquely associated with isolated myopathy.

    PubMed

    Lehmann, Diana; Schubert, Kathrin; Joshi, Pushpa R; Hardy, Steven A; Tuppen, Helen A L; Baty, Karen; Blakely, Emma L; Bamberg, Christian; Zierz, Stephan; Deschauer, Marcus; Taylor, Robert W

    2015-12-01

    Pathogenic mitochondrial DNA (mtDNA) point mutations are associated with a wide range of clinical phenotypes, often involving multiple organ systems. We report two patients with isolated myopathy owing to novel mt-tRNA(Ala) variants. Muscle biopsy revealed extensive histopathological findings including cytochrome c oxidase (COX)-deficient fibres. Pyrosequencing confirmed mtDNA heteroplasmy for both mutations (m.5631G>A and m.5610G>A) whilst single-muscle fibre segregation studies (revealing statistically significant higher mutation loads in COX-deficient fibres than in COX-positive fibres), hierarchical mutation segregation within patient tissues and decreased steady-state mt-tRNA(Ala) levels all provide compelling evidence of pathogenicity. Interestingly, both patients showed very high-mutation levels in all tissues, inferring that the threshold for impairment of oxidative phosphorylation, as evidenced by COX deficiency, appears to be extremely high for these mt-tRNA(Ala) variants. Previously described mt-tRNA(Ala) mutations are also associated with a pure myopathic phenotype and demonstrate very high mtDNA heteroplasmy thresholds, inferring at least some genotype:phenotype correlation for mutations within this particular mt-tRNA gene.

  15. Shifting with the Paradigm: LJ's Picks & Pans for ALA in Disneyland

    ERIC Educational Resources Information Center

    Berry, John N., III

    2008-01-01

    The feelings of librarians planning for the American Library Association (ALA) conference at Disneyland (aka Anaheim, California, June 26-July 2) range from moderate pleasure to dread. Some remember the joys and difficulties of Orlando, especially the exorbitant cab fares and mediocre restaurants. Others quail at screaming kids and tourists in…

  16. ALA-based fluorescent diagnosis of malignant oral lesions in the presence of bacterial porphyrin formation

    NASA Astrophysics Data System (ADS)

    Schleier, P.; Berndt, A.; Zinner, K.; Zenk, W.; Dietel, W.; Pfister, W.

    2006-02-01

    The aminolevulinic acid (5-ALA) -based fluorescence diagnosis has been found to be promising for an early detection and demarcation of superficial oral squamous cell carcinomas (OSCC). This method has previously demonstrated high sensitivity, however this clinical trial showed a specificity of approximately 62 %. This specificity was mainly restricted by tumor detection in the oral cavity in the presence of bacteria. After topical ALA application in the mouth of patients with previously diagnosed OSSC, red fluorescent areas were observed which did not correlate to confirm histological findings. Swabs and plaque samples were taken from 44 patients and cultivated microbiologically. Fluorescence was investigated (OMA-system) from 32 different bacteria strains found naturally in the oral cavity. After ALA incubation, 30 of 32 strains were found to synthesize fluorescent porphyrins, mainly Protoporphyrin IX. Also multiple fluorescent spectra were obtained having peak wavelengths of 636 nm and around 618 nm - 620 nm indicating synthesis of different porphyrins, such as the lipophylic Protoporphyrin IX (PpIX) and hydrophylic porphyrins (water soluble porphyrins, wsp). Of the 32 fluorescent bacterial strains, 18 produced wsp, often in combination with PpIX, and 5 produced solely wsp. These results clarify that ALA-based fluorescence diagnosis without consideration or suppression of bacteria fluorescence may lead to false-positive findings. It is necessary to suppress bacteria fluorescence with suitable antiseptics before starting the procedure. In this study, when specific antiseptic pre-treatment was performed bacterial associated fluorescence was significantly reduced.

  17. Optimization of Influencing Factors on Biomass Accumulation and 5-Aminolevulinic Acid (ALA) Yield in Rhodobacter sphaeroides Wastewater Treatment.

    PubMed

    Liu, Shuli; Li, Xiangkun; Zhang, Guangming; Zhang, Jie

    2015-11-01

    This study aimed to optimize four factors affecting biomass accumulation and 5-aminolevulinic acid (ALA) yield together with pollutants removal in Rhodobacter sphaeroides wastewater treatment. Results showed that it was feasible to produce biomass and ALA in R. sphaeroides wastewater treatment. Microaerobic, 1,000-3,000 lux, and pH 7.0 were optimal conditions for the highest ALA yield of 4.5 ± 0.5 mg/g-biomass. Under these conditions, COD removal and biomass production rate were 93.3 ± 0.9% and 31.8 ± 0.5 mg/l/h, respectively. In addition, trace elements Fe(2+), Mg(2+), Ni(2+), and Zn(2+) further improved the ALA yield, COD removal, and biomass production rate. Specifically, the highest ALA yield (12.5 ± 0.6 mg/g-biomass) was achieved with Fe(2+) addition.

  18. ALA-mediated photodynamic therapy of experimental malignant glioma in the BD-IX rat model

    NASA Astrophysics Data System (ADS)

    Hirschberg, Henry; Angell-Petersen, Even; Peng, Qian; Sun, Chung-Ho; Sorensen, Dag R.; Carper, Steven W.; Madsen, Steen J.

    2005-04-01

    Introduction: Failure of treatment for high grade gliomas is usually due to local recurrence at the site of surgical resec-tion indicating that a more aggressive form of local therapy could be of benefit. Photodynamic therapy (PDT) is a local form of treatment involving the administration of a tumor-localizing photosensitizing drug that is activated by light of a specific wavelength The results of in vitro experiments indicated that PDT, given at low fluence rates was substantially more effective at inhibiting glioma spheroid growth than short term high fluence rate regimes. This prompted the initia-tion of in vivo studies of low fluence rate 5-aminolevulinic acid (ALA) PDT in a rat glioma model. Methods:BT4C cell line tumors were established in the brains of inbred BD- IX rats. Eighteen days following tumor induction the animals were injected with 125 mg/kg ALA ip. and four hours later light treatment at various fluences and fluence rates were given after the introduction of an optical fiber. Tumor histology and animal survival were examined. Results: In vitro experiments verified that the cell line was sensitive to ALA PDT. Microfluorometry of frozen tissue sections showed that PpIX is produced with a greater than 20:1 tumor to normal tissue selectivity ratio four hours after ALA injection. Histological examination demonstrated neutrophil infiltration and tumor central necrosis in low fluence rate treated tumors. Conclusions: Low fluence rate long term ALA mediated PDT had a more pronounced effect on tumor histology than single shot short duration treatments at similar total fluence levels.

  19. Peroxisome proliferator-activated receptor alpha controls hepatic heme biosynthesis through ALAS1.

    PubMed

    Degenhardt, Tatjana; Väisänen, Sami; Rakhshandehroo, Maryam; Kersten, Sander; Carlberg, Carsten

    2009-05-01

    Heme is an essential prosthetic group of proteins involved in oxygen transport, energy metabolism and nitric oxide production. ALAS1 (5-aminolevulinate synthase) is the rate-limiting enzyme in heme synthesis in the liver and is highly regulated to adapt to the metabolic demand of the hepatocyte. In the present study, we describe human hepatic ALAS1 as a new direct target for the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha). In primary human hepatocytes and in HepG2 cells, PPARalpha agonists induced an increase in ALAS1 mRNA levels, which was abolished by PPARalpha silencing. These effects are mediated by two functional PPAR binding sites at positions -9 and -2.3 kb relative to the ALAS1 transcription start site. PPARalpha ligand treatment also up-regulated the mRNA levels of the genes ALAD (5-aminolevulinate dehydratase), UROS (uroporphyrinogen III synthase), UROD (uroporphyrinogen decarboxylase), CPOX (coproporphyrinogen oxidase) and PPOX (protoporphyrinogen oxidase) encoding for enzymes controlling further steps in heme biosynthesis. In HepG2 cells treated with PPARalpha agonists and in mouse liver upon fasting, the association of PPARalpha, its partner retinoid X receptor, PPARgamma co-activator 1alpha and activated RNA polymerase II with the transcription start site region of all six genes was increased, leading to higher levels of the metabolite heme. In conclusion, these data strongly support a role of PPARalpha in the regulation of human ALAS1 and of five additional genes of the pathway, consequently leading to increased heme synthesis.

  20. Influence of formulation factors on methyl-ALA-induced protoporphyrin IX accumulation in vivo.

    PubMed

    Donnelly, Ryan F; Juzenas, Petras; McCarron, Paul A; Ma, Li-Wei; Woolfson, A David; Moan, Johan

    2006-09-01

    Photodynamic therapy (PDT) is a medical treatment by which a combination of a photosensitising drug and visible light cause the destruction of selected cells. Thick lesions, such as nodular basal cell carcinomas (BCCs), or lesions with overlying keratinous debris, are reported as being difficult to eradicate using 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT). Such treatment failures have been attributed to the shallow penetration of water-soluble drugs like ALA. In addition, the current scarcity of sophisticated drug delivery research centered on PDT applications has meant that accurate comparison of similar clinical studies is difficult. This paper investigates, for the first time, novel drug delivery systems for controlled drug delivery of methyl-ALA (M-ALA). Pressure sensitive adhesive (PSA) and bioadhesive patches containing defined M-ALA loadings and a standard cream containing equivalent amounts of drug were applied to the skin of mice for defined periods of time and the fluorescence of the protoporphyrin IX (PpIX) induced measured over 24h. Of major importance, the PSA patches containing low drug loadings induced high PpIX levels, which were limited to the site of application, after only 1h applications. Such systems have the potential to improve selectivity of PpIX accumulation, increase simplicity of treatment and, due to the low drug loadings required, reduce costs of clinical PDT. PSA patches would be most suitable for application to areas of dry skin, while bioadhesive patches would be suitable for moist areas, such as the mouth or lower female reproductive tract and have been shown here to induce significant PpIX production at the site of application after 4h applications of patches containing high drug loadings.

  1. Characterization of the Ala62Pro polymorphic variant of human cytochrome P450 1A1 using recombinant protein expression

    SciTech Connect

    Lee, Seung Heon; Kang, Sukmo; Dong, Mi Sook; Park, Jung-Duck; Park, Jinseo; Rhee, Sangkee; Ryu, Doug-Young

    2015-06-15

    Cytochrome P450 (CYP) 1A1 is a heme-containing enzyme involved in detoxification of hydrophobic pollutants. Its Ala62Pro variant has been identified previously. Ala62 is located in α-helix A of CYP1A1. Residues such as Pro and Gly are α-helix breakers. In this study, the Ala62Pro variant was characterized using heterologous expression. E. coli expressing the Ala62Pro variant, and the purified variant protein, had lower CYP (i.e. holoenzyme) contents than their wild-type (WT) equivalents. The CYP variant from E. coli and mammalian cells exhibited lower 7-ethoxyresorufin O-dealkylation (EROD) and benzo[a]pyrene hydroxylation activities than the WT. Enhanced supplementation of a heme precursor during E. coli culture did not increase CYP content in E. coli expressing the variant, but did for the WT. As for Ala62Pro, E. coli expressing an Ala62Gly variant had a lower CYP content than the WT counterpart, but substitution of Ala62 with α-helix-compatible residues such as Ser and Val partially recovered the level of CYP produced. Microsomes from mammalian cells expressing Ala62Pro and Ala62Gly variants exhibited lower EROD activities than those expressing the WT or Ala62Val variant. A region harboring α-helix A has interactions with another region containing heme-interacting residues. Site-directed mutagenesis analyses suggest the importance of interactions between the two regions on holoenzyme expression. Together, these findings suggest that the Ala62Pro substitution leads to changes in protein characteristics and function of CYP1A1 via structural disturbance of the region where the residue is located. - Highlights: • Ala62 is located in α-helix A of the carcinogen-metabolizing enzyme CYP1A1. • Pro acts as an α-helix breaker. • A variant protein of CYP1A1, Ala62Pro, had lower heme content than the wild-type. • The variant of CYP1A1 had lower enzyme activities than the wild-type.

  2. Preclinical Development of a Subcutaneous ALAS1 RNAi Therapeutic for Treatment of Hepatic Porphyrias Using Circulating RNA Quantification

    PubMed Central

    Chan, Amy; Liebow, Abigail; Yasuda, Makiko; Gan, Lin; Racie, Tim; Maier, Martin; Kuchimanchi, Satya; Foster, Don; Milstein, Stuart; Charisse, Klaus; Sehgal, Alfica; Manoharan, Muthiah; Meyers, Rachel; Fitzgerald, Kevin; Simon, Amy; Desnick, Robert J; Querbes, William

    2015-01-01

    The acute hepatic porphyrias are caused by inherited enzymatic deficiencies in the heme biosynthesis pathway. Induction of the first enzyme 5-aminolevulinic acid synthase 1 (ALAS1) by triggers such as fasting or drug exposure can lead to accumulation of neurotoxic heme intermediates that cause disease symptoms. We have demonstrated that hepatic ALAS1 silencing using siRNA in a lipid nanoparticle effectively prevents and treats induced attacks in a mouse model of acute intermittent porphyria. Herein, we report the development of ALN-AS1, an investigational GalNAc-conjugated RNAi therapeutic targeting ALAS1. One challenge in advancing ALN-AS1 to patients is the inability to detect liver ALAS1 mRNA in the absence of liver biopsies. We here describe a less invasive circulating extracellular RNA detection assay to monitor RNAi drug activity in serum and urine. A striking correlation in ALAS1 mRNA was observed across liver, serum, and urine in both rodents and nonhuman primates (NHPs) following treatment with ALN-AS1. Moreover, in donor-matched human urine and serum, we demonstrate a notable correspondence in ALAS1 levels, minimal interday assay variability, low interpatient variability from serial sample collections, and the ability to distinguish between healthy volunteers and porphyria patients with induced ALAS1 levels. The collective data highlight the potential utility of this assay in the clinical development of ALN-AS1, and in broadening our understanding of acute hepatic porphyrias disease pathophysiology. PMID:26528940

  3. The Mode of Action of Cyclo(l-Ala-l-Pro) in Inhibiting Aflatoxin Production of Aspergillus flavus.

    PubMed

    Iimura, Kurin; Furukawa, Tomohiro; Yamamoto, Toshiyoshi; Negishi, Lumi; Suzuki, Michio; Sakuda, Shohei

    2017-07-12

    Cyclo(l-Ala-l-Pro) inhibits aflatoxin production in aflatoxigenic fungi without affecting fungal growth. The mode of action of cyclo(l-Ala-l-Pro) in inhibiting aflatoxin production of Aspergillus flavus was investigated. A glutathione S-transferase (GST) of the fungus, designated AfGST, was identified as a binding protein of cyclo(l-Ala-l-Pro) in an experiment performed using cyclo(l-Ala-l-Pro)-immobilized Sepharose beads. Cyclo(l-Ala-l-Pro) specifically bound to recombinant AfGST and inhibited its GST activity. Ethacrynic acid, a known GST inhibitor, inhibited the GST activity of recombinant AfGST and aflatoxin production of the fungus. Ethacrynic acid reduced the expression level of AflR, a key regulatory protein for aflatoxin production, similar to cyclo(l-Ala-l-Pro). These results suggest that cyclo(l-Ala-l-Pro) inhibits aflatoxin production by affecting GST function in A. flavus, and that AfGST inhibitors are possible candidates as selective aflatoxin production inhibitors.

  4. Refined molecular and crystal structure of silk I based on Ala-Gly and (Ala-Gly)(2)-Ser-Gly peptide sequence.

    PubMed

    Okuyama, K; Somashekar, R; Noguchi, K; Ichimura, S

    2001-10-15

    The molecular and crystal structure of one of the crystalline modifications of Bombyx mori, silk I, was determined by x-ray diffraction method. Cell dimensions are essentially the same as those found in the synthetic model peptide poly(L-Ala-Gly). The (straight phi, psi) values of L-Ala and Gly in the repeating unit are (-112 degrees, -6 degrees ), and (71 degrees, -99 degrees ) respectively, which are in the Bridge and the forth quadrant regions of the Ramachandran map, respectively. The observed molecular conformation in the present study has a "crank-shaft" or a S-shaped zigzag arrangement, leading to a remarkable agreement of observed and calculated structure amplitudes for both dipeptide and hexapeptide sequences, and has a reasonable hydrogen bond networks. Obtained (straight phi, psi) values are quite different from those reported by Lotz and Keith, even though overall appearances are quite similar to each other. In spite of intra- and intermolecular hydrogen-bond networks, silk I structure changes easily to the silk II by a mechanical deformation. This fragility may be due to the above peculiar crank-shaft conformation deduced from the alternating structure of alanine and glycine. Copyright 2001 John Wiley & Sons, Inc.

  5. N.m.r. study on conformation of Ac-Thr(alpha-GalNAc)-Ala-Ala-OMe as a model for mucin type glycoprotein.

    PubMed

    Mimura, Y; Inoue, Y; Maeji, N J; Chûjô, R

    1989-11-01

    This study report on the results of high resolution 1H n.m.r. investigations on Ac-Thr(alpha-GalNAc)-Ala-Ala-OMe 1 as a mucin type model glycopeptide of antifreeze glycoprotein (AFGP) in both dimethyl sulfoxide (DMSO) and H2O. The temperature dependence of amide proton chemical shifts strongly suggested the presence of the intramolecular hydrogen bond between the amide proton of GalNAc and the carbonyl oxygen of the Thr residues. Due to this bond, the orientation of the sugar residue of 1 appears to be fairly restricted relative to its peptide backbone. Despite the lack of the clear evidence for such intramolecular hydrogen bond in H2O, 1H coupling constant data suggested the structural similarity of 1 in DMSO and H2O, indicating the presence of the intramolecular hydrogen bond even in H2O, which may play an important role in determining the orientation of the sugar moiety with respect to the peptide backbone in glycoprotein.

  6. Prevalence of the Pro12Ala missense mutation in the PPARG2 gene in Kuwaiti patients with primary knee osteoarthritis.

    PubMed

    Al-Jarallah, Khaled F; Shehab, Diaa K; Haider, Mohammad Z

    2011-01-01

    Peroxisome proliferator-activated receptors (PPARs) play an important role in a number of cellular and metabolic functions. This study was carried out to determine the prevalence of a missense mutation (Pro12Ala) in the PPARG2 gene in Kuwaiti Arab patients with primary knee osteoarthritis (OA) and healthy controls with the aim of identifying a possible association. A prospective cross-sectional study carried out at three major teaching hospitals (referral centers) in the country over a one-year period. The prevalence of PPARG2 gene Pro12Ala missense mutation was determined in 104 Kuwaiti Arab patients with primary knee OA and 111 ethnically matched healthy controls. The prevalence of this Pro12Ala missense mutation was also determined in clinical subgroups of OA patients divided on the basis of age at onset, function and radiologic grading. The Pro-Pro genotype of the PPARG2 gene Pro12Ala missense mutation was detected in 95/104 (91.3%) cases compared to 111/111 (100%) in the control subjects. The heterozygous Pro-Ala genotype was detected in 9/104 (8.7%) of the OA patients, while it was not detected in any of the controls. The Ala-Ala genotype was not detected in any of the OA patients or the controls. No significant differences were detected in the PPARG2 gene Pro12Ala genotypes in the subgroups of patients classified on the basis of age at onset, functional assessment using Lequesne's functional index, and radiological grading using Kellgren-Lawrence (K-L) grading. This study found no significant association between the PPARG2 gene Pro12Ala missense mutation and knee OA. However, the presence of the Pro-Pro genotype of the PPARG2 gene mutation has a protective effect against development of OA.

  7. ALA Inhibits ABA-induced Stomatal Closure via Reducing H2O2 and Ca2+ Levels in Guard Cells

    PubMed Central

    An, Yuyan; Liu, Longbo; Chen, Linghui; Wang, Liangju

    2016-01-01

    5-Aminolevulinic acid (ALA), a newly proved natural plant growth regulator, is well known to improve plant photosynthesis under both normal and stressful conditions. However, its underlying mechanism remains largely unknown. Stomatal closure is one of the major limiting factors for photosynthesis and abscisic acid (ABA) is the most important hormone in provoking stomatal closing. Here, we showed that ALA significantly inhibited ABA-induced stomatal closure using wild-type and ALA-overproducing transgenic Arabidopsis (YHem1). We found that ALA decreased ABA-induced H2O2 and cytosolic Ca2+ accumulation in guard cells with stomatal bioassay, laser-scanning confocal microscopy and pharmacological methods. The inhibitory effect of ALA on ABA-induced stomatal closure was similar to that of AsA (an important reducing substrate for H2O2 removal), CAT (a H2O2-scavenging enzyme), DPI (an inhibitor of the H2O2-generating NADPH oxidase), EGTA (a Ca-chelating agent), and AlCl3 (an inhibitor of calcium channel). Furthermore, ALA inhibited exogenous H2O2- or Ca2+-induced stomatal closure. Taken together, we conclude that ALA inhibits ABA-induced stomatal closure via reducing H2O2, probably by scavenging, and Ca2+ levels in guard cells. Moreover, the inhibitive effect of ALA on ABA-induced stomatal closure was further confirmed in the whole plant. Finally, we demonstrated that ALA inhibits stomatal closing, but significantly improves plant drought tolerance. Our results provide valuable information for the promotion of plant production and development of a sustainable low-carbon society. PMID:27148309

  8. Electron paramagnetic resonance study of the nuclear spin dynamics in an AlAs quantum well

    NASA Astrophysics Data System (ADS)

    Shchepetilnikov, A. V.; Frolov, D. D.; Nefyodov, Yu. A.; Kukushkin, I. V.; Tiemann, L.; Reichl, C.; Dietsche, W.; Wegscheider, W.

    2016-12-01

    The nuclear spin dynamics in an asymmetrically doped 16-nm AlAs quantum well grown along the [001] direction has been studied experimentally using the time decay of the Overhauser shift of paramagnetic resonance of conduction electrons. The nonzero spin polarization of nuclei causing the initial observed Overhauser shift is due the relaxation of the nonequilibrium spin polarization of electrons into the nuclear subsystem near electron paramagnetic resonance owing to the hyperfine interaction. The measured relaxation time of nuclear spins near the unity filling factor is (530 ± 30) min at the temperature T = 0.5 K. This value exceeds the characteristic spin relaxation times of nuclei in GaAs/AlGaAs heterostructures by more than an order of magnitude. This fact indicates the decrease in the strength of the hyperfine interaction in the AlAs quantum well in comparison with GaAs/AlGaAs heterostructures.

  9. Endoscopic fluorescence of gastrointestinal neoplasia after sensitization with 5-aminolaevulinic acid (ALA) or Photofrin

    NASA Astrophysics Data System (ADS)

    Messmann, Helmut; Mlkvy, Peter; Montan, Sune; Wang-Nordman, Ingrid; Nilsson, Annika M.; Svanberg, Katarina; Svanberg, Sune; MacRobert, Alexander J.; Bown, Stephen G.

    1995-03-01

    Fluorescence after photosensitization has the potential to identify lesions not visible on conventional endoscopy. We assessed 12 patients at high risk of or with established GI cancers (u ulcerative colitis, 1 colon polyp, 2 familial polyposis with duodenal polyps, 2 early oesophageal cancers). Fluorescence images (excitation 390 nm) were recorded with endoscopic equipment and additional spot measurements (optical multichannel analyzer). Patients were given 10 - 60 mg/kg ALA orally or 2 mg/kg Photofrin i.v. 60 mg/kg ALA gave high levels of PP IX (proto-porphyrin IX) in all areas, but 10 - 15 mg/kg resulted in selectivity in macroscopically inflamed colon. Photofrin gave oesophageal tumors selectivity at 4 and 48 hours. Photofrin patients subsequently had PDT. Photobleaching was documented in 3. We conclude that these techniques have potential as `optical biopsy tools' and for screening for early neoplastic changes.

  10. Biotransformation of linoleic acid by Clavibacter sp. ALA2: heterocyclic and heterobicyclic fatty acids.

    PubMed

    Gardner, H W; Hou, C T; Weisleder, D; Brown, W

    2000-10-01

    Clavibacter sp. ALA2 transformed linoleic acid into a variety of oxylipins. In previous work, three novel fatty acids were identified, (9Z)-12, 13, 17-trihydroxy-9-octadecenoic acid and two tetrahydrofuran-(di)hydroxy fatty acids. In this report, we confirm the structures of the tetrahydrofuran-(di)hydroxy fatty acids by nuclear magnetic resonance as (9Z)-12-hydroxy-13,16-epoxy-9-octadecenoic acid and (9Z)-7,12-dihydroxy-13,16-epoxy-9-octadecenoic acid. Three other products of the biotransformation were identified as novel heterobicyclic fatty acids, (9Z)-12,17;13, 17-diepoxy-9-octadecenoic acid, (9Z)-7-hydroxy-12,17;13,17-diepoxy-9-octadecenoic acid, and (9Z)-12,17;13,17-diepoxy-16-hydroxy-9-octadecenoic acid. Thus, Clavibacter ALA2 effectively oxidized linoleic acid at C-7, -12, -13, -16, and/or -17.

  11. Photodynamic therapy (ALA-PDT) in the treatment of pathological states of the cornea

    NASA Astrophysics Data System (ADS)

    Switka-Wieclawska, Iwona; Kecik, Tadeusz; Kwasny, Miroslaw; Graczyk, Alfreda

    2003-10-01

    Each year an increasing amount of research is published on the use of photodynamic therapy in medicine. The most recent research has focused mostly on the use of photosensitizer called vertoporphyrin (Visudyne) is the treatment of subretinal neovascularization in age-related macular degeneration (AMD) or myopia, following a substantial amount of ophthalmology research mostly experimental on the application of the method in diagnosis and treatment of some eye tumors. In the Department of Ophthalmology of Polish Medical University in Warsaw, PDT was used as supplementary method in a selected group of patients with chronic virus ulcer of the cornea and keratopathies. During the treatment 5-aminolevulinic acid (5-ALA) was applied in ointment form as a photosensitizer activated with light wave of 633 nm. It appears, on the basis of the results obtained, that photodynamic therapy (ALA-PDT) may become in the future a valuable supplement to the methods being used at the present treating pathological states of the cornea.

  12. Rolled-Up Nanotech: Illumination-Controlled Hydrofluoric Acid Etching of AlAs Sacrificial Layers

    NASA Astrophysics Data System (ADS)

    Costescu, Ruxandra M.; Deneke, Christoph; Thurmer, Dominic J.; Schmidt, Oliver G.

    2009-12-01

    The effect of illumination on the hydrofluoric acid etching of AlAs sacrificial layers with systematically varied thicknesses in order to release and roll up InGaAs/GaAs bilayers was studied. For thicknesses of AlAs below 10 nm, there were two etching regimes for the area under illumination: one at low illumination intensities, in which the etching and releasing proceeds as expected and one at higher intensities in which the etching and any releasing are completely suppressed. The “etch suppression” area is well defined by the illumination spot, a feature that can be used to create heterogeneously etched regions with a high degree of control, shown here on patterned samples. Together with the studied self-limitation effect, the technique offers a way to determine the position of rolled-up micro- and nanotubes independently from the predefined lithographic pattern.

  13. Density limits of high temperature and multiple local droplet etching on AlAs

    NASA Astrophysics Data System (ADS)

    Kerbst, J.; Heyn, Ch.; Slobodskyy, T.; Hansen, W.

    2014-03-01

    The density of nanoholes created by self-assembled Al droplet etching of AlAs surfaces during molecular beam epitaxy is studied. We find a clear decrease of the hole density with increasing etching temperature T up to a threshold temperature T = 620 ° C. At T > 620 ° C, the hole density saturates at a minimum of 2 ×108cm-2. We attribute this saturation to a change of the AlAs surface reconstruction. On the other hand, at reduced T, hole densities up to 2 ×109cm-2 have been achieved. However, this hole density increase is accompanied by a reduction of the hole depth. To generate high density holes with larger depth suited for quantum dot fabrication, we have studied the effect of repeated etching steps.

  14. Scavengers modifying the phototoxicity induced by ALA-mediated photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Casas, Adriana; Perotti, Christian; Fukuda, Haydee; Batlle, Alcira

    2001-04-01

    The exogenously stimulated formation of intracellularly generated Protoporphyrin IX, a precursor of heme, is becoming one of the fastest developing areas in the field of Photodynamic Therapy (PDT). We have examined the degree of protection of several scavengers, aminoacids and compounds related to glutathione metabolism, to the photodamage induced by 5-aminolevulinic acid (ALA)-mediated PDT, employing the LM2 cell line, derived from a mammary murine adenocarcinoma. We have exposed the cells to different concentrations of the scavengers, 24 before PDT, during PDT, and 19 hr after treatment. We defined the protection grade (PG) as the ratio between cell survival after ALA-PDT treatment in the presence of the protector and cell survival after ALA-PDT treatment. We found that L-tryptophan (PG=8.3 at 2mM), N-acetyl-L-cysteine (PG= 7.9 at 30 mM), L-cysteine (PG=7.81 at 8mM), S-adenosyl-L-methionine (PG= 7.86 at 8mM), melatonin (PG=6.81 at 8mM) and glycine (PG=6.8 at 40 mM) are the best protectors to PDT damage, followed by L-methionine (PG=4.38 at 0.8 mM), mannitol (PG=2.32 at 2 mM) and reduced glutathione (PG=3.41 at 0.8 mM), whereas oxidized glutathione does not exert any protection. The implications of these results in the photodamage induced by ALA-PDT is discussed.

  15. The peroxisome proliferator-activated receptor-gamma2 Pro12Ala polymorphism.

    PubMed

    Stumvoll, Michael; Häring, Hans

    2002-08-01

    Peroxisome proliferator-activated receptor (PPAR)-gamma is a transcription factor with a key role in adipocyte differentiation. The Ala allele of the common Pro12Ala polymorphism in the isoform PPAR-gamma2 is associated with reduced risk for type 2 diabetes. The effect on the individual is weak, but because of a prevalence of >75% of the high-risk Pro allele, the population-attributable risk is enormous. The in vivo effects of the polymorphism are secondary to alterations in adipose tissue, where PPAR-gamma2 is predominantly expressed. Moderate reduction in transcriptional activity of PPAR-gamma as a result of the polymorphism modulates production and release of adipose-derived factors. Both decreased release of insulin-desensitizing free fatty acids, tumor necrosis factor-alpha, and resistin and increased release of the insulin-sensitizing hormone adiponectin result in secondary improvement of insulin sensitivity of glucose uptake and suppression of glucose production. The population effect of this polymorphism may be modulated by environmental or genetic factors such as obesity, ethnicity, ratio of unsaturated to saturated fatty acids, and genetic background. Once diabetes has developed, the protective effect of the Ala allele may be lost, since increased vascular complications and more pronounced beta-cell dysfunction have been reported. These observations, however, are currently unexplained. In conclusion, the Pro12Ala polymorphism in PPAR-gamma2 represents the first genetic variant with a broad impact on the risk of common type 2 diabetes. The precise understanding of its mechanism may lead to novel diagnostic, preventive, and therapeutic approaches for improving the management of type 2 diabetes.

  16. Feasibility of Raman spectroscopy in vitro after 5-ALA-based fluorescence diagnosis in the bladder

    NASA Astrophysics Data System (ADS)

    Grimbergen, M. C. M.; van Swol, C. F. P.; van Moorselaar, R. J. A.; Mahadevan-Jansen, A.,; Stone, N.

    2006-02-01

    Photodynamic diagnosis (PDD) has become popular in bladder cancer detection. Several studies have however shown an increased false positive biopsies rate under PDD guidance compared to conventional cystoscopy. Raman spectroscopy is an optical technique that utilizes molecular specific, inelastic scattering of light photons to interrogate biological tissues, which can successfully differentiate epithelial neoplasia from normal tissue and inflammations in vitro. This investigation was performed to show the feasibility of NIR Raman spectroscopy in vitro on biopsies obtained under guidance of 5-ALA induced PPIX fluorescence imaging. Raman spectra of a PPIX solution was measured to obtain a characteristic signature for the photosensitzer without contributions from tissue constituents. Biopsies were obtained from patients with known bladder cancer instilled with 50ml, 5mg 5-ALA two hours prior to trans-urethral resection of tumor (TURT). Additional biopsies were obtained at a fluorescent and non-fluorescent area, snap-frozen in liquid nitrogen and stored at -80 °C. Each biopsy was thawed before measurements (10sec integration time) with a confocal Raman system (Renishaw Gloucestershire, UK). The 830 nm excitation (300mW) source is focused on the tissue by a 20X ultra-long-working-distance objective. Differences in fluorescence background between the two groups were removed by means of a special developed fluorescence subtraction algorithm. Raman spectra from ALA biopsies showed different fluorescence background which can be effectively removed by a fluorescence subtraction algorithm. This investigation shows that the interaction of the ALA induced PPIX with Raman spectroscopy in bladder samples. Combination of these techniques in-vivo may lead to a viable method of optical biopsies in bladder cancer detection.

  17. Nuclear transcription factors: a new approach to enhancing cellular responses to ALA-mediated photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Maytin, Edward V.; Anand, Sanjay; Sato, Nobuyuki; Moore, Brian; Mack, Judith; Gasbarre, Christopher; Keevey, Samantha; Ortel, Bernhard; Sinha, Alok; Khachemoune, Amor

    2006-02-01

    Photodynamic therapy (PDT) using aminolevulinic acid (ALA) relies upon the uptake of ALA into cancer cells, where it is converted into a porphyrin intermediate, protoporphyrin IX (PpIX) that is highly photosensitizing. For large or resistant tumors, however, ALA/PDT is often not completely effective due to inadequate PpIX levels. Therefore, new approaches to enhance the intracellular production of PpIX are sought. Here, we describe a general approach to improve intracellular PpIX accumulation via manipulations that increase the expression of an enzyme, coproporphyrinogen oxidase (CPO), that is rate-determining for PpIX production. We show that nuclear hormones that promote terminal differentiation, e.g. vitamin D or androgens, can also increase the accumulation of PpIX and the amount of killing of the target cells upon exposure to light. These hormones bind to intracellular hormone receptors that translocate to the nucleus, where they act as transcription factors to increase the expression of target genes. We have found that several other transcription factors associated with terminal differentiation, including members of the CCAAT enhancer binding (C/EBP) family, and a homeobox protein named Hoxb13, are also capable of enhancing PpIX accumulation. These latter transcription factors appear to interact directly with the CPO gene promoter, resulting in enhanced CPO transcriptional activity. Our data in several different cell systems, including epithelial cells of the skin and prostate cancer cells, indicate that enhancement of CPO expression and PpIX accumulation represents a viable new approach toward improving the efficacy of ALA/PDT.

  18. ALA16VAL-MnSOD gene polymorphism and stroke: Association with dyslipidemia and glucose levels.

    PubMed

    Flores, Ariane Ethur; Pascotini, Eduardo Tanuri; Kegler, Aline; Gabbi, Patricia; Bochi, Guilherme Vargas; Barbisan, Fernanda; Duarte, Thiago; Prado, Ana Lucia Cervi; Duarte, Marta M M F; da Cruz, Ivana B M; Moresco, Rafael Noal; Santos, Adair Roberto Soares; Bresciani, Guilherme; Royes, Luiz Fernando Freire; Fighera, Michele Rechia

    2017-09-05

    Stroke risk has been associated to the progression of carotid plaques due to high glucose levels and lipid accumulation, which are greatly associated to cerebral injury, brain oxidative stress, and apoptosis. The ALA16VAL-MnSOD gene single nucleotide polymorphism (SNP) has shown to modulate risk factors of several metabolic and vascular diseases, such as blood glucose (GLU) and lipid levels. However, the association of these factors in stroke patients has not been studied to date. Thus, we evaluated the influence of the Ala16Val-MnSOD SNP on lipid profile, GLU levels, oxidative and DNA damage of 44 patients in a late phase of stroke (>6months). The statistical analysis showed a greater proportion of VV carries in stroke patients. The results also indicated that stroke patients had higher cholesterol (CHO) and GLU levels when compared to healthy counterparts. Interestingly, V allele carriers with stroke showed higher levels of CHO and GLU when compared to AA stroke and healthy counterparts. Our findings suggest that oxidative stress markers are still increased even after 6 months of cerebral injury. Furthermore, we propose that the Ala16Val-MnSOD SNPs may contribute to hypercholesterolemia and higher GLU levels, increasing the risk to neurovascular events that may lead to stroke. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Establishment of treatment parameters for ALA-PDT of plaque psoriasis

    NASA Astrophysics Data System (ADS)

    Stringer, Mark R.; Robinson, Dominic J.; Collins, P.

    1996-12-01

    We report an investigation into the use of photodynamic therapy (PDT), following topically applied 5-aminolaevulinic acid (ALA), as a treatment for plaque psoriasis. Treatment was performed 4 hours post-ALA, using white light doses of 2 - 16 J cm-2 delivered at 10 - 40 mW cm-2. The fluorescence emission of protoporphyrin IX was used as an indicator of the relative concentration of photosensitizer within each plaque before, during, and after therapy. Results show that the rate of sensitizer photo- oxidation is proportional to both pre-treatment fluorescence intensity and surface irradiance, consistent with a rate- equation analysis. A correlation of fluorescence measurements with clinical response of plaques indicates that the effectiveness of PDT is dominated by the level of PpIX at the onset of treatment, and is much less dependent upon light dose. Using these findings we have established a PDT treatment protocol that involves the delivery of 8 J cm-2 of white light, at a rate of 15 mW cm-2. The possibility of ALA-PDT being established as the therapy of choice is discussed.

  20. Ab-initio study of structural and electronic properties of AlAs

    NASA Astrophysics Data System (ADS)

    Munjal, N.; Sharma, G.; Vyas, V.; Joshi, K. B.; Sharma, B. K.

    2012-08-01

    The structural properties, i.e. equilibrium lattice constant, transition pressure, bulk modulus and its pressure derivatives, together with electronic properties, i.e. energy bands, Compton profile and autocorrelation function, of AlAs are presented in this work. The linear combination of atomic orbitals (LCAO) method of the CRYSTAL code was applied considering the Perdew-Burke-Ernzerhof correlation energy functional and Becke's ansatz for the exchange. The total energy of AlAs as a function of primitive cell volume has also been calculated for the zincblende (B3), nickel arsenide (B8), sodium chloride (B1) and cesium chloride (B2) phases. Structural parameters of the B3, B8, B1 and B2 phases are determined. The calculated structural parameters are found to be in good agreement with the results of previous investigations. The spherically averaged theoretical values of Compton profile are in good agreement with an earlier measurement. The LCAO calculation shows an indirect band gap of 1.85 eV, in reasonable agreement with earlier data. On the basis of the equal-valence-electron-density Compton profile, it is found that AlAs is more ionic compared to AlSb.

  1. Characterization of a TK6-Bcl-xL gly-159-ala Human Lymphoblast Clone

    SciTech Connect

    Chyall, L.: Gauny, S.; Kronenberg, A.

    2006-01-01

    TK6 cells are a well-characterized human B-lymphoblast cell line derived from WIL-2 cells. A derivative of the TK6 cell line that was stably transfected to express a mutated form of the anti-apoptotic protein Bcl-xL (TK6-Bcl-xL gly-159- ala clone #38) is compared with the parent cell line. Four parameters were evaluated for each cell line: growth under normal conditions, plating efficiency, and frequency of spontaneous mutation to 6‑thioguanine resistance (hypoxanthine phosphoribosyl transferase locus) or trifluorothymidine resistance (thymidine kinase locus). We conclude that the mutated Bcl-xL protein did not affect growth under normal conditions, plating efficiency or spontaneous mutation frequencies at the thymidine kinase (TK) locus. Results at the hypoxanthine phosphoribosyl transferase (HPRT) locus were inconclusive. A mutant fraction for TK6‑Bcl-xL gly-159-ala clone #38 cells exposed to 150cGy of 160kVp x-rays was also calculated. Exposure to x-irradiation increased the mutant fraction of TK6‑Bcl-xL gly-159-ala clone #38 cells.

  2. Laser biospectroscopy and 5-ALA fluorescence navigation as a helpful tool in the meningioma resection.

    PubMed

    Potapov, A A; Goryaynov, S A; Okhlopkov, V A; Shishkina, L V; Loschenov, V B; Savelieva, T A; Golbin, D A; Chumakova, A P; Goldberg, M F; Varyukhina, M D; Spallone, A

    2016-07-01

    5-aminolevulinic acid (5-ALA) is a natural precursor of protoporphyrin IX (PP IX), which possesses fluorescent properties and is more intensively accumulated in tumor cells than in normal tissue. Therefore, the use of 5-ALA in the surgical treatment of intracranial tumors, particularly gliomas, has gained popularity in the last years, whereas its use in other intracranial pathological entities including meningiomas has been reported occasionally. This study describes a series of 28 patients with intracranial meningiomas, who were administered 5-ALA for a better visualization of tumor boundaries. Twelve patients underwent also laser spectroscopic analysis in order to confirm the visual impression of tumor tissue visualization. Bone infiltration was readily demonstrated. In one case, the tumor recurrence could have been prevented by removal of a tumor remnant, which would possibly have been better recognized if spectroscopic analysis had been used. Fluorescent navigation (FN) is a useful method for maximizing the radicality of meningioma surgery, particularly if the tumor infiltrates the bone, the skull base, and/or the surrounding structures.

  3. Challenges for Community-Based Forest Management in the KoloAla Site Manompana

    NASA Astrophysics Data System (ADS)

    Urech, Zora Lea; Sorg, Jean-Pierre; Felber, Hans Rudolph

    2013-03-01

    Following the IUCN 5th World Congress on Protected Areas in 2003, the then-President of Madagascar decided to increase the area of Madagascar's protected areas from 1.7 to 6 million ha. To combine the aims of protection and timber production, a new concept was developed through the establishment of community-based forest management (CBFM) sites, called KoloAla. However, experience shows that similar management transfers to communities in Madagascar have only been successful in a very few cases. We aimed to explore the success to be expected of this new approach in the particular case of the Manompana corridor at Madagascar's eastern coast. In a first step, the readiness of the corridor's resource users for CBFM has been analysed according to the seven resource users' attributes developed by Ostrom that predict an effective self-organized resource management. In a second step, we explored how KoloAla addresses known challenges of Madagascar's CBFM. Analyses lead in a rather sober conclusion. Although KoloAla attempts to address the goals of poverty alleviation, biodiversity conservation and timber production under a single umbrella, it does so in a rather non-innovative way. Challenges with regard to the state's environmental governance, agricultural inefficiency and thus deforestation remain unsolved.

  4. Structural and morphological features of ultrathin epitaxial InSb films in AlAs matrix

    NASA Astrophysics Data System (ADS)

    Kolotovkina, D. A.; Gutakovskii, A. K.

    2016-11-01

    This work presents results of the investigation of structural and morphological features of epitaxial InSb layers in the AlAs matrix. Our research group used transmission electron microscopy (TEM). The specimens were grown by molecular beam epitaxy and prepared in the cross section (110) and plan view foils (100). We found a formation of the embedded epitaxial layer of solid solution InxAl1-xSbyAs1-y in the AlAs matrix during precipitation of In and Sb on the AlAs surface. The embedded layer had continuous area (wetting layer) and islands. The study revealed two types of islands in the epitaxial layer the first having coherent interfacing with the matrix lattice and the second a relaxed island. We estimated concentration of In, Sb in the solid solution by the indirect method. We used the method of geometric phase to analyze the distribution of misfit dislocation cores on the interface. Every misfit dislocation was formed by two close 600-dislocations with the Burgers vectors like a /2 <110>. The sum Burgers vector of the dislocation pair was in the plane of the interface.

  5. Bilateral nasal ala reconstruction of the cocaine-injured nose with 2 free reverse-flow helical rim flaps.

    PubMed

    Castello, Jose R; Taglialatela Scafati, Salvatore; Sánchez, Olaya

    2014-09-01

    Cocaine abuse can lead to nasal deformity because of local ischemia and subsequent fibrosis. Reconstruction can be challenging. We present a case of bilateral microsurgical nasal ala reconstruction with 2 reverse-flow helical rim flap.

  6. Selective gastrointestinal uptake of ALA and its benefits for laserlight-induced fluorescence diagnostics (LIFD) and photodynamic therapy (PDT)

    NASA Astrophysics Data System (ADS)

    Pressmar, Jochen; Stern, Josef; Boehm, J.; Kohl, B.; Gahlen, Johannes

    1997-12-01

    LIFD and PDT are based on the selective uptake of photosensitizers resp. the selective metabolism of their precursors in malignant tissue. Excitation with laserlight results in fluorescence or phototoxic reactions which can be used for the detection or destruction of colorectal carcinoma and dysplasia. General photosensibilization resulting in an increased photosensitivity of the whole body represents the main side and necessitates avoidance of daylight for days up to weeks. Local application of (delta) - aminolevulinic acid (ALA) may reduce systemic uptake. Rats with DMH induced colorectal cancer were photosensitized for LIFD by oral, intravenous or local application of ALA. Urine concentrations of ALA and porphobilinogen (PBG) representing systemic photosensibilization were determined by two-column chromatography. Local colon application of ALA not only increases the quality of LIFD of colorectal cancer, it also provokes three times lower concentrations of PBG in comparison to oral or intravenous administration and reduces in consequence general photosensibilization.

  7. Immobilization of ALA-Zn(II) Coordination Polymer Pro-photosensitizers on Magnetite Colloidal Supraparticles for Target Photodynamic Therapy of Bladder Cancer.

    PubMed

    Tan, Jing; Sun, Chuanyu; Xu, Ke; Wang, Changchun; Guo, Jia

    2015-12-16

    5-Aminolevulinic acid (ALA) is a widely used photodynamic therapy (PDT) prodrug in the clinic. It can be metalized to the photosensitizer PpIX, which produces toxic singlet oxygen to kill cancer cells upon visible light irradiation. Herein, a core/shell-structured vehicle is designed to comprise magnetite colloidal supraparticles (MCSPs) as cores and ALA-Zn(II) coordination polymers as shells (Fe3O4@ALA-Zn(II) ) for target pro-photosensitizer delivery. The coordination polymers with 2D layered structures are locally deposited on the MCSPs by the complexation of the ALA and Zn(II) ions, and are readily controlled by varying the feed precursors and reaction temperatures. The maximum conjugated ALA amount is up to 17%. The Fe3O4@ALA-Zn(II) microspheres exhibit pH-sensitive release of ALA in acidic environment and rapid magnetic responsiveness. Cytotoxicity results demonstrate that Fe3O4@ALA-Zn(II) shows a significant inhibitory effect to T24 cells and is nontoxic to 293T normal cells as exposed to the 630 nm visible light for a very short time, which may due to the selective accumulation of ALA-induced PpIX in T24 cancer cells. Compared to the ALA used alone, the coordination polymer form is more efficient because of the bioactivity of incorporated Zn ions despite underlying the same apoptosis mechanism as ALA agent. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Association of peroxisome proliferator-activated receptor γ Pro12Ala gene polymorphism with type 2 diabetic nephropathy risk in Caucasian population.

    PubMed

    Zhou, Tian-Biao; Guo, Xue-Feng; Yin, Sheng-Sheng

    2014-06-01

    Association of peroxisome proliferator-activated receptor gamma (PPARγ) Pro12Ala gene polymorphism with type 2 diabetic nephropathy (T2DN) risk in Caucasians is still not clear. This investigation was conducted to assess if there was an association between the PPARγ Pro12Ala gene polymorphism and T2DN risk in Caucasians using meta-analysis. The relevant literatures were identified from PubMed, and Cochrane Library on 10 October 2013, and eligible studies were included and synthesized. Six reports including eight studies were recruited into this meta-analysis for the association of the PPARγ Pro12Ala gene polymorphism with T2DN risk in Caucasians. The Pro/Pro genotype was shown to be associated with T2DN risk in Caucasians. However, the Ala/Ala genotype and Ala allele were not associated with T2DN risk in Caucasians. In the sensitivity analysis, according to the control source from hospital, the control source from population, the genotyping methods using PCR-RFLP, Taqman, sample size of case <100, the association of the PPARγ Pro12Ala gene polymorphism with T2DN risk was similar to those in non-sensitivity analysis. In conclusion, the PPARγ Pro/Pro genotype was associated with T2DN risk in Caucasians, but the Ala/Ala genotype and Ala allele not. However, additional studies are required to firmly establish a correlation between the PPARγ Pro12Ala gene polymorphism and T2DN risk in Caucasians.

  9. Delta-aminolevulinic acid dehydratase (ALAD) polymorphism in lead exposed Bangladeshi children and its effect on urinary aminolevulinic acid (ALA)

    SciTech Connect

    Tasmin, Saira; Furusawa, Hana; Ahmad, Sk. Akhtar; Watanabe, Chiho

    2015-01-15

    Background and objective: Lead has long been recognized as a harmful environmental pollutant. People in developing countries like Bangladesh still have a higher risk of lead exposure. Previous research has suggested that the delta-aminolevulinic acid dehydratase (ALAD) genotype can modify lead toxicity and individual susceptibility. As children are more susceptible to lead-induced toxicity, this study investigated whether the ALAD genotype influenced urinary excretion of delta-aminolevulinic acid (U-ALA) among children exposed to environmental lead in Bangladesh. Methods: Subjects were elementary schoolchildren from a semi-urban industrialized area in Bangladesh. A total of 222 children were studied. Blood and urine were collected to determine ALAD genotypes, blood lead levels and urinary aminolevulinic acid (U-ALA). Results: The mean BPb level was 9.7 µg/dl for the study children. BPb was significantly positively correlated with hemoglobin (p<0.01). In total, allele frequency for ALAD 1 and 2 was 0.83 and 0.17 respectively. The mean U-ALA concentration was lower in ALAD1-2/2-2 carriers than ALAD1-1 carriers for boys (p=0.001). But for girls, U-ALA did not differ significantly by genotype (p=0.26). When U-ALA was compared by genotype at the same exposure level in a multiple linear regression analysis, boys who were ALAD1-2/2-2 carriers still had a lower level of U-ALA compared to ALAD1-1carriers. Conclusion: This study provides information about the influence of ALAD polymorphism and its association with U-ALA in Bangladeshi children. Our results indicate that the ALAD1-2/2-2 genotype may have a protective effect in terms of U-ALA for environmentally lead exposed boys. - Highlights: • High blood lead level for the environmentally exposed schoolchildren. • BPb was significantly correlated with U-ALA and Hb. • Effect of ALAD genotype on U-ALA is differed by sex. • Lower U-ALA in ALAD2 than ALAD1 carriers only for boys at same exposure.

  10. ALA-PDT of the normal rat esophagus: efficiency and safety largely depends on the timing of illumination

    NASA Astrophysics Data System (ADS)

    van den Boogert, Jolanda; de Bruin, Ron W. F.; van Staveren, Hugo J.; Siersema, Peter D.; van Hillegersberg, Richard

    1999-02-01

    Photodynamic therapy (PDT) is an experimental treatment modality for (pre)malignant oesophageal lesions. 5- Aminolevulinic acid (ALA)-induced, protoporphyrin IX (PpIX)- mediated photo-sensitization could be very useful as ALA- induced porphrin accumulation selectively occurs in the oesophageal epithelium. The present study aimed to optimize the time between illumination and the administration of ALA. 200 mg/kg ALA was given orally to 24 rats (allocated to 6 groups of 4 animals each). Four animals served as controls and received phosphate buffered saline orally. The animals were illuminated at various time-points (either 1, 2, 3, 4, 6, or 12 hours) after ALA administration. Illumination was performed with a cylindrical diffuser placed in a balloon catheter. The device was originally made for percutaneous transluminal coronary angioplasty and consisted of a semi-flexible catheter and an inflatable cylindric optically clear balloon. The diffuser was placed centrally in the catheter. The same illumination parameters (633 nm, 25 J radiant energy/cm diffuser, power output 100 mW/cm diffuser) were used for each animal. During illumination, fluorescence measurements and light dosimetry were performed. The animals were sacrificed at 48 hours after PDT for histological assessment. Highest PpIX fluorescence was found at 2, 3, and 4 hours after ALA administration. Dosimetric measurements showed a 2 - 3 times higher in vivo fluence rate compared to the estimated fluence rate. Histology at 48 hours after PDT showed diffuse epithelial damage at the laser site only in rats illuminated at 2 hours after ALA administration. Illumination at 3, 4, and 6 hours after ALA administration resulted in diffuse epithelial damage in only one of four rats. In none of the rats illuminated at 1 and 12 hours after administration of ALA epithelial damage was found. These results show that illumination at 2 hours after oral ALA administration provides an efficient and safe scheme for ALA-PDT in the

  11. Role of 5-aminolevulinic acid (ALA) on active oxygen-scavenging system in NaCl-treated spinach (Spinacia oleracea).

    PubMed

    Nishihara, Eiji; Kondo, Kensuke; Parvez, Mohammad Masud; Takahashi, Kuniaki; Watanabe, Keitaro; Tanaka, Kiyoshi

    2003-09-01

    ALA is a key precursor in the biosynthesis of porphyrins such as chlorophyll and heme, and was found to induce temporary elevations in the photosynthesis rate, APX, and CAT; furthermore, treatment with ALA at a low concentration might be correlated to the increase of NaCl tolerance of spinach plants. The photosynthetic rate and the levels of active oxygen-scavenging system in the 3rd leaf of spinach (Spinacia oleracea) plants grown by foliar treatment with 0, 0.18, 0.60 and 1.80 mmol/L 5-aminolevulinic acid under 50 and 100 mmol/L NaCl were analyzed. Plants treated with 0.60 and 1.80 mmol/L ALA showed significant increases in the photosynthetic rate at 50 and 100 mmol/L NaCl, while that of 0.18 mmol/L ALA did not show any changes at 50 mmol/L NaCl and a gradual decrease at 100 mmol/L NaCl. In contrast, the rate with 0 mmol/L ALA showed reduction at both concentrations of NaCl. The increase of hydrogen peroxide content by treatment with 0.60 and 1.80 mmol/L ALA were more controlled than that of 0 mmol/L ALA under both NaCl conditions. These ALA-treated spinach leaves also exhibited a lower oxidized/reduced ascorbate acid ratio and a higher reduced/oxidized glutathione ratio than the 0 mmol/L-treated spinach leaves when grown at both NaCl conditions. With regard to the antioxidant enzyme activities in the leaves, ascorbate peroxidase, catalase, and glutathione reductase activities were enhanced remarkably, most notably at day 3, by treatment with 0.60 and 1.80 mmol/L ALA under both NaCl conditions in comparison to that of 0 and 0.18 mmol/L ALA. These data indicate that the protection against oxidative damage by higher levels of antioxidants and enzyme activities, and by a more active ascorbate-glutathione cycle related to the increase of the photosynthesis rate, could be involved in the increased salt tolerance observed in spinach by treatment with 0.60 to 1.80 mmol/L ALA with NaCl.

  12. 5-ALA Fluorescence in Native Pituitary Adenoma Cell Lines: Resection Control and Basis for Photodynamic Therapy (PDT)?

    PubMed Central

    Poeschke, Stephan; Greve, Burkhard; Prevedello, Daniel; Santacroce, Antonio; Stummer, Walter; Senner, Volker

    2016-01-01

    Objective: Pituitary adenomas (PA), especially invasive ones, are often not completely resectable. Usage of 5-aminolevulinic acid (5-ALA) for fluorescence guided surgery could improve the rate of total resection and, additionally, open the doors for photodynamic therapy (PDT) in case of unresectable or partially resected PAs. The aim of this study was to investigate the uptake of 5-ALA and the effect of 5-ALA based PDT in cell lines. Methods: GH3 and AtT-20 cell lines were incubated with different concentrations of 5-ALA, protoporphyrin IX (PPIX) fluorescence was measured by flow cytometry and fluorescencespectrometry. WST-1 assays were performed to determine the surviving fraction of cells after PDT. PPIX fluorescence intensities and PDT effect of the pituitary adenoma cells were compared to U373MG, a well-known glioblastoma cell line. Results: Both cell lines showed a 5-ALA dependent intracellular PPIX fluorescence. Significant differences after 24hrs of incubation were observed in AtT-20 cells in comparison to GH3. Regardless of the incubation or metabolism time, there was a proliferation inhibiting effect after PDT, with no statistical significance. Conclusion: Since GH3 cells showed a heterogenous uptake of 5-ALA in the flow cytometry profile, but not constantly high concentrations they might have a 5-ALA efflux mechanism, which still needs to be determined. In the case of AtT-20, the cells might need a longer time for the uptake due to their size or slow metabolism. We showed that the different cell lines have different uptake and metabolism mechanisms, which needs to be further investigated. The general uptake of 5-ALA allows the possibility of resection control and PDT for pituitary adenomas. But, the role of PDT for unresectable pituitary adenomas deserves further investigations. PMID:27583461

  13. Delta-aminolevulinic acid dehydratase (ALAD) polymorphism in lead exposed Bangladeshi children and its effect on urinary aminolevulinic acid (ALA).

    PubMed

    Tasmin, Saira; Furusawa, Hana; Ahmad, Sk Akhtar; Faruquee, M H; Watanabe, Chiho

    2015-01-01

    Lead has long been recognized as a harmful environmental pollutant. People in developing countries like Bangladesh still have a higher risk of lead exposure. Previous research has suggested that the delta-aminolevulinic acid dehydratase (ALAD) genotype can modify lead toxicity and individual susceptibility. As children are more susceptible to lead-induced toxicity, this study investigated whether the ALAD genotype influenced urinary excretion of delta-aminolevulinic acid (U-ALA) among children exposed to environmental lead in Bangladesh. Subjects were elementary schoolchildren from a semi-urban industrialized area in Bangladesh. A total of 222 children were studied. Blood and urine were collected to determine ALAD genotypes, blood lead levels and urinary aminolevulinic acid (U-ALA). The mean BPb level was 9.7 µg/dl for the study children. BPb was significantly positively correlated with hemoglobin (p<0.01). In total, allele frequency for ALAD 1 and 2 was 0.83 and 0.17 respectively. The mean U-ALA concentration was lower in ALAD1-2/2-2 carriers than ALAD1-1 carriers for boys (p=0.001). But for girls, U-ALA did not differ significantly by genotype (p=0.26). When U-ALA was compared by genotype at the same exposure level in a multiple linear regression analysis, boys who were ALAD1-2/2-2 carriers still had a lower level of U-ALA compared to ALAD1-1 carriers. This study provides information about the influence of ALAD polymorphism and its association with U-ALA in Bangladeshi children. Our results indicate that the ALAD1-2/2-2 genotype may have a protective effect in terms of U-ALA for environmentally lead exposed boys. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. The Association between RAD23B Ala249Val Polymorphism and Cancer Susceptibility: Evidence from a Meta-Analysis

    PubMed Central

    Ying, Xiaojiang; Song, Junmin; Zhang, Ruoxin; Li, Zhen; Chen, Hongliang; Ye, Pingjiang; Shen, Yi; Pan, Weihuo; Chen, Zhiliang

    2014-01-01

    Background A number of studies have investigated associations of genetic variation in RAD23B Ala249Val (rs1805329 C>T) with cancer susceptibility; however, the findings are inconsistent. We performed a meta-analysis to acquire a more precise estimation of the relationship. Method We searched literatures from PubMed, Embase and Web of Science. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the association between Ala249Val polymorphism and cancer risk. Results A total of 23 studies consisting of 10837 cases and 13971 controls were included in this meta-analysis. Overall, no significant associations were found between RAD23B Ala249Val polymorphism and cancer risk (Val/Val vs. Ala/Ala: OR = 0.97, 95% CI = 0.75–1.25; Ala/Val vs. Ala/Ala: OR = 1.08, 95% CI = 0.96–1.22; recessive model: OR = 0.93, 95% CI = 0.76–1.14 and dominant model: OR = 1.07, 95% CI = 0.94–1.20). We did not find any significant associations in the further stratification analyses by cancer type, ethnicity and source of control. Conclusions Despite some limitations, this meta-analysis indicates that it is unlikely that the RAD23B 249Val/Val polymorphism may contribute to the individual susceptibility to cancer risk. However, further advanced designed studies with larger sample size and different ethnicities should be conducted to confirm our results. PMID:24643114

  15. Pro12Ala polymorphism of the peroxisome proliferator-activated receptor γ2 in patients with fatty liver diseases

    PubMed Central

    Rey, Johannes W; Noetel, Andrea; Hardt, Aline; Canbay, Ali; Alakus, Hakan; zur Hausen, Axel; Dienes, Hans Peter; Drebber, Uta; Odenthal, Margarete

    2010-01-01

    AIM: To test the occurrence of the Pro12Ala mutation of the peroxisome proliferator-activated receptor-γ (PPARγ)2-gene in patients with non-alcoholic fatty liver disease (NAFLD) or alcoholic fatty liver disease (AFLD). METHODS: DNA from a total of 622 specimens including 259 blood samples of healthy blood donors and 363 histologically categorized liver biopsies of patients with NAFLD (n = 263) and AFLD (n = 100) were analyzed by Real-time polymerase chain reaction using allele-specific probes. RESULTS: In the NAFLD and the AFLD collective, 3% of the patients showed homozygous occurrence of the Ala12 PPARγ2-allele, differing from only 1.5% cases in the healthy population. In NAFLD patients, a high incidence of the Ala12 mutant was not associated with the progression of fatty liver disease. However, we observed a significantly higher risk (odds ratio = 2.50, CI: 1.05-5.90, P = 0.028) in AFLD patients carrying the mutated Ala12 allele to develop inflammatory alterations. The linkage of the malfunctioning Ala12-positive PPARγ2 isoform to an increased risk in patients with AFLD to develop severe steatohepatitis and fibrosis indicates a more prominent anti-inflammatory impact of PPARγ2 in progression of AFLD than of NAFLD. CONCLUSION: In AFLD patients, the Pro12Ala single nuclear polymorphism should be studied more extensively in order to serve as a novel candidate in biomarker screening for improved prognosis. PMID:21155004

  16. Association of the Pro12Ala Polymorphism with the Metabolic Parameters in Women with Polycystic Ovary Syndrome.

    PubMed

    Zaki, Moushira; Hassan, Naglaa; El-Bassyouni, Hala T; Kamal, Sanaa; Basha, Walaa; Azmy, Osama; Amr, Khalda

    2017-06-15

    To investigate the association of peroxisome proliferator-activated receptor gamma (PPARG) Pro12Ala polymorphism with polycystic ovary syndrome (PCOS) and its effect on the metabolic parameters in PCOS women. The study used PCR to identify the presence of the PPARG Pro12Ala polymorphism in 100 PCOS women and 120 age-matched healthy women. All participants were subjected to anthropometry, biochemical and metabolic evaluation. Significant difference in the genotypes distributions of PPARG Pro12Ala polymorphism was observed among PCOS women and controls (p = 0.03). The frequency of the polymorphic allele Ala was significantly higher in PCOS cases than that in the controls (OR = 2.01, p = 0.01). The carries of the variant allele Ala in PCOS women showed significant higher values in body mass index (BMI), systolic and diastolic blood pressure, waist circumference, waist to hip ratio, sum of skin folds, fasting blood glucose, fasting blood insulin, HOMA-IR, fasting triglycerides, total cholesterol and low-density lipoprotein than non-carriers. The PPARG Pro12Ala polymorphism might contribute to the risk of PCOS and abnormal metabolic parameters and could be considered as a biomarker for early diagnosis and clinic prediction of metabolic complications.

  17. Association of peroxisome proliferator-activated receptor-gamma 2 Pro12Ala polymorphism with advanced-stage endometriosis.

    PubMed

    Hwang, Kyu Ri; Choi, Young Min; Kim, Jong Mee; Lee, Gyoung Hoon; Kim, Jin Ju; Chae, Soo Jin; Moon, Shin Yong

    2010-11-01

    To investigate whether the peroxisome proliferator-activated receptor (PPAR)-γ2 Pro12Ala polymorphism is associated with a risk of advanced-stage endometriosis in a Korean population.   Case-control study in a collective of 446 patients and 427 controls. The Pro12Ala polymorphism of PPAR-γ2 gene was genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. The distribution of the PPAR-γ2 Pro12Ala polymorphism was different between the advanced-stage endometriosis group and the control group (non-CC rates were 5.2% for patients with advanced endometriosis and 10.1% for the control group, respectively, P = 0.006). The frequency for the Ala-12 allele variant was significantly lower in patients with advanced stage of endometriosis (2.7%) than in the control group (5.3%) (P = 0.006). These findings suggest that the PPAR-γ2 Pro12Ala polymorphism is associated with advanced-stage endometriosis in the Korean population. Unlike results from other studies reported so far, the Ala-12 allele may have protective effects against advanced-stage endometriosis in the Korean population. © 2010 John Wiley & Sons A/S.

  18. Association of the Pro12Ala Polymorphism with the Metabolic Parameters in Women with Polycystic Ovary Syndrome

    PubMed Central

    Zaki, Moushira; Hassan, Naglaa; El-Bassyouni, Hala T.; Kamal, Sanaa; Basha, Walaa; Azmy, Osama; Amr, Khalda

    2017-01-01

    AIM: To investigate the association of peroxisome proliferator-activated receptor gamma (PPARG) Pro12Ala polymorphism with polycystic ovary syndrome (PCOS) and its effect on the metabolic parameters in PCOS women. METHODS: The study used PCR to identify the presence of the PPARG Pro12Ala polymorphism in 100 PCOS women and 120 age-matched healthy women. All participants were subjected to anthropometry, biochemical and metabolic evaluation. RESULTS: Significant difference in the genotypes distributions of PPARG Pro12Ala polymorphism was observed among PCOS women and controls (p = 0.03). The frequency of the polymorphic allele Ala was significantly higher in PCOS cases than that in the controls (OR = 2.01, p = 0.01). The carries of the variant allele Ala in PCOS women showed significant higher values in body mass index (BMI), systolic and diastolic blood pressure, waist circumference, waist to hip ratio, sum of skin folds, fasting blood glucose, fasting blood insulin, HOMA-IR, fasting triglycerides, total cholesterol and low-density lipoprotein than non-carriers. CONCLUSION: The PPARG Pro12Ala polymorphism might contribute to the risk of PCOS and abnormal metabolic parameters and could be considered as a biomarker for early diagnosis and clinic prediction of metabolic complications. PMID:28698741

  19. Pro12Ala PPAR γ2 gene polymorphism in PCOS women: the role of compounds regulating satiety.

    PubMed

    Bidzińska-Speichert, Bożena; Lenarcik, Agnieszka; Tworowska-Bardzińska, Urszula; Slęzak, Ryszard; Bednarek-Tupikowska, Grażyna; Milewicz, Andrzej

    2012-03-01

    Five to ten percent of women of reproductive age suffer from polycystic ovary syndrome (PCOS). Leptin, NPY, galanin, cholecystokinin (CCK) are involved in the regulation of eating behavior. PPARγ are receptors that are probably involved in hyperandrogenism. This study was designed to assess associations between the Pro12Ala PPARγ2 gene polymorphism and satiety factors in PCOS. Fifty-four PCOS women and 51 healthy women were studied. Leptin, NPY, galanin, CCK levels, and genetic studies to detect Pro12Ala PPARγ2 gene polymorphism were assessed. The leptin levels in the PCOS women carrying Pro12Ala genotype were higher than in those with Pro12Pro and Ala12Ala. The PCOS women had higher leptin and NPY levels and lower galanin levels. Obese PCOS patients had lower CCK levels. In the PCOS women, a single Ala allele may have a protective role as far as hyperleptinemia is concerned. The PCOS women may reveal a disrupted central leptin/NPY feedback loop with some shifts in food intake.

  20. Comparsion of light dose on topical ALA-mediated photodynamic therapy for DMBA-induced hamster buccal pouch premalignant lesions

    NASA Astrophysics Data System (ADS)

    Yang, Deng-Fu; Tseng, Meng-Ke; Liu, Chung-Ji; Hsu, Yih-Chih

    2012-03-01

    Oral cancer has becomes the most prominent male cancer disease due to the local betel nut chewing habit combing with smoking and alcohol-drinking lifestyle. In order to minimize the systemic phototoxic effect of 5-aminolevulinic acid (ALA), this study was designed to use a topical ALA-mediated PDT for treatment of DMBA-induced hamster buccal pouch cancerous lesions. DMBA was applied to one of the buccal pouches of hamsters thrice a week for 8 to 10 weeks. Precancerous lesions were induced and proven by histological examination. These DMBA-induced cancerous lesions were used for testing the efficacy of topical ALA -mediated PDT. We found that ALA reached its peak level in cancerous lesions about 2.5 hrs after topical application of ALA gel. The precancerous lesions in hamsters were then treated with topical ALA -mediated PDT with light exposure dose of 75 and 100 J/cm2 using LED 635 nm Wonderlight device. It is suggesting that optimization of the given light dose is critical to the success of PDT results.

  1. Effects of ALA, EPA and DHA in high-carbohydrate, high-fat diet-induced metabolic syndrome in rats.

    PubMed

    Poudyal, Hemant; Panchal, Sunil K; Ward, Leigh C; Brown, Lindsay

    2013-06-01

    We compared the cardiovascular, hepatic and metabolic responses to individual dietary n-3 fatty acids (α-linolenic acid, ALA; eicosapentaenoic acid, EPA; and docosahexaenoic acid, DHA) in a high-carbohydrate, high-fat diet-induced model of metabolic syndrome in rats. Additionally, we measured fatty acid composition of plasma, adipose tissue, liver, heart and skeletal muscle in these rats. The same dosages of ALA and EPA/DHA produced different physiological responses to decrease the risk factors for metabolic syndrome. ALA did not reduce total body fat but induced lipid redistribution away from the abdominal area and favorably improved glucose tolerance, insulin sensitivity, dyslipidemia, hypertension and left ventricular dimensions, contractility, volumes and stiffness. EPA and DHA increased sympathetic activation, reduced the abdominal adiposity and total body fat and attenuated insulin sensitivity, dyslipidemia, hypertension and left ventricular stiffness but not glucose tolerance. However, ALA, EPA and DHA all reduced inflammation in both the heart and the liver, cardiac fibrosis and hepatic steatosis. These effects were associated with complete suppression of stearoyl-CoA desaturase 1 activity. Since the physiological responses to EPA and DHA were similar, it is likely that the effects are mediated by DHA with EPA serving as a precursor. Also, ALA supplementation increased DHA concentrations but induced different physiological responses to EPA and DHA. This result strongly suggests that ALA has independent effects in metabolic syndrome, not relying on its metabolism to DHA.

  2. ALA-containing transparent applicators on the basis of biodegradable polymers for photodynamic therapy of superficial malignancies

    NASA Astrophysics Data System (ADS)

    Meerovich, Gennadii A.; Loschenov, Victor B.; Shental, Victor V.; Vakoulovskaya, Elena G.; Davydov, Anatoly B.; Khromov, Gennady L.; Kuzmin, Sergei G.; Lukyanets, Eugeny A.; Tkach, Iosif I.; Vorozhtsov, Georgy N.

    2002-06-01

    The efficiency of photodynamic therapy (PDT) using 5- aminolevulinic acid (5-ALA) is essentially determined by an optimal choice of sensitization means, among which the application method is one of the most perspective due to high permeability of a skin for 5-ALA. The aim of present work is optimization of sensitization process with ALA. We have used the possibility of 5-ALA transparency in applicator (outside of tissue) while protoporphyrin-IX, formed in sensitized tissue, has sufficient absorption for providing PDT. We have developed 5-ALA containing applicator on the basis of transparent biodegradable polymers, which serve as a programmed source of 5-ALA in the zone of their contact with pathological tissue. The investigations carried out on mice with the solid form of leucosis p-388, have shown that developed applicator provides effective sensitization of pathological tissue, supporting high concentration of photosensitizer in tissue during the whole time of application (up to week). The experiments in vivo have demonstrated high efficiency of PDT. The preliminary clinical researches allow to draw a conclusion about its perspectivity for photodynamic treatment of skin malignancies.

  3. Aminolevulinic acid (ALA)-protoporphyrin IX fluorescence guided tumour resection. Part 1: Clinical, radiological and pathological studies.

    PubMed

    Colditz, Michael J; Jeffree, Rosalind L

    2012-11-01

    The intraoperative identification and resection of glioma is a significant and important challenge in neurosurgery. Complete resection of the enhancing tumour increases the median survival time in glioblastoma compared to partial glioma resection; however, it is achieved in fewer than half of eligible patients when conventional tumour identification methods are used. Increasing the incidence of complete resection, without causing excess morbidity, requires new methods to accurately identify neoplastic tissue intraoperatively, such as use of the drug 5-amino-levulinic acid (ALA). After ALA ingestion, the fluorescent molecule protoporphyrin IX (PpIX) accumulates in high grade glioma, allowing the neurosurgeon to more easily detect and accurately resect tumour. The utility of ALA has been demonstrated in a large, multicentre phase III randomised control trial of 243 patients with high grade glioma. ALA use led to a significant increase in the incidence of complete resection (65% compared to 36%), improved progression-free survival at 6 months (41% compared to 21%), fewer reinterventions, and delayed onset of neurological deterioration. This review provides a broad assessment of ALA-PpIX fluorescence-guided resection, with Part 1 focusing on its clinical efficacy, and correlations with imaging and histology. The theoretical, biochemical and practical aspects of ALA use are reviewed in Part 2.

  4. Lifelong imbalanced LA/ALA intake impairs emotional and cognitive behavior via changes in brain endocannabinoid system.

    PubMed

    Zamberletti, Erica; Piscitelli, Fabiana; De Castro, Valentina; Murru, Elisabetta; Gabaglio, Marina; Colucci, Paola; Fanali, Chiara; Prini, Pamela; Bisogno, Tiziana; Maccarrone, Mauro; Campolongo, Patrizia; Banni, Sebastiano; Rubino, Tiziana; Parolaro, Daniela

    2017-02-01

    Imbalanced dietary n-3 and n-6 PUFA content has been associated with a number of neurological conditions. Endocannabinoids are n-6 PUFA derivatives, whose brain concentrations are sensitive to modifications of fatty acid composition of the diet and play a central role in the regulation of mood and cognition. As such, the endocannabinoid system appears to be an ideal candidate for mediating the effects of dietary fatty acids on mood and cognition. Lifelong administration of isocaloric α-linolenic acid (ALA)-deficient and -enriched diets induced short-term memory deficits, whereas only dietary ALA enrichment altered emotional reactivity in adult male rats compared with animals fed a standard diet that was balanced in ALA/linoleic acid (LA) ratio. In the prefrontal cortex, both diets reduced 2-AG levels and increased MAG lipase expression, whereas only the enriched diet reduced AEA levels, simultaneously increasing FAAH expression. In the hippocampus, an ALA-enriched diet decreased AEA content and NAPE-PLD expression, and reduced 2-AG content while increasing MAG lipase expression. These findings highlight the importance of a diet balanced in fatty acid content for normal brain functions and to support a link between dietary ALA, the brain endocannabinoid system, and behavior, which indicates that dietary ALA intake is a sufficient condition for altering the endocannabinoid system in brain regions modulating mood and cognition. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

  5. Comparing desferrioxamine and light fractionation enhancement of ALA-PpIX photodynamic therapy in skin cancer

    PubMed Central

    de Souza, Ana Luiza Ribeiro; Marra, Kayla; Gunn, Jason; Samkoe, Kimberley S; Kanick, Stephen Chad; Davis, Scott C; Chapman, M Shane; Maytin, Edward V; Hasan, Tayyaba; Pogue, Brian W

    2016-01-01

    Background: Aminolevulinic acid (ALA)-based photodynamic therapy (PDT) provides selective uptake and conversion of ALA into protoporphyrin IX (PpIX) in actinic keratosis and squamous cell carcinoma, yet large response variations in effect are common between individuals. The aim of this study was to compare pre-treatment strategies that increase the therapeutic effect, including fractionated light delivery during PDT (fPDT) and use of iron chelator desferrioxamine (DFO), separately and combined. Methods: Optical measurements of fluorescence were used to quantify PpIX produced, and the total amount of PpIX photobleached as an implicit measure of the photodynamic dose. In addition, measurements of white light reflectance were used to quantify changes in vascular physiology throughout the PDT treatment. Results: fPDT produced both a replenishment of PpIX and vascular re-oxygenation during a 2 h dark interval between the first and second PDT light fractions. The absolute photodynamic dose was increased 57% by fPDT, DFO and their combination, as compared with PDT group (from 0.7 to 1.1). Despite that light fractionation increased oedema and scab formation during the week after treatment, no significant difference in long-term survival has been observed between treatment groups. However, outcomes stratified on the basis of measured photodynamic dose showed a significant difference in long-term survival. Conclusions: The assessment of implicit photodynamic dose was a more significant predictor of efficacy for ALA-PDT skin cancer treatments than prescription of an enhanced treatment strategy, likely because of high individual variation in response between subjects. PMID:27575852

  6. Comparing desferrioxamine and light fractionation enhancement of ALA-PpIX photodynamic therapy in skin cancer.

    PubMed

    de Souza, Ana Luiza Ribeiro; Marra, Kayla; Gunn, Jason; Samkoe, Kimberley S; Kanick, Stephen Chad; Davis, Scott C; Chapman, M Shane; Maytin, Edward V; Hasan, Tayyaba; Pogue, Brian W

    2016-09-27

    Aminolevulinic acid (ALA)-based photodynamic therapy (PDT) provides selective uptake and conversion of ALA into protoporphyrin IX (PpIX) in actinic keratosis and squamous cell carcinoma, yet large response variations in effect are common between individuals. The aim of this study was to compare pre-treatment strategies that increase the therapeutic effect, including fractionated light delivery during PDT (fPDT) and use of iron chelator desferrioxamine (DFO), separately and combined. Optical measurements of fluorescence were used to quantify PpIX produced, and the total amount of PpIX photobleached as an implicit measure of the photodynamic dose. In addition, measurements of white light reflectance were used to quantify changes in vascular physiology throughout the PDT treatment. fPDT produced both a replenishment of PpIX and vascular re-oxygenation during a 2 h dark interval between the first and second PDT light fractions. The absolute photodynamic dose was increased 57% by fPDT, DFO and their combination, as compared with PDT group (from 0.7 to 1.1). Despite that light fractionation increased oedema and scab formation during the week after treatment, no significant difference in long-term survival has been observed between treatment groups. However, outcomes stratified on the basis of measured photodynamic dose showed a significant difference in long-term survival. The assessment of implicit photodynamic dose was a more significant predictor of efficacy for ALA-PDT skin cancer treatments than prescription of an enhanced treatment strategy, likely because of high individual variation in response between subjects.

  7. ALA-induced PpIX spectroscopy for brain tumor image-guided surgery

    NASA Astrophysics Data System (ADS)

    Valdes, Pablo A.; Leblond, Frederic; Kim, Anthony; Harris, Brent T.; Wilson, Brian C.; Paulsen, Keith D.; Roberts, David W.

    2011-03-01

    Maximizing the extent of brain tumor resection correlates with improved survival and quality of life outcomes in patients. Optimal surgical resection requires accurate discrimination between normal and abnormal, cancerous tissue. We present our recent experience using quantitative optical spectroscopy in 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) fluorescence-guided resection. Exogenous administration of ALA leads to preferential accumulation in tumor tissue of the fluorescent compound, PpIX, which can be used for in vivo surgical guidance. Using the state of the art approach with a fluorescence surgical microscope, we have been able to visualize a subset of brain tumors, but the sensitivity and accuracy of fluorescence detection for tumor tissue with this system are low. To take full advantage of the biological selectivity of PpIX accumulation in brain tumors, we used a quantitative optical spectroscopy system for in vivo measurements of PpIX tissue concentrations. We have shown that, using our quantitative approach for determination of biomarker concentrations, ALA-induced PpIX fluorescence-guidance can achieve accuracies of greater than 90% for most tumor histologies. Here we show multivariate analysis of fluorescence and diffuse reflectance signals in brain tumors with comparable diagnostic performance to our previously reported quantitative approach. These results are promising, since they show that technological improvements in current fluorescence-guided surgical technologies and more biologically relevant approaches are required to take full advantage of fluorescent biomarkers, achieve better tumor identification, increase extent of resection, and subsequently, lead to improve survival and quality of life in patients.

  8. Hydrologic Modelling of Katsina-Ala River Basin: AN Emerging Scenario from Lake Nyos Threat

    NASA Astrophysics Data System (ADS)

    Akinyede, J. O.; Babamaaji, R.; Vaatough, M.; Adepoju, K. A.

    2012-07-01

    Understanding the hydrologic system surrounding crater lakes is of great importance for prevention of flooding damages, conservation of ecological environment, and assessment of socio-economic impact of dam failure on the civilians in the downstream regions. Lake Nyos is a crater lake formed by volcanic activities at the Oku volcanic field on the Cameroon Volcanic Line. It is a freshwater lake with a maximum depth of 200 meter. In 1986, a limnic eruption at the lake emitted 1.6 million tonnes of carbon dioxide from the bottom of saturated water into the air and suffocated up to 1,800 people and 3,500 livestock at nearby villages. The lake waters are held in place by a natural dam composed of loosely consolidated volcanic rock, which is now at the verge of collapse due to accelerated erosion. This study was carried out to determine the flood risks and vulnerability of population and infrastructure along Katsina-Ala drainage basins. The project integrated both satellite images and field datasets into a hydrologic model for Katsina-Ala River Basin and its vicinity including the Lake Nyos. ArcHydro was used to construct a hydrologic database as 'data models' and MIKE SHE was employed to conduct hydrologic simulations. Vulnerable infrastructures, population and socio-economic activities were identified to assist the Federal and State governments in disaster mitigation and management plans. The result of the project provides comprehensive knowledge of hydrologic system of Katsina-Ala drainage basin to mitigate potential future disasters from a potential dam failure and manage water resources against such disasters.

  9. Disruption of the blood brain barrier following ALA mediated photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Hirschberg, Henry; Peng, Qian; Uzal, Francisco A.; Chighvinadze, David; Zhang, Michelle J.; Madsen, Steen J.

    2008-02-01

    Introduction: Failure of treatment for high grade gliomas is usually due to local recurrence at the site of surgical resection indicating that a more aggressive form of local therapy, such as PDT, could be of benefit. PDT causes damage to tumor cells as well as degradation of the blood brain barrier (BBB). We have evaluated the ability of ALA mediated PDT to open the BBB in rats. This will permit access of chemotherapeutic agents to brain tumor cells remaining in the resection cavity wall, but limit their penetration into normal brain remote from the site of illumination. Materials and Methods: ALA-PDT was performed on non tumor bearing inbred Fisher rats at increasing fluence levels. T2 weighted MRI scans were used to evaluate edema formation and post-contrast T I MRI scans were used to monitor the degree BBB disruption which could be inferred from the intensity and volume of the contrast agent visualized. Results. PDT at increasing fluence levels between 9J and 26J demonstrated an increasing contrast flow rate. No effect on the BBB was observed if 26J of light were given in the absence of ALA. A similar increased contrast volume was observed with increasing fluence rates. The BBB was found to be disrupted 2hrs. following PDT and 80-100% restored 72hrs later. Conclusion: PDT was highly effective in opening the BBB in a limited region of the brain. The degradation of the BBB was temporary in nature, opening rapidly following treatment and significantly restored during the next 72 hrs.

  10. Fluorescence imaging and spectroscopy of ALA-induced protoporphyrin IX preferentially accumulated in tumor tissue

    NASA Astrophysics Data System (ADS)

    Stepp, Herbert G.; Baumgartner, Reinhold; Beyer, Wolfgang; Knuechel, Ruth; Koerner, T. O.; Kriegmair, M.; Rick, Kai; Steinbach, Pia; Hofstetter, Alfons G.

    1995-12-01

    In a clinical pilot study performed on 104 patients suffering from bladder cancer it could be shown that intravesical instillation of a solution of 5-aminolevulinic acid (5-ALA) induces a tumorselective accumulation of Protoporphyrin IX (PPIX). Malignant lesions could be detected with a sensitivity of 97% and a specificity of 67%. The Kr+-laser as excitation light source could successfully be replaced by a filtered short arc Xe-lamp. Its emission wavelength band (375 nm - 440 nm) leads to an efficiency of 58% for PPIX- excitation compared to the laser. Two-hundred-sixty mW of output power at the distal end of a slightly modified cystoscope could be obtained. This is sufficient for recording fluorescence images with a target integrating color CCD-camera. Red fluorescence and blue remitted light are displayed simultaneously. Standard white light observation is possible with the same instrumentation. Pharmacokinetic measurements were performed on 18 patients after different routes of 5-ALA application (oral, inhalation and intravesical instillation). PPIX-fluorescence measurements were made on the skin and on the blood plasma. Pharmacokinetic of 5-ALA could be performed on blood plasma. Endoscopical florescence spectroscopy showed the high fluorescence contrast between tumor and normal tissue with a mean value of 10.7. Forthcoming clinical multicenter studies require an objective measure of the fluorescence intensity. Monte Carlo computer simulations showed that artifacts due to observation geometry and varying absorption can largely be reduced by ratioing fluorescence (red channel of camera) to remission (blue channel). Real time image ratioing provides false color images with a reliable fluorescence information.

  11. Functional and Histological Evaluation following Canine Vocal Fold Reconstruction Using Composite Thyroid Ala Perichondrium Flaps.

    PubMed

    Hoffman, Matthew R; Glab, Rachel; Gunderson, McLean; Maytag, Allison L; Yang, David T; Jiang, Jack J; Dailey, Seth H

    2015-07-01

    We evaluated the effects of vocal fold reconstruction using a composite thyroid ala perichondrium flap (CTAP) after unilateral vocal fold stripping in beagles. We hypothesized that CTAP would improve glottic closure, decrease phonation threshold pressure, and decrease perturbation. In addition, vocal folds with CTAP would exhibit neovascularization and fat with increased von Willebrand factor (vWF) and smooth muscle actin (SMA), reflecting neoangiogenesis and flap viability. Randomized controlled trial using beagles. University laboratory. Ten beagles underwent unilateral vocal fold stripping. Dogs in the scar-only group (n = 5) were sacrificed at 1 month. Dogs in the CTAP group (n = 5) underwent ipsilateral reconstruction with CTAP at 1 month and were sacrificed at 2 months. Excised larynx experiments evaluated vocal fold vibration using aerodynamic, acoustic, and mucosal wave measurements. Qualitative evaluation of vocal fold morphology and quantitative analysis of elastin, collagen, glycosaminoglycans, vWF, SMA, and hyaluronic acid were performed. Phonation threshold pressure (P = .005), percent jitter (P = .010), percent shimmer (P = .007), and open quotient (P = .007) were lower in the CTAP group. Neovascularization (P = .0079) and fat (P = .1667) occurred more with CTAP, although the difference in fat was not significant. von Willebrand factor was higher with CTAP vs contralateral normal fold (P = .110), although not statistically significant. Smooth muscle actin was higher with CTAP vs contralateral normal fold (P = .038) and scarred vocal folds (P = .022). Composite thyroid ala perichondrium flap restored glottic closure and vibratory periodicity following vocal fold scarring. Additional investigation on biologic response is warranted. Composite thyroid ala perichondrium flap offers an autologous, vascularized implant that can improve both vocal fold structure and function. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.

  12. Reduction of the invasiveness of human glioma cells by ALA-mediated photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Hirschberg, Henry; Sun, Chung-Ho; Madsen, Steen

    2006-02-01

    Introduction: High grade gliomas are characterised by rapid and invasive growth, that cause massive tissue destruction at both the tumour- brain boarder as well as in regions remote from the tumor core. Eradication or inhibition of infiltrating glioma cells poses a significant clinical challenge that is unlikely to be solved using conventional treatment regimens consisting of ionizing radiation and chemotherapeutic agents. In this study we evaluated the effects of ALA mediated photodynamic therapy (PDT) on the invesivness of human glioma cells migrating from implanted multicell tumor spheroids. Materials and method 3-400nm diameter tumor spheroids, derived from the human glioma cell line ACBT, were implanted into a gel matrix of collagen type I. 24 hours following implantation there was a significant invasion of the surrounding gel by individual tumor cells to an average distance of 400nm. The cultures were incubated in increasing concentrations of ALA (10-1000 ug/ml) for four hours and then exposed to 635nm laser light in a titration of both fluence level and fluence rate. Results Fluences of 25J/cm2 were clearly cytotoxic for both the infiltrating cells as well as the spheroids at all ALA concentrations. Fluence levels of 6J did not stop the spheroid growth or prove cytotoxic to the glioma cells that had previously migrated into the gel, in a majority of cultures but inhibited further migration of the cells by 80-90% compared to control. Conclusion: Measurement of cell survival and cell proliferation indices seemed to indicate a direct migratory inhibition effect on the invading cells and not cytotoxicity as the most likely mechanism for this observation.

  13. α-Linolenic acid (ALA) is an anti-inflammatory agent in inflammatory bowel disease.

    PubMed

    Reifen, Ram; Karlinsky, Anna; Stark, Aliza H; Berkovich, Zipi; Nyska, Abraham

    2015-12-01

    Studies suggest that consumption of omega-3 (n-3) polyunsaturated fatty acids (PUFA) plays a protective role in inflammatory bowel disease; however, the use of plant-derived oils rich in α-linolenic acid (ALA) has not been widely investigated. The aims of this study were to test the effects of two different sources of (n-3) PUFA, fish and plant-derived oils, in two animal models of experimental colitis and to determine whether the (n-3) PUFA-enriched diets could ameliorate the inflammatory status. Rats were fed diets rich in corn, fish or sage oil with or without vitamin A supplementation for 3weeks then colitis was induced by adding dextran sodium sulfate to the drinking water or by injecting 2,4,6-trinitrobenzene sulfonic acid. We show that colitic rats fed the sage oil diets had a lower inflammatory response, improved histological repair and had less necrotic damage in the mucosa when compared to the corn and fish oil groups. Colonic damage and myeloperoxidase activity were significantly lower. Colonic mRNA levels of pro-inflammatory genes including interleukin IL-6, cyclooxygenase 2 and tumor necrosis factor α were markedly down-regulated in rats fed fish and sage oils compared to control. These results were supported by experiments in the human colonic epithelial cell line Caco-2, where ALA supplementation was shown to be effective in inhibiting inflammation induced by IL-1β by down-regulating mRNA levels of pro-inflammatory genes including IL-8, COX2 and inducible nitric oxide synthase. Taken together, these results suggest that plant-derived oil rich in ALA could ameliorate the inflammatory damage in colitis.

  14. AT-50ALA-BASED PHOTODYNAMIC THERAPY IN RECURRENT MALIGNANT GLIOMA - A PILOT STUDY

    PubMed Central

    Schroeteler, Juliane; Schipmann, Steffanie; Molina, Eric Suero; Grauer, Oliver; Stummer, Walter; Ewelt, Christian

    2014-01-01

    OBJECTIVE: Recurrent malignant glioma (RMG) is an orphan disease without standard therapeutic recommendation. ALA-based photodynamic therapy (PDT) for malignant gliomas has been investigated in-vivo and in-vitro, suggesting potential efficacy. We report our experience with ALA-PDT in malignant recurrent glioma patients. METHODS: Data of seven patients with diagnosis of RMG, treated by PDT in a compassionate setting between 02/2011-05/2014 were analyzed. All seven patients received 20 mg/kg bodyweight ALA orally 4-6 hours prior to surgery. A stereotactic biopsy was taken followed by PDT administration with a constant tissue power of 200 mW/cm being applied by diode laser into the target area for one hour. RESULTS: Prior to PDT, patients underwent two brain surgeries (median). Six patients received radiotherapy with a minimum of 60 Gy, temozolamide (TMZ) was taken by four patients and two patients were TMZ naive prior to PDT. Histologically, five glioblastomas (GBM), one anaplastic oligodendroglioma (AO) and one anaplastic astrocytoma (AA) were detected. MGMT negative promotor methylation status (PMS) was observed in five cases and positive MGMT-PMS in one tumor. After PDT, three patients received TMZ, one Avastin, one Lomustine, one was given no further chemotherapy, and in one patient data was missing. A median PFS of two and OAS of 13 months after PDT treatment, as well as a median OAS from first diagnosis of 24 months was reached. Brain edema responding to steroids was detected in three patients during first 24 hours after PDT. One patient treated with Bevacizumab showed wound healing complication. No other severe effects occurred. CONCLUSION: PDT was well tolerated and a median OAS of 13 months and complete OAS of 24 months suggest a survival advantage by PDT as an additive surgical treatment option in RMG.

  15. Imiquimod immunotherapy and ALA photodynamic therapy combination for the treatment of genital bowenoid papulosis

    NASA Astrophysics Data System (ADS)

    Wang, Xiu-Li; Wang, Hong-Wei; Guo, Ming-Xia; Huang, Zheng

    2007-02-01

    To investigate the feasibility and efficacy of combination of imiquimod immunotherapy and 5- aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) for the treatment of genital bowenoid papulosis (BP). A total of twenty seven BP patients were randomized into two groups: (I) fifteen patients (12 male and 3 female, age 22-56 years old) were treated with topical application of 5% imiquimod cream (three times a week) and ALA-PDT (100 J/cm2 at 100 mW/cm2, once a week) for 1-4 times in one week interval. (II) Twelve patients (6 male and 6 female, age 29-58 years old) were treated with CO II laser vaporization as a control. Patients were followed up for 3 to 12 months. Results: In combined therapy group, 60% (9/15) patients showed complete remission and only one recurred (11.1%) during follow up. Local side effects included mild erythema, edema, erosion and burning and/or stinging sensation. No systemic side effect was found. In CO II laser vaporization group, 83.3% (10/12) patients showed complete remission. However, recurrence occurred in 6 patients (60.0%). Local side effects included mild to moderate edema, erosion, ulceration, delayed healing, prolonged pain and scarring. The difference of recurrence rate between two groups was statistically significant (P < 0.05). Topical application of imiquimod cream and ALA-PDT is safe, effective and associated with low recurrence and less side effect. Its true clinical value needs to be further investigated by a long-term follow-up of large scale trial.

  16. Ala42S100A8 Ameliorates Psychological-Stress Impaired Cutaneous Wound Healing

    PubMed Central

    Sroussi, Herve Y.; Williams, Richard L.; Zhang, Qing. L.; Villines, Dana.; Marucha, Phillip. T.

    2009-01-01

    Although wound healing is generally a successful, carefully orchestrated and evolutionary sound process, it can be disregulated by extrinsic factors such as psychological stress. In the SKH-1 restraint stress model of cutaneous wound healing, the rate of wound closure is approximately 30% slower in stressed mice. Delay in healing is associated with exaggerated acute inflammation and deficient bacterial clearance at the wound site. It has been suggested that wound hypoxia may contribute to the mechanisms of impaired cutaneous wound healing in the mouse SKH-1 model. Optimal healing of a cutaneous wound is a stepwise repair program. In its early phase, an inflammatory oxidative burst generated by neutrophils is observed. 40% of neutrophils cytosolic protein weight is comprised of two calcium binding proteins S100A8 and S100A9. Our previous work has shown that S100A8 act as an oxidation sensitive repellent of human neutrophils in-vitro. Ala42S100A8, a site-directed mutant protein is resistant to oxidative inhibition and inhibits neutrophil recruitment in-vivo. Accordingly, we tested the hypothesis that S100A8 may ameliorate wound healing in this model. We examined the effect of wild type and ala42S100A8 for their ability to ameliorate wound closure rates. The data indicated that a single local application of ala42S100A8 ameliorated the decreased rate of wound closure resulting from stress. This occurred without significantly affecting wound bacterial clearance. Wild type S100A8 only had a partial beneficial effect on the rate of wound closure. Those findings support further translational studies of S100 based intervention to ameliorate impaired wound healing. PMID:19336252

  17. Anti-allergic effects of His-Ala-Gln tripeptide in vitro and in vivo.

    PubMed

    Tanaka, Mamoru; Watanabe, Hiroyuki; Yoshimoto, Yoshinobu; Kozai, Hana; Okamoto, Takeaki

    2017-02-01

    We examined the inhibitory effects of HAQ (His-Ala-Gln) peptide on type-1 allergy in vitro and in vivo. HAQ peptide inhibited β-hexosaminidase release and intracellular Ca(2+) levels of rat basophilic leukemia RBL-2H3 cells. Oral administration of a HAQ peptide-added diet (1 mg/mouse/administration) to C3H/HeJ mice for 14 days led to significant suppression of allergic symptoms, but did not reduce allergen-specific IgE or IgG1.

  18. Switching in of Ac-(Ala)10-NHMe at a solid surface.

    PubMed

    Biggs, Mark J; Mijajlovic, Milan

    2008-09-01

    Using molecular simulation, we show how Ac-(Ala)(10)-NHMe adsorbed on a solid surface switches between three conformations at distinct surface energies. The first switch is from an alpha-helix to a 3.1(10)-helix. The second involves further stretching to a 2(7)-helix. This switching has several potential applications including memory in molecular computers to motility elements in nanotechnology, and could be relevant to biological activity of proteins near solid surfaces (e.g., nano and aerosol particles) and disease processes induced by such interactions.

  19. PPARγ Pro12Ala and ACE ID polymorphisms are associated with BMI and fat distribution, but not metabolic syndrome

    PubMed Central

    2011-01-01

    Background Metabolic Syndrome (MetS) results from the combined effect of environmental and genetic factors. We investigated the possible association of peroxisome proliferator-activated receptor-γ2 (PPARγ2) Pro12Ala and Angiotensin Converting Enzyme (ACE) I/D polymorphisms with MetS and interaction between these genetic variants. Methods Three hundred sixty four unrelated Caucasian subjects were enrolled. Waist circumference, blood pressure, and body mass index (BMI) were recorded. Body composition was estimated by impedance analysis; MetS was diagnosed by the NCEP-ATPIII criteria. A fasting blood sample was obtained for glucose, insulin, lipid profile determination, and DNA isolation for genotyping. Results The prevalence of MetS did not differ across PPARγ2 or ACE polymorphisms. Carriers of PPARγ2 Ala allele had higher BMI and fat-mass but lower systolic blood pressure compared with Pro/Pro homozygotes. A significant PPARγ2 gene-gender interaction was observed in the modulation of BMI, fat mass, and blood pressure, with significant associations found in women only. A PPARγ2-ACE risk genotype combination for BMI and fat mass was found, with ACE DD/PPARγ2 Ala subjects having a higher BMI (p = 0.002) and Fat Mass (p = 0.002). Pro12Ala was independently associated with waist circumference independent of BMI and gender. Conclusions Carriers of PPARγ2 Ala allele had higher BMI and fat-mass but not a worse metabolic profile, possibly because of a more favorable adipose tissue distribution. A gene interaction exists between Pro12Ala and ACE I/D on BMI and fat mass. Further studies are needed to assess the contribution of Pro12Ala polymorphism in adiposity distribution. PMID:22168210

  20. PPARγ Pro12Ala and ACE ID polymorphisms are associated with BMI and fat distribution, but not metabolic syndrome.

    PubMed

    Passaro, Angela; Dalla Nora, Edoardo; Marcello, Caterina; Di Vece, Francesca; Morieri, Mario Luca; Sanz, Juana M; Bosi, Cristina; Fellin, Renato; Zuliani, Giovanni

    2011-12-14

    Metabolic Syndrome (MetS) results from the combined effect of environmental and genetic factors. We investigated the possible association of peroxisome proliferator-activated receptor-γ2 (PPARγ2) Pro12Ala and Angiotensin Converting Enzyme (ACE) I/D polymorphisms with MetS and interaction between these genetic variants. Three hundred sixty four unrelated Caucasian subjects were enrolled. Waist circumference, blood pressure, and body mass index (BMI) were recorded. Body composition was estimated by impedance analysis; MetS was diagnosed by the NCEP-ATPIII criteria. A fasting blood sample was obtained for glucose, insulin, lipid profile determination, and DNA isolation for genotyping. The prevalence of MetS did not differ across PPARγ2 or ACE polymorphisms. Carriers of PPARγ2 Ala allele had higher BMI and fat-mass but lower systolic blood pressure compared with Pro/Pro homozygotes. A significant PPARγ2 gene-gender interaction was observed in the modulation of BMI, fat mass, and blood pressure, with significant associations found in women only. A PPARγ2-ACE risk genotype combination for BMI and fat mass was found, with ACE DD/PPARγ2 Ala subjects having a higher BMI (p = 0.002) and Fat Mass (p = 0.002). Pro12Ala was independently associated with waist circumference independent of BMI and gender. Carriers of PPARγ2 Ala allele had higher BMI and fat-mass but not a worse metabolic profile, possibly because of a more favorable adipose tissue distribution. A gene interaction exists between Pro12Ala and ACE I/D on BMI and fat mass. Further studies are needed to assess the contribution of Pro12Ala polymorphism in adiposity distribution.

  1. Peroxisome Proliferator–Activated Receptor γ Polymorphism Pro12Ala Is Associated With Nephropathy in Type 2 Diabetes

    PubMed Central

    Zhang, Hui; Zhu, Shimiao; Chen, Jing; Tang, Yang; Hu, Hailong; Mohan, Viswanathan; Venkatesan, Radha; Wang, Jianmin; Chen, Haiping

    2012-01-01

    OBJECTIVE Insulin resistance plays a part in diabetic nephropathy (DN). The association between the peroxisome proliferator–activated receptor γ Pro to Ala alteration at codon 12 (Pro12Ala) polymorphism and the risk of insulin resistance has been confirmed. The association between the polymorphism and DN risk has also been widely studied recently, but no consensus was available up to now. RESEARCH DESIGN AND METHODS A systematic search of electronic databases (MEDLINE, Embase, and China National Knowledge Infrastructure) and reference lists of relevant articles was carried out, and then 18 case-control studies involving 3,361 DN cases and 5,825 control subjects were identified. RESULTS In the overall analysis, the Ala12 variant was observed to be significantly associated with decreased DN risk (odds ratio 0.76 [95% CI 0.61–0.93]). Some evidence of heterogeneity among the included studies was detected, which could be explained by the difference of ethnicity and stage of DN. Subgroup analyses stratified by ethnicity and stage of DN were performed, and results indicated the Pro12Ala polymorphism was associated with the risk of DN in Caucasians but no similar association was observed in Asians. Additionally, we observed that Ala12 was associated with decreased risk of albuminuria. With only a few of subjects were available, we failed to detect statistically significant association between the polymorphism and end-stage renal disease (ESRD). CONCLUSIONS Our results indicated that the Ala12 variant is a significantly protective factor for DN. Future research should focus on the effect of Pro12Ala polymorphism on ESRD and gathering data of Africans. PMID:22619290

  2. Maternal PPARG Pro12Ala polymorphism is associated with infant's neurodevelopmental outcomes at 18 months of age.

    PubMed

    Torres-Espínola, Francisco J; Altmäe, Signe; Segura, Maria Teresa; Jerez, Antonio; Anjos, Tania; Chisaguano, Maribel; Carmen López-Sabater, M; Entrala, Carmen; Alvarez, Juan Carlos; Agil, Ahmad; Florido, Jesus; Catena, Andres; Pérez-García, Miguel; Campoy, Cristina

    2015-08-01

    Peroxisome proliferator activated receptors (PPARs) are ligand activated transcription factors with crucial functions in lipid homeostasis, glucose metabolism, anti-inflammatory processes, placental development, and are involved in cognitive functions and neurodegenerative diseases. Polymorphisms in PPAR genes are shown to influence the activity of these receptors. 1) To examine the association of PPARG Pro12Ala polymorphism in pregnant women and their offspring on infant's neurodevelopmental outcomes during the first 18 months of life; 2) to determine the influence of Pro12Ala polymorphism on fatty acid concentrations in plasma phospholipids and placental tissue. 138 mother-infant pairs from the PREOBE observational study were genotyped for PPARG Pro12Ala. Plasma phospholipids and placental fatty acid concentrations were measured at delivery. Infants' neuropsychological assessment at 6 and 18 months of age was performed using Bayley III. The effect of Pro12Ala on infant's neurodevelopmental outcomes was detected at 18 months, but not at 6 months of age. 18 months old infants born to mothers with wild-type Pro12 genotype had better cognitive (OR=5.11, 95% CI: 1.379-18.96, p=0.015), language (OR=3.41, 95% CI: 1.35-11.24, p=0.044), and motor development scores (OR=4.77, 95% CI: 1.243-18.33, p=0.023) than the Ala allele carriers. Pro12Ala variants did not seem to affect fatty acids concentrations in blood nor in placenta at delivery. Infants born to mothers with Pro12 genotype have better neurodevelopmental outcomes at 18 months of age than Ala allele carriers, indicating a long-term transplacental action of PPARγ variants on foetal brain development. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  3. Antitumor effect of combined Dkk-3 and 5-ALA mediated photodynamic therapy in breast cancer cell's colony.

    PubMed

    Mohammadpour, Hemn; Fekrazad, Reza

    2016-06-01

    Dickkopf 3 (Dkk-3), a Wnt signaling inhibitor, is a characterized DKK family member that efficiently suppresses tumor growth in several types of cancer. Photodynamic therapy (PDT) is commonly used for treatment of different types of cancer and antitumor efficacy of PDT increased upon Wnt signaling inhibition. The objective of this study is to evaluate the effects of Dkk-3 and 5-aminolevulinic acid (5-ALA) mediated photodynamic therapy in breast cancer cell line. 4T1 breast cell line were treated with either Dkk-3 (20, 40 and 80ng/ml) 24h followed by 5-ALA-PDT (1, 3 and 6J/cm2). Also, 5-ALA was used at dose 1mM. The apoptosis and post apoptotic necrosis were evaluated by FITC-Annexin-PI apoptosis detection kit. Obtained findings showed that both Dkk-3 and ALA-PDT have cytotoxic effects on cancer cells in a dose-dependent manner. The subtracted mean of death cell percentage in 20, 40 and 80ng/ml of Dkk-3 were 6.8±0.7%, 10.4±0.84% and 16.1±1.55% respectively. The subtracted mean of cell death induction in 5-ALA mediated PDT was 5.3±0.77% at 6J/cm2. Dkk-3 with ALA-PDT significantly increased cell death compared to either Dkk-3 or 5-ALA mediated PDT in cancer 4T1 cancer cell line (P˂0.001). In this study, observed results revealed that Dkk-3 induced the apoptosis in 4T1 breast cancer cells and apoptotic effects of Dkk-3 intensified following photodynamic therapy. This study provided a novel insight into the development of therapeutic strategies for treatment of breast cancer using Dkk-3 combined with PDT. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. ALA-PDT elicits oxidative damage and apoptosis in UVB-induced premature senescence of human skin fibroblasts.

    PubMed

    Zhou, Bing-Rong; Zhang, Li-Chao; Permatasari, Felicia; Liu, Juan; Xu, Yang; Luo, Dan

    2016-06-01

    5-Aminolevulinic acid photodynamic therapy (ALA-PDT) has been used for the treatment of skin photoaging. It can significantly improve the appearance of fine lines, dotted pigmentation, and roughness of photoaged skin. However, the mechanisms by which ALA-PDT yields rejuvenating effects on photoaged skin have not been well elucidated. Thus, in this study we explored the effects of ALA-PDT in photoaged fibroblasts. We established a stress-induced premature senescence (SIPS) model by repeated exposures of human dermal fibroblasts (HDFs) to ultraviolet B (UVB) irradiation. Cells were irradiated by red light laser at 635nm wavelength (50mW/cm(2)). Intracellular protoporphyrin IX (PpIX) was detected by confocal microscopy. Intracellular reactive oxygen species (ROS) level and mitochondrial membrane potential (MMP) change were detected by fluorescence microscopy and flow cytometry. Morphological changes were observed by optical microscopy. Proliferative activity was measured by a cell counting kit-8 (CCK-8). Cell apoptosis was detected by fluorescence microscopy using Hoechst staining and flow cytometry using annexin V/propidium Iodide double staining. Intracellular PpIX fluorescence in UVB-induced premature senescent HDFs (UVB-SIPS-HDFs) reached the highest intensity after incubation with 1.00mmol/L ALA for 6h (P<0.05). Compared with control group, intracellular ROS level, MMP, and apoptotic rate were increased (P<0.05) and proliferative activity was decreased (P<0.05) in UVB-SIPS-HDFs treated with ALA-PDT, which were positively correlated to ALA incubation time and red light laser dose. Our study demonstrated that ALA-PDT elicits oxidative damage and apoptosis in photoaged fibroblasts in vitro, which may be the basis for the rejuvenating effects on photoaged skin. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. [ANALYSIS OF THE ASSOCIATION BETWEEN THR83ALA POLYMORPHISM OF MATRIX GLA-PROTEIN GENE AND LOWER EXTREMITY ARTERIAL CALCIFICATION].

    PubMed

    Ataman, Yu; Еrmolenko, Т; Grek, A; Zharkova, A; Ovechkin, D

    2016-03-01

    Lower extremity arterial calcification (AC) is a common pathological process that has independent significance in the pathogenesis of many cardiovascular diseases. There is evidence that development of AC associated with Thr83Ala polymorphism of matrix GLA-protein gene. The objective of this study was to examine the association between Thr83Ala polymorphism of matrix Cla protein (MGP) gene and AC in male and female subjects of the Ukrainian population. 40 AC and 40 healthy controls were recruited to the study. MGP exon 4 Thr83Ala polymorphism (rs 4236) was examined using the polymerase chain reaction with subsequent restriction fragment length polymorphism analysis. The obtained data show that the substitution of threonin by alanine at position 83 in a molecule of MGP can affect its functional characteristics and anticalcinogenic properties. The distribution of homozygous carriers of a major allelic variant, and heterozygous and homozygous minor allele variants of Thr83Ala polymorphism in patients with AC was 40,0%, 47,5%, and 12,5% respectively. The corresponding distribution of variants in the control group was 32,5%, 42,5% and 25,0% (p=0,352 by χ2 -test). In women who are carriers of Ala/Ala-variant, CA occurs more rarely than in men with the same genotype (p=0,036 by χ2 -test). The substitution of threonine by alanine due to MGP exon 4 Thr83Ala polymorphism is related to a decrease in the likelihood of CA in female persons in the Ukrainian population.

  6. Effects of Ala-Gln feeding strategies on growth, metabolism, and crowding stress resistance of juvenile Cyprinus carpio var. Jian.

    PubMed

    Chen, Xiu-Mei; Guo, Gui-Liang; Sun, Li; Yang, Qiu-Shi; Wang, Gui-Qin; Qin, Gui-Xin; Zhang, Dong-Ming

    2016-04-01

    The present study was conducted to evaluate the effects of different L-alanyl-l-glutamine (Ala-Gln) feeding strategies on the growth performance, metabolism and crowding stress resistance related parameters in juvenile Jian carp (Cyprinus carpio var. Jian) under crowded condition (80 g/L). Juvenile Jian carp (initial weight 26.1 ± 0.6 g) were distributed into five groups which fed with graded concentrations (0% or 1.0%) of Ala-Gln for eight weeks. Control group (I, 0/0) fed with control diet (0% Ala-Gln) throughout the feeding trial. The other four groups employed different control and experimental diet feeding strategies ranging from two weeks control diet fed and two weeks experimental diet (1% Ala-Gln) fed (II, 0/2) to eight weeks experimental diet fed (V, 4/4). Results revealed that Mean weight gain (MEG) under all different feeding strategies of Ala-Gln were significantly higher than that of the control group (p < 0.05), and MEG of group II (201.90%) was even higher than that of group IV (184.70%). Liver glycogen and blood total protein of groups II, III and V were significantly higher than that in groups I and IV (p < 0.05). The highest level of serum thyroxine (10.07 ng/ml), insulin-like growth factor-I (52.40 ng/ml) and insulin (9.73 μ IU/mL) were observed in group V. However, diet supplemented with Ala-Gln did not affect the levels of serum glucose, cortisol and catecholamine in fish. The mRNA expression of GR1a, GR1b and GR2 were also significantly changed in Ala-Gln supplementation groups compared with control group (p < 0.05). After fish intraperitoneally injected with virulent Aeromonas hydrophila, the fish survival rates were significantly increased in all Ala-Gln supplementation groups compared with control group (p < 0.05). Results from the present experiment showed the importance of dietary supplementation of Ala-Gln in benefaction of the growth performance, metabolism and crowding stress resistance in Jian carp breeding. The

  7. The Simplified Aircraft-Based Paired Approach With the ALAS Alerting Algorithm

    NASA Technical Reports Server (NTRS)

    Perry, Raleigh B.; Madden, Michael M.; Torres-Pomales, Wilfredo; Butler, Ricky W.

    2013-01-01

    This paper presents the results of an investigation of a proposed concept for closely spaced parallel runways called the Simplified Aircraft-based Paired Approach (SAPA). This procedure depends upon a new alerting algorithm called the Adjacent Landing Alerting System (ALAS). This study used both low fidelity and high fidelity simulations to validate the SAPA procedure and test the performance of the new alerting algorithm. The low fidelity simulation enabled a determination of minimum approach distance for the worst case over millions of scenarios. The high fidelity simulation enabled an accurate determination of timings and minimum approach distance in the presence of realistic trajectories, communication latencies, and total system error for 108 test cases. The SAPA procedure and the ALAS alerting algorithm were applied to the 750-ft parallel spacing (e.g., SFO 28L/28R) approach problem. With the SAPA procedure as defined in this paper, this study concludes that a 750-ft application does not appear to be feasible, but preliminary results for 1000-ft parallel runways look promising.

  8. Mortality in experimental adjuvant intraoperative photodynamic therapy (AIOPDT) using ALA, Photofrin II, and mTHPC

    NASA Astrophysics Data System (ADS)

    Winkler, Steffi; Prosst, Ruediger L.; Stern, Josef; Rheinwald, Markus; Haase, Thomas; Herfarth, Christian; Gahlen, Johannes

    2001-01-01

    A clinical problem in the treatment of colorectal cancer is the high rate of local tumor recurrence. Adjuvant therapy methods are necessary to receive a better clinical outcome in minimizing local tumor relapse. Adjuvant intraoperative photodynamic therapy (AIOPDT) seems to be a promising alternative therapy in the treatment of malignant colorectal diseases. IN experimental settings the success of AIOPDT depends on the accumulation of the photosensitizer (PS) in tumor tissue and may be jeopardized by high mortality rates, due to inadequate energy doses. Our study evaluated mortality rates of nude mice after AIOPDT with ALA, Photofrin II and mTHPC using the following various light doses: ALA/Photofrin II: 100J, 50J, 25J; mTHPC: 30J, 15J, 5J generated by an Argon-Dye-laser system. There was a close correlation between laser energy applied for AIOPDT and postoperative mortality rate. Initial high mortality rates were lowered by stepwise reduction of the energy dose. Mortality rates reached a maximum 24 hours after AIOPDT in all groups.

  9. Integral photodynamic therapy of bladder cancer using 5-ALA and white light

    NASA Astrophysics Data System (ADS)

    Baumgartner, Reinhold; Waidelich, Raphaela; Beyer, Wolfgang; Stepp, Herbert G.; Knuechel-Clarke, Ruth; Hofstetter, Alfons

    2005-04-01

    We report on clinical experiences with photodynamic therapy in patients with recurrent, multifocal superficial transitional cell carcinoma of the urinary bladder. PDT is performed by intravesically applied 5-aminolevulinic acid and a Xe arc lamp as a light source delivering more than 5 Watt white light for activation of 5-ALA induced Protoporphyrin IX. For whole bladder wall irradiation a special irrigation catheter system has been developed. Based on that technology we determined whether this treatment modality was effective in destroying urothelial carcinoma and preventing recurrent disease. The study should help defining the optimal target group of patients and is considered as basis for a long term and multicenter clinical trial. The initial clinical results indicate that white light photodynamic therapy with 5-ALA is an effective organ-preserving procedure for treating multifocal superficial transitional cell carcinoma of the bladder, even in patients with refractory urothelial carcinoma and is effective in selectively destroying flat neoplastic lesions like carcinoma in situ. None of the patients showed phototoxic skin reactions or loss of bladder capacity.

  10. Fold deformations of the paleozoic basement roof in the Chunkurchak Trough, Kyrgyz Ala-Too Range

    NASA Astrophysics Data System (ADS)

    Przhiyalgovskii, E. S.; Lavrushina, E. V.

    2017-07-01

    A structural-geological study has been performed on the northern slope of the Kyrgyz Ala-Too Range. Deformations of the peneplaned Paleozoic basement surface, structures of granite disintegration, and morphostructural manifestation of Late Cenozoic tectonic movements have been investigated. Based on the location of pre-Paleocene peneplain remnants with the retained weathering mantle partly overlapped by Paleocene-Miocene sedimentary complexes, we have reconstructed the morphology of the folded surface of the Chunkurchak Trough separated from the Chu Basin at the early Miocene. The dome-fold forms, the morphology and arrangement of which are controlled by disintegration of the basement, have been described for the basement surface. It has been established that granites are broken by systems of steeply dipping, fanshaped, and gently dipping faults and fractures. Variously oriented insignificant offsets along slickensides, as well as displacements deduced from the geometry of fracture intersections, are a result of volumetric cataclastic flow of rocks. The tectonic mobility of disintegrated granites, which are abundant in the Paleozoic-Precambrian basement, explains the complexity and scale of tectonic processes initiated by Cenozoic activation. In paleotectonic reconstructions, which take into consideration tectonic flow and the redistribution of basement masses, the estimates of Cenozoic relative rapprochement of the Chu Basin and the Kyrgyz Ala-Too Range decrease substantially to 4-6 km.

  11. Electron diffraction studies of light-induced conformational changes in the Leu-93 --> Ala bacteriorhodopsin mutant.

    PubMed

    Subramaniam, S; Faruqi, A R; Oesterhelt, D; Henderson, R

    1997-03-04

    We previously have presented evidence for prominent structural changes in helices F and G of bacteriorhodopsin during the photocycle. These changes were determined by carrying out electron diffraction analysis of illuminated two-dimensional crystals of wild-type bacteriorhodopsin or the Asp-96 --> Gly mutant that were trapped at a stage in the photocycle after light-driven proton release, but preceding proton uptake from the aqueous medium. Here, we report structural analysis of the long-lived O intermediate observed in the photocycle of the Leu-93 --> Ala mutant, which accumulates after the release and uptake of protons, but before the reisomerization of retinal to its initial all-trans state. Projection Fourier difference maps show that upon illumination of the Leu-93 --> Ala mutant, significant structural changes occur in the vicinity of helices C, B, and G, and to a lesser extent near helix F. Our results suggest that (i) all four helices that line the proton channel (B, C, F, and G) participate in structural changes during the late stages of the photocycle, and (ii) completion of the photocycle involves significant conformational changes in addition to those that are associated with steps in proton transport.

  12. The influence of photodynamic therapy (PDT) with δ-aminolevulinic acid (ALA) on J-774A.1 macrophage cell line

    NASA Astrophysics Data System (ADS)

    Kawczyk-Krupka, Aleksandra; Czuba, Zenon; Ledwon, Aleksandra; Latos, Wojciech; Sliszka, Ewelina; Mianowska, Marta; Krol, Wojciech; Sieron, Aleksander

    2008-02-01

    Introduction. The whole mechanism of the cellular level of tumor destruction by photodynamic therapy (PDT) is still unknown. Despite necrotic and apoptotic ways of cell death, there is a variety of events leading to and magnifying the inactivation of tumor cells. Material and methods. J-774A.1 were incubated with δ-aminolevulinic acid (ALA) at different concentrations (125, 250, 500, 1000 μM) and then irradiated with VIS (400 - 750 nm) at the dose of 5,10 and 30 J/cm2 delivered from the incoherent light source. The effects of the application of ALA-PDT were evaluated on the basis of cell viability, nitric oxide (NO), tumor necrosis factor α- (TNF-α) and interleukin-1β (IL-1β) produced by the J-774A.1 cells. Results. The cell viability (assessed using MTT test) was comparable with control group at 5,10 and 30 J/cm2. At these doses of energy using different concentrations of ALA we have observed that at the higher energy doses, the greater increase of TNF-α release, lowering of the level of IL-1β production and decrease of NO release were observed. There was also observed the dependence of the secretional activity of the cells on the ALA concentrations. Conclusion. The cell viability and production of cytokines depended on ALA concentrations and energy doses of the light. The higher some cytokines' release after PDT could be an additional factor for the complete eradication of tumor.

  13. The Pro12Ala polymorphism of the PPAR-gamma gene is not associated with the polycystic ovary syndrome.

    PubMed

    Xita, Nectaria; Lazaros, Leandros; Georgiou, Ioannis; Tsatsoulis, Agathocles

    2009-01-01

    Insulin resistance is a key factor in the pathogenesis of polycystic ovary syndrome (PCOS). Peroxisome proliferator-activated- receptor-gamma (PPAR-gamma) has been implicated in insulin resistance and adiposity. The aim of the study was to investigate the possible involvement of the Pro12Ala polymorphism of the PPAR-gamma gene in the pathogenesis of PCOS. We studied 180 women with PCOS and 140 healthy controls. Body mass index (BMI) was recorded. Blood samples were drawn after overnight fasting and serum glucose, insulin, lipid and hormonal profiles were determined. The fasting glucose/insulin ratio and HOMA index were calculated. Moreover, 100 women with PCOS underwent a 75g oral glucose tolerance test and the area under the curve for insulin and glucose was estimated. DNA was extracted from peripheral blood leucocytes and the Pro12Ala polymorphism was genotyped. The PPAR-gamma genotypes were found to be in the Hardy-Weinberg equilibrium in both study groups. No difference was found in the distribution of the Pro12Ala polymorphism between PCOS and controls. Insulin resistance indices and lipid and hormonal profile were not different among the various genotypes of the Pro12Ala polymorphism. The Pro12Ala polymorphism of the PPAR-gamma gene is not involved in the pathogenesis or the phenotypic expression of PCOS.

  14. A meta-analysis on the association between PPAR-γ Pro12Ala polymorphism and polycystic ovary syndrome.

    PubMed

    He, Junli; Wang, Li; Liu, Junhong; Liu, Feng; Li, Xuliang

    2012-07-01

    To investigate the influence of the peroxisome proliferator activated receptor gamma (PPAR-γ) Pro12Ala polymorphism on the susceptibility of polycystic ovary syndrome (PCOS) and body mass index (BMI), fast insulin levels, homeostasis model assessment of insulin resistance (HOMA-IR) in PCOS patients. PubMed, EMBASE, MEDLINE and CENTRAL databases were searched to identify eligible studies. We then conducted a meta-analysis to examine the association between Pro12Ala polymorphism and PCOS. Seventeen eligible studies, including 2,149 patients and 2,124 controls were enrolled in this meta-analysis. Pro12Ala polymorphism was significantly associated with the susceptibility of PCOS (odds ratio [OR] 0.74, 95 % confidence interval [CI] [0.61, 0.90] for allele; OR 0.70, 95 % CI [0.57, 0.86] for genotype). In the European subgroup of PCOS, the X/Ala genotype was associated with lower BMI (mean difference [MD] -1.08, 95 % CI [-2.08, -0.09]) and fast insulin levels (MD -19.82, 95 % CI [-34.07, -5.58]). However, this polymorphism did not display an impact on HOMA-IR in PCOS patients. Ala variant would decrease the risk of PCOS and result in lower BMI and fast insulin levels in a European population, but had no impact on HOMA-IR in PCOS patients. Further studies are required to elucidate these associations more clear.

  15. Optical scatter imaging as an apoptosis assay for cells undergoing ALA-mediated photodynamic therapy in vitro

    NASA Astrophysics Data System (ADS)

    Rossi, Vincent M.; Baugher, Paige J.; Jacques, Steven L.

    2013-02-01

    Aminolevulinic acid (ALA) is converted to protoporphyrin-IX (PpIX) within mitochondria, causing the assumption that ALA-mediated photodynamic therapy (PDT) results in mitochondrial damage and therefore an apoptotic response. Mitochondria within apoptosing cells swell, forming pores in their outer mitochondrial membranes which release cytochrome-c, triggering apoptosis. Optical scatter imaging (OSI) makes use of scattered fields in order to indicate the morphology of subcellular components, and is used here in order to measure changes in mitochondrial size as a response to ALA-mediated PDT. Two images of the same field of view are spatially filtered in the Fourier plane of a 4-F system. Both spatial filters block directly transmitted light, while accepting different angles of scattered light through an adjustable iris. The optical scatter image ratio (OSIR) of the local intensities of these two spatially filtered images is indicative of scattering particle size. Mie theory is used to calculate the predicted OSIR as a function of scattering particle size. In this fashion, the OSI system is calibrated using polystyrene microspheres of know sizes. Comparison of the measured OSIR from cellular images to theoretical values predicted for mitochondria then serves as an indication as to whether cells are apoptosing. Cells are treated at varying concentrations of ALA and varying exposures of 635 nm light and imaged at varying time points in order to develop a broader understanding of an apoptotic response of cells undergoing ALA mediated PDT.

  16. Urinary delta-aminolevulinic acid (ALA) excretion in humans and cattle as an index of exposure to lead

    SciTech Connect

    Adaudi, A.O.; Aliu, Y.O.

    1980-12-01

    Disposable ion-exchange chromatographic columns were used to determine delta-aminolevulinic acid (ALA) concentrations in 11 bovine and 184 human urine samples. The mean urinary ALA concentrations in persons working as battery chargers, autopainters, automechanics, and urban first-grade pupils were 11.61 +/- 14.23, 6.51 +/- 3.31, 6.48 +/- 3.36, and 5.71 +/- 2.91 micrograms/ml respectively. These values were higher than those found in urine from gasoline station attendants, university students and laboratory assistants, rural adult farmers, and rural first-grade pupils, which were 4.90 +/- 1.95, 4.93 +/- 1.76, 4.40 +/- 1.79 and 4.51 +/- 2.65 micrograms/ml respectively. In cattle (Holstein Friesian/White Fulani cross) the mean urinary ALA concentration was 1.84 +/- 0.04 micron/ml. The data indicates that persons working around automobile, lead batteries and leaded gasoline had elevated ALA concentrations in urine. Rural humans and cattle did not have significant elevations of urinary ALA.

  17. Association analysis of PPARγ (p.Pro12Ala) polymorphism with type 2 diabetic retinopathy in patients from north India.

    PubMed

    Kaur, Navdeep; Vanita, Vanita

    2017-01-01

    The present study aimed to examine the association of PPARγ (p.Pro12Ala) polymorphism with type 2 diabetic retinopathy (DR) in patients from north India. In this case-control association study a total of 1325 subjects (717 DR patients and 608 individuals with confirmed type 2 diabetes mellitus (T2DM) without retinopathy taken as controls (CDR)), were recruited. Genotyping for PPARγ (p.Pro12Ala) polymorphism was performed by Taqman SNP Genotyping Assays using Real time PCR. Statistically significant differences were observed between the two analyzed groups in the duration of diabetes and random blood glucose levels (p = 0.000 and p = 0.011, respectively). However, genotype and allele frequency distribution of PPARγ (p.Pro12Ala) polymorphism did not differ significantly between DR and CDR groups (p = 0.507 and 0.625, respectively). These findings suggest no significant association of p.Pro12Ala polymorphism with retinopathy in tested type 2 diabetic retinopathy patients as compared to T2DM individuals take as controls. To our knowledge, this is the first report of association analysis of p.Pro12Ala polymorphism in PPARγ in DR patients from India.

  18. Erythrocyte ALA-d activity in experimentally lead-poisoned ducks and its change during treatment with disodium calcium EDTA.

    PubMed

    Murase, T; Horiba, N; Goto, I; Yamato, O; Ikeda, T; Sato, K; Jin, K; Inaba, M; Maede, Y

    1993-09-01

    To determine useful procedures for the diagnosis and prognosis of lead poisoning in waterfowl caused by ingestion of lead pellets, erythrocyte delta-aminolevulinic acid dehydratase (ALA-d) was investigated in experimentally lead-poisoned ducks. A highly positive correlation was observed between the concentration of blood lead and the ALA-d activity ratio (the ratio of activated:non-activated enzyme activity) in those birds given seven lead pellets (3 mm diameter). The ALA-d activity ratio rapidly increased after the administration of lead pellets, but began to fall immediately after the initiation of disodium calcium ethylenediamine tetra-acetate (CaEDTA) therapy which resulted in a rapid decrease in the concentration of lead in the blood of these birds. In contrast, the ALA-d activity remained inhibited even after blood lead levels began to decrease following treatment. These results demonstrated that the ALA-d activity ratio is a very useful and sensitive indicator for the diagnosis and evaluation of therapeutic effects after lead poisoning in waterfowl.

  19. Comparative in vivo study of precursors of PpIX (ALA and MAL) used topically in photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Rego, Raquel F.; Inada, Natalia M.; Ferreira, Juliana; Araújo-Moreira, Fernando M.; Bagnato, Vanderlei S.

    2009-06-01

    The efficacy of Photodynamic Therapy (PDT) combined with aminolevulinic acid (ALA) or methyl aminolevulinate (MAL) in treatment of cancer has been studied for over ten years. However, there is no established dose for the topical use of these drugs in PDT. The purpose of this study was the comparison of induced PDT response of ALAsense (5-aminolevulinic acid - ALA) and Metvix (methyl aminolevulinate - MAL). Depth of necrosis induced by PDT was analyzed in normal liver of male Wistar rats, using different light doses and topical application of both PpIX precursors - ALA and MAL. PDT was performed with a diode laser at 630 nm with different doses of light (20, 50, 100 and 200 J/cm2), and intensity of 250 mW/cm2. Depth of necrosis analysis was used to calculate the threshold dose for each drug. The results showed that MAL-PDT presented a better response than ALA-PDT, mainly due to formulation differences. Moreover, the ability of the ALA PpIX production was more efficient.

  20. Structural and functional analysis of the ASM p.Ala359Asp mutant that causes acid sphingomyelinase deficiency.

    PubMed

    Acuña, Mariana; Castro-Fernández, Víctor; Latorre, Mauricio; Castro, Juan; Schuchman, Edward H; Guixé, Victoria; González, Mauricio; Zanlungo, Silvana

    2016-10-21

    Niemann-Pick disease (NPD) type A and B are recessive hereditary disorders caused by deficiency in acid sphingomyelinase (ASM). The p.Ala359Asp mutation has been described in several patients but its functional and structural effects in the protein are unknown. In order to characterize this mutation, we modeled the three-dimensional ASM structure using the recent available crystal of the mammalian ASM as a template. We found that the p.Ala359Asp mutation is localized in the hydrophobic core and far from the sphingomyelin binding site. However, energy function calculations using statistical potentials indicate that the mutation causes a decrease in ASM stability. Therefore, we investigated the functional effect of the p.Ala359Asp mutation in ASM expression, secretion, localization and activity in human fibroblasts. We found a 3.8% residual ASM activity compared to the wild-type enzyme, without changes in the other parameters evaluated. These results support the hypothesis that the p.Ala359Asp mutation causes structural alterations in the hydrophobic environment where ASM is located, decreasing its enzymatic activity. A similar effect was observed in other previously described NPDB mutations located outside the active site of the enzyme. This work shows the first full size ASM mutant model describe at date, providing a complete analysis of the structural and functional effects of the p.Ala359Asp mutation over the stability and activity of the enzyme. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Substitution of Gly with Ala enhanced the melanoma uptake of technetium-99m-labeled Arg-Ala-Asp-conjugated alpha-melanocyte stimulating hormone peptide.

    PubMed

    Yang, Jianquan; Miao, Yubin

    2012-02-15

    The purpose of this study was to determine the melanoma targeting property of (99m)Tc-RAD-Lys-(Arg(11))CCMSH in B16/F1 melanoma-bearing C57 mice and compare with (99m)Tc-RGD-Lys-(Arg(11))CCMSH we previously reported. (99m)Tc-RAD-Lys-(Arg(11))CCMSH exhibited rapid and high tumor uptake (19.91±4.02% ID/g at 2h post-injection) in B16/F1 melanoma-bearing C57 mice. The tumor uptake of (99m)Tc-RAD-Lys-(Arg(11))CCMSH was 1.51, 1.34 and 1.43 times the tumor uptake of (99m)Tc-RGD-Lys-(Arg(11))CCMSH at 0.5, 2 and 4h post-injection, respectively. Flank B16/F1 melanoma lesions were clearly imaged at 2h post-injection using (99m)Tc-RAD-Lys-(Arg(11))CCMSH as an imaging probe. The substitution of Gly with Ala significantly enhanced the melanoma uptake of (99m)Tc-RAD-Lys-(Arg(11))CCMSH compared to (99m)Tc-RGD-Lys-(Arg(11))CCMSH in B16/F1 melanoma-bearing C57 mice, providing a new insight into the design of α-MSH peptides for melanoma targeting.

  2. Three-dimensional analysis of pulmonary nodules by MSCT with Advanced Lung Analysis (ALA1) software.

    PubMed

    Volterrani, L; Mazzei, M A; Scialpi, M; Carcano, M; Carbone, S F; Ricci, V; Guazzi, G; Lupattelli, L

    2006-04-01

    The purpose of this study was to test the reproducibility of the three-dimensional (3D) Advanced Lung Analysis software (3D-ALA, GE Healthcare) in the estimation of pulmonary nodule volume. We retrospectively reviewed the unenhanced multislice CT scans (Lightspeed Pro 16 GE) of 77 patients with a solitary pulmonary nodule (n=71) or metastatic pulmonary disease (n=6). A total of 103 pulmonary nodules (19 well-circumscribed, 45 juxtavascular and 39 juxtapleural) were analysed grouped into five classes based on diameter: <5 mm, 10 nodules (9.7%); >or=5 to <10 mm, 25 nodules (24.2%); >or=10 mm to <15 mm, 41 nodules (39.8%); >or=5 to <18 mm, 14 nodules (13.6% ); >or=8 to <30 mm, 13 nodules (12.62%). The following acquisition parameters were used: slice thickness 0.625 mm, reconstruction interval 0.4 mm, pitch 0.562:1, 140 kV, 300 mAs, field of view 13 cm, bone kernel. For each of the 103 nodules three, 3D volume measurements were obtained by the 3D-ALA software. The reproducibility of nodule segmentation was evaluated according to a visual score (1=optimal, >or=95%; 2=fair, 90-95%; 3=poor, ALA-1 software allowed segmentation in all nodules (type 1 segmentation n=43, type 2 n=35, type 3 segmentation n=25). ALA-1 provided an identical 3D volume measurement in 62 nodules: [16 out of 19 well circumscribed (84.2%), 31 out of 45 juxtavascular (68.8%), 15 out of 39 juxtapleural (38.4%)]. Repeatability of 3D volume measurement was not possible in 41 out of 103 nodules [3 out of 19 (15.7%) well-circumscribed, 14 out of 45 (31.1%) juxtavascular, 24 out of 39 (61.5%) juxtapleural]. Among the 41 nodules with nonrepeatable 3D volume measurement, segmentation was scored as 1 in 2 out of 41 (4.8%), as 2 in 15 out of 41 (36.5%) and as 3 in 24 out of 41 (58.5%). The

  3. Photodynamic therapy with low-strength ALA, repeated applications and short contact periods (40-60 minutes) in acne, photoaging and vitiligo.

    PubMed

    Serrano, Gabriel; Lorente, Matilde; Reyes, Madga; Millán, Fernando; Lloret, Adrián; Melendez, Joaquín; Navarro, Maria; Navarro, Miguel

    2009-06-01

    Topical aminolevulinic acid (ALA) photodynamic therapy (PDT) is currently being used for the treatment of actinic keratosis of the face and scalp. This study reports the results obtained after three to four treatments with ALA-PDT in patients with acne (n=12), photoaging (n=8) and vitiligo (n=6). ALA was applied on large areas (e.g., full face) and at very low strengths (1-2%). Side effects were minimal and self-limited.

  4. Controlled self-assembling structures of ferrocene-dipeptide conjugates composed of Ala-Pro-NHCH2CH2SH chain.

    PubMed

    Moriuchi, Toshiyuki; Nishiyama, Taiki; Tayano, Yoshiki; Hirao, Toshikazu

    2017-05-18

    Bioorganometallic ferrocene-dipeptide conjugates with the Ala-Pro-cysteamine chain, Fc-L-Ala-L-Pro-NHCH2CH2SH (2) and Fc-L-Ala-D-Pro-NHCH2CH2SH (4) (Fc=ferrocenoyl), were prepared by the reduction of the ferrocene-dipeptide conjugates, Fc-L-Ala-L-Pro-cystamine-L-Pro-L-Ala-Fc (1) or Fc-L-Ala-D-Pro-cystamine-D-Pro-L-Ala-Fc (3), respectively. Control of the self-assembling structures of the ferrocene-dipeptide conjugates was demonstrated by changing the chirality of the amino acid. The molecular structure of 2 composed of the L-Ala-L-Pro-NHCH2CH2SH chain confirmed the formation of intramolecular hydrogen bond of N-H⋯N pattern between the NH of cysteamine moiety and the nitrogen of Pro moiety. Furthermore, intermolecular hydrogen bonds between NH (Ala) and CO (Pro of another molecule) and between NH (cysteamine) and CO (the ferrocenoyl moiety of another molecule) were formed, wherein each molecule is connected to four neighboring molecules by continuous intermolecular hydrogen bonds to form the hydrogen-bonded molecular assembling structure. On the contrary, the left-handed helical assembly through an intermolecular hydrogen-bonding network of 15-membered intermolecularly hydrogen-bonded ring between NH (Ala) and CO (the ferrocenoyl moiety of another molecule) and between NH (the cysteamine moiety of another molecule) and CO (Ala) was observed in the crystal packing of 4 composed of the L-Ala-D-Pro-NHCH2CH2SH chain. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Evaluation of single nucleotide polymorphisms of Pro12Ala in peroxisome proliferator-activated receptor-γ and Gly308Ala in tumor necrosis factor-α genes in obese Asian Indians: a population-based study.

    PubMed

    Bhagat, Namita; Agrawal, Mukta; Luthra, Kalpana; Vikram, Naval K; Misra, Anoop; Gupta, Rajeev

    2010-10-11

    A population-based case control study was performed to determine the associations of Pro12Ala polymorphism in peroxisome proliferator-activated receptor-γ (PPARG) and Gly308Ala polymorphism in tumor necrosis factor-α (TNFA) genes in obese subjects. Of 1,400 eligible subjects, ≧20 years, we recruited only 1,127. For extreme phenotype case-control design, we evaluated 201 subjects with body mass index (BMI) ≧30 kg/m(2) (Group 1) and 143 with BMI <20 kg/m(2) (Group 2). Clinical, anthropometric, biochemical, and nutritional details and polymorphisms were estimated. In Group 1, the dietary intake of calories and fats was higher, physical activity was lower, and prevalence of truncal obesity, hypertension, high total cholesterol, low high-density lipoprotein cholesterol, and diabetes was greater than in Group 2. There were no homozygous polymorphisms of either gene. Heterozygous Pro12Ala polymorphism in PPARG was found in 15 (7.5%) subjects in Group 1 and 3 (2.1%) subjects in Group 2 (P = 0.028), and heterozygous Gly308Ala polymorphism in TNFA was found in 19 (9.5%) in Group 1 and 7 (4.9%) in Group 2 (P = 0.115). Presence of heterozygous polymorphism in PPARG and TNFA-predicted obesity with univariate odds ratio ([OR], 95% confidence intervals) of 2.25 (1.32-3.84, P = 0.003) and 1.48 (1.10-1.99, P = 0.009) and with multivariate OR 1.74 (1.03-2.93, P = 0.038) and 1.46 (1.05-2.03, P = 0.024), respectively. The addition of dietary and physical activity variables did not result in significant change. Obese Asian Indians have greater prevalence of heterozygous polymorphisms of Pro12Ala in PPARG and Gly308Ala in TNFA genes.

  6. Properties of myelin altered peptide ligand cyclo(87-99)(Ala91,Ala96)MBP87-99 render it a promising drug lead for immunotherapy of multiple sclerosis.

    PubMed

    Deraos, George; Rodi, Maria; Kalbacher, Hubert; Chatzantoni, Kokona; Karagiannis, Fotios; Synodinos, Loukas; Plotas, Panayiotis; Papalois, Apostolos; Dimisianos, Nikolaos; Papathanasopoulos, Panagiotis; Gatos, Dimitrios; Tselios, Theodore; Apostolopoulos, Vasso; Mouzaki, Athanasia; Matsoukas, John

    2015-08-28

    Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system, and it has been established that autoreactive T helper (Th) cells play a crucial role in its pathogenesis. Myelin basic protein (MBP) epitopes are major autoantigens in MS, and the sequence MBP87-99 is an immunodominant epitope. We have previously reported that MBP87-99 peptides with modifications at principal T-cell receptor (TCR) contact sites suppressed the induction of EAE symptoms in rats and SJL/J mice, diverted the immune response from Th1 to Th2 and generated antibodies that did not cross react with the native MBP protein. In this study, the linear and cyclic analogs of the MBP87-99 epitope, namely linear (Ala91,Ala96)MBP87-99 (P2) and cyclo(87-99)(Ala91,Ala96)MBP87-99 (P3), were evaluated for their binding to HLA-DR4, stability to lysosomal enzymes, their effect on cytokine secretion by peripheral blood mononuclear cells (PBMC) derived from MS patients or healthy subjects (controls), and their effect in rat EAE. P1 peptide (wild-type, MBP87-99) was used as control. P2 and P3 did not alter significantly the cytokine secretion by control PBMC, in contrast to P1 that induced moderate IL-10 production. In MS PBMC, P2 and P3 induced the production of IL-2 and IFN-γ, with a simultaneous decrease of IL-10, whereas P1 caused a reduction of IL-10 secretion only. The cellular response to P3 indicated that cyclization did not affect the critical TCR contact sites in MS PBMC. Interestingly, the cyclic P3 analog was found to be a stronger binder to HLA-DR4 compared to linear P2. Moreover, cyclic P3 was more stable to proteolysis compared to linear P2. Finally, both P2 and P3 suppressed EAE induced by an encephalitogenic guinea pig MBP74-85 epitope in Lewis rats whereas P1 failed to do so. In conclusion, cyclization of myelin altered peptide ligand (Ala91,Ala96)MBP87-99 improved binding affinity to HLA-DR4, resistance to proteolysis and antigen-specific immunomodulation

  7. Association between the Pro12Ala polymorphism of peroxisome proliferator-activated receptor gamma 2 and inflammatory bowel disease: a meta-analysis.

    PubMed

    Zhang, Zhi-Feng; Yang, Ning; Zhao, Gang; Zhu, Lei; Wang, Li-Xia

    2012-01-01

    Peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor, has been implicated playing a role in the development of inflammatory bowel disease (IBD). However, previous studies evaluating the association between the PPARγ2 Pro12Ala polymorphism and IBD are inconsistent. We performed a meta-analysis to determine whether the PPARγ2 Pro12Ala mutation was associated with the presence of IBD. Electronic databases were searched for case-control studies evaluating the association between the Pro12Ala mutation and the presence of IBD. Effects were summarized with the methods recommended by the Cochrane Collaboration. A total of 7 studies including 1002 ulcerative colitis (UC) cases, 1090 Crohǹs disease (CD) cases and 1983 controls were involved in this meta-analysis. In the overall analysis, no significant association of this polymorphism with UC or CD was found. In the subgroup analyses in different populations, AlaAla genotype seemed to protect the European Caucasian population against the development of CD (Pro vs Ala: OR = 1.135, 95%CI = 0.951-1.354, P = 0.162, Bon = 1.000; ProPro vs ProAla: OR = 1.042, 95%CI = 0.852-1.273, P = 0.690, Bon = 1.000; ProPro vs AlaAla: OR = 2.379, 95%CI = 1.110-5.100, P = 0.026, Bon = 0.156; ProAla vs AlaAla: OR = 2.315, 95%CI = 1.064-5.037, P = 0.034, Bon = 0.204; Pro homozygotes vs Ala positives: OR = 1.094, 95%CI = 0.899-1.330, P = 0.371, Bon = 1.000; Pro positives vs Ala homozygotes: OR = 2.360, 95%CI = 1.103-5.053, P = 0.027, Bon = 0.162; heterozygotes vs all homozygotes: OR = 0.976, 95%CI = 0.799-1.192, P = 0.809, Bon = 1.000). There was no significant association of this polymorphism with UC or CD in the East Asian population and the Turkish population. AlaAla genotype may be a protective factor in the European Caucasian population against the development of CD in a recessive way.

  8. Manganese superoxide dismutase Ala-9Val polymorphism and risk of breast cancer in a population-based case–control study of African Americans and whites

    PubMed Central

    Millikan, Robert C; Player, Jon; de Cotret, Allan René; Moorman, Patricia; Pittman, Gary; Vannappagari, Vani; Tse, Chiu-Kit J; Keku, Temitope

    2004-01-01

    Introduction A polymorphism in the manganese superoxide dismutase (MnSOD) gene, Ala-9Val, has been examined in association with breast cancer risk in several epidemiologic studies. Results suggest that the Ala allele increases the risk of breast cancer and modifies the effects of environmental exposures that produce oxidative damage to DNA. Methods We examined the role of the MnSOD Ala-9Val polymorphism in a population-based case–control study of invasive and in situ breast cancer in North Carolina. Genotypes were evaluated for 2025 cases (760 African Americans and 1265 whites) and for 1812 controls (677 African Americans and 1135 whites). Results The odds ratio for MnSOD Ala/Ala versus any MnSOD Val genotypes was not elevated in African Americans (odds ratio = 0.9, 95% confidence interval = 0.7–1.2) or in whites (odds ratio = 1.0, 95% confidence interval = 0.8–1.2). Greater than additive joint effects were observed for the Ala/Ala genotype and smoking, radiation to the chest, and occupational exposure to ionizing radiation. Antagonism was observed between the Ala/Ala genotype and the use of nonsteroidal anti-inflammatory drugs. Conclusions The MnSOD genotype may contribute to an increased risk of breast cancer in the presence of specific environmental exposures. These results provide further evidence for the importance of reactive oxygen species and of oxidative DNA damage in the etiology of breast cancer. PMID:15217492

  9. Association of Pro12Ala (rs1801282) variant of PPAR gamma with rheumatoid arthritis in a Pakistani population.

    PubMed

    Jalil, Syed Fazal; Ahmed, Iltaf; Gauhar, Zeeshan; Ahmed, Mushtaq; Malik, Javaid M; John, Peter; Bhatti, Attya

    2014-05-01

    Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) belongs to a receptor superfamily of ligand-activated transcription factors, encoded by PPARG gene. Role of PPARγ has been well established in variety of metabolic disorders and in regulation of inflammation. In the present study, we aimed to investigate the association of PPARG (Pro12Ala; rs1801282) in clinically definite Pakistani Rheumatoid Arthritis (RA) patients and matching controls. The genotypes of the Pro12Ala variant in the PPARG were determined in a sample of 300 Pakistanis, including 150 RA cases and 150 controls. The genotyping was performed using Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR) method, and the data was analyzed through Graphpad Prism 5 V software. Allele-specific primer set (two forward: PPARG-F1, PPARG-F2 and a common reverse primer: PPARG-R) was used for amplification, and the product was resolved on 2 % agarose gel. The CC (ProPro) genotype has higher frequency in controls than RA cases [75 (50.0 %) vs. 51 (34.0 %)], whereas the CG (ProAla) genotype has relatively same frequencies in both cases and controls [72 (48.0 %) vs. 70 (46.6 %)]. However, significantly higher frequency of GG (AlaAla) genotype was observed in cases [27 (18.0 %) vs. 5 (3.3 %); χ2 18.54; p < 0.0001]. Furthermore, the minor allele G has significantly higher allele frequency in cases having same trend and direction of association (OR 1.991(1.412-2.808); p < 0.0001). These observations suggest that Pro12Ala (rs1801282), a coding variant in the PPARG gene, is associated with Rheumatoid Arthritis in Pakistanis.

  10. No association of Pro12Ala polymorphism of PPAR-gamma gene with coronary artery disease in Korean subjects.

    PubMed

    Rhee, Eun Jung; Kwon, Chang Hee; Lee, Won Young; Kim, Se Yeon; Jung, Chan Hee; Kim, Byung Jin; Sung, Ki Chul; Kim, Bum Soo; Oh, Ki Won; Kang, Jin Ho; Park, Sung Woo; Kim, Sun Woo; Lee, Man Ho; Park, Jung Roe

    2007-03-01

    Peroxisome proliferator-activated receptor (PPAR)-gamma, a member of the nuclear hormone receptor family, which is involved in the differentiation of adipose tissue, is reported to be associated with the pathogenesis of type 2 diabetes mellitus, insulin resistance and atherosclerosis. Whether the prevalence of coronary artery disease (CAD) is associated with Pro12Ala polymorphism in exon B of PPAR-gamma was investigated in Korean adults. The study was conducted in 267 subjects (158 males, 109 females, mean age 58 years) who underwent coronary angiography because of chest pain. Cardiovascular risk factors, such as blood pressure, body mass index (BMI), fasting blood sugar and serum lipid profiles, were assessed in all subjects, who were divided into 4 groups according to the number of stenosed coronary arteries: normal, 1-vessel, 2-vessel and 3-vessel disease. Genotyping of Pro12Ala polymorphism was done with real-time polymerase chain reaction. Allelic frequency for proline was 0.955 and 0.045 for alanine, which was in Hardy-Weinberg equilibrium (p=0.74). One hundred and seventeen subjects (43.8%) had normal coronary arteries, 88 (33%) had 1-vessel disease, 39 (14.6%) had 2-vessel disease and 23 (8.6%) had 3-vessel disease. When the cardiovascular risk factors were compared among the 4 groups, there were no meaningful differences except for age and FBG levels, which were significant even after adjustment for age and BMI. There were no significant differences in the prevalence or severity of CAD according to the different genotypes of Pro12Ala, and in logistic regression analysis Pro12Ala polymorphism was not a predictor for CAD. There was no significant association between Pro12Ala polymorphism in exon B of PPAR-gamma and prevalence or severity of CAD in Korean adults. Further studies on the correlation between Pro12Ala polymorphism and CAD should be carried out in a larger Korean population in the future.

  11. Effect of Proliferator-Activated Receptor-γ Pro12Ala Polymorphism on Colorectal Cancer Risk: A Meta-Analysis

    PubMed Central

    Wei, Zhijiang; Han, Guoda; Bai, Xiyong

    2015-01-01

    Background The association between peroxisome proliferators-activated receptor γ (PPARγ) Pro12Ala polymorphism and colorectal cancer (CRC) risk is still controversial. A meta-analysis was performed. Material/Methods We conducted a literature search using PubMed, EMBASE, and Cochran databases. The pooled odds ratio (OR) with 95% confidence intervals (CIs) were calculated. Fixed-effects and random-effects models were used. Dominant model, recessive model, and additive model were used in this meta-analysis. Results Fifteen studies including 13575 cases and 17085 controls were included in our meta-analysis. Result of this meta-analysis found that PPARγ Pro12Ala polymorphism was significantly associated with a reduced risk of CRC (OR=0.90; 95% CI 0.83–0.98; P=0.01). No significant association was found between PPARγ Pro12Ala polymorphism and CRC risk in Asians (OR=0.80; 95% CI 0.60–1.09; P=0.15). However, PPARγ Pro12Ala polymorphism was significantly associated with a reduced risk of CRC in Caucasians (OR=0.91; 95% CI 0.83–0.99; P=0.03). When stratified analysis was performed by CRC site, no positive association was found between PPARγ Pro12Ala polymorphism and rectal cancer (OR=0.95; 95% CI 0.74–1.22; P=0.71). However, a reduced risk of colon cancer was observed (OR=0.85; 95% CI 0.76–0.94; P=0.002). Conclusions In summary, this study suggests that PPARγ Pro12Ala polymorphism was a protective factor of CRC. PMID:26049557

  12. Effect of Proliferator-Activated Receptor-γ Pro12Ala Polymorphism on Colorectal Cancer Risk: A Meta-Analysis.

    PubMed

    Wei, Zhijiang; Han, Guoda; Bai, Xiyong

    2015-06-02

    The association between peroxisome proliferators-activated receptor γ (PPARγ) Pro12Ala polymorphism and colorectal cancer (CRC) risk is still controversial. A meta-analysis was performed. We conducted a literature search using PubMed, EMBASE, and Cochran databases. The pooled odds ratio (OR) with 95% confidence intervals (CIs) were calculated. Fixed-effects and random-effects models were used. Dominant model, recessive model, and additive model were used in this meta-analysis. Fifteen studies including 13575 cases and 17085 controls were included in our meta-analysis. Result of this meta-analysis found that PPARγ Pro12Ala polymorphism was significantly associated with a reduced risk of CRC (OR=0.90; 95% CI 0.83-0.98; P=0.01). No significant association was found between PPARγ Pro12Ala polymorphism and CRC risk in Asians (OR=0.80; 95% CI 0.60-1.09; P=0.15). However, PPARγ Pro12Ala polymorphism was significantly associated with a reduced risk of CRC in Caucasians (OR=0.91; 95% CI 0.83-0.99; P=0.03). When stratified analysis was performed by CRC site, no positive association was found between PPARγ Pro12Ala polymorphism and rectal cancer (OR=0.95; 95% CI 0.74-1.22; P=0.71). However, a reduced risk of colon cancer was observed (OR=0.85; 95% CI 0.76-0.94; P=0.002). In summary, this study suggests that PPARγ Pro12Ala polymorphism was a protective factor of CRC.

  13. The current status of 5-ALA fluorescence-guided resection of intracranial meningiomas-a critical review.

    PubMed

    Motekallemi, Arash; Jeltema, Hanne-Rinck; Metzemaekers, Jan D M; van Dam, Gooitzen M; Crane, Lucy M A; Groen, Rob J M

    2015-10-01

    Meningiomas are the second most common primary tumors affecting the central nervous system. Surgical treatment can be curative in case of complete resection. 5-aminolevulinic acid (5-ALA) has been established as an intraoperative tool in malignant glioma surgery. A number of studies have tried to outline the merits of 5-ALA for the resection of intracranial meningiomas. In the present paper, we review the existing literature about the application of 5-ALA as an intraoperative tool for the resection of intracranial meningiomas. PubMed was used as the database for search tasks. We included articles published in English without limitations regarding publication date. Tumor fluorescence can occur in benign meningiomas (WHO grade I) as well as in WHO grade II and WHO grade III meningiomas. Most of the reviewed studies report fluorescence of the main tumor mass with high sensitivity and specificity. However, different parts of the same tumor can present with a different fluorescent pattern (heterogenic fluorescence). Quantitative probe fluorescence can be superior, especially in meningiomas with difficult anatomical accessibility. However, only one study was able to consistently correlate resected tissue with histopathological results and nonspecific fluorescence of healthy brain tissue remains a confounder. The use of 5-ALA as a tool to guide resection of intracranial meningiomas remains experimental, especially in cases with tumor recurrence. The principle of intraoperative fluorescence as a real-time method to achieve complete resection is appealing, but the usefulness of 5-ALA is questionable. 5-ALA in intracranial meningioma surgery should only be used in a protocolled prospective and long-term study.

  14. Neuroprotective effects of D-Ala2GIP on Alzheimer's disease biomarkers in an APP/PS1 mouse model

    PubMed Central

    2013-01-01

    Introduction Type 2 diabetes mellitus has been identified as a risk factor for Alzheimer's disease (AD). An impairment of insulin signaling as well as a desensitization of its receptor has been found in AD brains. Glucose-dependent insulinotropic polypeptide (GIP) normalises insulin signaling by facilitating insulin release. GIP directly modulates neurotransmitter release, LTP formation, and protects synapses from the detrimental effects of beta-amyloid fragments on LTP formation, and cell proliferation of progenitor cells in the dentate gyrus. Here we investigate the potential therapeutic property of the new long lasting incretin hormone analogue D-Ala2GIP on key symptoms found in a mouse model of Alzheimer' disease (APPswe/PS1detaE9). Methods D-Ala2GIP was injected for 21 days at 25 nmol/kg ip once daily in APP/PS1 male mice and wild type (WT) littermates aged 6 or 12 months of age. Amyloid plaque load, inflammation biomarkers, synaptic plasticity in the brain (LTP), and memory were measured. Results D-Ala2GIP improved memory in WT mice and rescued the cognitive decline of 12 months old APP/PS1 mice in two different memory tasks. Furthermore, deterioration of synaptic function in the dentate gyrus and cortex was prevented in 12 months old APP/PS1 mice. D-Ala2GIP facilitated synaptic plasticity in APP/PS1 and WT mice and reduced the number of amyloid plaques in the cortex of D-Ala2GIP injected APP/PS1 mice. The inflammatory response in microglia was also reduced. Conclusion The results demonstrate that D-Ala2GIP has neuroprotective properties on key hallmarks found in AD. This finding shows that novel GIP analogues have the potential as a novel therapeutic for AD. PMID:23601582

  15. Toward Homogeneous Erythropoietin: Chemical Synthesis of the Ala1-Gly28 Glycopeptide Domain by “Alanine” Ligation

    PubMed Central

    Kan, Cindy; Trzupek, John D.; Wu, Bin; Wan, Qian; Chen, Gong; Tan, Zhongping; Yuan, Yu; Danishefsky, Samuel J.

    2009-01-01

    The Ala1—Gly28 glycopeptide fragment (28) of EPO was prepared by chemical synthesis as a single glycoform. Key steps in the synthesis include attachment of a complex dodecasaccharide (7) to a seven amino acid peptide via Lansbury aspartylation, native chemical ligation to join peptide 19 with the glycopeptide domain 18, and a selective desulfurization at the ligation site to reveal the natural Ala19. This glycopeptide fragment (28) contains both the requisite N-linked dodecasaccharide and a C-terminal αthioester handle, the latter feature permitting direct coupling with a glycopeptide fragment bearing N-terminal Cys29 without further functionalization. PMID:19334679

  16. Mechanistic details of energy transfer and soft landing in ala2-H(+) collisions with a F-SAM surface.

    PubMed

    Pratihar, S; Kim, N; Kohale, S C; Hase, W L

    2015-10-14

    Previous chemical dynamics simulations (Phys. Chem. Chem. Phys., 2014, 16, 23769-23778) were analyzed to delineate atomistic details for collision of N-protonated dialanine (ala2-H(+)) with a C8 perfluorinated self-assembled monolayer (F-SAM) surface. Initial collision energies Ei of 5-70 eV and incident angles θi of 0° and 45°, with the surface normal, were considered. Four trajectory types were identified: (1) direct scattering; (2) temporary sticking/physisorption on top of the surface; (3) temporary penetration of the surface with additional physisorption on the surface; and (4) trapping on/in the surface, by physisorption or surface penetration, when the trajectory is terminated. Direct scattering increases from 12 to 100% as Ei is increased from 5 to 70 eV. For the direct scattering at 70 eV, at least one ala2-H(+) heavy atom penetrated the surface for all of the trajectories. For ∼33% of the trajectories all eleven of the ala2-H(+) heavy atoms penetrated the F-SAM at the time of deepest penetration. The importance of trapping decreased with increase in Ei, decreasing from 84 to 0% with Ei increase from 5 to 70 eV at θi = 0°. Somewhat surprisingly, the collisional energy transfers to the F-SAM surface and ala2-H(+) are overall insensitive to the trajectory type. The energy transfer to ala2-H(+) is primarily to vibration, with the transfer to rotation ∼10% or less. Adsorption and then trapping of ala2-H(+) is primarily a multi-step process, and the following five trapping mechanisms were identified: (i) physisorption-penetration-physisorption (phys-pen-phys); (ii) penetration-physisorption-penetration (pen-phys-pen); (iii) penetration-physisorption (pen-phys); (iv) physisorption-penetration (phys-pen); and (v) only physisorption (phys). For Ei = 5 eV, the pen-phys-pen, pen-phys, phys-pen, and phys trapping mechanisms have similar probabilities. For 13.5 eV, the phys-pen mechanism, important at 5 eV, is unimportant. The radius of gyration of ala2-H

  17. Breast-feeding modifies the association of PPARgamma2 polymorphism Pro12Ala with growth in early life: the Generation R Study.

    PubMed

    Mook-Kanamori, Dennis O; Steegers, Eric A P; Uitterlinden, Andre G; Moll, Henriëtte A; van Duijn, Cornelia M; Hofman, Albert; Jaddoe, Vincent W V

    2009-04-01

    We examined whether the PPARgamma2 Ala12 allele influences growth in early life and whether this association is modified by breast-feeding. This study was embedded in the Generation R Study, a prospective cohort study from early fetal life onward. PPARgamma2 was genotyped in DNA obtained from cord blood samples in 3,432 children. Information about breast-feeding was available from questionnaires. Weight, head circumference, and femur length were repeatedly measured in second and third trimesters of pregnancy, at birth, and at the ages of 1.5, 6, 11, 14, and 18 months. Genotype frequency distribution was 77.6% (Pro12Pro), 20.7% (Pro12Ala), and 1.7% (Ala12Ala). Growth rates in weight from second trimester of pregnancy to 18 months were higher for Pro12Ala and Ala12Ala than for Pro12Pro carriers (differences 1.11 g/week [95% CI 0.47-1.74] and 2.65 g/week [0.45-4.87], respectively). We found an interaction between genotype and breast-feeding duration (P value for interaction <0.0001). In infants who were breast-fed for > or =4 months, PPARgamma2 Pro12Ala was not associated with growth rate. When breast-feeding duration was <2 months or 2-4 months, growth rate was higher in Ala12Ala than Pro12Pro carriers (differences 9.80 g/week [3.97-15.63] and 6.32 g/week [-1.04 to 13.68], respectively). The PPARgamma2 Ala12 allele is associated with an increased growth rate in early life. This effect may be influenced by breast-feeding duration. Further studies should replicate these findings, identify the underlying mechanisms, and assess whether these effects persist into later life.

  18. Impact of the Pro12Ala polymorphism of the PPARγ2 gene on diabetes and obesity in a highly consanguineous population.

    PubMed

    Bener, Abdulbari; Zirie, M; Al-Hamaq, Aoaa; Nawaz, Z; Samson, N; Mohammad, R

    2015-01-01

    The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor subfamily of transcription factors. It has been reported that they play important roles in obesity and the development of type 2 diabetes mellitus (T2DM). This case-control study was carried out among 764 Qatari patients with diabetes and 764 healthy subjects above 20 years of age at Primary Healthcare Clinics (PHCs) from January 2011 to December 2012. Face-to-face interviews were based on a questionnaire that included variables such as age, sex, sociodemographic status, body mass index (BMI) and other clinical parameters. The Pro12Ala in the PPARγ2 gene was detected on the LightCycler using two specific probes. Univariate and multivariate statistical analysis were performed. The study revealed that in the diabetes group, Pro/(10.2% vs 9.4%; P = 0.606) and Ala/Ala (1.4% vs 0.9%; P = 0.343) were higher than in controls, whereas Pro/Pro (88.4% vs 89.7%;P = 0.413) was lower in diabetes patients, but no significant difference was observed among the genotype groups. In obese patients with diabetes, Pro/Pro (89% vs 89.9%;P = 0.792) and Pro/Ala (8.9% vs 10.1%;P = 0.671) were lower than in obese healthy subjects. No homozygous Ala/Ala was found in obese healthy subjects, whereas 6 Ala/Ala homozygotes were in obese diabetes group. But in diabetes group, obese patients had higher homozygous of Pro/Pro (89.3% vs 87.8%;P = 0.523) and Ala/Ala (1.8% vs 1.2%;P = 0.771) compared to non-obese patients. The current study did not reveal an association between the Pro12Ala polymorphism of the PPAR γ2 gene and type 2 diabetes (T2D) in Qatari's population.

  19. Structural and functional characterization of VanG D-Ala:D-Ser ligase associated with vancomycin resistance in Enterococcus faecalis.

    PubMed

    Meziane-Cherif, Djalal; Saul, Frederick A; Haouz, Ahmed; Courvalin, Patrice

    2012-11-02

    d-Alanyl:d-lactate (d-Ala:d-Lac) and d-alanyl:d-serine ligases are key enzymes in vancomycin resistance of Gram-positive cocci. They catalyze a critical step in the synthesis of modified peptidoglycan precursors that are low binding affinity targets for vancomycin. The structure of the d-Ala:d-Lac ligase VanA led to the understanding of the molecular basis for its specificity, but that of d-Ala:d-Ser ligases had not been determined. We have investigated the enzymatic kinetics of the d-Ala:d-Ser ligase VanG from Enterococcus faecalis and solved its crystal structure in complex with ADP. The overall structure of VanG is similar to that of VanA but has significant differences mainly in the N-terminal and central domains. Based on reported mutagenesis data and comparison of the VanG and VanA structures, we show that residues Asp-243, Phe-252, and Arg-324 are molecular determinants for d-Ser selectivity. These residues are conserved in both enzymes and explain why VanA also displays d-Ala:d-Ser ligase activity, albeit with low catalytic efficiency in comparison with VanG. These observations suggest that d-Ala:d-Lac and d-Ala:d-Ser enzymes have evolved from a common ancestral d-Ala:d-X ligase. The crystal structure of VanG showed an unusual interaction between two dimers involving residues of the omega loop that are deeply anchored in the active site. We constructed an octapeptide mimicking the omega loop and found that it selectively inhibits VanG and VanA but not Staphylococcus aureus d-Ala:d-Ala ligase. This study provides additional insight into the molecular evolution of d-Ala:d-X ligases and could contribute to the development of new structure-based inhibitors of vancomycin resistance enzymes.

  20. TATA-Binding protein-TATA interaction is a key determinant of differential transcription of silkworm constitutive and silk gland-specific tRNA(Ala) genes.

    PubMed

    Ouyang, C; Martinez, M J; Young, L S; Sprague, K U

    2000-02-01

    We have investigated the contribution of specific TATA-binding protein (TBP)-TATA interactions to the promoter activity of a constitutively expressed silkworm tRNA(C)(Ala) gene and have also asked whether the lack of similar interactions accounts for the low promoter activity of a silk gland-specific tRNA(SG)(Ala) gene. We compared TBP binding, TFIIIB-promoter complex stability (measured by heparin resistance), and in vitro transcriptional activity in a series of mutant tRNA(C)(Ala) promoters and found that specific TBP-TATA contacts are important for TFIIIB-promoter interaction and for transcriptional activity. Although the wild-type tRNA(C)(Ala) promoter contains two functional TBP binding sequences that overlap, the tRNA(SG)(Ala) promoter lacks any TBP binding site in the corresponding region. This feature appears to account for the inefficiency of the tRNA(SG)(Ala) promoter since provision of either of the wild-type TATA sequences derived from the tRNA(C)(Ala) promoter confers robust transcriptional activity. Transcriptional impairment of the wild-type tRNA(SG)(Ala) gene is not due to reduced incorporation of TBP into transcription complexes since both the tRNA(C)(Ala) and tRNA(SG)(Ala) promoters form transcription complexes that contain the same amount of TBP. Thus, the deleterious consequences of the lack of appropriate TBP-TATA contacts in the tRNA(SG)(Ala) promoter must come from failure to incorporate some other essential transcription factor(s) or to stabilize the complete complex in an active conformation.

  1. Stabilization of a chitinase from Serratia marcescens by Gly-->Ala and Xxx-->Pro mutations.

    PubMed

    Gåseidnes, Sigrid; Synstad, Bjørnar; Jia, Xiaohong; Kjellesvik, Hege; Vriend, Gert; Eijsink, Vincent G H

    2003-11-01

    This paper describes attempts to increase the kinetic stability of chitinase B from Serratia marcescens (ChiB) by the introduction of semi-automatically designed rigidifying mutations of the Gly-->Ala and Xxx-->Pro type. Of 15 single mutants, several displayed significant increases in thermal stability, whereas most mutants showed minor effects. All mutations with non-marginal effects on stability clustered in a limited, surface-exposed region of the enzyme, indicating that this region is involved in a partial unfolding process that triggers irreversible thermal inactivation (aggregation). A double mutant containing two stabilizing mutations in this region (G188A, A234P) displayed a 10-fold increase in half-life at 57 degrees C and a 4.2 degrees C increase in apparent T(m). These results show that entropic stabilization works well for ChiB and they pinpoint a region whose unfolding may be crucial for the kinetic stability of this enzyme.

  2. The Helical Alanine Controversy: An (Ala)6 Insertion Dramatically Increases Helicity

    PubMed Central

    Lin, Jasper C.; Barua, Bipasha

    2013-01-01

    Employing chemical shift melts and hydrogen/deuterium exchange NMR techniques, we have determined the stabilization of the Trp-cage miniprotein due to multiple alanine insertions within the N-terminal α-helix. Alanine is shown to be uniquely helix-stabilizing and this stabilization is reflected in the global fold stability of the Trp-cage. The associated free energy change per alanine can be utilized to calculate the alanine propagation value. From the Lifson–Roig formulation, the calculated value (wAla = 1.6) is comparable to those obtained for short, solubilized, alanine-rich helices and is much larger than the values obtained by prior host–guest techniques or in N-terminally templated helices and peptides bearing long contiguous strings of alanines with no capping or solubilizing units present. PMID:15493925

  3. A model-based comparison of implicit and direct dosimetry for ALA-PDT of skin

    NASA Astrophysics Data System (ADS)

    Liu, Baochang; Farrell, Thomas J.; Patterson, Michael S.

    2011-07-01

    Photosensitizer fluorescence photobleaching and Singlet Oxygen (1O2) Luminescence Dosimetry (SOLD) are being studied as potential dosimetric tools for ALA-PDT of skin diseases. However, the correlation of both SOLD data and PpIX fluorescence to 1O2 distribution is difficult to interpret because of the temporal and spatial variations of the PDT parameters (light fluence rate, photosensitizer concentration and oxygen concentration). This work used our dynamic model to investigate both dosimetry approaches for varied PpIX concentration and distribution, and three commonly used treatment wavelengths. The results show that SOLD is much less dependent upon the treatment parameters, which implies it has better potential as a "gold standard" dosimetric tool for clinical PDT.

  4. The helical alanine controversy: an (Ala)6 insertion dramatically increases helicity.

    PubMed

    Lin, Jasper C; Barua, Bipasha; Andersen, Niels H

    2004-10-27

    Employing chemical shift melts and hydrogen/deuterium exchange NMR techniques, we have determined the stabilization of the Trp-cage miniprotein due to multiple alanine insertions within the N-terminal alpha-helix. Alanine is shown to be uniquely helix-stabilizing and this stabilization is reflected in the global fold stability of the Trp-cage. The associated free energy change per alanine can be utilized to calculate the alanine propagation value. From the Lifson-Roig formulation, the calculated value (wAla = 1.6) is comparable to those obtained for short, solubilized, alanine-rich helices and is much larger than the values obtained by prior host-guest techniques or in N-terminally templated helices and peptides bearing long contiguous strings of alanines with no capping or solubilizing units present. Copyright 2004 American Chemical Society

  5. Effective treatment of d-penicillamine induced elastosis perforans serpiginosa with ALA-PDT.

    PubMed

    Wang, Duoqin; Liang, Jun; Xu, Jinhua; Chen, Lianjun

    2015-03-01

    A case of D-penicillamine(DPA) induced elastosis perforans serpiginosa(EPS) in a 32-year-old Chinese man was reported. The presentation lasted two years and was refractory to traditional medical treatment. He was then commenced on 7.6% 5-aminolevulinic acid (ALA) induced photodynamic therapy(PDT) by a LED light of 633 nm at dose levels of 130J/ cm2 for each session with total 3 sessions at one week interval. The patient was tolerated and responded well to this new approach for DPA-induced EPS without any adverse events. The etiology, pathophysiology, natural history, and treatment options for DPA-induced EPS are reviewed, and the authors suggest this method of treatment to be effective and safe for patients of DPA-induced EPS refractory to conventional therapy.

  6. N-Protonated Isomers and Coulombic Barriers to Dissociation of Doubly Protonated Ala8Arg

    NASA Astrophysics Data System (ADS)

    Haeffner, Fredrik; Irikura, Karl K.

    2017-10-01

    Collision-induced dissociation (or tandem mass spectrometry, MS/MS) of a protonated peptide results in a spectrum of fragment ions that is useful for inferring amino acid sequence. This is now commonplace and a foundation of proteomics. The underlying chemical and physical processes are believed to be those familiar from physical organic chemistry and chemical kinetics. However, first-principles predictions remain intractable because of the conflicting necessities for high accuracy (to achieve qualitatively correct kinetics) and computational speed (to compensate for the high cost of reliable calculations on such large molecules). To make progress, shortcuts are needed. Inspired by the popular mobile proton model, we have previously proposed a simplified theoretical model in which the gas-phase fragmentation pattern of protonated peptides reflects the relative stabilities of N-protonated isomers, thus avoiding the need for transition-state information. For singly protonated Ala n ( n = 3-11), the resulting predictions were in qualitative agreement with the results from low-energy MS/MS experiments. Here, the comparison is extended to a model tryptic peptide, doubly protonated Ala8Arg. This is of interest because doubly protonated tryptic peptides are the most important in proteomics. In comparison with experimental results, our model seriously overpredicts the degree of backbone fragmentation at N9. We offer an improved model that corrects this deficiency. The principal change is to include Coulombic barriers, which hinder the separation of the product cations from each other. Coulombic barriers may be equally important in MS/MS of all multiply charged peptide ions. [Figure not available: see fulltext.

  7. An association of GRIK3 Ser310Ala functional polymorphism with personality traits.

    PubMed

    Minelli, Alessandra; Scassellati, Catia; Bonvicini, Cristian; Perez, Jorge; Gennarelli, Massimo

    2009-01-01

    Personality traits are under genetic control, and have been associated with genes implicated in dopaminergic, serotoninergic and noradrenergic neurotransmission systems, often with conflicting results. There have been few studies assessing the involvement of the glutamatergic pathway instead upon personality traits. In the gene family of glutamate receptors, there is a T/G polymorphism at codon 928 in the ionotropic glutamate receptor kainite 3 gene (GRIK3) that causes a serine to alanine change at position 310 in the extracellular N terminus of the protein. This polymorphism has been recently associated with susceptibility to some major psychoses such as major depression (MD). In order to test whether the functional Ser310Ala polymorphism is involved in the development of specific personality traits, and thus to MD, we conducted the first association study on 195 selected healthy Italian individuals. The personality traits were measured by the self-rating Temperament and Character Inventory (TCI) scale. The results indicated that the Ala allele in homozygosity is associated with higher scores in harm avoidance and respective subscales: anticipatory worry HA1 and shyness HA3, as well as lower scores in exploratory excitability NS1, responsibility SD1, resourcefulness SD3, helpfulness C3 and compassion C4 subscales, in addition to lower self-directedness and cooperativeness scores. This pattern of TCI scores is akin to that observed in depressed patients. Because of the small size of the sample, this work represents a pilot study, and reports the first pieces of evidence for a specific involvement of the GRIK3 gene in these traits, suggesting a role of the glutamatergic system in the genetic background of human personality traits.

  8. N-Protonated Isomers and Coulombic Barriers to Dissociation of Doubly Protonated Ala8Arg

    NASA Astrophysics Data System (ADS)

    Haeffner, Fredrik; Irikura, Karl K.

    2017-07-01

    Collision-induced dissociation (or tandem mass spectrometry, MS/MS) of a protonated peptide results in a spectrum of fragment ions that is useful for inferring amino acid sequence. This is now commonplace and a foundation of proteomics. The underlying chemical and physical processes are believed to be those familiar from physical organic chemistry and chemical kinetics. However, first-principles predictions remain intractable because of the conflicting necessities for high accuracy (to achieve qualitatively correct kinetics) and computational speed (to compensate for the high cost of reliable calculations on such large molecules). To make progress, shortcuts are needed. Inspired by the popular mobile proton model, we have previously proposed a simplified theoretical model in which the gas-phase fragmentation pattern of protonated peptides reflects the relative stabilities of N-protonated isomers, thus avoiding the need for transition-state information. For singly protonated Ala n (n = 3-11), the resulting predictions were in qualitative agreement with the results from low-energy MS/MS experiments. Here, the comparison is extended to a model tryptic peptide, doubly protonated Ala8Arg. This is of interest because doubly protonated tryptic peptides are the most important in proteomics. In comparison with experimental results, our model seriously overpredicts the degree of backbone fragmentation at N9. We offer an improved model that corrects this deficiency. The principal change is to include Coulombic barriers, which hinder the separation of the product cations from each other. Coulombic barriers may be equally important in MS/MS of all multiply charged peptide ions.

  9. Paleoglaciology of the Ala-Archa and Ak-Shyrak areas, Kyrgyz Tian Shan

    NASA Astrophysics Data System (ADS)

    Blomdin, R.; Beel, C.; Caffee, M. W.; Codilean, A.; Gribenski, N.; Harbor, J.; Heyman, J.; Hattestrand, C.; Ivanov, M.; Kassab, C.; Lifton, N. A.; Petrakov, D.; Rogozhina, I.; Stroeven, A. P.; Usubaliev, R.

    2012-12-01

    We employed detailed glacial geomorphological mapping of the Ala-Archa and Ak-Shyrak areas, Kyrgyz Tian Shan (Shan = Mountains) to build a paleoglaciological reconstruction. These two areas were selected because their glaciers constitute important freshwater reservoirs for downstream communities (the Kyrgyz capital Bishkek, and cities along the Syr Darja which drains towards the Aral Sea, respectively), and because fluctuations in their extent cause both variations in water supply and risks for glacial hazards. Five landform categories were mapped; glacial valleys, marginal moraines, glacial lineations, hummocky terrain, and melt-water channels. These landforms were mapped using a SRTM digital elevation model (DEM) with a 90 m resolution, Landsat 7 ETM+ satellite imagery with a 30 m resolution, Aster GDEM with a 30 m resolution, and Google Earth. This remotely sensed mapping was also checked and complemented by field mapping. The distribution of mapped landforms indicates restricted glaciations, mainly concentrated to the mountain areas. In both ranges marginal moraines extend beyond the furthest extent of glacial valleys. Furthermore, extensive areas of hummocky moraine in Ak-Shyrak extending beyond montane glacial valleys indicate glacial extents into the intermontane basins. Several series of lateral and terminal moraines in the Ala-Archa and Ak-Shyrak ranges have been identified and sampled for cosmogenic nuclide 10Be dating, while associated glaciofluvial sediment was sampled for optically-stimulated luminescence (OSL) and electron spin resonance (ESR) dating. Future work will involve using these samples to build a consistent chronology for glaciation and investigation of contrasts between paleoglaciological reconstructions of valleys within a single range but with different aspects, as well as between ranges. In the final stages of the project we will use intermediate complexity glacier flow models to examine paleoclimatic implications of the observed spatial

  10. An organic solvent-stable lipase from a newly isolated Staphylococcus aureus ALA1 strain with potential for use as an industrial biocatalyst.

    PubMed

    Ben Bacha, Abir; Moubayed, Nadine Ms; Al-Assaf, Alaa

    2016-05-01

    In this study, a new strain, ALA1, was identified as Staphylococcus aureus by biochemical tests, and its 16S ribosomal DNA sequence was isolated from dromedary milk. ALA1 lipase production was optimized in shake flask experiments and measured with varying pH (3-11), temperature (20-55 °C) and substrate concentrations. The maximum lipase production was recorded at pH 8 and 30 °C for up to 30 H of culture period for the S. aureus ALA1 strain. Among the substrates tested, selected carbon sources, xylose, nitrogen source, yeast extract, and olive oil (1%) were suitable for maximizing lipase production. The effects of surfactants were investigated and showed that Tween 20, Tween 80, and Triton X-100 prevented lipase production. Interestingly, isolate ALA1 was able to grow in high concentrations of benzene or toluene (up to 50% (v/v)). Moreover, the lipolytic activity of the S. aureus ALA1 lipase was stimulated by diethyl ether, whereas almost 100% of S. aureus ALA1 lipase activity was retained in 25% acetone, acetonitrile, benzene, 2-propanol, ethanol, methanol, or toluene. Because of its stability in organic solvent, the S. aureus ALA1 lipase was used as a biocatalyst to synthesize high levels of added value molecules. S. aureus ALA1 lipase could be considered as an ideal choice for applications in detergent formulations because of its high stability and compatibility with various surfactants, oxidizing agents, and commercial detergents.

  11. Kinetics and subcellular localization of 5-ALA-induced PpIX in DHL cells via two-photon excitation fluorescence microscopy.

    PubMed

    Chen, Rong; Huang, Zufang; Chen, Guannan; Li, Yongzeng; Chen, Xianlian; Chen, Jianxin; Zeng, Haishan

    2008-04-01

    Two-photon excitation fluorescence (TPEF) microscopy was used to measure the 5-aminolevulinic acid (5-ALA)-induced PpIX fluorescence in follicular lymphoma DHL cells. Kinetics of 5-ALA-induced PpIX accumulation in DHL cells under various 5-ALA concentrations was studied. We found that during the course of continuous incubation with 5-ALA, the relationship between the DHL cell fluorescence signal and the incubation time showed a biphasic variation. Initially the PpIX signal increased with the incubation time and reached the maximal value at about 3 h, and then it decreased with time during the subsequent incubation period. By labeling the 5-ALA incubated DHL cells with different organelle-specific fluorescence probes: Rhodamine 123 (for mitochondria), DioC6(3) (for endoplasmic reticulum) and LysoTracker Green (for lysosomes) respectively, we found that 5-ALA-induced PpIX was primarily localized in endoplasmic reticulum and mitochondria; its concentration in the lysosome was much lower. The results suggested that 5-ALA could potentially be an effective photosensitizer in photodynamic purging of DHL cells. Two-photon excitation fluorescence microscope is a useful tool for studying 5-ALA-induced PpIX subcellular localization.

  12. ALA10, a Phospholipid Flippase, Controls FAD2/FAD3 Desaturation of Phosphatidylcholine in the ER and Affects Chloroplast Lipid Composition in Arabidopsis thaliana.

    PubMed

    Botella, César; Sautron, Emeline; Boudiere, Laurence; Michaud, Morgane; Dubots, Emmanuelle; Yamaryo-Botté, Yoshiki; Albrieux, Catherine; Marechal, Eric; Block, Maryse A; Jouhet, Juliette

    2016-03-01

    The biogenesis of photosynthetic membranes relies on galactoglycerolipids, which are synthesized via pathways that are dispatched over several cell compartments. This membrane biogenesis requires both trafficking of lipid intermediates and a tight homeostatic regulation. In this work, we address the role of ALA10 (for aminophospholipid ATPase), a P4-type ATPase, in a process counteracting the monogalactosyldiacylglycerol (MGDG) shortage in Arabidopsis (Arabidopsis thaliana) leaves. ALA10 can interact with protein partners, ALIS1 (for ALA-interacting subunit1) or ALIS5, leading to differential endomembrane localizations of the interacting proteins, close to the plasma membrane with ALIS1 or to chloroplasts with ALIS5. ALA10 interacts also with FATTY ACID DESATURASE2 (FAD2), and modification of ALA10 expression affects phosphatidylcholine (PC) fatty acyl desaturation by disturbing the balance between FAD2 and FAD3 activities. Modulation of ALA10 expression downstream impacts the fatty acyl composition of chloroplast PC. ALA10 expression also enhances leaf growth and improves the MGDG-PC ratio, possibly through MGDG SYNTHASE1 (MGD1) activation by phosphatidic acid. The positive effect of ALA10 on leaf development is significant in conditions such as upon treatment of plants with Galvestine-1, an inhibitor of MGDG synthases, or when plants are grown at chilling temperature.

  13. ALA10, a Phospholipid Flippase, Controls FAD2/FAD3 Desaturation of Phosphatidylcholine in the ER and Affects Chloroplast Lipid Composition in Arabidopsis thaliana1

    PubMed Central

    Sautron, Emeline; Boudiere, Laurence; Michaud, Morgane; Dubots, Emmanuelle; Albrieux, Catherine; Marechal, Eric; Jouhet, Juliette

    2016-01-01

    The biogenesis of photosynthetic membranes relies on galactoglycerolipids, which are synthesized via pathways that are dispatched over several cell compartments. This membrane biogenesis requires both trafficking of lipid intermediates and a tight homeostatic regulation. In this work, we address the role of ALA10 (for aminophospholipid ATPase), a P4-type ATPase, in a process counteracting the monogalactosyldiacylglycerol (MGDG) shortage in Arabidopsis (Arabidopsis thaliana) leaves. ALA10 can interact with protein partners, ALIS1 (for ALA-interacting subunit1) or ALIS5, leading to differential endomembrane localizations of the interacting proteins, close to the plasma membrane with ALIS1 or to chloroplasts with ALIS5. ALA10 interacts also with FATTY ACID DESATURASE2 (FAD2), and modification of ALA10 expression affects phosphatidylcholine (PC) fatty acyl desaturation by disturbing the balance between FAD2 and FAD3 activities. Modulation of ALA10 expression downstream impacts the fatty acyl composition of chloroplast PC. ALA10 expression also enhances leaf growth and improves the MGDG-PC ratio, possibly through MGDG SYNTHASE1 (MGD1) activation by phosphatidic acid. The positive effect of ALA10 on leaf development is significant in conditions such as upon treatment of plants with Galvestine-1, an inhibitor of MGDG synthases, or when plants are grown at chilling temperature. PMID:26620528

  14. The Arabidopsis P4-ATPase ALA3 Localizes to the Golgi and Requires a β-Subunit to Function in Lipid Translocation and Secretory Vesicle Formation[W

    PubMed Central

    Poulsen, Lisbeth Rosager; López-Marqués, Rosa Laura; McDowell, Stephen C.; Okkeri, Juha; Licht, Dirk; Schulz, Alexander; Pomorski, Thomas; Harper, Jeffrey F.; Palmgren, Michael Gjedde

    2008-01-01

    Vesicle budding in eukaryotes depends on the activity of lipid translocases (P4-ATPases) that have been implicated in generating lipid asymmetry between the two leaflets of the membrane and in inducing membrane curvature. We show that Aminophospholipid ATPase3 (ALA3), a member of the P4-ATPase subfamily in Arabidopsis thaliana, localizes to the Golgi apparatus and that mutations of ALA3 result in impaired growth of roots and shoots. The growth defect is accompanied by failure of the root cap to release border cells involved in the secretion of molecules required for efficient root interaction with the environment, and ala3 mutants are devoid of the characteristic trans-Golgi proliferation of slime vesicles containing polysaccharides and enzymes for secretion. In yeast complementation experiments, ALA3 function requires interaction with members of a novel family of plant membrane-bound proteins, ALIS1 to ALIS5 (for ALA-Interacting Subunit), and in this host ALA3 and ALIS1 show strong affinity for each other. In planta, ALIS1, like ALA3, localizes to Golgi-like structures and is expressed in root peripheral columella cells. We propose that the ALIS1 protein is a β-subunit of ALA3 and that this protein complex forms an important part of the Golgi machinery required for secretory processes during plant development. PMID:18344284

  15. Genotyping of peroxisome proliferator-activated receptor gamma (PPAR-γ) polymorphism (Pro12Ala) in Iranian population

    PubMed Central

    Namvaran, Fatemeh; Rahimi-Moghaddam, Parvaneh; Azarpira, Negar

    2011-01-01

    BACKGROUND: The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear hormone receptor. It is predominantly expressed in adipose tissue and as a receptor for thiazolidinediones, it has drawn attentions towards itself as a key molecule to trigger pathways involving in some diseases such as cancers, type 2 diabetes, inflammations and osteoporosis. A proline changed to alanine in codon 12 of PPAR-γ gene (Pro12Ala) has been known to be responsible for decreased risk of type 2 diabetes. The aim of the present study is to investigate the frequency of Pro12Ala polymorphism in PPAR-γ in healthy Iranian population to compare with other populations. Understanding this polymorphism may help us in better diagnosis, prevention, and therapeutic approaches toward a better management of diseases such as type 2 diabetes and osteoporosis. METHODS: 128 healthy volunteers were enrolled in this study. To determine single nucleotide polymorphisms (SNPs), we did real time polymerase chain reaction (RT-PCR), using TaqMan allelic discrimination assays. RESULTS: Genotype frequencies for PPAR-γ gene Pro12Ala (rs1801282) polymorphism were 0.86 for CC, 0.14 for CG, 0.00 for GG while allelic frequencies were 0.93 and 0.0.07 for C and G, respectively. CONCLUSIONS: There are statistical differences between the distribution of the PPAR-γ-2 Pro12Ala polymorphism in other populations and Iranian population. PMID:22091247

  16. Association between PPARγ2 Pro12Ala polymorphism and myocardial infarction and obesity in Han Chinese in Hohhot, China.

    PubMed

    Wang, L P; Zhao, L R; Cui, H W; Yan, M R; Yang, L; Su, X L

    2012-08-29

    Activation of the peroxisome proliferator-activated receptor g (PPARg) improves insulin sensitivity and inhibits atherosclerosis. Whether PPARg2 Pro12Ala polymorphism affects myocardial infarction is not clearly understood. We investigated a possible association of PPARg2 Pro12Ala polymorphism with obesity and myocardial infarction in Han Chinese in Hohhot, Inner Mongolia, China. We included 121 subjects with myocardial infarction and 137 healthy controls in our study. Triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were measured. The following information was recorded for each subject: age, gender, body height, body weight, systolic blood pressure, and diastolic blood pressure; the body mass index was calculated. PCR-RFLP was used to examine Pro12Ala polymorphism. There were significant differences in clinical characteristics between myocardial infarction patients and healthy controls, except for diastolic blood pressure and triglycerides. The PP, PA/AA genotype frequencies were 88.4 and 11.6% in myocardial infarction patients and 95.6 and 4.4% in controls, respectively (P = 0.031). Individuals with the A allele had a significantly higher risk of myocardial infarction. The A allele was not an independent risk factor for obesity. We conclude that PPARg2 Pro12Ala polymorphisms are associated with increased risk for myocardial infarction in Han Chinese in Hohhot.

  17. Association between the PPARγ Pro12Ala polymorphism and risk of gestational diabetes mellitus: a meta-analysis.

    PubMed

    Shuai, H L; Lin, X Z; Chen, D L; Li, P; Luo, X

    2016-11-03

    The relationship between the Pro12Ala polymorphism of PPARγ and the risk of gestational diabetes mellitus remains unresolved. Here, we attempted to resolve this inconsistency. Case-control studies pertaining to the effect of the Pro12Ala polymorphism in the PPARγ protein and risk of gestational diabetes mellitus were extracted from the HuGE, PubMed, Web of Science, CNKI, and SinoMed databases after an extensive literature search. The studies were statistically analyzed using STATA (v.12.0) software. Twelve case-control studies composed of 2968 GDM cases and 5576 controls that fulfilled the inclusion criteria were included in this meta-analysis. We identified no significant relation between the Pro12Ala polymorphism of PPAR-γ and risk of GDM, when analyzed by the allele [G vs C: odds ratio (OR) = 0.85; 95% confidence interval (CI): 0.71-1.01] and dominant (CG+GG vs CC: OR = 0.86; 95% CI: 0.72-1.03) models. Subgroup analysis by ethnicity revealed that East Asian and Middle Eastern females expressing the A allele showed reduced susceptibility to GDM. Additionally, we observed significant differences between the East Asian, Middle Eastern, and Caucasian females (P = 0.008) with respect to GDM susceptibility. The results of this meta-analysis indicated the influence of ethnicity in determining GDM susceptibility, in the presence of a Pro12Ala polymorphism in PPARγ.

  18. Genotyping of peroxisome proliferator-activated receptor gamma (PPAR-γ) polymorphism (Pro12Ala) in Iranian population.

    PubMed

    Namvaran, Fatemeh; Rahimi-Moghaddam, Parvaneh; Azarpira, Negar

    2011-03-01

    The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear hormone receptor. It is predominantly expressed in adipose tissue and as a receptor for thiazolidinediones, it has drawn attentions towards itself as a key molecule to trigger pathways involving in some diseases such as cancers, type 2 diabetes, inflammations and osteoporosis. A proline changed to alanine in codon 12 of PPAR-γ gene (Pro12Ala) has been known to be responsible for decreased risk of type 2 diabetes. The aim of the present study is to investigate the frequency of Pro12Ala polymorphism in PPAR-γ in healthy Iranian population to compare with other populations. Understanding this polymorphism may help us in better diagnosis, prevention, and therapeutic approaches toward a better management of diseases such as type 2 diabetes and osteoporosis. 128 healthy volunteers were enrolled in this study. To determine single nucleotide polymorphisms (SNPs), we did real time polymerase chain reaction (RT-PCR), using TaqMan allelic discrimination assays. Genotype frequencies for PPAR-γ gene Pro12Ala (rs1801282) polymorphism were 0.86 for CC, 0.14 for CG, 0.00 for GG while allelic frequencies were 0.93 and 0.0.07 for C and G, respectively. There are statistical differences between the distribution of the PPAR-γ-2 Pro12Ala polymorphism in other populations and Iranian population.

  19. The role of sensitivity of ALA (PpIX)-based PDT on Human embryonic kidney cell line (HEK293T)

    NASA Astrophysics Data System (ADS)

    Fakhar-e-Alam, M.; Atif, M.; Rehman, T.; Sadia, H.; Firdous, S.

    2011-08-01

    Present study evaluates the effects of photodynamic therapy (PDT) with aminolevulinic acid (5-ALA) as photo sensitizer using Human embryonic kidney (HEK293T) cell line as an experimental model. Porphyrins derivatives are used as active cytotoxic antitumor agents in PDT. Above mentioned cell line were irradiated with red light (a diode laser, λ = 635 nm) at different doses (0-160 J/cm2) of light. The influence/effectiveness of incubation time, various concentrations of aminolevulinic acid (5-ALA) and light doses on the cellular viability was studied. HEK293T cells were deliberated by exposing the ALA-PpIX (0-1000 μg/ml) of concentrations. The optimal uptakes of photosensitizer (PS) in cell lines were investigated by means of spectro photo metric measurements. Cells viability was determined by means of neutral red assay (NRA). It was observed that alone, neither photosensitizer nor light dose have significant effect on cells viability, but optimal concentration of PS along with suitable dose of light exhibit effective impact on the viability of cell. Our results showed that light doses of 40 J/cm2 demonstrates effective PDT outcome for HEK293T cell line when incubated with 400 μg/ml, with wrapping up view that HEK293T cell line is very sensitive to ALA-mediated PDT as compared to cell line published in our data. At the end results has been verified by using reactive oxygen species (ROS) measure test.

  20. Books for Gerstner Field Aviators: The Mexican Border Traveling Library Service and ALA in Southwest Louisiana during World War I.

    ERIC Educational Resources Information Center

    Bordelon, Kathie

    This paper examines the efforts made by the American Library Association (ALA) and the Mexican Border Traveling Library Service (MBTLS) to ensure that remote World War I outposts, such as the Gerstner Field aviation and military training camp in Louisiana, would have adequate library service. A history of the MBTLS' early organizational success,…

  1. Novel Association of WNK4 Gene, Ala589Ser Polymorphism in Essential Hypertension, and Type 2 Diabetes Mellitus in Malaysia.

    PubMed

    Ghodsian, Nooshin; Ismail, Patimah; Ahmadloo, Salma; Heidari, Farzad; Haghvirdizadeh, Polin; Ataollahi Eshkoor, Sima; Etemad, Ali

    2016-01-01

    With-no-lysine (K) Kinase-4 (WNK4) consisted of unique serine and threonine protein kinases, genetically associated with an autosomal dominant form of hypertension. Argumentative consequences have lately arisen on the association of specific single nucleotide polymorphisms of WNK4 gene and essential hypertension (EHT). The aim of this study was to determine the association of Ala589Ser polymorphism of WNK4 gene with essential hypertensive patients in Malaysia. WNK4 gene polymorphism was specified utilizing mutagenically separated polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) method in 320 subjects including 163 cases and 157 controls. Close relation between Ala589Ser polymorphism and elevated systolic and diastolic blood pressure (SBP and DBP) was recognized. Sociodemographic factors including body mass index (BMI), age, the level of fasting blood sugar (FBS), low density lipoprotein (LDL), and triglyceride (TG) in the cases and healthy subjects exhibited strong differences (p < 0.05). The distribution of allele frequency and genotype of WNK4 gene Ala589Ser polymorphism showed significant differences (p < 0.05) between EHT subjects with or without type 2 diabetes mellitus (T2DM) and normotensive subjects, statistically. The WNK4 gene variation influences significantly blood pressure increase. Ala589Ser probably has effects on the enzymic activity leading to enhanced predisposition to the disorder.

  2. Novel Association of WNK4 Gene, Ala589Ser Polymorphism in Essential Hypertension, and Type 2 Diabetes Mellitus in Malaysia

    PubMed Central

    Ghodsian, Nooshin; Ismail, Patimah; Ahmadloo, Salma; Heidari, Farzad; Haghvirdizadeh, Polin; Ataollahi Eshkoor, Sima; Etemad, Ali

    2016-01-01

    With-no-lysine (K) Kinase-4 (WNK4) consisted of unique serine and threonine protein kinases, genetically associated with an autosomal dominant form of hypertension. Argumentative consequences have lately arisen on the association of specific single nucleotide polymorphisms of WNK4 gene and essential hypertension (EHT). The aim of this study was to determine the association of Ala589Ser polymorphism of WNK4 gene with essential hypertensive patients in Malaysia. WNK4 gene polymorphism was specified utilizing mutagenically separated polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) method in 320 subjects including 163 cases and 157 controls. Close relation between Ala589Ser polymorphism and elevated systolic and diastolic blood pressure (SBP and DBP) was recognized. Sociodemographic factors including body mass index (BMI), age, the level of fasting blood sugar (FBS), low density lipoprotein (LDL), and triglyceride (TG) in the cases and healthy subjects exhibited strong differences (p < 0.05). The distribution of allele frequency and genotype of WNK4 gene Ala589Ser polymorphism showed significant differences (p < 0.05) between EHT subjects with or without type 2 diabetes mellitus (T2DM) and normotensive subjects, statistically. The WNK4 gene variation influences significantly blood pressure increase. Ala589Ser probably has effects on the enzymic activity leading to enhanced predisposition to the disorder. PMID:27314050

  3. Improvement of DC vaccine with ALA-PDT induced immunogenic apoptotic cells for skin squamous cell carcinoma.

    PubMed

    Ji, Jie; Fan, Zhixia; Zhou, Feifan; Wang, Xiaojie; Shi, Lei; Zhang, Haiyan; Wang, Peiru; Yang, Degang; Zhang, Linglin; Chen, Wei R; Wang, Xiuli

    2015-07-10

    Dendritic cell (DC) based vaccines have emerged as a promising immunotherapy for cancers. However, most DC vaccines so far have achieved only limited success in cancer treatment. Photodynamic therapy (PDT), an established cancer treatment strategy, can cause immunogenic apoptosis to induce an effective antitumor immune response. In this study, we developed a DC-based cancer vaccine using immunogenic apoptotic tumor cells induced by 5-aminolevulinic acid (ALA) mediated PDT. The maturation of DCs induced by PDT-treated apoptotic cells was evaluated using electron microscopy, FACS, and ELISA. The anti-tumor immunity of ALA-PDT-DC vaccine was tested with a mouse model. We observed the maturations of DCs potentiated by ALA-PDT treated tumor cells, including morphology maturation (enlargement of dendrites and increase of lysosomes), phenotypic maturation (upregulation of surface expression of MHC-II, DC80, and CD86), and functional maturation (enhanced capability to secrete IFN-γ and IL-12, and to induce T cell proliferation). Most interestingly, PDT-induced apoptotic tumor cells are more capable of potentiating maturation of DCs than PDT-treated or freeze/thaw treated necrotic tumor cells. ALA-PDT-DC vaccine mediated by apoptotic cells provided protection against tumors in mice, far stronger than that of DC vaccine obtained from freeze/thaw treated tumor cells. Our results indicate that immunogenic apoptotic tumor cells can be more effective in enhancing a DC-based cancer vaccine, which could improve the clinical application of PDT-DC vaccines.

  4. Characterization of Al-As codoped p-type ZnO films by magnetron cosputtering deposition

    SciTech Connect

    Yun, Eui-Jung; Park, Hyeong-Sik; Lee, Kyu H.; Nam, Hyoung G.; Jung, Myunghee

    2008-04-01

    We report the preparation of Al-As codoped p-type ZnO films by rf magnetron cosputtering deposition. The p-type conductivity of the films was revealed by Hall measurements, x-ray photoelectron spectroscopy (XPS), and photoluminescence measurements after being annealed in O{sub 2}. It was observed by XPS that Al content increased with increasing AlAs target power from 80 to 160 W and reached a maximum value at an AlAs target power of 160 W. Hole concentration decreased with increasing Al content. With increasing AlAs target power greater than 160 W, the samples exhibit increases in As and O contents and decreases in Al and Zn contents, which contribute to the increase in hole concentration. A high hole concentration of 2.354x10{sup 20} cm{sup -3}, a low resistivity of 2.122x10{sup -2} {omega} cm, and a Hall mobility of 0.13 cm{sup 2}/V s for the films with high As content of 16.59% were obtained. XPS has also been used to address the unresolved issues related to the p-type formation mechanism of As-doped ZnO, supporting that the acceptor is As{sub Zn}-2V{sub Zn}.

  5. Some Properties of a Self-Sufficient Cytochrome P-450 Monooxygenase System from Bacillus megaterium Strain ALA2

    USDA-ARS?s Scientific Manuscript database

    We reviewed the many interesting and related in vivo products derived from reactions of the B. megaterium strain ALA2 and various related polyunsaturated fatty acids (PUFA) substrates. Products obtained from the omega-6 PUFAs (linoleic acid, gamma-linolenic acid, and arachidonic acid) possessed die...

  6. Role of Superoxide Dismutase 2 Gene Ala16Val Polymorphism and Total Antioxidant Capacity in Diabetes and its Complications

    PubMed Central

    Pourvali, Katayoun; Abbasi, Mehrnaz; Mottaghi, Azadeh

    2016-01-01

    Diabetes Mellitus (DM) is a chronic heterogeneous disorder and oxidative stress is a key participant in the development and progression of it and its complications. Anti-oxidant status can affect vulnerability to oxidative damage, onset and progression of diabetes and diabetes complications. Superoxide dismutase 2 (SOD2) is one of the major antioxidant defense systems against free radicals. SOD2 is encoded by the nuclear SOD2 gene located on the human chromosome 6q25 and the Ala16Val polymorphism has been identified in exon 2 of the human SOD2 gene. Ala16Val (rs4880) is the most commonly studied SOD2 single nucleotide polymorphism (SNP) in SOD2 gene. This SNP changes the amino acid at position 16 from valine (Val) to alanine (Ala), which has been shown to cause a conformational change in the target sequence of manganese superoxide dismutase (MnSOD) and also affects MnSOD activity in mitochondria. Ala16Val SNP and changes in the activity of the SOD2 antioxidant enzyme have been associated with altered progression and risk of different diseases. Association of this SNP with diabetes and some of its complications have been studied in numerous studies. This review evaluated how rs4880, oxidative stress and antioxidant status are associated with diabetes and its complications although some aspects of this line still remain unclear. PMID:27141263

  7. Redetermination of the structure of ALa2WO7 (A=Ba, Sr) with fluorite-like metal ordering

    NASA Astrophysics Data System (ADS)

    Fu, W. T.; IJdo, D. J. W.; Bontenbal, A.

    2013-05-01

    The crystal structures of ALa2WO7 (A=Ba, and Sr) at room temperature were re-determined by the Rietveld method using the combined X-ray and neutron powder diffraction data. The compounds are confirmed to be isomorphic, crystallizing in the space group P1121/b. In ALa2WO7 the ordering of metal atoms is fluorite-like, but it differs from that of the fluorite-defect compounds of the formula Ln3MO7 (Ln=lanthanide or Y, M=pentavalent metal). The structure of ALa2WO7 consists of isolated WO6 octahedra, whereas in the normal Ln3MO7 the MO6 octahedra share corners forming one-dimensional chains. Although ALa2WO7 has a centric space group, La ions are not situate at the centre of symmetry, which explains the 5D0→7F2 transition being dominant in emission spectrum of Eu-doped materials.

  8. An Automated Land Analysis System (ALAS) for applications at a range of spatial scales: Watershed to global

    SciTech Connect

    Miller, N.L.

    1995-08-01

    Recent advances in Digital Elevation Model (DEM) data availability and topographic analysis have enabled us to develop an Automated Land Analysis System (ALAS). ALAS is based on a series of codes which determine topographic and hydrologic characteristics at each pixel, watershed, and each large scale cell. The input requirements are a DEM from any location in the world, it`s resolution, and array size. A Motif accessed script reads in these inputs and generates a series of data sets which further describe the watershed properties such as flow directions, hydrologic characteristic probability density functions, etc.). Postscript files and arrays indicating the fme river networks and each subcatchment, as well as numerous other properties, are produced and catalogued. The motivation behind the development of ALAS is a direct response to the conceptualization of convergent scales between hydrologic and atmospheric models as defined by the World Climate Research Programme. The remainder of this paper highlights ALAS components, capabilities, and provides some discussion on its applications.

  9. Synthesis of peptide-cellulose conjugate mediated by a soluble cellulose derivative having β-Ala esters.

    PubMed

    Ohkawa, Kousaku; Nishibayashi, Mikiko; Devarayan, Kesavan; Hachisu, Masakazu; Araki, Jun

    2013-02-01

    A derivatization of cellulose was investigated for gaining up the solubility for subsequent conjugation reaction. N(β)-Boc-β-Ala, was introduced to the parent cellulose using carbonyl diimidazole. Degree of substitution towards the cellulose hydroxyls was 49%. Subsequent removal of Boc in trifluoroacetic acid (TFA) yielded β-Ala-cellulose·TFA salt. A protected hexapeptide, Boc-Ser(Bzl)-Gly-Tyr(Bzl)-Ser(Bzl)-Gly-Lys(Z) was synthesized via 9 steps of peptide elongation, and the C-end carboxyl groups of the peptide was coupled with the β-Ala-cellulose in a homogenous dimethyl sulfoxide solution, using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide monohydrochloride to ensure the N(β)-selective acylation. The degree of substitution of the protected peptide towards the β-amino groups of β-Ala-cellulose (DS%(/NH(2))) was 52% for 1.0 eq.mol of the protected peptide feed, and in the presence of N-hydroxysuccinimide, DS%(/NH(2)) was increased to 61%. At 4.0 eq.mol feed, almost quantitative conjugation was observed as DS%(/NH(2))=98-99%. Deprotection of the conjugate using thioanisole-TFA resulted in complete removal of Boc, Bzl on Tyr, and Z on Lys, while a very trace amount of Bzl on Ser seemed to be left uncleaved. Copyright © 2012 Elsevier B.V. All rights reserved.

  10. Sensitization and photodynamic therapy of esophageal,duodenal, and colonic tumors with 5-aminolaevulinic acid (ALA) induced protoporphyrin IX (PPIX)

    NASA Astrophysics Data System (ADS)

    Mlkvy, Peter; Messmann, Helmut; Regula, Jaroslaw; Conio, M.; Pauer, M.; Millson, Charles E.; MacRobert, Alexander J.; Bown, Stephen G.

    1995-03-01

    Five aminolaevulinic acid (ALA) is a promising agent for PDT sensitization as it can be given orally and only causes skin photosensitivity for 1 - 2 days. In fluorescence and photodynamic studies 26 patients with benign and malignant gastrointestinal tumors (M 17, F 9; mean age 79) were given 30 - 60 mg ALA orally (single or divided doses) and biopsies taken of tumor and normal tissue at 1 - 24 hours for fluorescence microscopy. With 30 mg/kg, highest protoporphyrin IX (PPIX) levels were seen in oesophagus, duodenum and less in colon, but without tumor selectivity. Better tumor selectivity was seen in the colon after 60 mg/kg (5:1). Six patients had transient rises in transaminases and five mild nausea. Sixteen patients were later treated (after further ALA) with red light (628 nm, bare fiber or diffuser, 50 - 100 J at 50 mW at each site). All but two showed subsequent necrosis, but only 0.5 - 1.5 mm depth. PDT with ALA is simple, safe, and promising for tumors in the GI tract. Modification of treatment parameters may make it suitable for larger lesions.

  11. In-vitro study on ALA-induced endogenous protoporphyrin IX as photosensitizer for photodynamic tumor diagnosis and therapy

    NASA Astrophysics Data System (ADS)

    Ueberriegler, K.; Fiedler, D.; Verwanger, Thomas; Schnitzhofer, Gerlinde; Banieghbal, E.; Krammer, Barbara E.

    1998-07-01

    Photodynamic tumor diagnosis and therapy is efficiently carried out by endogenous protoporphyrin IX as photosensitizer, induced by external addition of the precursor 5-aminolevulinic acid (ALA). In the present study, PpIX localization and photodynamically induced damage was investigated in normal and transformed human fibroblasts. PpIX formation reaches its maximum after incubation for at least 20 h with 700 (mu) g/m1 ALA, and increases with the pH- value. ALA has to be given 20-30 times more than external PpIX in order to produce the same cytotoxic damage. As detected by Low Light Imaging, PpIX is generated in the mitochondria, released to the cytoplasm and distributed to cytoplasma and nuclear membranes.The nucleus is not stained. Intracellular targets of PpIX damage after irradiation are mainly mitochondria, ER and nuclear membrane. The organelles show a decomposition pattern, which resembles apoptotic morphology and occurs faster in the co-cultivated transformed than in the normal cells. ALA-treated hepatocytes produce micronuclei and chromosomal aberrations, which indicates some mutagenic potential. Expression studies of the (proto)oncogenes c-myc and bcl-2 sublethally treated fibroblasts by quantitative RT-PCR show high deviations from the constitutive expression level, which are accompanied by cell cycle disturbances, indicating a possible precursor role to apoptosis introduction.

  12. Proteomics and SSH Analyses of ALA-Promoted Fruit Coloration and Evidence for the Involvement of a MADS-Box Gene, MdMADS1

    PubMed Central

    Feng, Xinxin; An, Yuyan; Zheng, Jie; Sun, Miao; Wang, Liangju

    2016-01-01

    Skin color is a key quality attribute of fruits and how to improve fruit coloration has long been a major concern. 5-Aminolevulinic acid (ALA), a natural plant growth regulator, can significantly increase anthocyanin accumulation in fruit skin and therefore effectively improve coloration of many fruits, including apple. However, the molecular mechanism how ALA stimulates anthocyanin accumulation in fruit skin remains unknown. Here, we investigated the impact of ALA on apple skin at the protein and mRNA levels. A total of 85 differentially expressed proteins in apple skins between ALA and water treatment (control) were identified by complementary gel-based and gel-free separation techniques. Most of these differentially expressed proteins were up-regulated by ALA. Function analysis suggested that 87.06% of the ALA-responsive proteins were associated with fruit ripening. To further screen ALA-responsive regulators, we constructed a subtracted cDNA library (tester: ALA treatment; driver: control) and obtained 104 differentially expressed unigenes, of which 38 unigenes were indicators for the fruit ripening-related genes. The differentially changed proteins and transcripts did not correspond well at an individual level, but showed similar regulated direction in function at the pathway level. Among the identified fruit ripening-related genes, the expression of MdMADS1, a developmental transcription regulator of fruit ripening, was positively correlated with expression of anthocyanin biosynthetic genes (MdCHS, MdDFR, MdLDOX, and MdUFGT) in apple skin under ALA treatment. Moreover, overexpression of MdMADS1 enhanced anthocyanin content in transformed apple calli, which was further enhanced by ALA. The anthocyanin content in MdMADS1-silenced calli was less than that in the control with ALA treatment, but higher than that without ALA treatment. These results indicated that MdMADS1 is involved in ALA-induced anthocyanin accumulation. In addition, anthocyanin

  13. Proteomics and SSH Analyses of ALA-Promoted Fruit Coloration and Evidence for the Involvement of a MADS-Box Gene, MdMADS1.

    PubMed

    Feng, Xinxin; An, Yuyan; Zheng, Jie; Sun, Miao; Wang, Liangju

    2016-01-01

    Skin color is a key quality attribute of fruits and how to improve fruit coloration has long been a major concern. 5-Aminolevulinic acid (ALA), a natural plant growth regulator, can significantly increase anthocyanin accumulation in fruit skin and therefore effectively improve coloration of many fruits, including apple. However, the molecular mechanism how ALA stimulates anthocyanin accumulation in fruit skin remains unknown. Here, we investigated the impact of ALA on apple skin at the protein and mRNA levels. A total of 85 differentially expressed proteins in apple skins between ALA and water treatment (control) were identified by complementary gel-based and gel-free separation techniques. Most of these differentially expressed proteins were up-regulated by ALA. Function analysis suggested that 87.06% of the ALA-responsive proteins were associated with fruit ripening. To further screen ALA-responsive regulators, we constructed a subtracted cDNA library (tester: ALA treatment; driver: control) and obtained 104 differentially expressed unigenes, of which 38 unigenes were indicators for the fruit ripening-related genes. The differentially changed proteins and transcripts did not correspond well at an individual level, but showed similar regulated direction in function at the pathway level. Among the identified fruit ripening-related genes, the expression of MdMADS1, a developmental transcription regulator of fruit ripening, was positively correlated with expression of anthocyanin biosynthetic genes (MdCHS, MdDFR, MdLDOX, and MdUFGT) in apple skin under ALA treatment. Moreover, overexpression of MdMADS1 enhanced anthocyanin content in transformed apple calli, which was further enhanced by ALA. The anthocyanin content in MdMADS1-silenced calli was less than that in the control with ALA treatment, but higher than that without ALA treatment. These results indicated that MdMADS1 is involved in ALA-induced anthocyanin accumulation. In addition, anthocyanin

  14. Obesity and Pro12Ala Polymorphism of Peroxisome Proliferator-Activated Receptor-Gamma Gene in Healthy Adults: A Systematic Review and Meta-Analysis.

    PubMed

    Mansoori, Anahita; Amini, Maryam; Kolahdooz, Fariba; Seyedrezazadeh, Ensiyeh

    2015-01-01

    The aim of this systematic review was to evaluate the relationship between obesity and peroxisome proliferator-activated receptor-gamma (PPARx03B3;) Pro12Ala polymorphism in healthy adults. Weighted mean differences (WMDs) of body mass index (BMI) were calculated for different inheritance models and subgroups. Fifty-six studies were eligible for inclusion in the meta-analysis. The result shows that the Ala allele of this polymorphism was associated with increased WMD in mean BMI (WMD = 0.29, 95% CI 0.10-0.48, p = 0.003). The Ala carriers were associated with increased WMD in mean BMI values in both genders and in the Caucasian subgroup. The associations were seen among people with higher levels of BMI (BMI ≥35). The Ala allele of the PPARx03B3; Pro12Ala polymorphism in healthy adults was associated with increased BMI under a dominant model of inheritance. © 2015 S. Karger AG, Basel.

  15. Thr92Ala polymorphism of human type 2 deiodinase gene (hD2) affects the development of Graves' disease, treatment efficiency, and rate of remission.

    PubMed

    Alina, Babenko; Daria, Popkova; Olga, Freylihman; Vladislav, Solncev; Anna, Kostareva; Elena, Grineva

    2012-01-01

    Clinical symptoms vary in thyrotoxicosis, and severity of these depends on many factors. Over the last years, impact of genetic factors upon the development and clinical significance of thyrotoxic symptoms became evident. It is known that a production of T3 in various tissues is limited by deiodinase 2 (D2). Recent studies revealed that certain single nucleotide polymorphisms (including threonine (Thr) to alanine (Ala) replacement in D2 gene codon 92, D2 Thr92Ala) affect T3 levels in tissues and in serum. Individuals with Ala92Ala genotype have lower D2 activity in tissues, compared with that in individuals with other genotypes. In our study, we have assessed an association of D2 Thr92Ala polymorphism with (1) frequency of disease development, (2) severity of clinical symptoms of thyrotoxicosis, and (3) rate of remissions, in Graves' disease patients.

  16. In vivo fluorescence spectroscopy and imaging of ALA-induced endogenous porphyrins in skin after Er:YAG ablation of human stratum corneum

    NASA Astrophysics Data System (ADS)

    Koenig, Karsten; Schneckenburger, Herbert; Boehncke, Wolf-Henning; Hibst, Raimund

    1994-09-01

    Limited regions of human stratum corneum were removed by laser ablation using an Er:YAG laser. Immediately after this procedure, an ointment containing 5-aminolevulinic acid (ALA) was applied topically to the laser-treated and surrounding skin. The time-dependent ALA- induced biosynthesis of protoporphyrin IX was measured by fluorescence detection. Fluorescence in the red spectral region was found to occur in the ablated skin regions only. Time-resolved measurements showed the formation of long-lived fluorophores (16 ns) indicating the presence of ALA-induced monomeric porphyrin. Naturally occurring fluorophores (NAD(P)H, flavins, collagen, elastin) possess shorter fluorescence decay times. Therefore, time-gated measurements in the nanosecond region enable the specific detection of ALA-stimulated porphyrin fluorescence by choosing an appropriate time-window. In addition, detection of backscattered excitation light can be avoided. High-contrast video images of ALA-incubated fluorescent areas were obtained using this novel imaging technique.

  17. PPARγ Pro12Ala and His447His polymorphisms and susceptibility to Alzheimer's disease: a meta-analysis.

    PubMed

    Lee, Y H; Song, G G

    2015-06-29

    We investigated whether Pro12Ala (C→G) and His447His (C→T) polymorphisms of the peroxisome proliferator-activated receptor gamma (PPARγ) gene are associated with susceptibility to Alzheimer's disease (AD). We conducted a meta-analysis of the associations between the PPARγ Pro12Ala and His447His polymorphisms and AD in subjects. The meta-analysis was performed according to the apolipoprotein E (APOE) ɛ4 allele status. A total of eight studies were considered in our meta-analysis, comprising 2948 patients with AD and 3753 controls. Meta-analysis showed no association between AD and the PPARγ Pro12Ala G allele in any of the study subjects [odds ratio (OR) = 1.013, 95% confidence interval (95%CI) = 0.906-1.132, P = 0.821] or in the European and Asian populations (OR = 0.997, 95%CI = 0.890-1.118, P = 0.965; OR = 1.409, 95%CI = 0.832-2.387, P = 0.202, respectively). We tested whether the APOE ɛ4 allele affects the association between the PPARγ Pro12Ala polymorphism and AD. Meta-analysis showed no association between AD and the PPARγ G allele in any of the study subjects with or without the APOE ɛ4 allele. Meta-analysis showed no association between AD and the PPARγ His447His T allele in the European population (OR for T allele = 0.912, 95%CI = 0.732-1.136, P = 0.409). This meta-analysis has shown that there is a lack of association between the PPARγ Pro12Ala and His447His polymorphisms and AD risk.

  18. Association of PPARG Pro12Ala polymorphism with insulin sensitivity and body mass index in patients with polycystic ovary syndrome.

    PubMed

    Baldani, Dinka Pavicic; Skrgatic, Lana; Cerne, Jasmina Z; Ferk, Polonca; Simunic, Velimir; Gersak, Ksenija

    2014-03-01

    Insulin resistance is one of the key factors in the pathogenesis of polycystic ovary syndrome (PCOS). The peroxisome proliferator-activated receptor gamma (PPARG) plays a role in the regulation of insulin sensitivity. The aim of the present study was to establish a possible association of the PPARG Pro12Ala polymorphism with PCOS and its effect on family and personal history, as well as on the metabolic and endocrine parameters in PCOS patients. A total of 151 PCOS patients and 179 healthy women of reproductive age were enrolled. History, body mass index (BMI), waist-to-hip ratio and the presence of phenotypic hyperandrogenism were recorded. Hormonal, metabolic and biochemical profiles were assessed. A molecular analysis for the genetic polymorphism was performed. One third (29.8%) of the PCOS patients were found to be carriers of at least one variant of the Ala allele (X/Ala), while 70.2% carried two wild-type Pro alleles (Pro/Pro), with an equal distribution observed in the control group. The PCOS patients carrying the X/Ala alleles exhibited lower serum fasting insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR) and BMI compared to Pro/Pro carriers. This finding was significant only in the lean PCOS group. The polymorphic genotype exerted no effect on history, hormonal and clinical hyperandrogenism, lipid status or C-reactive protein, leptin, adiponectin, resistin and ghrelin serum levels in women with PCOS. In conclusion, although the PPARG Pro12Ala polymorphism is not a major determinant of PCOS in the Croatian population, it may exert a positive effect on insulin sensitivity and BMI. As these associations were recorded exclusively in the lean group of patients with PCOS, this polymorphism potentially contributes to a protective role against hyperinsulinemia and obesity.

  19. Association of PPARG Pro12Ala polymorphism with insulin sensitivity and body mass index in patients with polycystic ovary syndrome

    PubMed Central

    BALDANI, DINKA PAVICIC; SKRGATIC, LANA; CERNE, JASMINA Z.; FERK, POLONCA; SIMUNIC, VELIMIR; GERSAK, KSENIJA

    2014-01-01

    Insulin resistance is one of the key factors in the pathogenesis of polycystic ovary syndrome (PCOS). The peroxisome proliferator-activated receptor gamma (PPARG) plays a role in the regulation of insulin sensitivity. The aim of the present study was to establish a possible association of the PPARG Pro12Ala polymorphism with PCOS and its effect on family and personal history, as well as on the metabolic and endocrine parameters in PCOS patients. A total of 151 PCOS patients and 179 healthy women of reproductive age were enrolled. History, body mass index (BMI), waist-to-hip ratio and the presence of phenotypic hyperandrogenism were recorded. Hormonal, metabolic and biochemical profiles were assessed. A molecular analysis for the genetic polymorphism was performed. One third (29.8%) of the PCOS patients were found to be carriers of at least one variant of the Ala allele (X/Ala), while 70.2% carried two wild-type Pro alleles (Pro/Pro), with an equal distribution observed in the control group. The PCOS patients carrying the X/Ala alleles exhibited lower serum fasting insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR) and BMI compared to Pro/Pro carriers. This finding was significant only in the lean PCOS group. The polymorphic genotype exerted no effect on history, hormonal and clinical hyperandrogenism, lipid status or C-reactive protein, leptin, adiponectin, resistin and ghrelin serum levels in women with PCOS. In conclusion, although the PPARG Pro12Ala polymorphism is not a major determinant of PCOS in the Croatian population, it may exert a positive effect on insulin sensitivity and BMI. As these associations were recorded exclusively in the lean group of patients with PCOS, this polymorphism potentially contributes to a protective role against hyperinsulinemia and obesity. PMID:24649096

  20. Correlation between PPARg2 gene Pro12Ala polymorphism and cerebral infarction in an Inner Mongolian Han Chinese population.

    PubMed

    Li, X; Zhang, B L; Zhang, X G; Su, X L

    2016-06-20

    The variant of PPAR-g2 has been shown to promote the increase of carotid IMT in patients suffering from cerebral infarction and the Pro12Ala polymorphism in the peroxisome proliferator-activated receptorg2 (PPARg2) gene may be associated with cerebral infarction. However, due to the different genetic background, race, and regional variations of cerebral infarction patient, the results of investigations into this subject differ. The aim of this study was to investigate this polymorphism in relation to cerebral infarction among the Inner Mongolian Han Chinese population. A total of 574 Han Chinese individuals from Inner Mongolian were selected randomly, including 302 patients with cerebral infarction and 272 healthy controls. Polymerase chain reaction-restriction fragment length polymorphism was used to determine genotypes of the PPARg2 Pro12Ala variant and results were confirmed by direct sequencing. Genotype frequencies were found to be 90.7 and 91.9% for P/P, 8.6 and 7.7% for P/A, and 0.7 and 0.4 for A/A in the cerebral infarction and control groups, respectively. No statistically significant differences in genotype distribution were observed between the two groups (P > 0.05). Moreover, PPARg2 Pro12Ala genotype was not significantly associated with altered fasting blood glucose, blood pressure, or serum lipid profiles. After adjustment for gender, body mass index, and smoking habit, logistic regression was used to analyze the relationship between the Pro12Ala polymorphism and cerebral infarction (odds ratio = 0.888, 95% confidence interval = 0.106-7.460, P > 0.05), revealing that this variant was not the main pathogenic factor involved. Therefore, the Pro12Ala mutation of PPARg2 may not be associated with cerebral infarction in the Inner Mongolian Han Chinese population.

  1. Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma (PPARgamma) gene in inflammatory bowel disease.

    PubMed

    Atug, Ozlen; Tahan, Veysel; Eren, Fatih; Tiftikci, Arzu; Imeryuz, Nese; Hamzaoglu, Hulya Over; Tozun, Nurdan

    2008-12-01

    Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has recently been implicated as an endogenous regulator of cellular proliferation and inflammation. Impaired expression of PPAR-gamma in colonic epithelial cells in ulcerative colitis (UC) and increased expression in hypertrophic mesenteric adipose tissue in Crohn's disease (CD) have been reported. Furthermore, PPAR-gamma ligands have been shown to inhibit tissue injury associated with immune activation in UC. Any mutation in PPAR-gamma gene may be responsible for the increase in inflammatory mediators and hence the perpetuation of inflammation in inflammatory bowel disease (IBD) patients. One common polymorphism in PPAR-gamma gene is proline to alanine substitution (Pro12Ala) which results from a CCA to GCA missense substitution in codon 12 of exon 2 of the PPAR-gamma gene. In this study, we aimed to explore Pro12Ala polymorphism in PPAR-gamma gene in IBD in Turkish patients. 69 patients with CD, 45 with UC and 100 controls of similar age and sex were studied. Genomic DNA was isolated from peripheral blood leucocytes and mutagenically separated-polymerase chain reaction (PCR) analyses were performed to determine the Pro12Ala polymorphism of the PPAR-gamma gene. We observed no significant differences in the frequency of the Pro12Ala polymorphism in the PPAR-gamma gene among subjects with CD, UC and controls (15.9%, 15.5% and 13%, respectively, p>0.05). These results suggest that Pro12Ala polymorphism in the PPAR-gamma gene relates neither to the risk of the development of inflammatory bowel disease nor to the clinical subtypes of CD in the Turkish population.

  2. Impact of an AlAs window layer upon the optical properties of Al x Ga1-x As photodiodes

    NASA Astrophysics Data System (ADS)

    Kang, T.; Chen, X. J.; Johnson, E. B.; Christian, J. F.; Lee, K.; Hammig, M. D.

    2016-05-01

    Recently developed advanced scintillators, which have the ability to distinguish gamma-ray interaction events from those that accompany neutron impact, require improved quantum efficiency in the blue to near UV region of the spectrum. We utilize GaAs/Al0.8Ga0.2As photodiode elements as components in a wide band-gap solid-state photomultiplier as a lower-cost, lower logistical burden, and higher quantum efficiency replacement for the photomultiplier tube. An AlAs window layer is employed as a means to increase the diode’s optical performance. Relative to structures absent the window layer, simulations and measurements demonstrate that the AlAs layer produces a spatial coincidence between regions of large drift fields with regions of high photon absorption. In addition to the AlAs layer, secondary ion mass spectrometry measurements show that an unexpected high degree of inter-diffusion of GaAs and AlAs quenches the photon-detection efficiency, a decrease that can be avoided by its post-growth removal. With the AlAs layer, the peak external quantum efficiency of 49% is achieved at 450 nm with 10 V reverse bias, which does not fully deplete the device. Simulations show that full depletion can result in efficiencies exceeding 90%. In order to enhance the optical response, a simple anti-reflective coating layer is designed using the existing passivation layer components that successfully minimizes the reflection at the wavelength range of interest (300 nm-500 nm).

  3. Relationship Between Occlusal Plane and Three Levels of Ala Tragus line in Dentulous and Partially Dentulous Patients in Different Age Groups: A Pilot Study.

    PubMed

    Shaikh, Saquib Ahmed; K, Lekha; Mathur, Gaurav

    2015-02-01

    Correct orientation of the occlusal plane plays a vital role in achieving optimal aesthetics, occlusal balance and function of complete dentures. The use of ala tragus line for determination of occlusal plane has been a topic of debate over past many years. Also, the effect of age on level of ala tragal line has not been investigated in the past. To determine the effect of age on location of Ala-Tragus line. A total of 180 patients (90 males and 90 females) were selected with complete dentition and were grouped according to their age in three age groups with 60 subjects in each age group (Group A: 20-35 y, Group B: 36-50 y, Group C: 51-65 y). Right lateral profile photographs were taken with subjects having fox plane placed intraorally parallel to occlusal plane. Reference points corresponding to inferior border, middle or superior border of tragus and inferior border of ala of nose were marked on photographs. These were joined to get three different levels of Ala-Tragus line. Images were analysed photometrically and most parallel relationship was determined in between arms of fox plane (that represented the occlusal plane) and three different levels of ala tragus line. Data obtained was subjected to statistical analysis using Pearson chi-square and Likelihood-ratio chi-square test. Significant correlation was found between age and level of Ala-Tragus line. The occlusal plane was found to be more parallel to Ala-tragus line when inferior border of tragus was considered as posterior reference point in young adult age group (20-35 y). In older age groups, occlusal plane was found to be more parallel to Ala-tragus line when middle of tragus was considered as posterior reference point. Within the limitations of this study, it can be concluded that a definite relationship exists in between age and level of ala tragus line.

  4. Urinary delta-ALA: a potential biomarker of exposure and neurotoxic effect in rats co-treated with a mixture of lead, arsenic and manganese.

    PubMed

    Andrade, Vanda; Mateus, M Luísa; Batoréu, M Camila; Aschner, Michael; dos Santos, A P Marreilha

    2013-09-01

    Lead (Pb), arsenic (As) and manganese (Mn) are neurotoxic elements that often occur in mixtures for which practically no information is available on biomarkers (BMs) for the evaluation of exposure/effects. Exposures to these metals may increase delta-aminolevulinic acid (delta-ALA), which in itself may potentiate neurotoxicity. The objective of this study was to investigate the utility of urinary delta-ALA (delta-ALA-U) levels as BM of exposure and/or neurotoxic effects induced by this mixture. Five groups of Wistar rats were treated for 8 days with Pb (5mg/kg), As (60mg/L), Mn (10mg/kg), the 3-metal mixture (same doses of the single metals), and control group. Motor activity was evaluated and 24-h urine collected before and after the treatment. 24-hours (h) after the last dose, the rats were sacrificed and the brains removed for analyses. Delta-ALA and metal levels were determined in brain and urine. Co-treated rats showed a significant (p<0.05) correlation between increased Pb, As, Mn and delta-ALA levels in the brain and decreased motor activity. Delta-ALA-U concentrations were higher in the mixture-treated group than the sum of the delta-ALA-U levels in each single-treated groups and discriminated (p<0.05) between the mixture and untreated rats. Moreover, delta-ALA-U was correlated (p<0.05) with brain delta-ALA levels. These results establish that treatments with this metal mixture exacerbate behavioral dysfunction, increasing most prominently brain Pb levels. This study is the first to establish that delta-ALA-U levels represent a sensitive BM of exposure/neurotoxic effect to this metal mixture.

  5. ALA-Induced Flavonols Accumulation in Guard Cells Is Involved in Scavenging H2O2 and Inhibiting Stomatal Closure in Arabidopsis Cotyledons

    PubMed Central

    An, Yuyan; Feng, Xinxin; Liu, Longbo; Xiong, Lijun; Wang, Liangju

    2016-01-01

    5-aminolevulinic acid (ALA), a new plant growth regulator, can inhibit stomatal closure by reducing H2O2 accumulation in guard cells. Flavonols are a main kind of flavonoids and have been proposed as H2O2 scavengers in guard cells. 5-aminolevulinic acid can significantly improve flavonoids accumulation in plants. However, whether ALA increases flavonols content in guard cells and the role of flavonols in ALA-regulated stomatal movement remains unclear. In this study, we first demonstrated that ALA pretreatment inhibited ABA-induced stomatal closure by reducing H2O2 accumulation in guard cells of Arabidopsis seedlings. This result confirms the inhibitory effect of ALA on stomatal closure and the important role of decreased H2O2 accumulation in this process. We also found that ALA significantly improved flavonols accumulation in guard cells using a flavonol-specific dye. Furthermore, using exogenous quercetin and kaempferol, two major components of flavonols in Arabidopsis leaves, we showed that flavonols accumulation inhibited ABA-induced stomatal movement by suppressing H2O2 in guard cells. Finally, we showed that the inhibitory effect of ALA on ABA-induced stomatal closure was largely impaired in flavonoid-deficient transparent testa4 (tt4) mutant. In addition, exogenous flavonols recovered stomatal responses of tt4 to the wild-type levels. Taken together, we conclude that ALA-induced flavonol accumulation in guard cells is partially involved in the inhibitory effect of ALA on ABA-induced H2O2 accumulation and stomatal closure. Our data provide direct evidence that ALA can regulate stomatal movement by improving flavonols accumulation, revealing new insights into guard cell signaling. PMID:27895660

  6. Urinary delta-ALA: a potential biomarker of exposure and neurotoxic effect in rats co-treated with a mixture of lead, arsenic and manganese

    PubMed Central

    Andrade, Vanda; Mateus, M. Luísa; Batoréu, M. Camila; Aschner, Michael; Marreilha dos Santos, A.P.

    2013-01-01

    Lead (Pb), arsenic (As) and manganese (Mn) are neurotoxic elements that often occur in mixtures for which practically no information is available on biomarkers (BMs) for the evaluation of exposure/effects. Exposures to these metals may increase delta-aminolevulinic acid (delta-ALA), which in itself may potentiate neurotoxicity. The objective of this study was to investigate the utility of urinary delta-ALA (delta-ALA-U) levels as BM of exposure and/or neurotoxic effects induced by this mixture. Five groups of Wistar rats were treated for 8 days with Pb (5 mg/kg), As (60 mg/L), Mn (10 mg/kg), the 3-metal mixture (same doses of the single metals), and control group. Motor activity was evaluated and 24-h urine collected before and after the treatment. 24-hours (h) after the last dose, the rats were sacrificed and the brains removed for analyses. Delta-ALA and metal levels were determined in brain and urine. Co-treated rats showed a significant (p<0.05) correlation between increased Pb, As, Mn and delta-ALA levels in the brain and decreased motor activity. Delta-ALA-U concentrations were higher in the mixture-treated group than the sum of the delta-ALA-U levels in each single-treated groups and discriminated (p<0.05) between the mixture and untreated rats. Moreover, delta-ALA-U was correlated (p<0.05) with brain delta-ALA levels. These results establish that treatments with this metal mixture exacerbate behavioral dysfunction, increasing most prominently brain Pb levels. This study is the first to establish that delta-ALA-U levels represent a sensitive BM of exposure/neurotoxic effect to this metal mixture. PMID:23764341

  7. Evaluation of single nucleotide polymorphisms of Pro12Ala in peroxisome proliferator-activated receptor-γ and Gly308Ala in tumor necrosis factor-α genes in obese Asian Indians: a population-based study

    PubMed Central

    Bhagat, Namita; Agrawal, Mukta; Luthra, Kalpana; Vikram, Naval K; Misra, Anoop; Gupta, Rajeev

    2010-01-01

    Background A population-based case control study was performed to determine the associations of Pro12Ala polymorphism in peroxisome proliferator-activated receptor-γ (PPARG) and Gly308Ala polymorphism in tumor necrosis factor-α (TNFA) genes in obese subjects. Patients and methods Of 1,400 eligible subjects, ≧20 years, we recruited only 1,127. For extreme phenotype case-control design, we evaluated 201 subjects with body mass index (BMI) ≧30 kg/m2 (Group 1) and 143 with BMI <20 kg/m2 (Group 2). Clinical, anthropometric, biochemical, and nutritional details and polymorphisms were estimated. Results In Group 1, the dietary intake of calories and fats was higher, physical activity was lower, and prevalence of truncal obesity, hypertension, high total cholesterol, low high-density lipoprotein cholesterol, and diabetes was greater than in Group 2. There were no homozygous polymorphisms of either gene. Heterozygous Pro12Ala polymorphism in PPARG was found in 15 (7.5%) subjects in Group 1 and 3 (2.1%) subjects in Group 2 (P = 0.028), and heterozygous Gly308Ala polymorphism in TNFA was found in 19 (9.5%) in Group 1 and 7 (4.9%) in Group 2 (P = 0.115). Presence of heterozygous polymorphism in PPARG and TNFA-predicted obesity with univariate odds ratio ([OR], 95% confidence intervals) of 2.25 (1.32–3.84, P = 0.003) and 1.48 (1.10–1.99, P = 0.009) and with multivariate OR 1.74 (1.03–2.93, P = 0.038) and 1.46 (1.05–2.03, P = 0.024), respectively. The addition of dietary and physical activity variables did not result in significant change. Conclusion Obese Asian Indians have greater prevalence of heterozygous polymorphisms of Pro12Ala in PPARG and Gly308Ala in TNFA genes. PMID:21437104

  8. Peroxisome proliferator-activated receptor Pro12Ala polymorphism and the risks of gestational diabetes mellitus

    PubMed Central

    Wang, Lihong; Xu, Wenting; Wang, Xu

    2016-01-01

    Abstract Background: Peroxisome proliferator-activated receptors-λ (PPAR-λ) is a member of nuclear receptor superfamily and acts as a ligand-dependent transcription factor often found in the adrenal gland, the spleen, and adipose tissue. The Pro12Ala polymorphism of PPAR-λ has been associated with the risks of gestational diabetes mellitus (GDM); however, association studies have provided conflicting results. The aim of this Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) compliant meta-analysis is to reach a more up-to-date and accurate estimation of the relationship between Pro12Ala genetic polymorphisms and the risks of GDM. Methods: Eligible studies were retrieved by searching PubMed, EMBASE, Web of Science, Ovid, WanFang, and Chinese National Knowledge Databases and selected according to a pre-defined inclusion criterion. The risk of bias was assessed using the Newcastle-Ottawa quality assessment scale. The per-allele odds ratio (OR) of risk allele proline (Pro) was compared between cases and controls in each study to describe the association between the Pro allele and an individual's risk of GDM. The ORs were pooled using both the random-effects model (the DerSimonian and Laird method) and the fixed effects model (the Mantel-Haenszel method) and the 95% confidence interval (95% CI) was calculated using Woolf method. Results: The final meta-analysis included a total of 11 articles of 12 data sets consisting of 7054 controls and 2980 GDM cases. Our results demonstrate that the Pro allele is not associated with GDM [OR: across multiple populations, 95% CI: 0.98–1.24; P(Z) = 0.01; P(Q) = 0.003]. In the stratified analysis by ethnicity, significantly increased risks were found for the Chinese (OR = 2.36; 95% CI: 1.47–3.78) and Korean (OR = 1.39; 95% CI: 1.00–1.93) populations. Conclusion: These data suggest the potential role of Pro allele in the pathogenesis of GDM in Asian populations. Although the funnel plot

  9. Pro1170 Ala polymorphism in HER2-neu is associated with risk of trastuzumab cardiotoxicity.

    PubMed

    Stanton, Sasha E; Ward, Maureen M; Christos, Paul; Sanford, Rachel; Lam, Christina; Cobham, Marta V; Donovan, Diana; Scheff, Ronald J; Cigler, Tessa; Moore, Anne; Vahdat, Linda T; Lane, Maureen E; Chuang, Ellen

    2015-04-11

    Variations in single nucleotide polymorphisms (SNPs) have been associated with enhanced drug efficacy and toxicity in cancer therapy. SNP variations in the ErbB2 gene have been identified that alter the protein sequence of the HER2-neu protein, but how these polymorphisms affect prognosis and response to HER2 targeted therapy is unknown. We examined eleven ErbB2 SNPs that alter the HER2-neu amino acid sequence to determine whether any of these particular polymorphisms were associated with increased trastuzumab cardiotoxicity in a case-control study. 140 subjects were enrolled from a single institution under Weill Cornell Medical College IRB protocol #0804009734. Patients were eligible if they had histologically or cytologically proven HER2-neu positive breast cancer and more than 3 months of trastuzumab therapy. Cases had either symptomatic CHF or a decline in LVEF of 15% (or if the LVEF <55%, a decline in LVEF of 10%) that resulted in at least temporary discontinuation of trastuzumab, whereas controls had no decline in their LVEF. Eleven ErbB2 single gene SNPs that resulted in an alteration in the HER2-neu protein amino acid sequence were studied. Single gene SNP analysis was carried out using SNP genotyping assays from genomic DNA obtained from peripheral blood or buccal swab. Only two of the ErbB2 SNPs (Ile 655 Val and Pro 1170 Ala) were found to have variation. There was no association between codon 665 and cardiotoxicity; however the proline variant of amino acid 1170 was more likely than the alanine variant to be found in cases with trastuzumab cardiotoxicity (35% of case patients as compared to 17% of controls, p = 0.04). This association remained significant in multivariable analysis taking into account age, race, and history of hypertension (adjusted OR = 2.60, 95% CI = 1.02, 6.62, p = 0.046). The Her2/neu Pro 1170 Ala polymorphism can be used to identify a subset of patients who are at increased risk of cardiotoxicity from trastuzumab

  10. Impact of the PPAR-γ2 Pro12Ala Polymorphism and ACE Inhibitor Therapy on New-Onset Microalbuminuria in Type 2 Diabetes: Evidence From BENEDICT

    PubMed Central

    De Cosmo, Salvatore; Motterlini, Nicola; Prudente, Sabrina; Pellegrini, Fabio; Trevisan, Roberto; Bossi, Antonio; Remuzzi, Giuseppe; Trischitta, Vincenzo; Ruggenenti, Piero

    2009-01-01

    OBJECTIVE Cross-sectional studies found less microalbuminuria in type 2 diabetic patients with the Ala12 allele of the peroxisome proliferator–activated receptor-γ2 (PPAR-γ2) Pro12Ala polymorphism. We prospectively evaluated the association between Pro12Ala polymorphism (rs1801282) and new-onset microalbuminuria. RESEARCH DESIGN AND METHODS Pro12Ala polymorphism was genotyped by TaqMan-based assay in genomic DNA of 1,119 consenting patients from BErgamo NEphrologic DIabetic Complications Trial (BENEDICT)—a prospective, randomized trial evaluating ACE inhibition effect on new-onset microalbuminuria (albuminuria 20–200 μg/min in at least two of three consecutive overnight urine collections in two consecutive visits) in hypertensive type 2 diabetes with albuminuria <20 μg/min at inclusion. RESULTS Baseline characteristics of Ala (Ala/Ala or Ala/Pro) carriers and Pro/Pro homozygotes were similar, with a nonsignificant trend to lower albuminuria (P = 0.1107) in the 177 Ala carriers. Over a median (interquartile range) of 44.0 (17.1–51.9) months, 7 (4%) Ala carriers and 86 (9.1%) Pro/Pro homozygotes developed microalbuminuria (hazard ratio [HR] 0.45 [95% CI 0.21–0.97]; P = 0.042). Final albuminuria was significantly lower in Ala carriers than Pro/Pro homozygotes (7.3 ± 9.1 vs. 10.5 ± 24.9 μg/min, respectively), even after adjustment for baseline albuminuria (P = 0.048). Baseline and follow-up blood pressure and metabolic control were similar in both groups. Incidence of microalbuminuria was significantly decreased by ACE versus non-ACE inhibitor therapy in Pro/Pro homozygotes (6.3 vs. 11.9%, respectively, HR 0.46 [0.29–0.72]; P < 0.001). CONCLUSIONS In type 2 diabetes, the Ala allele protects from worsening albuminuria and new-onset microalbuminuria, and ACE inhibition blunts the excess risk of microalbuminuria associated with the Pro/Pro genotype. Evaluating Pro12Ala polymorphism may help identifying patients at risk who may benefit the most from

  11. Impact of the PPAR-gamma2 Pro12Ala polymorphism and ACE inhibitor therapy on new-onset microalbuminuria in type 2 diabetes: evidence from BENEDICT.

    PubMed

    De Cosmo, Salvatore; Motterlini, Nicola; Prudente, Sabrina; Pellegrini, Fabio; Trevisan, Roberto; Bossi, Antonio; Remuzzi, Giuseppe; Trischitta, Vincenzo; Ruggenenti, Piero

    2009-12-01

    Cross-sectional studies found less microalbuminuria in type 2 diabetic patients with the Ala12 allele of the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) Pro12Ala polymorphism. We prospectively evaluated the association between Pro12Ala polymorphism (rs1801282) and new-onset microalbuminuria. Pro12Ala polymorphism was genotyped by TaqMan-based assay in genomic DNA of 1,119 consenting patients from BErgamo NEphrologic DIabetic Complications Trial (BENEDICT)-a prospective, randomized trial evaluating ACE inhibition effect on new-onset microalbuminuria (albuminuria 20-200 microg/min in at least two of three consecutive overnight urine collections in two consecutive visits) in hypertensive type 2 diabetes with albuminuria <20 microg/min at inclusion. Baseline characteristics of Ala (Ala/Ala or Ala/Pro) carriers and Pro/Pro homozygotes were similar, with a nonsignificant trend to lower albuminuria (P = 0.1107) in the 177 Ala carriers. Over a median (interquartile range) of 44.0 (17.1-51.9) months, 7 (4%) Ala carriers and 86 (9.1%) Pro/Pro homozygotes developed microalbuminuria (hazard ratio [HR] 0.45 [95% CI 0.21-0.97]; P = 0.042). Final albuminuria was significantly lower in Ala carriers than Pro/Pro homozygotes (7.3 +/- 9.1 vs. 10.5 +/- 24.9 microg/min, respectively), even after adjustment for baseline albuminuria (P = 0.048). Baseline and follow-up blood pressure and metabolic control were similar in both groups. Incidence of microalbuminuria was significantly decreased by ACE versus non-ACE inhibitor therapy in Pro/Pro homozygotes (6.3 vs. 11.9%, respectively, HR 0.46 [0.29-0.72]; P < 0.001). In type 2 diabetes, the Ala allele protects from worsening albuminuria and new-onset microalbuminuria, and ACE inhibition blunts the excess risk of microalbuminuria associated with the Pro/Pro genotype. Evaluating Pro12Ala polymorphism may help identifying patients at risk who may benefit the most from early renoprotective therapy.

  12. Association of Type II 5' Monodeiodinase Thr92Ala Single Nucleotide Gene Polymorphism and Circulating Thyroid Hormones Among Type 2 Diabetes Mellitus Patients.

    PubMed

    Yalakanti, Dhanunjaya; Dolia, Pragna B

    2016-04-01

    Diabetes mellitus and thyroid disorders are common endocrinopathies, which often occur parallel. Dyslipidemia is very common in both of these conditions. The development of hypothyroidism is well-known in type 1 diabetics, but it was not distinctly understood in type 2 diabetics. Thus we tried to examine the association between type II deiodinase (D2 or DIO2) Thr92Ala single nucleotide gene polymorphism and thyroid function among type 2 diabetes mellitus patients. A total of 130 type 2 diabetics were screened and genotyped for DIO2 Thr92Ala polymorphism. Fasting plasma glucose, Glycosylated haemoglobin, lipid and thyroid profiles, malondialdehyde (MDA) and paraoxonase were estimated according to standard procedures. A significant altered level of thyroid hormones (TH's) was found in Ala/Ala genotype when compared with Thr/Thr or Thr/Ala genotype. DIO2 and T3:T4 ratio significantly decreased, whereas total T4 and thyroid stimulating hormone levels significantly elevated among Ala/Ala genotype (131 ± 30 ng/ml; 0.12 ± 0.05; 7.17 ± 2.05 µg/dl; 4.77 ± 3.1 µIU/ml, respectively) when compared with Thr/Thr + Thr/Ala genotypes (176 ± 33 ng/ml; 0.21 ± 0.05; 5.21 ± 1.1 µg/dl; 2.59 ± 1.61 µIU/ml respectively). Moreover, D2 levels were significantly negatively correlated with TH's levels except total T4 among Ala/Ala genotypes. All the patients were having a poor glycemic control, and their glycemic status was positively correlating with MDA levels. On the other hand, serum paraoxonase activity decreased among Ala/Ala genotype (104 ± 21 vs. 118 ± 18 nmol/min/ml). In conclusion, DIO2 Ala92 homozygous variant found to be associated with altered levels of DIO2, Thyroid profile and paraoxonase. Hence, we recommend to do detail study of genetic factors related to thyroid function and prevent additional diabetic complications.

  13. The PPARγ2 Pro12Ala variant is protective against progression of nephropathy in people with type 2 diabetes.

    PubMed

    Lapice, Emanuela; Monticelli, Antonella; Cocozza, Sergio; Pinelli, Michele; Cocozza, Sara; Bruzzese, Dario; Riccardi, Gabriele; Vaccaro, Olga

    2015-03-12

    Cross-sectional studies suggest the association between diabetic nephropathy and the PPARγ2 Pro12Ala polymorphism of the peroxisome proliferator-activated receptor γ2 (PPARγ2). Prospective data are limited to microalbuminuria and no information on renal function is available to date. The present study evaluates the association between the Pro12Ala polymorphism of PPARγ2 and the progression of albuminuria and decay in glomerular filtration rate (GFR) in type 2 diabetes. We studied 256 patients with an average 5-year follow-up. Among others, urinary albumin excretion rate (UAER) was measured on spot sample, GFR was estimated with the CKD-EPI Equation. Baseline UAER and GFR were similar for carriers or non-carriers of the polymorphism. At follow-up no significant changes from baseline were observed for UAER or eGFR in carriers of the Pro12Ala polymorphism whereas a significant increase in UAER [17 (11.3-37.9) versus 24.5 (13.8-49.9) μg/mg, p < 0.006)] and a significant reduction in the eGFR (82.8 ± 14.5 versus 80.3 ± 17.3 ml/min/1.73, m(2) p = 0.02), were observed in non carriers of the Pro12Ala polymorphism. Progression of nephropathy - defined according to a combined end point of UAER and eGFR- i.e. doubling of baseline UAER to at least 100 μg/mg, or new onset microalbuminuria, or progression from micro to macroalbuminuria, or 25% reduction of eGFR, or annualized eGFR decline >3 ml/min/year - was significantly less frequent in Ala carriers than non carriers (11.4% vs 35.8%; p < 0.01); HR adjusted for baseline age, AER, eGFR, HbA1c, diabetes duration and blood pressure was 0.32 (0.12-0.80). This study found that among patients with type 2 diabetes, the PPARγ2 Pro12Ala polymorphism is protective against progression of nephropathy and decay of renal function independent of major confounders.

  14. Nuclear magnetic resonance and nuclear spin relaxation in AlAs quantum well probed by ESR

    NASA Astrophysics Data System (ADS)

    Shchepetilnikov, A. V.; Frolov, D. D.; Nefyodov, Yu. A.; Kukushkin, I. V.; Smirnov, D. S.; Tiemann, L.; Reichl, C.; Dietsche, W.; Wegscheider, W.

    2016-12-01

    The study of nuclear magnetic resonance and nuclear spin-lattice relaxation was conducted in an asymmetrically doped to n ˜1.8 ×1011cm-2 16 nm AlAs quantum well grown in the [001 ] direction. The dynamic polarization of nuclear spins due to a hyperfine interaction resulted in the so-called Overhauser shift of two-dimensional conduction electron spin resonance. The maximum shifts achieved in the experiments are several orders of magnitude smaller than in GaAs-based heterostructures, indicating that the hyperfine interaction is weak. The nuclear spin-lattice relaxation time extracted from the decay of the Overhauser shift over time turned out to depend on the filling factor of the two-dimensional electron system. This observation indicates that nuclear spin-lattice relaxation is mostly due to the interaction between electron and nuclear spins. The Overhauser shift diminishes resonantly when the rf radiation of certain frequencies was applied to the sample. This effect served as an indirect, yet powerful, method for nuclear magnetic resonance detection: NMR quadrupole splitting of 75As nuclei was clearly resolved. Theoretical calculations performed describe well these experimental findings.

  15. Nonpeptidic Lysosomal Modulators Derived from Z-Phe-Ala-Diazomethylketone for Treating Protein Accumulation Diseases

    PubMed Central

    2012-01-01

    Lysosomes are involved in protein turnover and removing misfolded species, and their enzymes have the potential to offset the defect in proteolytic clearance that contributes to the age-related dementia Alzheimer's disease (AD). The weak cathepsin B and L inhibitor Z-Phe-Ala-diazomethylketone (PADK) enhances lysosomal cathepsin levels at low concentrations, thereby eliciting protective clearance of PHF-τ and Aβ42 in the hippocampus and other brain regions. Here, a class of positive modulators is established with compounds decoupled from the cathepsin inhibitory properties. We utilized PADK as a departure point to develop nonpeptidic structures with the hydroxyethyl isostere. The first-in-class modulators SD1002 and SD1003 exhibit improved levels of cathepsin up-regulation but almost complete removal of cathepsin inhibitory properties as compared to PADK. Isomers of the lead compound SD1002 were synthesized, and the modulatory activity was determined to be stereoselective. In addition, the lead compound was tested in transgenic mice with results indicating protection against AD-type protein accumulation pathology. PMID:24900408

  16. 5-ALA-mediated photodynamic therapy reduces the parasite load in mice infected with Leishmania braziliensis.

    PubMed

    Souza, D M; Alves, P M; Silva, M L F; Paulino, T P; Coraspe, H O; Mendonça, M M S; Ribeiro, B M; da Silva, M V; Rodrigues Júnior, V; Rodrigues, D B R

    2017-03-01

    Photodynamic therapy (PDT) has proven to be an effective alternative for the treatment of cutaneous leishmaniasis. Skin lesions consist of ulcers with well-defined raised edges, and granular floor. Th1 immune response is the protective profile in patients infected with Leishmania. In this study, the photodynamic therapy with 5-aminolevulinic acid, the parasitic load, and the modulation of the immune response was evaluated in mice infected with Leishmania braziliensis. Balb/c mice were infected with L. braziliensis and subsequently treated with three sections of PDT. The parasite load and mRNA expression of cytokines (IFN-γ, IL-4, IL-17, IL-22, IL-27, IL-10) and transcription factors (GATA-3, Foxp3 and T-bet) were analysed by quantitative PCR. The parasite load in the treated group was significantly lower than in the untreated group (P<.0001); in PDT treated animals, we observed an increase in IFN-γ and T-bet mRNA (P=.012 and P=.0071). There was a significant reduction in mRNA expression of IL-22 associated with an increased expression of IL-27 mRNA in the animals treated with light only (P=.0001). 5-ALA associated with photodynamic therapy promotes a reduction in parasite load and an increased expression of IFN-γ and T-bet mRNA. © 2016 John Wiley & Sons Ltd.

  17. Comparing the effects of repetitive and chronic ALA mediated PDT on human glioma spheroids

    NASA Astrophysics Data System (ADS)

    Mathews, Marlon S.; Sun, Chung-Ho; Madsen, Steen J.; Hirschberg, Henry

    2007-02-01

    Following surgical removal of malignant brain tumors 80% of all cases develop tumor recurrence within 2 cm of the resected margin. The aim of postoperative therapy is therefore elimination of nests of tumor cells remaining in the margins of the resection cavity. However, it is unlikely that standard "one-shot" intraoperative PDT treatments can accomplish this goal. This is due mainly to the length of time required to deliver adequate light fluences to depths of 1-2 cm in the resection margin. Additionally, due to the short doubling time of malignant glioma cells, the kill rate per cell doubling indicates that it seems unlikely that a single relatively short treatment would be sufficient to prevent recurrence of the tumor. Multiple repetitive or chronic treatment protocols would therefore seem required. In repetitive PDT both phtosensitizer and light are given over relatively short treatment times (hours) with treatment repetition following relatively long intervals (weeks). In chronic PDT (also called metronomic), both the photosensitizer and light are delivered continuously at low rates for extended periods of time (days). The in vitro therapy response of human glioma spheroids to 5-aminolevulinic acid (ALA) mediated PDT in repetitive or chronic form were investigated. At 6J fluence, spheroid survival rates of 28 and 7% were observed for repetitive or chronic PDT protocols respectively. The results indicated that single chronic (24-48hrs) treatment) was more effective at inhibiting spheroid growth than PDT repeated at relatively long intervals (weeks) or daily fractionated PDT.

  18. Study of false positives in 5-ALA induced photodynamic diagnosis of bladder carcinoma

    NASA Astrophysics Data System (ADS)

    Draga, Ronald O. P.; Grimbergen, Matthijs C. M.; Kok, Esther T.; Jonges, Trudy G. N.; Bosch, J. L. H. R.

    2009-02-01

    Photodynamic diagnosis (PDD) is a technique that enhances the detection of tumors during cystoscopy using a photosensitizer which accumulates primarily in cancerous cells and will fluoresce when illuminated by violetblue light. A disadvantage of PDD is the relatively low specificity. In this retrospective study we aimed to identify predictors for false positive findings in PDD. Factors such as gender, age, recent transurethral resection of bladder tumors (TURBT), previous intravesical therapy (IVT) and urinary tract infections (UTIs) were examined for association with the false positive rates in a multivariate analysis. Data of 366 procedures and 200 patients were collected. Patients were instilled with 5-aminolevulinic acid (5-ALA) intravesically and 1253 biopsies were taken from tumors and suspicious lesions. Female gender and TURBT are independent predictors of false positives in PDD. However, previous intravesical therapy with Bacille Calmette-Guérin is also an important predictor of false positives. The false positive rate decreases during the first 9-12 weeks after the latest TURBT and the latest intravesical chemotherapy. Although shortly after IVT and TURBT false positives increase, PDD improves the diagnostic sensitivity and results in more adequate treatment strategies in a significant number of patients.

  19. Homozygous Ala65Pro Mutation with V89L Polymorphism in SRD5A2 Deficiency

    PubMed Central

    Eren, Erdal; Edgünlü, Tuba; Asut, Emre; Karakaş Çelik, Sevim

    2016-01-01

    Objective: Deficiency of steroid 5-alpha reductase type 2 (5αRD2) is a rare autosomal recessive disorder caused by mutations in the SRD5A2 gene. A defect in the 5-alpha reductase enzyme, which ensures conversion of testosterone into dihydrotestosterone, leads to disorders of sex development. This study presents the clinical and genetic results of patients with 5αRD2 deficiency. Methods: 5αRD2 deficiency was detected in 6 different patients from 3 unrelated families. All patients were reared as girls. Two of the patients presented with primary amenorrhea, one with primary amenorrhea and rejection of female gender, and the others with masses in their inguinal canals. Chromosome and sex-determining region Y (SRY) gene analyses were performed in all patients. Additionally, five exons of the SRD5A2 gene were amplified with polymerase chain reaction in the obtained DNA samples and evaluated. Results: While 46,XY was identified in 5 patients, 47,XXY was detected in one patient. The SRY gene was positive in all patients. The p.Ala65Pro (c193G>C) mutation and V89L polymorphism were observed in exon 1 of the SRD5A2 gene in all patients. Conclusion: Identification of this mutation and polymorphism is a significant indicator of presence of 5αRD2 deficiency in Southeastern Turkey, a geographical region where consanguineous marriages are also highly common. PMID:26761946

  20. Characterization of hemoglobin bassett (alpha94Asp-->Ala), a variant with very low oxygen affinity.

    PubMed

    Abdulmalik, Osheiza; Safo, Martin K; Lerner, Norma B; Ochotorena, Josiree; Daikhin, Evgueni; Lakka, Vinaysagar; Santacroce, Rosa; Abraham, Donald J; Asakura, Toshio

    2004-11-01

    Hemoglobin (Hb) Bassett, an abnormal Hb variant with a markedly reduced oxygen affinity, was discovered in a Caucasian (Anglo-Saxon) male child who experienced episodes of cyanosis. Cation-exchange and reversed-phase (RP) high-performance liquid chromatography (HPLC) showed that the patient has an abnormal Hb, with a mutation in the alpha-globin. Tryptic peptide digest of the abnormal alpha-globin with subsequent HPLC analysis revealed abnormal elution of the alpha-T11 peptide. Further studies with Edman sequencing and electrospray mass spectrometry of tryptic peptide alpha-T11, as well as structural analysis by X-ray crystallography revealed an Asp-->Ala substitution at the alpha94 (G1) position, a match for Hb Bassett. Detailed functional studies showed that this Hb variant had a markedly reduced oxygen affinity (P(50) at pH 7.0 = 22 mmHg; Hb A P(50) = 10.5 mmHg), reduced Bohr effect (-0.26 compared to - 0.54 in Hb A), and low subunit cooperativity (n = 1.4, compared to 2.6 in Hb A). X-ray crystallography results explain the probable effects of the structural modification on the oxygen-binding properties of this Hb variant.

  1. (RSS)-[N-Hydroxyethyloxy]-hexafluoroVal-MeLeu-Ala tert-butyl ester.

    PubMed

    Eberle, Marcel K; Stoeckli-Evans, Helen; Keese, Reinhart

    2009-10-28

    THE TITLE COMPOUND [SYSTEMATIC NAME: (2S,5S,8R)-tert-butyl 8-(1,1,1,3,3,3-hexafluoropropan-2-yl)-12-hydroxy-5-isobutyl-2,6-dimethyl-4,7-dioxo-10-oxa-3,6,9-triazadodecanoate], C(21)H(36)F(6)N(3)O(6), is a tripeptide crystallizing in the chiral ortho-rhom-bic spacegroup P2(1)2(1)2(1). The absolute configuration (R) of the chiral center in the hexa-fluoro-valine unit is based on the known stereochemistry of MeLeu and Ala (SS). The N-hydroxy-ethyl-oxy substituent of hexa-fluoro-valine is positionally disordered [occupancy ratio 0.543 (9):0.457 (9)]. In the solid state structure there are N-H⋯F and N-H⋯O intra-molecular hydrogen bonds supporting the coiled structure of this tripeptide with the three hydro-phobic substituents on the outside.

  2. Study of the efficacy of 5 ALA-mediated photodynamic therapy on human larynx squamous cell carcinoma (Hep2c) cell line

    NASA Astrophysics Data System (ADS)

    Khursid, A.; Atif, M.; Firdous, S.; Zaidi, S. S. Z.; Salman, R.; Ikram, M.

    2010-07-01

    5-aminolevulanic acid (ALA), a precursor of Protoporphyrin IX, was evaluated as an inducer of photodamage on Hep2c, human larynx squamous cell carcinoma, cell line. Porphyrins are used as active cytotoxic antitumor agents in photodynamic therapy (PDT). The present study evaluates the effects of photodynamic therapy (PDT) with 5-aminolevulinic acid (5-ALA) using human larynx cells as experimental model. Hep2c cell line was irradiated with red light (a diode laser, λ = 635 nm). The influence of different incubation times and concentrations of 5-ALA, different irradiation doses and various combinations of photosensitizer and light doses on the cellular viability of Hep2c cells were studied. The optimal uptake of photosensitizer ALA in Hep-2c cells was investigated by means of spectrometric measurement. Cells viability was determined by means of neutral red assay (NR). It was observed that sensitizer or light doses have no significant effect on cells viability when studied independently. The spectrometric measurements showed that the maximal cellular uptake of 5-ALA occurred after 7 h in vitro incubation. The photocytotoxic assay showed that light dose of 85 J/cm2 gives effective PDT outcome for Hep2c cell line incubated with 55 μg/ml of 5-ALA with a conclusion that Hep2c cell line is sensitive to ALA-mediated PDT.

  3. High-level expression, purification and study of bioactivity of fusion protein M-IL-2((88)Arg, (125)Ala) in Pichia pastoris.

    PubMed

    Li, Lin; Qian, Dongmeng; Shao, Guangcan; Yan, Zhiyong; Li, Ronggui; Hua, Xiaomin; Song, Xuxia; Wang, Bin

    2014-09-01

    M-IL-2((88)Arg, (125)Ala) is a fusion protein comprising melittin genetically linked to a mutant human interleukin 2((88)Arg, (125)Ala). In this study, we constructed an expression system of M-IL-2((88)Arg, (125)Ala) in Pichia pastoris: GS115/pPICZα A/M-IL-2((88)Arg, (125)Ala), and achieved the high-level expression of the fusion protein. The maximum yield of the fusion protein M-IL-2((88)Arg, (125)Ala) reached up to 814.5mg/L, higher than the system in Escherichiacoli. The fusion protein was purified by means of ammonium sulfate fractionation, dialysis and nickel ion affinity chromatography. The molecular weight of the fusion protein is about 26kDa, conforming the theoretical value. And M-IL-2((88)Arg, (125)Ala) possesses strong antigen-specificity by Western blot detection. Bioassay results indicated that the fusion protein could directly inhibit the growth of human ovarian cancer SKOV3 cells and Hela cells in vitro. This study provides an alternative strategy for large-scale production of bioactive M-IL-2((88)Arg, (125)Ala) using P. pastoris as an expression host and paves the way to clinical practice.

  4. The influence of the stereochemistry of alanine residue on the solid state conformation and crystal packing of opioid peptides containing D-Ala or L-Ala in message domain--XRD and NMR study.

    PubMed

    Trzeciak-Karlikowska, Katarzyna; Bujacz, Anna; Ciesielski, Włodzimierz; Bujacz, Grzegorz D; Potrzebowski, Marek J

    2011-08-18

    In this work, an X-ray diffraction (XRD) and solid state NMR study of two tetrapeptides with different stereochemistry of alanine residue is presented using Tyr-(D-Ala)-Phe-Gly (1), an N-terminal sequence of opioid peptide dermorphin, and its biologically inactive analog Tyr-(L-Ala)-Phe-Gly (2). Single-crystal XRD proved that 1 crystallized under different conditions from exclusively one structure: a monoclinic crystal with P2(1) space group. In contrast, 2 very easily formed at least three crystallographic modifications, 2a (monoclinic P2(1)), 2b (orthorhombic P2(1)2(1)2) and 2c (tetragonal P4(1)2(1)2). Solid-state NMR spectroscopy was employed to investigate the structure and molecular dynamics of 1, 2a, and 2b. By employing different NMR experiments (dipolar dephasing and PILGRIM) and an analysis of the (13)C principal elements of the chemical shift tensor (CST), it was proven that the main skeleton of tetrapeptides is rigid, whereas significant differences in the molecular motion of the aromatic residues were observed. Comparing current data with those of previous studies (J. Phys. Chem. B2004, 108, 4535-4545 and Cryst. Growth Des. 2009, 9, 4050-4059), it can be assumed that an important preorganization mechanism anticipating the formation of peptide crystals containing D-Ala in sequence is the intramolecular CH-π interaction, which occurs for the amino acid with D stereochemistry. This effect may be responsible for the formation of only one crystallographic form of D-Ala peptides.

  5. Association of serum lipid/lipoprotein with Pro12Ala polymorphism in PPAR-γ2 among Chinese nonagenarians/centenarians.

    PubMed

    Chang-Quan, Huang; Hui, Wang; Qing-Xiu, Liu; Gang, Cheng

    2011-10-01

    In previous studies, the Pro12Ala polymorphism in the peroxisome proliferator-activated receptor gamma 2 (PPAR-γ2) was shown to be associated with both lipid metabolism and longevity. We examined whether the polymorphism continued to be associated with abnormal levels of serum lipid/lipoprotein among elderly subjects (≥90 years). The Pro12Ala variant was examined using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Abnormal levels of serum lipid/lipoprotein were defined according to the criteria provided by the Chinese Medical Association (2004). Abnormal criteria were triglyceride (TG) >5.18 mmol/l, total cholesterol (TC) >1.7 mmol/l, low-density lipoprotein cholesterol (LDL-C) >3.37 mmol/l and high-density lipoprotein cholesterol (HDL-C) <1.04 mmol/l). The sample included 673 unrelated Chinese individuals aged 90-108 years (mean age: 93.54 ± 3.54 years) and 67.3% females. Genotype frequencies of the Pro12Ala polymorphism were 0% Ala12Ala, 8.9% Pro12Ala, 91.1% Pro12Pro. Neither differences in the levels of serum lipid/lipoprotein nor the prevalence of their abnormal levels was significant between subjects who were or were not 12Ala carriers. Unadjusted and adjusted multiple logistic regressions showed that the odds ratios (OR) for abnormal levels of serum lipid/lipoprotein were not associated with the Pro12Ala polymorphism in PPAR-γ2. Levels of serum lipid/lipoprotein were not associated with the Pro12Ala polymorphism in PPAR-γ2 among Chinese nonagenarians and centenarians, which was different from the general population. Copyright © 2011 IMSS. Published by Elsevier Inc. All rights reserved.

  6. [Association of the Pro12Ala and C1431T polymorphism of the PPAR gamma2 gene and their haplotypes with obesity and type 2 diabetes].

    PubMed

    Dong, Chun-ping; He, Lan; Li, Jian-ning; Ye, Feng; He, Ming; Wang, Yi

    2008-08-01

    To study the association of the Pro12Ala and C1431T polymorphism of the PPAR gamma2 gene and their haplotypes with obesity and type 2 diabetes in Chinese population. PCR-restriction fragment length polymorphism was used to determine the Pro12Ala and C1431T polymorphisms in 207 patients with type 2 diabetes and 101 non-diabetic control subjects. (1) In non-diabetic control population, the Ala allele frequency was 0.064, the T1431 allele frequency was 0.252. Haplotype analysis showed that the Pro12Ala and C1431T polymorphisms were in linkage disequilibrium (Do=0.63, r(2)=0.074), which constituted three major haplotypes Pro-C, Pro-T and Ala-T. (2) There were no significant differences of the distribution frequencies of the Pro12Ala and C1431T polymorphism and their haplotypes between the type 2 diabetes mellitus group and non-diabetic control group (P > 0.05). (3) The Pro12Ala polymorphism was associated with blood pressure and lipidemia in diabetic patients. The Ala allele significantly decreased the diastolic blood pressure of non-obese diabetic patients (P < 0.05), but it did not benefit to the obese diabetic patients for the lipidemia (P < 0.05). The C1431T polymorphism was associated with overweight and obesity in diabetic patients. The T1431 allele frequency in the body mass index > or = 25 layer was significantly higher than that in the body mass index < 25 layer (P < 0.05). The Pro12Ala and C1431T polymorphisms of the PPAR gamma2 gene might not be a major etiological factor for type 2 diabetes; the C1431T polymorphism was associated with overweight or obesity in diabetic patients.

  7. Microendoscopic partial resection of the sacral ala to relieve extraforaminal entrapment of the L-5 spinal nerve at the lumbosacral tunnel. Technical note.

    PubMed

    Matsumoto, Morio; Chiba, Kazuhiro; Ishii, Ken; Watanabe, Kota; Nakamura, Masaya; Toyama, Yoshiaki

    2006-04-01

    The authors report the cases of three patients with L-5 radiculopathy caused by extraforaminal entrapment of the L-5 spinal nerve at the lumbosacral tunnel; this structure comprises the lumbosacral ligament, the sacral ala, and the L-5 and S-1 vertebral bodies. All three patients suffered severe leg pain and neurological deficits compatible with L-5 radiculopathy. Decompressive surgery involved the microendoscopic partial resection of the sacral ala along the L-5 spinal nerve. All patients experienced immediate pain relief postoperatively. Microendoscopic partial resection of the sacral ala is an effective and minimally invasive surgical option for patients with extraforaminal entrapment of the L-5 spinal nerve.

  8. Relationship between PPARγ Pro12Ala gene polymorphism and type 2 diabetic nephropathy risk in Asian population: results from a meta-analysis.

    PubMed

    Liu, Guohui; Zhou, Tian-Biao; Jiang, Zongpei; Zheng, Dongwen; Yuan, Fei; Li, Yi; Hu, Haoqiang; Chen, Zijun

    2014-04-01

    The relationship between peroxisome proliferator-activated receptor gamma (PPARγ) Pro12Ala gene polymorphism and type 2 diabetic nephropathy (T2DN) risk in Asians is still unclear. This study was performed to evaluate if there was an association between the PPARγ Pro12Ala gene polymorphism and T2DN risk in Asians using meta-analysis. The relevant reports were searched and identified from PubMed, Cochrane Library and CBM-disc (China Biological Medicine Database) on 1 October 2013, and eligible studies were included and synthesized. Ten reports were recruited into this meta-analysis for the association of the PPARγ Pro12Ala gene polymorphism with T2DN risk. The Pro12Ala gene polymorphism in the Asian population was shown to be not associated with T2DN risk (Ala/Ala: OR = 0.67, 95% CI: 0.22-2.00, p = 0.47; Pro/Pro: OR = 1.77, 95% CI: 0.82-1.65, p = 0.39; Ala allele: OR = 0.74, 95% CI: 0.47-1.16, p = 0.19). In the sensitivity analysis according to Hardy-Weinberg equilibrium (HWE), the control source from hospital, the control source from population, the genotyping methods using PCR-RFLP, the genotyping methods using Taqman, sample size of case (≥ 100), the association of the PPARγ Pro12Ala gene polymorphism with T2DN risk was also not found. Interestingly, in the sensitivity analysis according to sample size of case (<100), Ala allele was associated with T2DN risk, but not the Pro/Pro genotype. However, the sample size for sensitivity analysis according to sample size of case (<100) was relatively small and therefore, the results should be interpreted with care. In conclusion, the PPARγ Pro12Ala gene polymorphism was not associated with T2DN risk in Asians. However, Ala allele was associated with T2DN risk when the sample size of case was less than 100. Nonetheless, additional studies are required to firmly establish a correlation between the PPARγ Pro12Ala gene polymorphism and T2DN risk in Asians.

  9. Australian Liver Association (ALA) expert consensus recommendations for the use of transient elastography in chronic viral hepatitis.

    PubMed

    Kemp, William; Levy, Miriam; Weltman, Martin; Lubel, John

    2015-03-01

    Since the introduction of Transient Elastography (TE) into Australia in 2008, non-invasive liver fibrosis assessments have integrated themselves into clinical hepatology. The Australian Liver Association (ALA) recognizes these technologies perform an important role in the assessment of chronic viral hepatitis B and C. However, in the setting of viral hepatitis and many other chronic liver diseases, there remains no consensus or guidelines regarding the performance, utility or reporting of TE. Accordingly, the ALA sought to produce an expert consensus statement for the use of TE in chronic viral hepatitis. The recommendations incorporated in this document are based upon a thorough literature review and draw on extensive clinical experience using TE. The initial draft was presented at Australian Gastroenterology Week (AGW) 2013. Through a collaborative process and expert external review a finalized document was presented at AGW 2014. © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  10. Hypofibrinogenemia and the α-Fibrinogen Thr312Ala Polymorphism may be Risk Factors for Early Pregnancy Loss.

    PubMed

    Kamimoto, Yuki; Wada, Hideo; Ikejiri, Makoto; Nakatani, Kaname; Sugiyama, Takashi; Osato, Kazuhiro; Murabayashi, Nao; Habe, Koji; Mizutani, Hitoshi; Matsumoto, Takeshi; Ohishi, Kohshi; Ikeda, Tomoaki

    2017-01-01

    We analyzed a cohort of 36 females with pregnancy loss. In addition to 11 patients with antiphospholipid antibody syndrome and 2 patients with congenital antithrombin (AT) or protein C deficiency, we identified 5 patients with low fibrinogen levels (median 110 mg/dL) prior to 10 weeks of gestation. Four of these 5 patients underwent a fibrinogen gene analysis, and all 4 were found to be heterozygotes for the α-fibrinogen (FGA) Thr321Ala polymorphism. One female without hypofibrinogenemia with a history of 8 pregnancy losses was found to be homozygous for the same polymorphism, and she also showed hypercoagulability without thrombosis. In conclusion, there was a relatively high frequency of pregnancy loss in the setting of hypofibrinogenemia and/or the FGA Thr312Ala polymorphism, and this may be an important risk factor for pregnancy loss and a hypercoagulable state in later pregnancy.

  11. Conformational and biological properties of the Ala10 analogue of human des-Trp1,Nle12-minigastrin.

    PubMed

    Mammi, S; Foffani, M T; Peggion, E; Galleyrand, J C; Bali, J P; Simonetti, M; Göhring, W; Moroder, L; Wünsch, E

    1989-09-05

    Synthesis, conformation, and biological properties of the Ala10 analogue of des-Trp1,Nle12-minigastrin are reported. Replacement of the Gly residue in the original sequence with Ala remarkably changes the conformational preference of the hormone in trifluoroethanol. CD and NMR results indicate that the conformational change is mainly located in the C-terminal portion of the molecule, with probable extension of the N-terminal alpha-helix throughout the entire sequence. The structural modification causes a 10-fold decrease in the biological potency of the hormone, which is about as active as the C-terminal tetrapeptide amide. These findings support our previous hypothesis that the optimal bioactive conformation of the native hormone is U-shaped, with mutual interactions among the two end segments.

  12. Vitamin D Combined with Aminolevulinate (ALA)-Mediated Photodynamic Therapy (PDT) for Human Psoriasis: A Proof-of-Principle Study.

    PubMed

    Maytin, Edward V; Honari, Golara; Khachemoune, Amor; Taylor, Charles R; Ortel, Bernhard; Pogue, Brian W; Sznycer-Taub, Nathaniel; Hasan, Tayyaba

    2012-09-01

    We previously showed that select agents (methotrexate or Vitamin D), when administered as a preconditioning regimen, are capable of promoting cellular differentiation of epithelial cancer cells while simultaneously enhancing the efficacy of 5-aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT). In solid tumors, pretreatment with Vitamin D simultaneously promotes cellular differentiation and leads to selective accumulation of target porphyrins (mainly protoporphyrin IX, PpIX) within diseased tissue. However, questions of whether or not the effects upon cellular differentiation are inexorably linked to PpIX accumulation, and whether these effects might occur in hyperproliferative noncancerous tissues, have remained unanswered. In this paper, we reasoned that psoriasis, a human skin disease in which abnormal cellular proliferation and differentiation plays a major role, could serve as a useful model to test the effects of pro-differentiating agents upon PpIX levels in a non-neoplastic setting. In particular, Vitamin D, a treatment for psoriasis that restores (increases) differentiation, might increase PpIX levels in psoriatic lesions and facilitate their responsiveness to ALA-PDT. This concept was tested in a pilot study of 7 patients with bilaterally-matched psoriatic plaques. A regimen in which calcipotriol 0.005% ointment was applied for 3 days prior to ALA-PDT with blue light, led to preferential increases in PpIX (~130%), and reductions in thickness, redness, scaling, and itching in the pretreated plaques. The results suggest that a larger clinical trial is warranted to confirm a role for combination treatments with Vitamin D and ALA-PDT for psoriasis.

  13. Vitamin D Combined with Aminolevulinate (ALA)-Mediated Photodynamic Therapy (PDT) for Human Psoriasis: A Proof-of-Principle Study

    PubMed Central

    Maytin, Edward V.; Honari, Golara; Khachemoune, Amor; Taylor, Charles R.; Ortel, Bernhard; Pogue, Brian W.; Sznycer-Taub, Nathaniel; Hasan, Tayyaba

    2012-01-01

    We previously showed that select agents (methotrexate or Vitamin D), when administered as a preconditioning regimen, are capable of promoting cellular differentiation of epithelial cancer cells while simultaneously enhancing the efficacy of 5-aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT). In solid tumors, pretreatment with Vitamin D simultaneously promotes cellular differentiation and leads to selective accumulation of target porphyrins (mainly protoporphyrin IX, PpIX) within diseased tissue. However, questions of whether or not the effects upon cellular differentiation are inexorably linked to PpIX accumulation, and whether these effects might occur in hyperproliferative noncancerous tissues, have remained unanswered. In this paper, we reasoned that psoriasis, a human skin disease in which abnormal cellular proliferation and differentiation plays a major role, could serve as a useful model to test the effects of pro-differentiating agents upon PpIX levels in a non-neoplastic setting. In particular, Vitamin D, a treatment for psoriasis that restores (increases) differentiation, might increase PpIX levels in psoriatic lesions and facilitate their responsiveness to ALA-PDT. This concept was tested in a pilot study of 7 patients with bilaterally-matched psoriatic plaques. A regimen in which calcipotriol 0.005% ointment was applied for 3 days prior to ALA-PDT with blue light, led to preferential increases in PpIX (~130%), and reductions in thickness, redness, scaling, and itching in the pretreated plaques. The results suggest that a larger clinical trial is warranted to confirm a role for combination treatments with Vitamin D and ALA-PDT for psoriasis. PMID:23264699

  14. Relation between iron metabolism and antioxidants enzymes and δ-ALA-D activity in rats experimentally infected by Fasciola hepatica.

    PubMed

    Bottari, Nathieli B; Mendes, Ricardo E; Baldissera, Matheus D; Bochi, Guilherme V; Moresco, Rafael N; Leal, Marta L R; Morsch, Vera M; Schetinger, Maria R C; Christ, Ricardo; Gheller, Larissa; Marques, Éder J; Da Silva, Aleksandro S

    2016-06-01

    The aim of this study was to evaluate the iron metabolism in serum, as well as antioxidant enzymes, in addition to the Delta-Aminolevulinic Acid Dehydratase (δ-ALA-D) activity in the liver of rats experimentally infected by Fasciola hepatica. Thirty male adult rats (Wistar) specific pathogen free were divided into four groups: two uninfected group (CTRL 1 and CTRL 2) with five animals each and two infected groups (INF 1 and INF 2) with 10 animals each. Infection was performed orally with 20 metacercariae at day 1. On day 15 (CTRL 1 and INF 1 groups) and 87 PI (CTRL 2 and INF 2 groups) blood and bone marrow were collected and the animals were subsequently euthanized for liver sampling. Blood was allocated in tubes without anticoagulant for serum acquisition to measure iron, transferrin and unsaturated iron binding capacity (UIBC). δ-ALA-D, superoxide dismutase (SOD), and catalase (CAT) activities were measured in the liver. A decrease in iron, transferrin and UIBC levels was observed in all infected animals compared to control groups (P < 0.05). Furthermore, iron accumulation was observed in bone marrow of infected mice. Infected animals showed an increase in δ-ALA-D activity at 87 post-infection (PI) (INF 2) as well as in SOD activity at days 15 (INF 1) and 87 PI (INF 2). On the other hand, CAT activity was reduced in rats infected by F. hepatica during acute and chronic phase of fasciolosis (INF 1 and INF 2 groups), when moderate (acute) and severe necrosis in the liver histopathology were observed. These results may suggest that oxidative damage to tissues along with antioxidant mechanisms might have taken part in fasciolosis pathogenesis and are also involved in iron deficiency associated to changes in δ-ALA-D activity during chronic phase of disease.

  15. Interaction of PPARG Pro12Ala with dietary fat influences plasma lipids in subjects at cardiometabolic risk[S

    PubMed Central

    AlSaleh, Aseel; O'Dell, Sandra D.; Frost, Gary S.; Griffin, Bruce A.; Lovegrove, Julie A.; Jebb, Susan A.; Sanders, Thomas A. B.

    2011-01-01

    The PPARγ2 gene single nucleotide polymorphism (SNP) Pro12Ala has shown variable association with metabolic syndrome traits in healthy subjects. The RISCK Study investigated the effect of interaction between genotype and the ratio of polyunsaturated:saturated (P:S) fatty acid intake on plasma lipids in 367 white subjects (ages 30-70 years) at increased cardiometabolic risk. Interaction was determined after habitual diet at recruitment, at baseline after a 4-week high-SFA (HS) diet, and after a 24-week reference (HS), high-MUFA (HM), or low-fat (LF) diet. At recruitment, there were no significant associations between genotype and plasma lipids; however, P:S × genotype interaction influenced plasma total cholesterol (TC) (P = 0.02), LDL-cholesterol (LDL-C) (P = 0.002), and triglyceride (TG) (P = 0.02) concentrations. At P:S ratio ≤ 0.33, mean TC and LDL-C concentrations in Ala12 allele carriers were significantly higher than in noncarriers (respectively, P = 0.003; P = 0.0001). Significant trends in reduction of plasma TC (P = 0.02) and TG (P = 0.002) concentrations occurred with increasing P:S (respectively, ≤0.33 to >0.65; 0.34 to >0.65) in Ala12 allele carriers. There were no significant differences between carriers and noncarriers after the 4-week HS diet or 24-week interventions. Plasma TC and TG concentrations in PPARG Ala12 allele carriers decrease as P:S increases, but they are not dependent on a reduction in SFA intake. PMID:21949049

  16. Peroxisome proliferator-activated receptor-γ (PPARγ) Pro12Ala polymorphism and colorectal cancer (CRC) risk.

    PubMed

    Wang, Wei; Shao, Yan; Tang, Shenhua; Cheng, Xianyong; Lian, Haifeng; Qin, Chengyong

    2015-01-01

    The association between the peroxisome proliferator-activated receptor-γ (PPARγ) Pro12Ala polymorphism and colorectal cancer (CRC) risk was inconclusive. We conducted a meta-analysis to evaluate the association between PPARγ Pro12Ala polymorphism and CRC risk. We searched Pubmed, EMBASE, and China National Knowledge Infrastructure databases. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. A total of 17 case-control studies with 12635 and 15803 controls were included in this meta-analysis. Overall, PPARγ Pro12Ala polymorphism was associated with CRC risk (OR = 0.84, 95% CI 0.75-0.94, P = 0.003, I(2) = 35%). In the subgroup analysis by ethnicity, a significant association was found among Caucasians (OR = 0.85, 95% CI 0.75-0.96, P = 0.007, I(2) = 38%) but not among Asians (OR = 0.76, 95% CI 0.51-1.12, P = 0.17, I(2) = 28%). In the subgroup analysis by CRC site, a significant association was found among colon cancer (OR = 0.81, 95% CI 0.66-0.98, P = 0.03, I(2) = 16%) but not among rectal cancer (OR = 0.83, 95% CI 0.57-1.21, P = 0.34, I(2) = 63%). The sensitivity analysis did not influence the result by omitting low-quality studies (OR = 0.76, 95% CI 0.63-0.93, P = 0.006, I(2) = 51%). In conclusion, this meta-analysis suggested that PPARγ Pro12Ala polymorphism was significant associated with CRC risk.

  17. Peroxisome proliferator-activated receptor-γ (PPARγ) Pro12Ala polymorphism and colorectal cancer (CRC) risk

    PubMed Central

    Wang, Wei; Shao, Yan; Tang, Shenhua; Cheng, Xianyong; Lian, Haifeng; Qin, Chengyong

    2015-01-01

    Background: The association between the peroxisome proliferator-activated receptor-γ (PPARγ) Pro12Ala polymorphism and colorectal cancer (CRC) risk was inconclusive. We conducted a meta-analysis to evaluate the association between PPARγ Pro12Ala polymorphism and CRC risk. Material and Method: We searched Pubmed, EMBASE, and China National Knowledge Infrastructure databases. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. Results: A total of 17 case-control studies with 12635 and 15803 controls were included in this meta-analysis. Overall, PPARγ Pro12Ala polymorphism was associated with CRC risk (OR = 0.84, 95% CI 0.75-0.94, P = 0.003, I2 = 35%). In the subgroup analysis by ethnicity, a significant association was found among Caucasians (OR = 0.85, 95% CI 0.75-0.96, P = 0.007, I2 = 38%) but not among Asians (OR = 0.76, 95% CI 0.51-1.12, P = 0.17, I2 = 28%). In the subgroup analysis by CRC site, a significant association was found among colon cancer (OR = 0.81, 95% CI 0.66-0.98, P = 0.03, I2 = 16%) but not among rectal cancer (OR = 0.83, 95% CI 0.57-1.21, P = 0.34, I2 = 63%). The sensitivity analysis did not influence the result by omitting low-quality studies (OR = 0.76, 95% CI 0.63-0.93, P = 0.006, I2 = 51%). Conclusions: In conclusion, this meta-analysis suggested that PPARγ Pro12Ala polymorphism was significant associated with CRC risk. PMID:26064311

  18. Alpha-linolenic acid (ALA) is inversely related to development of adiposity in school-age children

    PubMed Central

    Perng, Wei; Villamor, Eduardo; Mora-Plazas, Mercedes; Marin, Constanza; Baylin, Ana

    2015-01-01

    Background/Objectives Studies in adults indicate that dietary polyunsaturated fatty acid (PUFA) composition may play a role in development of adiposity. Because adipocyte quantity is established between late childhood and early adolescence, understanding the impact of PUFAs on weight gain during the school-age years is crucial to developing effective interventions. Subjects/Methods We quantified N-3 and N-6 PUFAs in serum samples of 668 Colombian schoolchildren aged 5–12 years at the time of recruitment into a cohort study, using gas-liquid chromatography. Serum concentrations of N-3 (ALA, EPA, DHA) and N-6 PUFAs (LA, GLA, DGLA, AA) were determined as % total fatty acids. Children’s anthropometry was measured annually for a median of 30 months. We used mixed-effects models with restricted cubic splines to construct population body mass index-for-age z-score (BAZ) growth curves for age-and sex-specific quartiles of each PUFA. Results N-3 ALA was inversely related to BAZ gain after adjustment for sex, baseline age and weight status, and household socioeconomic level. Estimated BAZ change between 6 and 14 years among children in the highest quartile of ALA compared to those in the lowest quartile was 0.45 (95% CI: 0.07, 0.83) lower (P-trend=0.006). Conclusions N-3 ALA may be protective against weight gain in school-age children. Whether improvement in PUFA status reduces adiposity in pediatric populations deserves evaluation in randomized trials. PMID:25271016

  19. Insights on the structural perturbations in human MTHFR Ala222Val mutant by protein modeling and molecular dynamics.

    PubMed

    Abhinand, P A; Shaikh, Faraz; Bhakat, Soumendranath; Radadiya, Ashish; Bhaskar, L V K S; Shah, Anamik; Ragunath, P K

    2016-01-01

    Methylenetetrahydrofolate reductase (MTHFR) protein catalyzes the only biochemical reaction which produces methyltetrahydrofolate, the active form of folic acid essential for several molecular functions. The Ala222Val polymorphism of human MTHFR encodes a thermolabile protein associated with increased risk of neural tube defects and cardiovascular disease. Experimental studies have shown that the mutation does not affect the kinetic properties of MTHFR, but inactivates the protein by increasing flavin adenine dinucleotide (FAD) loss. The lack of completely solved crystal structure of MTHFR is an impediment in understanding the structural perturbations caused by the Ala222Val mutation; computational modeling provides a suitable alternative. The three-dimensional structure of human MTHFR protein was obtained through homology modeling, by taking the MTHFR structures from Escherichia coli and Thermus thermophilus as templates. Subsequently, the modeled structure was docked with FAD using Glide, which revealed a very good binding affinity, authenticated by a Glide XP score of -10.3983 (kcal mol(-1)). The MTHFR was mutated by changing Alanine 222 to Valine. The wild-type MTHFR-FAD complex and the Ala222Val mutant MTHFR-FAD complex were subjected to molecular dynamics simulation over 50 ns period. The average difference in backbone root mean square deviation (RMSD) between wild and mutant variant was found to be ~.11 Å. The greater degree of fluctuations in the mutant protein translates to increased conformational stability as a result of mutation. The FAD-binding ability of the mutant MTHFR was also found to be significantly lowered as a result of decreased protein grip caused by increased conformational flexibility. The study provides insights into the Ala222Val mutation of human MTHFR that induces major conformational changes in the tertiary structure, causing a significant reduction in the FAD-binding affinity.

  20. A new G(gamma) chain variant: Hb F-Bron [gamma20(B2)val-->Ala].

    PubMed

    Lacan, Philippe; Burnichon, Nelly; Becchi, Michel; Zanella-Cleon, Isabelle; Aubry, Martine; Couprie, Nicole; Francina, Alain

    2005-01-01

    A new G(gamma) hemoglobin (Hb) variant, Hb F-Bron [gamma20(B2)Val-->Ala] on the first exon of the G(gamma)-globin gene is described. The variant was characterized by DNA sequencing and mass spectrometry (MS). Hematological abnormalities included hypochromia and microcytosis and were probably caused by an interaction with an alpha-thalassemia (thal) (3.7 kb) deletion in the heterozygous state.

  1. Computational Prediction of the Protonation Sites of Ac-Lys-(Ala)n-Lys-NH2 Peptides through Conceptual DFT Descriptors.

    PubMed

    Sastre, Sebastián; Frau, Juan; Glossman-Mitnik, Daniel

    2017-03-13

    Six density functionals (M11, M11L, MN12L, MN12SX, N12, and N12SX) in connection with the Def2TZVP basis set and the SMD solvation model (water as a solvent) have been assessed for the calculation of the molecular structure and properties of several peptides with the general formulaAc-Lys-(Ala)n-Lys-NH2,withn=0to5  [...].

  2. In vitro effects of Ala16Val manganese superoxide dismutase gene polymorphism on human white blood cells exposed to methylmercury.

    PubMed

    Algarve, T D; Barbisan, F; Ribeiro, E E; Duarte, M M M F; Mânica-Cattani, M F; Mostardeiro, C P; Lenz, A F; da Cruz, I B M

    2013-10-29

    Environmental contamination by methylmercury (MeHg) is an enormous public health problem in world regions such as Amazonia. MeHg toxic effects seem to be influenced by environmental and genetic factors. However, few studies have evaluated the genetic influences of MeHg toxicity in humans. Therefore, the aim of this study was to evaluate the genetic influence of Ala16Val manganese superoxide dismutase gene polymorphism (Ala16Val-MnSOD) on the cytotoxic effects of in vitro human leukocytes exposed to MeHg. Subjects were selected from 100 individuals aged 26.4 ± 7.3 years genotyped to Ala16Val-MnSOD polymorphism (AA = 6, VV = 6, and AV = 12) to perform in vitro testing using white blood cells (WBCs). Reactive oxygen species production was measured using 2',7'-dichlorofluorescein diacetate fluorimetric assay, and cell viability was measured using MTT assay on WBC samples from the same subjects that were both exposed and not exposed to MeHg (2.5 µM for 6 h). The results showed that AA- and VV-WBCs exposed to MeHg did not display increased reactive oxygen species levels compared to those in cells that were not exposed. However, AV-leukocytes exposed to MeHg displayed increased ROS levels. Cellular viability comparison among genotypes exposed to MeHg showed that the viability of AA-WBCs was lower than that of VV-WBC, with mean values of 3.46 ± 0.13 and 3.08 ± 0.77 (standard error), respectively (P = 0.033), whereas heterozygous cells (AV) displayed intermediate values. This difference was likely due to the higher basal H2O2 production of AA-WBCs compared to that of other genotypes. These results suggest that the Ala16Val-MnSOD polymorphism has toxicogenetic effects in human cells exposed to MeHg.

  3. Association between Ala379Val polymorphism of lipoprotein-associated phospholipase A2 and migraine without aura in Iranian population

    PubMed Central

    Haghdoost, Faraidoon; Gharzi, Mahsa; Faez, Farough; Hosseinzadeh, Elinaz; Tajaddini, Mohamadhasan; Rafiei, Laleh; Asgari, Fatemeh; Banihashemi, Mahboobeh; Masjedi, Samaneh Sadat; Zandifar, Alireza; Haghjooy-Javanmard, Shaghayegh

    2016-01-01

    Background: Migraine is a common neurovascular disorder with multifactorial and polygenic inheritance. The aim of this study was to investigate the association of a migraine without aura and Ala379Val polymorphism of lipoprotein-associated phospholipase A2 (Lp-PLA2) gene in the Iranian population. Methods: In this study, 103 migraine patients and 100 healthy controls were enrolled. DNA samples were extracted and the Ala379Val polymorphism of Lp-PLA2 gene was investigated. To assess severity of a headache, patients filled out the headache impact test (HIT-6) and migraine severity (MIGSEV) questionnaires. Results: Allele V had significantly lower frequency in the case group than control subjects [P = 0.001, odds ratio (OR) = 0.25, confidence interval (CI): 0.15-0.40]. The frequency of migraine patients that were a carrier of V allele (V/V and A/V) was statistically significant lower than the control group (P = 0.003, OR = 2.39, CI: 1.35-4.23). There was no significant difference of alleles frequency between three grades of MIGSEV (P = 0.316). Furthermore, total HIT-6 score was not significantly different between different genotypes (P = 0.466). Conclusion: Our results showed that Ala379Val gene polymorphism of LP-PLA2 is associated with lower risk of migraine but not with severity of headaches in an Iranian population. PMID:27326362

  4. COMT Val158Met and PPARγ Pro12Ala polymorphisms and susceptibility to Alzheimer's disease: a meta-analysis.

    PubMed

    Lee, Young Ho; Song, Gwan Gyu

    2014-05-01

    The aim of this study was to explore whether the catechol-O-methyltransferase (COMT) Val158Met or the peroxisome proliferator-activated receptor-gamma (PPARγ) Pro12Ala polymorphisms are associated with susceptibility to Alzheimer's disease (AD). We conducted a meta-analysis of the associations between the COMT Val158Met and the PPARγ Pro12Ala polymorphisms and AD in subjects. Meta-analysis showed no association between AD and the COMT G allele in any of the study subjects [odds ratio (OR) = 0.972, 95 % confidence intervals (95 % CI) = 0.893-1.059, p = 0.515]. Stratification by ethnicity indicated an association between the COMT GG+GA genotype and AD in an Asian group (OR = 0.702, 95 % CI = 0.517-0.953, p = 0.023), but not in Europeans (OR = 1.058, 95 % CI = 0.868-1.289, p = 0.579). Homozygote contrast analysis showed the same pattern for the COMT GG+GA genotype. Meta-analysis showed no association between AD and the PPARγ polymorphism (OR for the C allele = 0.963, 95 % CI = 0.818-1.134, p = 0.649). This meta-analysis identified an association between AD and the COMT Val158Met polymorphism in Asians but not in Europeans, but it revealed no association between AD and the PPARγ Pro12Ala polymorphism.

  5. Association between Ala379Val polymorphism of lipoprotein-associated phospholipase A2 and migraine without aura in Iranian population.

    PubMed

    Haghdoost, Faraidoon; Gharzi, Mahsa; Faez, Farough; Hosseinzadeh, Elinaz; Tajaddini, Mohamadhasan; Ra Ei, Laleh; Asgari, Fatemeh; Banihashemi, Mahboobeh; Masjedi, Samaneh Sadat; Zandifar, Alireza; Haghjooy-Javanmard, Shaghayegh

    2016-04-03

    Migraine is a common neurovascular disorder with multifactorial and polygenic inheritance. The aim of this study was to investigate the association of a migraine without aura and Ala379Val polymorphism of lipoprotein-associated phospholipase A2 (Lp-PLA2) gene in the Iranian population. In this study, 103 migraine patients and 100 healthy controls were enrolled. DNA samples were extracted and the Ala379Val polymorphism of Lp-PLA2 gene was investigated. To assess severity of a headache, patients filled out the headache impact test (HIT-6) and migraine severity (MIGSEV) questionnaires. Allele V had significantly lower frequency in the case group than control subjects [P = 0.001, odds ratio (OR) = 0.25, confidence interval (CI): 0.15-0.40]. The frequency of migraine patients that were a carrier of V allele (V/V and A/V) was statistically significant lower than the control group (P = 0.003, OR = 2.39, CI: 1.35-4.23). There was no significant difference of alleles frequency between three grades of MIGSEV (P = 0.316). Furthermore, total HIT-6 score was not significantly different between different genotypes (P = 0.466). Our results showed that Ala379Val gene polymorphism of LP-PLA2 is associated with lower risk of migraine but not with severity of headaches in an Iranian population.

  6. Hydrological behavior of the confined Aba'ala graben along the western margin of the Danakil depression, Northern Ethiopia

    NASA Astrophysics Data System (ADS)

    Meaza, Hailemariam; Frankl, Amaury; Poesen, Jean; Zenebe, Amanuel; Van Eetvelde, Veerle; Demissie, Biadgilgn; Ghebreyohannes Asfaha, Tesfaalem; Nyssen, Jan

    2017-04-01

    Marginal grabens are considered as major development corridors in Ethiopia. Despite the increasing pressure on water resources, the hydrological behavior of marginal grabens is poorly documented to develop management options. Here we investigate the hydrological behavior of Aba'ala marginal graben (553 km2) along the western margin of the Danakil depression. We implemented rain gauges, pressure transducers, and staff gauges at representative rivers to collect the required data. Transect studies across the escarpments were undertaken to understand the runoff mechanisms. We developed rating curves and hydrographs for each gauging station to analyze the discharges. The study shows that seasonal rainfall is erratic that led to 27.6x106m3 of runoff in 2016. About 88% of the river discharges took place in the form of flash floods between July and August. Furthermore, travertine dams situated in the upper catchment of Murga and Aba'ala Rivers indicate the position of springs that recharge the productive graben bottom. However, about 25.2x106m3 volume of water is lost through the single outlet from the marginal graben bottom. Moreover, high evapotranspiration rates make the available moisture insufficient for crop production in the graben bottom. Therefore, partitioning of flash and regular floods could improve onsite water productivity in the confined Aba'ala marginal graben.

  7. Haplotype analysis of the PPARγ Pro12Ala and C1431T variants reveals opposing associations with body weight

    PubMed Central

    Doney, Alex; Fischer, Bettina; Frew, David; Cumming, Alastair; Flavell, David M; World, Michael; Montgomery, Hugh E; Boyle, Douglas; Morris, Andrew; Palmer, Colin NA

    2002-01-01

    Background Variation at the PPARG locus may influence susceptibility to type 2 diabetes and related traits. The Pro12Ala polymorphism may modulate receptor activity and is associated with protection from type 2 diabetes. However, there have been inconsistent reports of its association with obesity. The silent C1431T polymorphism has not been as extensively studied, but the rare T allele has also been inconsistently linked to increases in weight. Both rare alleles are in linkage disequilibrium and the independent associations of these two polymorphisms have not been addressed. Results We have genotyped a large population with type 2 diabetes (n = 1107), two populations of non-diabetics from Glasgow (n = 186) and Dundee (n = 254) and also a healthy group undergoing physical training (n = 148) and investigated the association of genotype with body mass index. This analysis has demonstrated that the Ala12 and T1431 alleles are present together in approximately 70% of the carriers. By considering the other 30% of individuals with haplotypes that only carry one of these polymorphisms, we have demonstrated that the Ala12 allele is consistently associated with a lower BMI, whilst the T1431 allele is consistently associated with higher BMI. Conclusion This study has therefore revealed an opposing interaction of these polymorphisms, which may help to explain previous inconsistencies in the association of PPARG polymorphisms and body weight. PMID:12429071

  8. Triangular with Ala nasi (TAN) repair of unilateral cleft lips: a personal technique and early outcomes.

    PubMed

    Tan, Onder; Atik, Bekir

    2007-01-01

    The triangular flap repair is one of the most common techniques used in cleft lip surgery. However, inability to address the nasal deformity and loss of orbicularis wholeness accompanied with incomplete reorientation have been two major handicaps of the triangular repair. Therefore, we developed our personal technique, called the triangular with ala nasi (TAN) repair, including a perialar incision and a distinct approach to the skin and muscle. We applied the TAN technique to 32 consecutive (19 male and 13 female) patients with unilateral cleft. The mean age at repair was 2.5 (1-32) years. The cleft lip appeared completely and incompletely in 11 and 21 patients, respectively. The postoperative outcomes were assessed subjectively by Williams test and objectively by Lindsay-Farkas method.The mean follow-up time was 17.1 months. No early complication involving hematoma, infection, wound dehiscence, or partial or total flap loss was encountered. The recoveries of 79.1% and 86.2% on average, when compared with the noncleft side, were obtained postoperatively. With our technique, we aimed at combining the useful properties of the two popular techniques, Millard and Tennison-Randall. The TAN repair lengthens the vertical lip using a triangular flap, resulting in a nonlinear, zig-zag scar on the philtral ridge and forming a symmetrical cupid's bow, superiorities of the Tennison-Randall repair. On the other hand, our method also presents an excellent approximation of both the deep and superficial muscle groups and reduces the nasal deformity with a perialar incision, features of the Millard's technique.

  9. Saturation Mutagenesis of TsrA Ala4 Unveils a Highly Mutable Residue of Thiostrepton A

    PubMed Central

    Zhang, Feifei; Kelly, Wendy L.

    2016-01-01

    Thiopeptides are posttranslationally processed macrocyclic peptide metabolites, characterized by extensive backbone and side chain modifications that include a six-membered nitrogeneous ring, thiazol(in)e/oxazol(in)e rings, and dehydrated amino acid residues. Thiostrepton A, one of the more structurally complex and well-studied thiopeptides, contains a second macrocycle bearing a quinaldic acid moiety. Antibacterial, antimalarial, and anticancer properties have been described for thiostrepton A and other thiopeptides, although the molecular details for binding the cellular target in each case are not fully elaborated. We previously demonstrated that a mutation of the TsrA core peptide, Ala4Gly, supported the successful production of the corresponding thiostrepton variant. To more thoroughly probe the thiostrepton biosynthetic machinery’s tolerance toward structural variation at the fourth position of the TsrA core peptide, we report here the saturation mutagenesis of this residue using a fosmid-dependent biosynthetic engineering method and the isolation of 16 thiostrepton analogs. Several types of side chain substitutions at the fourth position of TsrA, including those that introduce polar or branched, hydrophobic residues, are accepted, albeit with varied preferences. In contrast, proline and amino acid residues inherently charged at physiological pH are not well-tolerated at the queried site by the thiostrepton biosynthetic system. These newly generated thiostrepton analogs were assessed for their antibacterial activities and abilities to inhibit the proteolytic functions of the eukaryotic 20S proteasome. We demonstrate that the identity of the fourth amino acid residue in the thiostrepton scaffold is not critical for either ribosome or proteasome inhibition. PMID:25572285

  10. Crystal structure of the O intermediate of the Leu93→Ala mutant of bacteriorhodopsin.

    PubMed

    Zhang, Jin; Yamazaki, Yoshikazu; Hikake, Masanori; Murakami, Midori; Ihara, Kunio; Kouyama, Tsutomu

    2012-10-01

    The lifetime of the O intermediate of bacteriorhodopsin (BR) is extended by a factor of ∼250 in the Leu93-to-Ala mutant (BR_L93A). To clarify the structural changes occurring in the last stage of the proton pumping cycle of BR, we crystallized BR_L93A into a hexagonal P622 crystal. Diffraction data from the unphotolyzed state showed that the deletion of three carbon atoms from Leu93 is compensated by the insertion of four water molecules in the cytoplasmic vicinity of retinal. This insertion of water is suggested to be responsible for the blue-shifted λ(max) (540 nm) of the mutant. A long-lived substate of O with a red-shifted λ(max) (~565 nm) was trapped when the crystal of BR_L93A was flash-cooled after illumination with green light. This substate (O(slow)) bears considerable similarity to the M intermediate of native BR; that is, it commonly shows deformation of helix C and the FG loop, downward orientation of the side chain of Arg82, and disruption of the Glu194/Glu204 pair. In O(slow), however, the main chain of Lys216 is less distorted and retinal takes on the 13-cis/15-syn configuration. Another significant difference is seen in the pH dependence of the structure of the proton release group, the pK(a) value of which is suggested to be much lower in O(slow) than in M.

  11. How Ala-->Gly mutations in different helices affect the stability of the apomyoglobin molten globule.

    PubMed

    Luo, Y; Baldwin, R L

    2001-05-01

    The apomyoglobin molten globule has a complex, partly folded structure with a folded A[B]GH subdomain; the factors determining its stability are not yet known in detail. Ala-->Gly mutations, made at solvent-exposed positions, are used to probe the role of helix propensity of individual helices in stabilizing the molten globule. Molten globule stability is measured by reversible urea unfolding, monitored both by circular dichroism and by tryptophan fluorescence. Two-state unfolding is tested by superposition of these two unfolding curves, and stability data are reported only for variants which satisfy the superposition test. Results for sites Q8 in the A helix and E109 in the G helix confirm that the helix propensities of the A and G helices both strongly affect molten globule stability, in contrast to results for the G65A/G73A double mutant which show that changing the helix propensity of the E-helix sequence has no significant stabilizing effect. Changing the helix propensity of the B-helix sequence with the G23A/G25A double mutant affects molten globule stability to an intermediate extent, confirming an earlier report that this mutant has increased stability. These results are consistent with the bipartite structure for the molten globule in which the A, G, and H helices are stably folded, while the long E helix is unfolded and the B helix has intermediate stability. Some differences are found in the shapes of the unfolding curves of different mutants even though they satisfy the superposition test for two-state unfolding, and possible explanations are discussed.

  12. Peroxisome proliferator-activated receptor-gamma Pro12Ala polymorphism could be a risk factor for gastric cancer.

    PubMed

    Zhao, Jing; Zhi, Zheng; Song, Guangyao; Wang, Juan; Wang, Chao; Ma, Huijuan; Yu, Xian; Sui, Aixia; Zhang, Hongtao

    2015-01-01

    Due to the strong inhibitory effects of PPARγ gene on the growth of cancer cells, the role of Pro12Ala polymorphism in PPARγ gene has been extensively investigated in cancer recently. However, the results were inconsistent according to cancer type. The aim of this study was to comprehensively evaluate the PPARγ Pro12Ala polymorphism and gastric cancer susceptibility. Search strategies were conducted in Pubmed, Medline (Ovid), Chinese biomedical database (CBM), China national knowledge infrastructure (CNKI), VIP, and Wanfang database, covering all publications, with the last search up to November 01, 2014. The strength of association between PPARγ Pro12Ala polymorphism and gastric cancer risk was assessed by OR with 95%CI. A total of 546 cases and 827 controls in 5 case-control studies were included in this meta-analysis. The results indicated that the variant G allele carriers (CG+GG) had a 2.31 times higher risk for gastric cancer when compared with the homozygote CC (odds ratio (OR)=2.31, 95% confidence interval (CI)=1.67- 3.21 for CG+GG vs. CC). In the subgroup analysis by ethnicity, significantly elevated risks were both found in Asians (OR=2.56, 95% CI=1.42-4.64) and Caucasians (OR=2.20, 95% CI=1.48-3.25). Similarly, in the subgroup analysis by H. pylori status, a significantly increased risk was identified in H. pylori (+) populations (OR=3.68, 95%CI=2.07-6.52), but not in H. pylori(-) populations (OR=1.17, 95%CI=0.58-2.39). This pooled analysis suggested that the PPARγ Pro12Ala polymorphism could be an independent predictive risk factor for gastric cancer especially in H. pylori infected populations in Asians and Caucasians. Nevertheless, prospectively designed cohort studies are needed to further investigate gene-gene and gene-environment interactions to confirm the combined effects of PPARγ Pro12Ala polymorphisms and H. pylori infection on gastric cancer risk.

  13. Functional IL6R 358Ala Allele Impairs Classical IL-6 Receptor Signaling and Influences Risk of Diverse Inflammatory Diseases

    PubMed Central

    Cutler, Antony J.; Howson, Joanna M. M.; Rainbow, Daniel B.; Smyth, Deborah J.; Kaptoge, Stephen; Clarke, Pamela; Boreham, Charlotte; Coulson, Richard M.; Pekalski, Marcin L.; Chen, Wei-Min; Onengut-Gumuscu, Suna; Rich, Stephen S.; Butterworth, Adam S.; Malarstig, Anders; Danesh, John; Todd, John A.

    2013-01-01

    Inflammation, which is directly regulated by interleukin-6 (IL-6) signaling, is implicated in the etiology of several chronic diseases. Although a common, non-synonymous variant in the IL-6 receptor gene (IL6R Asp358Ala; rs2228145 A>C) is associated with the risk of several common diseases, with the 358Ala allele conferring protection from coronary heart disease (CHD), rheumatoid arthritis (RA), atrial fibrillation (AF), abdominal aortic aneurysm (AAA), and increased susceptibility to asthma, the variant's effect on IL-6 signaling is not known. Here we provide evidence for the association of this non-synonymous variant with the risk of type 1 diabetes (T1D) in two independent populations and confirm that rs2228145 is the major determinant of the concentration of circulating soluble IL-6R (sIL-6R) levels (34.6% increase in sIL-6R per copy of the minor allele 358Ala; rs2228145 [C]). To further investigate the molecular mechanism of this variant, we analyzed expression of IL-6R in peripheral blood mononuclear cells (PBMCs) in 128 volunteers from the Cambridge BioResource. We demonstrate that, although 358Ala increases transcription of the soluble IL6R isoform (P = 8.3×10−22) and not the membrane-bound isoform, 358Ala reduces surface expression of IL-6R on CD4+ T cells and monocytes (up to 28% reduction per allele; P≤5.6×10−22). Importantly, reduced expression of membrane-bound IL-6R resulted in impaired IL-6 responsiveness, as measured by decreased phosphorylation of the transcription factors STAT3 and STAT1 following stimulation with IL-6 (P≤5.2×10−7). Our findings elucidate the regulation of IL-6 signaling by IL-6R, which is causally relevant to several complex diseases, identify mechanisms for new approaches to target the IL-6/IL-6R axis, and anticipate differences in treatment response to IL-6 therapies based on this common IL6R variant. PMID:23593036

  14. Association between the Pro12Ala Polymorphism of Peroxisome Proliferator-Activated Receptor Gamma 2 and Inflammatory Bowel Disease: A Meta-Analysis

    PubMed Central

    Zhao, Gang; Zhu, Lei; Wang, Li-Xia

    2012-01-01

    Background Peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor, has been implicated playing a role in the development of inflammatory bowel disease (IBD). However, previous studies evaluating the association between the PPARγ2 Pro12Ala polymorphism and IBD are inconsistent. We performed a meta-analysis to determine whether the PPARγ2 Pro12Ala mutation was associated with the presence of IBD. Methods and Findings Electronic databases were searched for case-control studies evaluating the association between the Pro12Ala mutation and the presence of IBD. Effects were summarized with the methods recommended by the Cochrane Collaboration. A total of 7 studies including 1002 ulcerative colitis (UC) cases, 1090 Crohǹs disease (CD) cases and 1983 controls were involved in this meta-analysis. In the overall analysis, no significant association of this polymorphism with UC or CD was found. In the subgroup analyses in different populations, AlaAla genotype seemed to protect the European Caucasian population against the development of CD (Pro vs Ala: OR = 1.135, 95%CI = 0.951–1.354, P = 0.162, Bon = 1.000; ProPro vs ProAla: OR = 1.042, 95%CI = 0.852–1.273, P = 0.690, Bon = 1.000; ProPro vs AlaAla: OR = 2.379, 95%CI = 1.110–5.100, P = 0.026, Bon = 0.156; ProAla vs AlaAla: OR = 2.315, 95%CI = 1.064–5.037, P = 0.034, Bon = 0.204; Pro homozygotes vs Ala positives: OR = 1.094, 95%CI = 0.899–1.330, P = 0.371, Bon = 1.000; Pro positives vs Ala homozygotes: OR = 2.360, 95%CI = 1.103–5.053, P = 0.027, Bon = 0.162; heterozygotes vs all homozygotes: OR = 0.976, 95%CI = 0.799–1.192, P = 0.809, Bon = 1.000). There was no significant association of this polymorphism with UC or CD in the East Asian population and the Turkish population. Conclusion AlaAla genotype may be a protective factor in the European Caucasian population against the

  15. Mobile and Prichard, Ala., Among 22 Communities Selected Nationally to Receive EPA Assistance to Advance Sustainability Goals and Foster Economic Development

    EPA Pesticide Factsheets

    ATLANTA - The U.S. Environmental Protection Agency (EPA) today announced that Mobile and Prichard, Ala., are among 22 communities selected to receive technical assistance to pursue development strategies that support smart growth and sustainability

  16. PPAR-gamma2 pro12Ala polymorphism is associated with post-challenge abnormalities of glucose homeostasis in children and adolescents with obesity.

    PubMed

    Jermendy, Agnes; Körner, Anna; Kovács, Margit; Madácsy, László; Cseh, Károly

    2011-01-01

    The aim of the study was to investigate the association between PPAR-gamma2 Pro12Ala polymorphism and laboratory characteristics of carbohydrate metabolism in children and adolescents with obesity. In addition, serum levels of tumor necrosis factor (TNF)-alpha, and soluble form of its receptors (sTNFR1 and sTNFR2) were assessed. In a cross-sectional study, 79 obese children and adolescents of Caucasian origin were investigated. PPAR-gamma2 Pro12Ala polymorphism was determined using polymerase chain reaction--restriction fragment length polymorphism technique. Serum levels of TNF-alpha, sTNFR1 and sTNFR2 were measured by enzyme amplified sensitivity immunoassay. The minor Ala allele frequency was found to be 14.56% in our cohort. No significant differences in age, BMI, waist circumference, blood pressure, serum lipid, uric acid, TNF-alpha, sTNFR1 and sTNFR2 values were found between carriers of the Ala allele (Pro/Ala and Ala/Ala; n=21) vs. homozygous carriers of the Pro allele (Pro/Pro; n=58). However, post-challenge (120 min) plasma glucose and insulin values were significantly lower in Ala allele carriers vs. homozygous Pro allele carriers (6.56 +/- 0.26 vs. 7.36 +/- 0.25 mmol/L and 65.9 +/- 13.8 vs. 111.8 +/- 20.7 microU/mL, respectively; p < 0.05); while no significant differences were found at fasting state. The association between PPAR-gamma2 Prol2Ala polymorphism and glucose metabolism is already present in children and adolescents with obesity who might be at the very beginning of the natural course of type 2 diabetes. At this stage, higher insulin sensitivity can be detected in Ala allele carriers compared to homozygous Pro subjects at post-challenge but not in fasting state; however, the TNF-system seems not to be involved in the alteration of glucose homeostasis due to PPAR-gamma2 Pro12Ala polymorphism.

  17. The association of Pro12Ala polymorphism of peroxisome proliferator-activated receptor-gamma gene with serum osteoprotegerin levels in healthy Korean women.

    PubMed

    Rhee, Eun-Jung; Oh, Ki-Won; Yun, Eun-Joo; Jung, Chan-Hee; Park, Cheol-Young; Lee, Won-Young; Oh, Eun-Sook; Baek, Ki-Hyun; Kang, Moo-Il; Park, Sung-Woo; Kim, Sun-Woo

    2007-12-31

    Recent evidences suggest that the activation of peroxisome proliferator-activated receptor (PPAR)-gamma, which is an important transcriptional factor in adipocyte differentiation, also plays an important role in the bone microenvironment. The objective of the study was to clarify whether Pro12Ala polymorphism was related to the serum OPG levels and bone mineral metabolism in healthy Korean women. In 239 Korean women (mean age 51 years), who participated in medical check-up program in a health promotion center, anthropometric measurements, lumbar spine and femoral neck bone mineral density (BMD), bone turnover markers, such as serum total alkaline phosphatase (ALP) levels, urine deoxypyridinoline levels, and 24-h urine calcium excretion were measured. Serum levels of OPG were measured with ELISA method. DNAs were extracted from the samples and the genotyping of the Pro12Ala polymorphism (rs1801282) in the PPAR-gamma gene was performed via an allelic discrimination assay using a TaqMan probe. In addition, we examined the haplotype analysis between two polymorphisms of PPAR-gamma gene, Pro12Ala in exon B and C161T in exon 6 (rs3856806). Allelic frequencies were 0.950 for Pro allele and 0.050 for Ala allele, which was in compliance with Hardy- Weinberg equilibrium, and there was no Ala12Ala genotype among the genotyped subjects. Mean serum OPG level was significantly lower (P=0.035), and serum total ALP was significantly higher (P=0.014) in the Pro12Ala genotype group compared with the Pro12Pro genotype group, which were consistently significant even after adjustment for weight, height, and serum follicle stimulating hormone (FSH). In multiple regression analysis with serum OPG as the dependent variable and age, weight, ALP, femoral neck BMD and Pro12Ala genotype included in the model, only Pro12Ala genotype was significant determinant of serum OPG level (b=??0.136, P=0.035). The haplotype analysis with C161T polymorphism revealed that subjects with Ala and T alleles

  18. Impact of the Pro12Ala polymorphism of the PPARγ2 gene on diabetes and obesity in a highly consanguineous population

    PubMed Central

    Bener, Abdulbari; Zirie, M; Al-Hamaq, AOAA; Nawaz, Z; Samson, N; Mohammad, R

    2015-01-01

    Background: The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor subfamily of transcription factors. It has been reported that they play important roles in obesity and the development of type 2 diabetes mellitus (T2DM). Materials and Methods: This case-control study was carried out among 764 Qatari patients with diabetes and 764 healthy subjects above 20 years of age at Primary Healthcare Clinics (PHCs) from January 2011 to December 2012. Face-to-face interviews were based on a questionnaire that included variables such as age, sex, sociodemographic status, body mass index (BMI) and other clinical parameters. The Pro12Ala in the PPARγ2 gene was detected on the LightCycler using two specific probes. Univariate and multivariate statistical analysis were performed. Results: The study revealed that in the diabetes group, Pro/(10.2% vs 9.4%; P = 0.606) and Ala/Ala (1.4% vs 0.9%; P = 0.343) were higher than in controls, whereas Pro/Pro (88.4% vs 89.7%;P = 0.413) was lower in diabetes patients, but no significant difference was observed among the genotype groups. In obese patients with diabetes, Pro/Pro (89% vs 89.9%;P = 0.792) and Pro/Ala (8.9% vs 10.1%;P = 0.671) were lower than in obese healthy subjects. No homozygous Ala/Ala was found in obese healthy subjects, whereas 6 Ala/Ala homozygotes were in obese diabetes group. But in diabetes group, obese patients had higher homozygous of Pro/Pro (89.3% vs 87.8%;P = 0.523) and Ala/Ala (1.8% vs 1.2%;P = 0.771) compared to non-obese patients. Conclusion: The current study did not reveal an association between the Pro12Ala polymorphism of the PPAR γ2 gene and type 2 diabetes (T2D) in Qatari's population. PMID:25593831

  19. Genetic polymorphism of peroxisome proliferator-activated receptor-gamma 2 Pro12Ala on ethnic susceptibility to diabetes in Uygur, Kazak and Han subjects.

    PubMed

    Li, Lin-Lin; Ma, Xiao-Li; Ran, Jian-Xin; Sun, Xiao-Feng; Xu, Li-Ming; Ren, Jun; Mao, Xin-Min

    2008-02-01

    1. The aim of the present study was to determine whether the peroxisome proliferator-activated receptor (PPAR)-g Pro12Ala polymorphism affects susceptibility to diabetes in Uygur, Kazak and Han subjects in Xinjiang, China. 2. Uygur, Kazak and Han subjects from Kashi, Yili and Shawan (Xinjiang, China) were enrolled in the present study. The PPAR-g Pro12Ala polymorphism was determined using restriction fragment length polymorphism. Anthropometric and serum biological indices were monitored among different genotype carriers to examine the PPAR-g Pro12Ala gene polymorphism and the prevalence of type 2 diabetes. 3. The distribution frequency of the Pro12Ala genotype did not differ between diabetic and non-diabetic Uygur, Kazak and Han subjects. However, the frequency of the A allele of Pro12Ala was significant different among non-diabetics, with frequencies of 11, 9 and 5% in Uygur, Kazak and Han groups, respectively. Using the c(2) test, it was shown that the frequency of the A allele in Uygurs (11%) was significantly higher than that in Han subjects (5%). To compare the wild-type (Pro/Pro) carriers in diabetics from each ethnic group, Ugyur subjects, who carry PPAR-g Pro12Ala (Pro/Ala), had a larger waist circumference and lower low-density lipoprotein-cholesterol level, Kazaks subjects showed larger waist circumference and higher high-density lipoprotein levels and Han subjects exhibited a high waist-to-hip ratio and body mass index. 4. The present study revealed that the allele and genotype frequency did not differ in diabetics and non-diabetics of each ethnic group. However, the frequency of the A allele was significantly different in non-diabetics from various ethnic groups. These data suggest that PPAR-g Pro12Ala may affect blood lipid levels and the abdominal fat storage of diabetic Ugyurs and Kazaks and may be associated with fat storage and insulin resistance in Hans.

  20. Gender-specific effect of Pro12Ala polymorphism in peroxisome proliferator-activated receptor gamma-2 gene on obesity risk and leptin levels in a Tunisian population.

    PubMed

    Ben Ali, Samir; Ben Yahia, Fatma; Sediri, Yousra; Kallel, Amani; Ftouhi, Bochra; Feki, Moncef; Elasmi, Monia; Haj-Taieb, Sameh; Souheil, Omar; Sanhagi, Haifa; Slimane, Hedia; Jemaa, Riadh; Kaabachi, Naziha

    2009-11-01

    This study was undertaken to investigate the impact of the Pro12Ala (rs1801282) polymorphism of the peroxisome proliferator-activated receptor gamma-2 (PPARgamma-2) gene on obesity or body mass index (BMI) and plasma leptin, insulin, adiponectin and lipid levels in a sample of the Tunisian population. The study included 387 obese patients and 288 control subjects. The Pro12Ala genotype was determined by polymerase chain reaction followed by a digestion with the restriction of endonuclease BstUI. In the whole population, there is no significant difference in genotype frequencies of the Pro12Ala polymorphism between obese patients and controls. However, separate analysis by gender revealed that obese men (but not women) had significantly higher frequency of Pro/Ala genotypes compared to controls (12.2% vs. 4.1%; chi(2)=6.76, p=0.009). In comparison to Pro/Pro homozygotes, Ala-allele bearers had a significantly higher risk of obesity [OR (95% CI)=3.26 (1.28-8.33)]. When obese subjects were stratified according to type 2 diabetes status, the association with obesity was only significant in obese non-diabetic patients [OR (95% CI)=3.74 (1.43-9.74), p=0.007]. Additionally, obese male patients carrying the Ala-allele had significantly higher body mass index (p=0.007) and plasma leptin levels (p=0.023) compared to those homozygous for Pro-allele. The significant effect of Pro12Ala polymorphism on plasma leptin levels disappeared after adjustment for age and BMI. The present study provides evidence that the Pro12Ala polymorphism of the PPARgamma-2 gene is associated with obesity in non-diabetic men from Tunisian origin.

  1. PPARγ Pro12Ala interacts with fat intake for obesity and weight loss in a behavioural treatment based on the Mediterranean diet.

    PubMed

    Garaulet, Marta; Smith, Caren E; Hernández-González, Teresa; Lee, Yu-Chi; Ordovás, Jose M

    2011-12-01

    The goal of this study was to examine whether the Pro12Ala polymorphism of peroxisome proliferator-activated receptor γ (PPARγ) is associated with insulin resistance, obesity and weight loss and to analyze potential interactions between fat intake and PPARγ polymorphism in a Spanish overweight/obese population. We recruited 1465 subjects enrolled in a behavioural treatment program for obesity based on a Mediterranean diet, which included the following: dietary treatment, physical activity, nutritional education and behavioral techniques. A significant association was found between PPARγ2 Pro12Ala genotype and plasma insulin concentration and homeostasis model assessment insulin resistance. Subjects with the Ala12 genotype had lower insulin levels than those with the Pro12Pro genotype. We detected a gene-diet interaction between the PPARγ Pro12Ala polymorphism and MUFA for BMI and body fat. Furthermore, we detected an interaction between the PPARγ Pro12Ala polymorphism and fat intake for total weight loss (p<0.001). When total fat intake was high, Ala12-carriers exhibited a significantly lower percentage of total weight loss than major-allele-carriers (p=0.037). Data are consistent with previous results showing a protective role for the Ala12 allele against insulin resistance, and replicate an earlier study that detected an interaction between dietary MUFA and PPARγ2 for BMI. Our detection of a gene-diet interaction between PPARγ Pro12Ala and fat intake for weight loss may explain previous discrepancies among different studies. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. PPARγ Pro12Ala interacts with fat intake for obesity and weight loss in a behavioural treatment based on the Mediterranean diet

    PubMed Central

    Garaulet, Marta; Smith, Caren E; Hernández-González, Teresa; Lee, Yu-Chi; Ordovás, Jose M.

    2014-01-01

    Scope The goal of this study was to examine whether the Pro12Ala polymorphism of peroxisome proliferator-activated receptor γ (PPARγ) is associated with insulin resistance, obesity and weight loss and to analyze potential interactions between fat intake and PPARγ polymorphism in a Spanish overweight/obese population. Materials and methods We recruited 1465 subjects enrolled in a behavioural treatment program for obesity based on a Mediterranean diet, which included the following: dietary treatment, physical activity, nutritional education and behavioral techniques. A significant association was found between PPARγ2 Pro12Ala genotype and plasma insulin concentration and homeostasis model assessment insulin resistance. Subjects with the Ala12 genotype had lower insulin levels than those with the Pro12Pro genotype. We detected a gene–diet interaction between the PPARγ Pro12Ala polymorphism and MUFA for BMI and body fat. Furthermore, we detected an interaction between the PPARγ Pro12Ala polymorphism and fat intake for total weight loss (p<0.001). When total fat intake was high, Ala12-carriers exhibited a significantly lower percentage of total weight loss than major-allele-carriers (p=0.037). Conclusion Data are consistent with previous results showing a protective role for the Ala12 allele against insulin resistance, and replicate an earlier study that detected an interaction between dietary MUFA and PPARγ2 for BMI. Our detection of a gene–diet interaction between PPARγ Pro12Ala and fat intake for weight loss may explain previous discrepancies among different studies. PMID:22102511

  3. CaAlaAT1 catalyzes the alanine: 2-oxoglutarate aminotransferase reaction during the resistance response against Tobacco mosaic virus in hot pepper.

    PubMed

    Kim, Ki-Jeong; Park, Chang-Jin; An, Jong-Min; Ham, Byung-Kook; Lee, Boo-Ja; Paek, Kyung-Hee

    2005-08-01

    Hot pepper (Capsicum annuum L. cv. Bugang) plants exhibit a hypersensitive response (HR) upon infection by Tobacco mosaic virus (TMV) pathotype P0. To elucidate molecular mechanism that underlies this resistance, hot pepper cv. Bugang leaves were inoculated with TMV-P0 and genes specifically up-regulated during the HR were isolated by differential screening. One of the clones, CaAlaAT1 encoding a putative alanine aminotransferase (EC 2.6.1.2) exhibited organ-specific expression pattern and the transcript accumulated abundantly in red (ripe) fruit tissues. CaAlaAT1 transcript was also induced in older leaves during senescence. The expression of CaAlaAT1 gene was increased in the incompatible interaction with TMV-P0 but was not in the compatible interaction with TMV-P1.2. When a strain of Xanthomonas campestris pv. vesicatoria (Xcv) carrying an AvrBs2 gene was infiltrated into the leaves of a pepper cv. ECW 20R carrying Bs2 resistance gene, a marked induction and maintenance of CaAlaAT1 gene expression was observed. The expression of CaAlaAT1 gene was triggered by salicylic acid (SA) and ethylene but not by methyl jasmonate (MeJA). CaAlaAT1 seemed to be localized mostly at the cytosol from the polyethylene glycol (PEG)-mediated transformation experiment. CaAlaAT1 seemed to catalyze alanine: 2-oxoglutarate aminotransferase (AKT) reaction, which was a main activity among the four activities in vitro, during the resistance response against TMV in hot pepper. These results suggest that CaAlaAT1, a protein known to be involved in metabolic reactions, might be one of the components in the plant's defense signal pathway against pathogens.

  4. Effects of sub-lethal and chronic lead concentrations on blood and liver ALA-D activity and hematological parameters in Nile tilapia.

    PubMed

    Dos Santos, Carlucio Rocha; Cavalcante, Ana Luiza Michel; Hauser-Davis, Rachel Ann; Lopes, Renato Matos; Mattos, Rita De Cássia Oliveira Da Costa

    2016-07-01

    Liver and blood δ-aminolevulinic acid dehydratase (ALA-D) inhibition by exposure to sub-lethal lead concentrations over time in Nile tilapia (Oreochromis niloticus) were investigated. All three lead concentrations (1mgkg(-1), 10mgkg(-1) and 100mgkg(-1)) significantly inhibited ALA-D activity in blood (319±29.2; 180±14.6 and 172±19µmols(-1)h(-1)L(-1) respectively) and liver (302±5.84; 201±41.4 and 93±22.1µmols(-1)h(-1)L(-1)) 24h after injection relative to controls (blood: 597±37.0µmols(-1)h(-1)L(-1); liver: 376±23.1µmols(-1)h(-1)L(-1)). Blood ALA-D was greatly inhibited in all but the highest lead dose. Fish were then exposed to 1mgkg(-1) lead for 9 days, and presented short-term hyperglycemia, decreased hemoglobin and hematocrit values and time-dependent blood ALA-D activity inhibition, corroborating blood ALA-D activity as being more suitable for investigating lead effects, showing dose and time-dependent ALA-D inhibition after lead exposure. The results of the present study also demonstrated that fish size affects blood ALA-D activity, as fish from the 24-h assay, which were slightly smaller (approximately 200g), showed higher ALA-D inhibition in response to lead exposure when compared to the fish from the 9-day assay (approximately 500g). Thus, fish size should always be taken into account both in the field and in laboratory settings, and efforts should be made to obtain uniform fish size samples for biomarker studies.

  5. Pro12Ala polymorphism of the PPARγ2 gene interacts with a mediterranean diet to prevent telomere shortening in the PREDIMED-NAVARRA randomized trial.

    PubMed

    García-Calzón, Sonia; Martínez-González, Miguel A; Razquin, Cristina; Corella, Dolores; Salas-Salvadó, Jordi; Martínez, J Alfredo; Zalba, Guillermo; Marti, Amelia

    2015-02-01

    The gene variant Pro/Ala (rs1801282) in the PPARγ2 has been associated with lower cardiovascular risk and greater benefit from lifestyle interventions. This polymorphism also seems to be associated with longer lifespan, but no information on telomere length (TL) is available. Our aim was to study the association between the Ala allele and changes in TL in high cardiovascular risk subjects and the potential interaction with a Mediterranean dietary pattern. A total of 521 subjects (55-80 years) participating in the Prevención con Dieta Mediterránea randomized trial were genotyped. Changes in TL, measured by quantitative real-time polymerase chain reaction (PCR), were assessed over 5 years of a nutritional intervention, which promoted adherence to the Mediterranean diet (MeDiet). Interestingly, Ala carriers showed lower telomere shortening after 5 years compared with the Pro/Pro genotype (P=0.031). This association was modulated by MeDiet because those Ala carriers who reported better conformity to the MeDiet exhibited increased TL (P<0.001). Moreover, a reduction in carbohydrate intake (≤9.5 g/d) resulted in increased TL among Ala carriers. Notably, an apparent gene-diet interaction was found through the observed changes in the MUFA+PUFA/carbohydrates ratio: as this ratio increased, TL lengthening was detected to a greater extent in the Ala carriers compared with the Pro/Pro subjects (P for interaction <0.001). The Pro12Ala polymorphism is associated with TL homeostasis after 5 years follow-up in subjects at high cardiovascular risk. In addition, a higher adherence to the MeDiet pattern strengthens the prevention of telomere shortening among Ala carriers. www.controlled-trials.com; Unique Identifier: ISRCTN35739639. © 2014 American Heart Association, Inc.

  6. The life and work of Abu ul-Ala Shirazi (d. 1001): a Persian pioneer in the treatment of malaria, in the style of Rhazes (865-925).

    PubMed

    Mahmoudian, Masoud; Rahimi-Moghaddam, Parvaneh

    2008-11-01

    Abu ul-Ala Shirazi, who lived around the 10th century at the Court of Amir Azud ul-Duleh Bueieh (902-951) from the Dailami Dynasty, found that arsenic, known as sam-al-far, could cure malaria. A clinical trial dating from the 10th century demonstrates Abu ul-Ala's intelligence and careful clinical observation, in the tradition of Rhazes' practice based on experimentation and clinical trial.

  7. PRO12ALA POLYMORPHISM ASSOCIATION OF PPAR-γ GENE WITH BIOCHEMICAL PARAMETERS OF THE BLOOD IN PATIENTS WITH CHRONIC DIFFUSE LIVER DISEASES.

    PubMed

    Prysyazhnyuk, V

    2015-09-01

    The connection of Pro12Ala polymorphism of PPAR-γ gene with blood biochemical parameters in patients with nonalcoholic fatty liver disease (NAFLD) and nonviral chronic hepatitis (CH) were analyzed. The frequency of incidence of minor Ala-allele of PPAR-γ gene in those patients was not found to be significantly different from that in healthy individuals. Aspartate aminotransferase activity in NAFLD patients, Ala-allele carriers, was significantly higher on 55,5% (p=0,007) than in patients with Pro/Pro-genotype. At the same time, alanine aminotransferase activity in patients with Ala-allele was significantly higher on 80,0% (p=0,03) than in patients with Pro/Pro -genotype PPAR-γ gene. In this cohort of patients with minor Ala-allele high gamma-glutamyltransferase activity was diagnosed, which in 2,1 times (p=0,04) prevailed that in patients, Pro/Pro-genotype carriers. Patients with CH showed no significant association between Pro12Ala polymorphism of PPAR-γ gene and activity of biochemical markers of pathological process in the liver.

  8. The Pro12Ala polymorphism in the PPAR-γ2 gene is not associated to obesity and type 2 diabetes mellitus in a Cameroonian population.

    PubMed

    Mato, Edith Pascale M; Pokam-Fosso, Priscille Eunice; Atogho-Tiedeu, Barbara; Noubiap, Jean Jacques N; Evehe, Marie-Solange; Djokam-Dadjeu, Rosine; Donfack, Olivier Sontsa; Ngwa, Elvis Ndonwi; Guewo-Fokeng, Magellan; Mbacham, Wilfred F; Sobngwi, Eugene; Mbanya, Jean Claude

    2016-01-01

    Peroxisome proliferator-activated receptor gamma 2 (PPAR-γ2) is a transcription factor with a key role in adipocyte differentiation, lipid storage and glucose homeostasis. The Ala allele of the common Pro12Ala polymorphism in the isoform PPAR-γ2 is at the center of many controversies because in some populations, it has been observed to be associated with T2DM or obesity but, not in others. The aim of this study was to investigate the association of Pro12Ala polymorphism in the PPAR-γ2 gene with susceptibility to obesity or T2DM in a Cameroonian population. This case-control study included 62 obese, 60 T2DM patients and 120 controls (60 non obese and 60 patients without T2DM), all unrelated and of Cameroonian origin. PPAR-γ2 was examined by genotyping for Pro12Ala using the Restriction Fragment Length Polymorphism - Polymerase Chain Reaction (PCR - RFLP). A portion of the 270 base pair bands of the PPAR-γ2 gene was successfully amplified. The Ala12 variant was totally absent from the study population, all participants being homozygote Pro/Pro. PPAR-γ2 Pro12Ala gene polymorphism may not be associated with obesity and T2DM. These results suggest that, PPAR-γ2 is unlikely a major gene for obesity or T2DM in the study population.

  9. [Meta-analysis of the association of Pro12Ala polymorphism of peroxisome proliferator activated receptor gamma gene with type 2 diabetes in Chinese Han population].

    PubMed

    Guo, Wu-Lan; Tang, Yong; Han, Xue-Yao; Ji, Li-Nong

    2011-12-01

    To evaluate the association of Pro12Ala polymorphism of peroxisome proliferator activated receptor gamma (PPARgamma) gene with type 2 diabetes (T2DM) in Chinese Han population. The present investigation was carried out using the keywords "PPARgamma", "pparg", "Pro12Ala", "type 2 diabetes", and "Chinese. The odds ratios (OR) for Ala12 used as the metric of choice were calculated in the dominant and additive model separately. The Meta-analysis was conducted by software STATA 11.0. (1) We identified 22 studies, of which 17 studies involving 3927 type 2 diabetes cases and 3364 controls fell into the inclusion criteria. The analysis indicated no significant inter-study heterogeneity and publication bias. (2) The frequencies of the minor allele Ala12 in type 2 diabetes and control groups were 4.8% and 4.6% respectively. (3) The combined overall OR of dominant and additive model calculated by fix-effects meta-analysis for type 2 diabetes and the Pro12Ala polymorphism, were 0.95 (95% CI: 0.80, 1.12) and 0.93 (95% CI: 0.79, 1.09) respectively. In this meta-analysis, the Pro12Ala gene variant (rs1801282) is not found to be associated with the susceptibility for type 2 diabetes in Chinese Han population.

  10. The Pro12Ala Polymorphism of PPAR-γ Gene Is Associated with Sepsis Disease Severity and Outcome in Chinese Han Population.

    PubMed

    Ma, Guoda; Wang, Haiyang; Mo, Guixi; Cui, Lili; Li, You; Shao, Yiming; Liu, Xin; Xie, Yuliu; Li, Jia; Fu, Jiawu; Tao, Hua; Zhao, Bin; Zhang, Liangqing; Li, Keshen

    2014-01-01

    Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a ligand-binding nuclear receptor, and its activation plays a prominent role in regulating the inflammatory response. Therefore, PPAR-γ has been suggested as a candidate gene for sepsis. In the present study, we investigated the association between the Pro12Ala polymorphism of PPAR-γ and sepsis in a Han Chinese population. A total of 308 patients with sepsis and 345 healthy controls were enrolled in this study. Genotyping was performed using the polymerase chain reaction-ligation detection reaction (PCR-LDR) method. No significant differences were detected in the allele and genotype distributions of the PPAR-γ Pro12Ala SNP between septic patients and controls (P = 0.622 for genotype; P = 0.629 for allele). However, stratification by subtypes (sepsis, septic shock, and severe sepsis) revealed a statistically significant difference in the frequency of the Ala allele and Ala-carrier genotype between the patients with the sepsis subtype and the healthy controls (P = 0.014 for allele and P = 0.012, for genotype). Moreover, significant differences were found in the frequency of the Ala allele and genotype between the sepsis survivors and nonsurvivors (all P = 0.002). In the survivors, the PPAR-γ Pro12Ala genotype was significantly associated with decreased disease severity and recovery time (all P < 0.001). Thus, genetic polymorphism is thought to play a role in the development and outcome of sepsis.

  11. The Pro12Ala Polymorphism of PPAR-γ Gene Is Associated with Sepsis Disease Severity and Outcome in Chinese Han Population

    PubMed Central

    Ma, Guoda; Wang, Haiyang; Mo, Guixi; Cui, Lili; Li, You; Shao, Yiming; Liu, Xin; Xie, Yuliu; Li, Jia; Fu, Jiawu; Tao, Hua; Zhao, Bin; Zhang, Liangqing; Li, Keshen

    2014-01-01

    Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a ligand-binding nuclear receptor, and its activation plays a prominent role in regulating the inflammatory response. Therefore, PPAR-γ has been suggested as a candidate gene for sepsis. In the present study, we investigated the association between the Pro12Ala polymorphism of PPAR-γ and sepsis in a Han Chinese population. A total of 308 patients with sepsis and 345 healthy controls were enrolled in this study. Genotyping was performed using the polymerase chain reaction-ligation detection reaction (PCR-LDR) method. No significant differences were detected in the allele and genotype distributions of the PPAR-γ Pro12Ala SNP between septic patients and controls (P = 0.622 for genotype; P = 0.629 for allele). However, stratification by subtypes (sepsis, septic shock, and severe sepsis) revealed a statistically significant difference in the frequency of the Ala allele and Ala-carrier genotype between the patients with the sepsis subtype and the healthy controls (P = 0.014 for allele and P = 0.012, for genotype). Moreover, significant differences were found in the frequency of the Ala allele and genotype between the sepsis survivors and nonsurvivors (all P = 0.002). In the survivors, the PPAR-γ Pro12Ala genotype was significantly associated with decreased disease severity and recovery time (all P < 0.001). Thus, genetic polymorphism is thought to play a role in the development and outcome of sepsis. PMID:25152754

  12. The Association between the Pro12Ala Variant in the PPARγ2 Gene and Type 2 Diabetes Mellitus and Obesity in a Chinese Population

    PubMed Central

    Wang, Xia; Liu, Jun; Ouyang, Yingying; Fang, Min; Gao, Hui; Liu, Liegang

    2013-01-01

    Background Conflicting results have been reported on the association of the Pro12Ala polymorphism of the PPARγ2 gene with the risk of type 2 diabetes or obesity. Methods and Findings A total of 3146 subjects with 1145 cases of type 2 diabetes and 2001 healthy controls were included in the study. Genomic DNA was obtained from blood samples and the screening for the gene polymorphisms was done using an allelic discrimination assay-by-design TaqMan method. Overall, the Ala allele frequency was 5.6% in control subjects and 3.9% in diabetes subjects (P = 0.023). We found a statistically significant association of carriers of the Ala allele with greater homoeostasis model assessment of beta cell function index in all subjects (P = 0.046). After controlling for confounders, carriers of the Ala allele had a decreased risk of diabetes compared with noncarriers [odds ratio (OR) 0.64, 95% confidence interval (CI) 0.49–0.83; P = 0.001]. A beneficial effect of the Ala allele was also observed for obesity (OR 0.64, 95% CI 0.42–0.96; P = 0.030). Conclusion Our results suggested that the presence of the Ala allele may contribute to improved insulin secretory capacity and may confer protection from type 2 diabetes and obesity in the Chinese population. PMID:23991018

  13. Usefulness of diagnostic laparoscopy with 5-aminolevulinic acid (ALA)-mediated photodynamic diagnosis for the detection of peritoneal micrometastasis in advanced gastric cancer after chemotherapy.

    PubMed

    Kishi, Kentaro; Fujiwara, Yoshiyuki; Yano, Masahiko; Motoori, Masaaki; Sugimura, Keijiro; Takahashi, Hidenori; Ohue, Masayuki; Sakon, Masato

    2016-12-01

    Successful cases have shown that conversion surgery after chemotherapy improves the prognosis of advanced gastric cancer. However, it is necessary to carefully select patients who have no unresectable factors prior to surgery. We recently reported that diagnostic laparoscopy with photodynamic diagnosis using oral 5-aminolevulinic acid (ALA-PDD) is a promising tool for diagnosing early peritoneal metastasis in gastric cancer. We herein evaluated the usefulness of this technique for detecting peritoneal metastases of advanced gastric cancer after chemotherapy. Diagnostic laparoscopy using sequential white light (WL) and ALA-PDD observations was performed in 38 patients with advanced gastric cancer after chemotherapy. The sensitivity of ALA-PDD for detecting peritoneal disease was compared with that of WL. The relationship between the state of peritoneal metastasis assessed by ALA-PDD and a cytological examination of the peritoneal fluid was evaluated. Twelve of the 38 patients (32 %) were diagnosed with peritoneal metastases by conventional laparoscopy. However, laparoscopy with ALA-PDD detected peritoneal metastases in 4 (11 %) of the 26 remaining patients. Three of these 4 patients had negative cytological results from the evaluation of the peritoneal fluid. Diagnostic laparoscopy using ALA-PDD is a useful technique for detecting metastases and determining treatment strategies to select patients with advanced gastric cancer who have received chemotherapy.

  14. Improved peptide prodrugs of 5-ALA for PDT: rationalization of cellular accumulation and protoporphyrin IX production by direct determination of cellular prodrug uptake and prodrug metabolization.

    PubMed

    Giuntini, Francesca; Bourré, Ludovic; MacRobert, Alexander J; Wilson, Michael; Eggleston, Ian M

    2009-07-09

    Twenty-seven dipeptide derivatives of general structure Ac-Xaa-ALA-OR were synthesized as potential prodrugs for 5-aminolaevulinic acid-based photodynamic therapy (ALA-PDT). Xaa is an alpha-amino acid, chosen to provide a prodrug with appropriately tailored lipophilicity and water solubility. Although no simple correlation is observed between downstream production of protoporphyrin IX (PpIX) in PAM212 keratinocytes and HPLC-derived descriptors of compound lipophilicity, quantification of prodrug uptake reveals that most of the dipeptides are actually more efficiently accumulated than ALA in PAM212 and also A549 and Caco-2 cell lines. Subsequent ALA release is the limiting factor, which emphasizes the importance of decoupling prodrug uptake and intracellular metabolization when assessing the efficacy of ALA derivatives for PDT. In agreement with PpIX fluorescence studies, at a concentration of 0.1 mM, l-Phe derivatives 4m and 4o, and l-Leu, l-Met, and l-Glu derivatives 4f, 4k, and 4u, exhibit significantly enhanced photoxicity in PAM212 cells compared to ALA.

  15. Loss of the Arabidopsis thaliana P4-ATPase ALA3 Reduces Adaptability to Temperature Stresses and Impairs Vegetative, Pollen, and Ovule Development

    PubMed Central

    McDowell, Stephen C.; López-Marqués, Rosa L.; Poulsen, Lisbeth R.; Palmgren, Michael G.; Harper, Jeffrey F.

    2013-01-01

    Members of the P4 subfamily of P-type ATPases are thought to help create asymmetry in lipid bilayers by flipping specific lipids between the leaflets of a membrane. This asymmetry is believed to be central to the formation of vesicles in the secretory and endocytic pathways. In Arabidopsis thaliana, a P4-ATPase associated with the trans-Golgi network (ALA3) was previously reported to be important for vegetative growth and reproductive success. Here we show that multiple phenotypes for ala3 knockouts are sensitive to growth conditions. For example, ala3 rosette size was observed to be dependent upon both temperature and soil, and varied between 40% and 80% that of wild-type under different conditions. We also demonstrate that ala3 mutants have reduced fecundity resulting from a combination of decreased ovule production and pollen tube growth defects. In-vitro pollen tube growth assays showed that ala3 pollen germinated ∼2 h slower than wild-type and had approximately 2-fold reductions in both maximal growth rate and overall length. In genetic crosses under conditions of hot days and cold nights, pollen fitness was reduced by at least 90-fold; from ∼18% transmission efficiency (unstressed) to less than 0.2% (stressed). Together, these results support a model in which ALA3 functions to modify endomembranes in multiple cell types, enabling structural changes, or signaling functions that are critical in plants for normal development and adaptation to varied growth environments. PMID:23667493

  16. Optimization and therapeutic effects of PDT mediated by ALA and MAL in the treatment of cutaneous malignant lesions: A comparative study.

    PubMed

    Lima, Cassio Aparecido; Goulart, Viviane Pereira; Bechara, Etelvino Jose Henriques; Correa, Luciana; Zezell, Denise Maria

    2016-12-01

    5-aminolevulinic acid (ALA) and its methylated ester (MAL) are the most common topical agents used in photodynamic therapy (PDT) as precursors of the photosensitizer protoporphyrin IX (PpIX). The induction of newly PpIX depends on incubation time of each photosensitizer in the tissue and the presence of high intralesional porphyrin levels is an important parameter for the PDT effectiveness. This study used laser-induced fluorescence (LIF) spectroscopy to evaluate the optimum time to light exposure of PDT mediated by ALA (20% w/w) and MAL (10% w/w) to treat malignant lesions precursors of cutaneous squamous cell carcinoma induced in mice. The therapeutic effects obtained by optimized ALA- and MAL-PDT were assessed 10 and 20 days after treatments. Higher PpIX levels were evidenced in the lesions photosensitized by ALA than MAL and according to LIF measurements the PDT irradiation was performed, respectively, at 300 and 330 minutes after ALA and MAL incubation. Histopathological analysis evidenced necrosis and epithelial atrophy after 10 days of PDT using both prodrugs, as well as reepitelization and collagen deposition at 20 days. Thus, despite the distinct concentration of ALA and MAL used in the formulation of each photosensitizing cream, PDT mediated by both photosensitizing agents obtained similar therapeutic outcomes. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. ALA-mediated fluorescence-guided resection (FGR) and PDT of glioma

    NASA Astrophysics Data System (ADS)

    Johansson, Ann; Stepp, Herbert; Beck, Tobias; Beyer, Wolfgang; Pongratz, Thomas; Sroka, Ronald; Meinel, Thomas; Stummer, Walter; Kreth, Friedrich-Wilhelm; Tonn, Jörg-Christian; Baumgartner, Reinhold

    2009-06-01

    A summary of clinical trials employing photodynamic diagnosis (PDD) and photodynamic therapy (PDT) for the diagnosis and treatment of brain malignancies is presented. Intra-cavity PDT has been performed within the surgical cavity following FGR, employing oral administration of 5-aminolevulinic acid (5-ALA), either targeting fluorescing tissue regions that were not removed during FGR due to safety reasons (referred to as focal PDT, n=20) or illuminating the entire resection cavity (referred to as integral PDT, n=9). Both approaches proved technically feasible and safe. Spectroscopic measurements performed pre-, during and post-PDT revealed Protoporphyrin IX (PpIX)-photobleaching of more than 95% after the delivery of 200 J/cm2. This light dose did not induce any side effects. Furthermore, interstitial PDT (iPDT) has been employed within one feasibility trial (n=10) and one Phase I/II trial (n=15). Here, three to six cylindrical light diffusors (20-30 mm length, 200 mW/cm, 720 J/cm) were positioned within the target tissue under stereotactic guidance. Pre-treatment planning was performed with the intent to target the entire tumour volume with a sufficient light dose while also minimising the risk of any light-induced temperature increase. For the feasibility trial patients with small, recurrent gliomas were included, resulting in a median survival of 15 months as well as some unexpected longterm survivals (up to 5 years). The Phase I/II trial employed the same clinical procedures. Here, the 12-month survival was 35% and the median progression-free survival was 6 months. In summary, stereotactic iPDT in combination with treatment-planning could be shown to be a safe and feasible treatment modality. These trials are presently being extended to also include on-line monitoring of PpIX fluorescence and photobleaching kinetics. Preliminary data has revealed dramatically different PpIX levels and photobleaching kinetics. Such data could possibly be employed for realtime

  18. Three most common nonsynonymous UGT1A6*2 polymorphisms (Thr181Ala, Arg184Ser and Ser7Ala) and therapeutic response to deferiprone in β-thalassemia major patients.

    PubMed

    Dadheech, Sneha; Rao, A Venkateswara; Shaheen, Uzma; Hussien, Mohammed Dyia; Jain, Suman; Jyothy, A; Munshi, Anjana

    2013-12-01

    Deferiprone is used as a chelation agent in chronic iron overload in β-thalassemia patients. Patients on deferiprone therapy show variable response to this drug in terms of reduction in iron overload as well as adverse drug reactions (ADRs). The pharmacogenetic studies on deferiprone have not carried out in patients with blood disorders in India. Therefore, the present study was carried out to evaluate the three most common nonsynonymous UGT1A6 polymorphisms Thr181Ala (541 A/G), Arg184Ser (552 A/C) and Ser7Ala (19 T/G) and therapeutic response to deferiprone in β-thalassemia major patients. Two hundred and eighty six (286) β-thalassemia major patients were involved in the study. Serum ferritin levels were estimated periodically to assess the status of the iron overload and the patients were grouped into responders and non-responders depending on the ferritin levels. The UGT1A6 2 polymorphisms were detected by PCR-RFLP methods. The association between the genotypes and outcome as well as ADRs was evaluated by Open EPI software. A significant difference was observed in the genotypic distribution of UGT1A6 2 Thr181Ala polymorphism in responders and non-responders. However, there was no difference in the genotypic distribution between patients with and without ADRs. As far as the UGT1A6 2 Arg184Ser polymorphism is concerned, no significant difference was observed between responders and non-responders. Further, evaluating the association of UGT1A6 2 Ser7Ala polymorphism with drug response, there was no significant difference in the genotypic distribution between responders and non-responders. However, there was a significant difference between responders with and without ADRs and non-responders with and without ADRs. In addition to this haplotype analysis was also carried out. However, we did not find any specific haplotype to be significantly associated with the deferiprone response in β-thalassemia major patients. © 2013 Elsevier B.V. All rights reserved.

  19. The Folding of Acetyl(Ala)28NH2 and Acetyl(Ala)40NH2 Extended Strand Peptides into Antiparallel β-Sheets. A Density Functional Theory Study of β-Sheets with β-Turns

    PubMed Central

    Ali-Torres, Jorge

    2012-01-01

    We report ONIOM calculations using B3LYP/D95** and AM1 on β-sheet formation from acetyl(Ala)NNH2 (N=28 or 40). The sheets contain from one to four β-turns for N=28 and up to six for N=40. We have obtained four types of geometrically optimized structures. All contain only β-turns. They differ from each other in the types of β-turns formed. The unsolvated sheets containing two turns are most stable. Aqueous solvation (using the SM5.2 and CPCM methods) reduces the stabilities of the folded structures compared to the extended strands. PMID:23157432

  20. Association of PPARγ2 gene variant Pro12Ala polymorphism with hypertension and obesity in the aboriginal Qatari population known for being consanguineous.

    PubMed

    Bener, Abdulbari; Darwish, Sarah; Al-Hamaq, Abdulla Oaa; Mohammad, Ramzi M; Yousafzai, Mohammad T

    2013-01-01

    The aim of this study was to investigate the association of the Pro12Ala polymorphism of the human peroxisome proliferator-activated receptor gamma 2 (PPARγ2) gene with hypertension and obesity in a highly consanguineous aboriginal Qatari population. A cross-sectional survey conducted from January 2011-December 2012. Primary health care clinics. A random sample of 1,528 Qatari male and female population older than 20 years of age. Data on age, sex, income, level of education, occupation status, body mass index, and blood pressure and lipid profile were obtained. The Pro12Ala in the PPARγ2 gene was detected on the LightCycler® using two specific probes: (Sensor [G] 5'-CTC CTA TTG ACG CAG AAA GCG-FL and PPAR Anchor 5' LC Red 640- TCC TTC ACT GAT ACA CTG TCT GCA AAC ATA TC-PH). Univariate and multivariate logistic regression were performed. Out of a total 1,528 participants, 220 were diagnosed with essential hypertension, and 420 were obese. Participants with consanguinity were significantly higher among hypertensive than normotensive (41.9% versus 30.8%; P=0.001). Altogether, more than three-fourths (89%) of the participants had a wild genotype (Pro12Pro), 9.8% were heterozygous with Pro12Ala, and only 1.2% was homozygous with the Ala12Ala genotype. The frequency of the Pro allele was 94.5% in normotensive versus 90.5% in hypertensive, while the distribution of the Ala allele was 5.5% in normotensive versus 9.5% in the hypertensive group (P=0.001). The odds of hypertension were 1.7 times higher among the participants with the Ala allele as compared to those with the Pro, while adjusting for other potential confounders (adjusted odds ratio 1.69; 95% confidence interval 1.12-2.55; P=0.012). There was no association between the PPARγ2Ala allele and obesity (P=0.740). The current study revealed an association between the PPARγ2Ala allele and hypertension in Qatar's population. On the other hand, this study found no association between the Ala allele and obesity.

  1. Association of PPARγ2 gene variant Pro12Ala polymorphism with hypertension and obesity in the aboriginal Qatari population known for being consanguineous

    PubMed Central

    Bener, Abdulbari; Darwish, Sarah; Al-Hamaq, Abdulla OAA; Mohammad, Ramzi M; Yousafzai, Mohammad T

    2013-01-01

    Aim The aim of this study was to investigate the association of the Pro12Ala polymorphism of the human peroxisome proliferator-activated receptor gamma 2 (PPARγ2) gene with hypertension and obesity in a highly consanguineous aboriginal Qatari population. Design A cross-sectional survey conducted from January 2011–December 2012. Setting Primary health care clinics. Subjects A random sample of 1,528 Qatari male and female population older than 20 years of age. Materials and methods Data on age, sex, income, level of education, occupation status, body mass index, and blood pressure and lipid profile were obtained. The Pro12Ala in the PPARγ2 gene was detected on the LightCycler® using two specific probes: (Sensor [G] 5′-CTC CTA TTG ACG CAG AAA GCG-FL and PPAR Anchor 5′ LC Red 640- TCC TTC ACT GAT ACA CTG TCT GCA AAC ATA TC-PH). Univariate and multivariate logistic regression were performed. Result Out of a total 1,528 participants, 220 were diagnosed with essential hypertension, and 420 were obese. Participants with consanguinity were significantly higher among hypertensive than normotensive (41.9% versus 30.8%; P=0.001). Altogether, more than three-fourths (89%) of the participants had a wild genotype (Pro12Pro), 9.8% were heterozygous with Pro12Ala, and only 1.2% was homozygous with the Ala12Ala genotype. The frequency of the Pro allele was 94.5% in normotensive versus 90.5% in hypertensive, while the distribution of the Ala allele was 5.5% in normotensive versus 9.5% in the hypertensive group (P=0.001). The odds of hypertension were 1.7 times higher among the participants with the Ala allele as compared to those with the Pro, while adjusting for other potential confounders (adjusted odds ratio 1.69; 95% confidence interval 1.12–2.55; P=0.012). There was no association between the PPARγ2Ala allele and obesity (P=0.740). Conclusion The current study revealed an association between the PPARγ2Ala allele and hypertension in Qatar’s population. On the other

  2. Effects of peroxisome proliferator activated receptor-gamma 2 gene Pro12Ala polymorphism on fasting blood lipids: a meta-analysis.

    PubMed

    Huang, Xiao; Zhao, Jiangpei; Zhao, Tongfeng

    2011-03-01

    Results from the published studies on the association of peroxisome proliferator activated receptor-gamma 2 (PPARγ2) Pro12Ala polymorphism with blood lipids are conflicting. In this meta-analysis, we investigated the association of the Pro12Ala polymorphism with total cholesterol, triglycerides, low density lipoprotein cholesterol, and high-density lipoprotein cholesterol. 74 studies with 52,998 subjects were included in this meta-analysis. Dominant model and additive model were used for this meta-analysis. We did not detect significant overall association of the Pro12Ala polymorphism with total cholesterol, low density lipoprotein cholesterol, or high-density lipoprotein cholesterol (P>0.05). Under dominant model, significant association between the PPARγ2 Pro12Ala polymorphism and increased blood TC in male subjects was detected: standardized mean difference=0.10, 95% confidence interval (0.02, 0.22), P=0.02, Pheterogeneity=0.14. We found a marginal association of the Pro12Ala polymorphism with increased HDL-C in healthy subjects under dominant model: standardized mean difference=0.10, 95% confidence interval (-0.00, 0.20), P=0.06, Pheterogeneity=0.96. We also found subjects with genotype AlaAla have lower blood TG than subjects with genotype ProPro in Caucasians: for analysis including the outlier studies: SMD=-0.40, 95% CI (-0.76, -0.05), P=0.02, Pheterogeneity<0.00001, and for analysis excluding the outlier studies: SMD=-0.23, 95% CI (-0.39, -0.06), P=0.006, Pheterogeneity=0.86. Our meta-analysis suggests that, compared with non-carriers, carriers of Ala allele have significant increased blood TC in male subjects, and marginally significant increased blood HDL-C in healthy subjects. Our meta-analysis also supports that subjects with genotype AlaAla have lower blood TG than subjects with genotype ProPro in Caucasians. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  3. Associations between C1431T and Pro12Ala variants of PPARγ gene and their haplotypes with susceptibility to metabolic syndrome in an Iranian population.

    PubMed

    Rooki, Hassan; Haerian, Monir-sadat; Azimzadeh, Pedram; Mirhafez, Reza; Ebrahimi, Mahmoud; Ferns, Gordon; Ghayour-Mobarhan, Majid; Zali, Mohammad-Reza

    2014-05-01

    Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear hormone receptor that regulates a number of genes involved in lipid and carbohydrate metabolism. The aim of this study was to investigate the association of C1431T and Pro12Ala polymorphisms of PPARγ gene and their haplotypes and diplotypes with risk of metabolic syndrome (MetS) in an Iranian population. A total of 340 unrelated Iranian subjects, including 175 MetS patients and 165 normal controls were enrolled. Each group was then divided into two subgroups according to the genotype (Pro/Pro and Pro/Ala+Ala/Ala for Pro12Ala, CC and CT+TT for C1431T). Genotypes were determined using a TaqMan method. Anthropometric indices, fasting plasma glucose and fasting lipid profile were measured by routine methods. A significant difference in the frequencies of the C1431T genotypes was observed between MetS and control subjects (P=0.014), whereas no association was found for the Pro12Ala. The T allele carriers had a significantly increased risk of MetS compared to the CC genotype (P=0.016) even after correction for multiple-testing and adjustment for age, sex and genotype. The T allele may therefore be considered as a risk factor for MetS (P=0.003). Analysis of combined groups showed that X/Ala-CC and Pro/Pro-X/T diplotypes were associated with a higher body weight, waist circumference and waist to hip ratio among the individuals with MetS. Moreover the Ala-T haplotype was weakly associated with a higher level of triglyceride and lower level of HDL, suggesting the possibility of an interaction between Ala and T alleles. This study suggests that the PPARγ C1431T polymorphism is related to an increased risk of MetS in an Iranian population and interacts with the Pro12Ala polymorphism, further increasing the risk of MetS.

  4. Environmental boron exposure and activity of delta-aminolevulinic acid dehydratase (ALA-D) in a newborn population.

    PubMed

    Huel, Guy; Yazbeck, Chadi; Burnel, Daniel; Missy, Pascale; Kloppmann, Wolfram

    2004-08-01

    Following boron intake, multiple effects have been observed in animal experiments. However, human data is lacking, and no data is available on the ability of boron to accumulate in fetal tissues. Positive responses in animal species suggest that developmental toxicity may be an area of concern in humans, following exposure to boron. Two hypotheses have seemed to account for the multiple effects described in scientific findings. One hypothesis is that boron is a negative regulator that influences a number of metabolic pathways by competitively inhibiting some key enzyme reactions. The other hypothesis is that boron has a role in ionic membrane transport regulations. To better understand boron potential toxicity, the present study examined the relationship between boron exposure and some key enzymes, well-known for their affinity for mineral elements, such as delta-aminolevulinic acid dehydratase (ALA-D), and two fundamental enzymes having a role in ionic membrane transport regulations (Ca-pump and Na(+)K(+)-ATPase). We investigated the potential effects of an environmental boron exposure on the activity of these enzymes in an urban population of 197 "normal" newborns. Environmental boron exposure was assessed in placental tissue. Because of the well-known inhibiting effect of lead on these enzymes, cord blood and placental lead were also analyzed. After adjustment for potential confounders, including lead, placental boron levels were negatively significantly correlated to ALA-D activity while Ca-pump and Na(+)K(+)-ATPase activities did not seem to be affected by the level of boron exposure. Given boron's ability, as a Lewis acid, to complex with hydroxyl groups, we suggest that such a mechanism would explain the inhibiting effect of boron on ALA-D.

  5. A new unstable hemoglobin variant Hb Acharnes or [β53(D4) Ala - Thr]: a case report.

    PubMed

    Karmakar, A; Ghosh, S; Ghosh, T K

    2012-04-01

    Hb Acharnes or [β53(D4) Ala - Thr] is a newly discovered unstable hemoglobin variant. It has been reported in very few literatures across the world and no cases have been reported from India till date. Hb Acharnes is known to interact with β°-thalassemia to produce thalassemia intermedia and heterozygotes may present with borderline HbA2 levels. Here we report a rare case discovered during routine screening of thalassemia and hemoglobinopathies in a 19 year old pregnant lady. To emphasize the diagnostic difficulties and importance of detection of a rare hemoglobin variant Hb Acharnes [β53(D4) Ala - Thr] in an asymptomatic patient in West Bengal, India. The 19 year old asymptomatic pregnant lady P1+0, LMP - 21.01.2011 reported in antenatal OPD of Burdwan Medical College & Hospital, Burdwan, West Bengal, India for routine follow up. After proper antenatal check up her blood was collected as a routine screening for Thalassemia, EDTA blood was taken on 5th April 2011 and was subjected to Hemoglobin estimation by Cyanmethemoglobin method, Cell parameters in automated cell counter (SYSMEX KX21) and Hemoglobin analysis by HPLC in BIORAD VARIANT system. The patient was normal with respect to clinical examination and urinalysis. Routine blood counts revealed mild microcytic hypochromic anemia and on HPLC an unknown band (retention time 2.2 minutes, 21.2%, appearing as a shoulder of HbA0 band) of hemoglobin variant was discovered with normal level of HbF and HbA2. Hemoglobin analysis of her mother showed similar pattern while her father and her husband had normal Hb-HPLC pattern. The unknown hemoglobin variant was identified as Hemoglobin Acharnes or [β53 (D4) Ala - Thr] by the Biorad laboratories upon consulting the standard chromatogram patterns for this particular hemoglobin variant. Only Haemoglobin Electrophoresis by conventional gel technique may miss the case and the HPLC pattern may be used as a standard control for identification.

  6. ALA, fatty fish or marine n-3 fatty acids for preventing DM?: a systematic review and meta-analysis.

    PubMed

    Muley, Arti; Muley, Prasad; Shah, Monali

    2014-05-01

    Diabetes mellitus (T2DM) has become a global problem. Role of n-3 FA in its prevention is still not completely understood. We carried out this systematic review and meta-analysis to assess the relation of dietary intake of fish and n-3PUFA with risk of diabetes. We searched PUBMED, EMBASE and GOOGLE with cross references to identify relevant articles. Since no RCTs were available, we searched for prospective cohort studies. Sixteen studies with 6,79,763 participants which assessed the association of dietary intake of fish and n-3 PUFA (marine or alpha-linolenic acid) with incidence of T2DM in > 18 years population and provided relative risk (RR) or hazard ratio (HR) with the corresponding 95% confidence interval (CI) of T2DM for each category of fish or n-3 PUFA intake were included. Three independent reviewers reviewed all eligible studies and abstracted the relevant information from individual studies. Meta-analysis confirmed the previous finding that marine n-3 FA increased risk of T2DM in Americans but reduced the same in Asians. We observed that two and seven times increased intake of ALA and fatty fish respectively reduced the risk of T2DM significantly and ALA did not increase the risk in Americans. We concluded that ALA may have some role in preventing T2DM, but is not studied widely. Hence, it should be studied in greater details (with higher degrees of intake; more than two times) to aid in developing effective preventive strategies against diabetes.

  7. Amyotrophic Lateral Sclerosis–Frontotemporal Lobar Dementia in 3 Families With p.Ala382Thr TARDBP Mutations

    PubMed Central

    Chiò, Adriano; Calvo, Andrea; Moglia, Cristina; Restagno, Gabriella; Ossola, Irene; Brunetti, Maura; Montuschi, Anna; Cistaro, Angelina; Ticca, Anna; Traynor, Bryan J.; Schymick, Jennifer C.; Mutani, Roberto; Marrosu, Maria Giovanna; Murru, Maria Rita; Borghero, Giuseppe

    2012-01-01

    Background TAR DNA-binding protein 43, encoded by the TARDBP gene, has been identified as the major pathological protein of frontotemporal lobar dementia (FTLD) with or without amyotrophic lateral sclerosis (ALS) and sporadic ALS. Subsequently, mutations in the TARDBP gene have been detected in 2% to 3% of patients with ALS (both familial and sporadic ALS). However, to our knowledge, there is only 1 description of 2 patients with FTLD and TARDBP gene mutations who later developed motor neuron disease. Objective To describe cognitive abnormalities in 3 Italian families with familial ALS and TARDBP gene mutations. Design, Setting, and Participants Genetic, neuropsychological, and neuroimaging analyses in 36 patients with familial non–superoxide dismutase 1 gene (SOD1) ALS and 280 healthy controls. Main Outcome Measure We identified 3 index cases of familial ALS carrying the p.Ala382Thr missense mutation of the TARDBP gene and with clinical, neuroimaging, and neuropsychological features of FTLD. Results The p.Ala382Thr missense mutation of the TARDBP gene was absent in the 280 controls. It was present in all affected members of the 3 families for whom DNA was available. All affected members of the 3 families developed FTLD after the onset of ALS, confirmed by neuropsychological testing and hypometabolism in frontal associative areas assessed with fludeoxyglucose F 18 positron emission tomography and computed tomography. Conclusions Three apparently unrelated families with familial ALS carrying the p.Ala382Thr TARDBP missense mutation developed FTLD. In these families, FTLD co-segregates with ALS. Patients with ALS carrying TARDBP mutations may develop FTLD. PMID:20697052

  8. [Mutation in the ED1, Ala349Thr in a patient with X-linked hypohidrotic ectodermal dysplasia].

    PubMed

    Salas-Alanis, Julio C; Cepeda-Valdés, Rodrigo; González-Santos, Adriana; Amaya-Guerra, Mario; Kurban, Mazen; Christiano, Angela M

    2011-12-01

    Hypohidrotic ectodermal dysplasia (HED) is a very rare disease characterized by the absence of eccrine glands, dry skin, scanty hair, and dental abnormalities. It is caused by mutations within the ED1 gene, which encodes a protein, ectodysplasin-A (EDA). Clinical characteristic are frontal bossing, saddle nose, pointed chin, a prominent supraorbital ridge with periorbital hyperpigmenta-tion, and anodontia. Those affected show great intolerance to heat. We report the first Mexican 2-year-old boy with an Ala349Thr missense mutation from Tamaulipas, México.

  9. In search of best fitted composite model to the ALAE data set with transformed Gamma and inversed transformed Gamma families

    NASA Astrophysics Data System (ADS)

    Maghsoudi, Mastoureh; Bakar, Shaiful Anuar Abu

    2017-05-01

    In this paper, a recent novel approach is applied to estimate the threshold parameter of a composite model. Several composite models from Transformed Gamma and Inverse Transformed Gamma families are constructed based on this approach and their parameters are estimated by the maximum likelihood method. These composite models are fitted to allocated loss adjustment expenses (ALAE). In comparison to all composite models studied, the composite Weibull-Inverse Transformed Gamma model is proved to be a competitor candidate as it best fit the loss data. The final part considers the backtesting method to verify the validation of VaR and CTE risk measures.

  10. What is influencing the phenotype of the common homozygous polymerase-γ mutation p.Ala467Thr?

    PubMed Central

    Neeve, Vivienne C. M.; Samuels, David C.; Bindoff, Laurence A.; van den Bosch, Bianca; Van Goethem, Gert; Smeets, Hubert; Lombès, Anne; Jardel, Claude; Hirano, Michio; DiMauro, Salvatore; De Vries, Maaike; Smeitink, Jan; Smits, Bart W.; de Coo, Ireneus F. M.; Saft, Carsten; Klopstock, Thomas; Keiling, Bianca-Cortina; Czermin, Birgit; Abicht, Angela; Lochmüller, Hanns; Hudson, Gavin; Gorman, Grainne G.; Turnbull, Doug M.; Taylor, Robert W.; Holinski-Feder, Elke; Chinnery, Patrick F.

    2012-01-01

    Polymerase-γ (POLG) is a major human disease gene and may account for up to 25% of all mitochondrial diseases in the UK and in Italy. To date, >150 different pathogenic mutations have been described in POLG. Some mutations behave as both dominant and recessive alleles, but an autosomal recessive inheritance pattern is much more common. The most frequently detected pathogenic POLG mutation in the Caucasian population is c.1399G>A leading to a p.Ala467Thr missense mutation in the linker domain of the protein. Although many patients are homozygous for this mutation, clinical presentation is highly variable, ranging from childhood-onset Alpers-Huttenlocher syndrome to adult-onset sensory ataxic neuropathy dysarthria and ophthalmoparesis. The reasons for this are not clear, but familial clustering of phenotypes suggests that modifying factors may influence the clinical manifestation. In this study, we collected clinical, histological and biochemical data from 68 patients carrying the homozygous p.Ala467Thr mutation from eight diagnostic centres in Europe and the USA. We performed DNA analysis in 44 of these patients to search for a genetic modifier within POLG and flanking regions potentially involved in the regulation of gene expression, and extended our analysis to other genes affecting mitochondrial DNA maintenance (POLG2, PEO1 and ANT1). The clinical presentation included almost the entire phenotypic spectrum of all known POLG mutations. Interestingly, the clinical presentation was similar in siblings, implying a genetic basis for the phenotypic variability amongst homozygotes. However, the p.Ala467Thr allele was present on a shared haplotype in each affected individual, and there was no correlation between the clinical presentation and genetic variants in any of the analysed nuclear genes. Patients with mitochondrial DNA haplogroup U developed epilepsy significantly less frequently than patients with any other mitochondrial DNA haplotype. Epilepsy was reported

  11. What is influencing the phenotype of the common homozygous polymerase-γ mutation p.Ala467Thr?

    PubMed

    Neeve, Vivienne C M; Samuels, David C; Bindoff, Laurence A; van den Bosch, Bianca; Van Goethem, Gert; Smeets, Hubert; Lombès, Anne; Jardel, Claude; Hirano, Michio; Dimauro, Salvatore; De Vries, Maaike; Smeitink, Jan; Smits, Bart W; de Coo, Ireneus F M; Saft, Carsten; Klopstock, Thomas; Keiling, Bianca-Cortina; Czermin, Birgit; Abicht, Angela; Lochmüller, Hanns; Hudson, Gavin; Gorman, Grainne G; Turnbull, Doug M; Taylor, Robert W; Holinski-Feder, Elke; Chinnery, Patrick F; Horvath, Rita

    2012-12-01

    Polymerase-γ (POLG) is a major human disease gene and may account for up to 25% of all mitochondrial diseases in the UK and in Italy. To date, >150 different pathogenic mutations have been described in POLG. Some mutations behave as both dominant and recessive alleles, but an autosomal recessive inheritance pattern is much more common. The most frequently detected pathogenic POLG mutation in the Caucasian population is c.1399G>A leading to a p.Ala467Thr missense mutation in the linker domain of the protein. Although many patients are homozygous for this mutation, clinical presentation is highly variable, ranging from childhood-onset Alpers-Huttenlocher syndrome to adult-onset sensory ataxic neuropathy dysarthria and ophthalmoparesis. The reasons for this are not clear, but familial clustering of phenotypes suggests that modifying factors may influence the clinical manifestation. In this study, we collected clinical, histological and biochemical data from 68 patients carrying the homozygous p.Ala467Thr mutation from eight diagnostic centres in Europe and the USA. We performed DNA analysis in 44 of these patients to search for a genetic modifier within POLG and flanking regions potentially involved in the regulation of gene expression, and extended our analysis to other genes affecting mitochondrial DNA maintenance (POLG2, PEO1 and ANT1). The clinical presentation included almost the entire phenotypic spectrum of all known POLG mutations. Interestingly, the clinical presentation was similar in siblings, implying a genetic basis for the phenotypic variability amongst homozygotes. However, the p.Ala467Thr allele was present on a shared haplotype in each affected individual, and there was no correlation between the clinical presentation and genetic variants in any of the analysed nuclear genes. Patients with mitochondrial DNA haplogroup U developed epilepsy significantly less frequently than patients with any other mitochondrial DNA haplotype. Epilepsy was reported

  12. Production of novel tetrahydroxyfuranyl fatty acids from alpha-linolenic acid by Clavibacter sp. strain ALA2.

    PubMed

    Hosokawa, Masashi; Hou, Ching T; Weisleder, David

    2003-07-01

    Previously, it was reported that a newly isolated microbial culture, Clavibacter sp. strain ALA2, produced trihydroxy unsaturated fatty acids, diepxoy bicyclic fatty acids, and tetrahydroxyfuranyl fatty acids (THFAs) from linoleic acid (C. T. Hou, J. Am. Oil Chem. Soc. 73:1359-1362, 1996; C. T. Hou and R. J. Forman III, J. Ind. Microbiol. Biotechnol. 24:275-276, 2000; C. T. Hou, H. Gardner, and W. Brown, J. Am. Oil Chem. Soc. 75:1483-1487, 1998; C. T. Hou, H. W. Gardner, and W. Brown, J. Am. Oil Chem. Soc. 78:1167-1169, 2001). In this study, we found that Clavibacter sp. strain ALA2 produced novel THFAs, including 13,16-dihydroxy-12-THFA, 15-epoxy-9(Z)-octadecenoic acid (13,16-dihydroxy-THFA), and 7,13,16-trihydroxy-12, 15-epoxy-9(Z)-octadecenoic acid (7,13,16-trihydroxy-THFA), from alpha-linolenic acid (9,12,15-octadecatrienoic acid). The chemical structures of these products were determined by gas chromatography-mass spectrometry and proton and (13)C nuclear magnetic resonance analyses. The optimum incubation temperature was 30 degrees C for production of both hydroxy-THFAs. 13,16-Dihydroxy-THFA was detected after 2 days of incubation, and the concentration reached 45 mg/50 ml after 7 days of incubation; 7,13,16-trihydroxy-THFA was not detected after 2 days of incubation, but the concentration reached 9 mg/50 ml after 7 days of incubation. The total yield of both 13,16-dihydroxy-THFA and 7,13,16-trihydroxy-THFA was 67% (wt/wt) after 7 days of incubation at 30 degrees C and 200 rpm. In previous studies, it was reported that Clavibacter sp. strain ALA2 oxidized the C-7, C-12, C-13, C-16, and C-17 positions of linoleic acid (n-6) into hydroxy groups. In this case, the bond between the C-16 and C-17 carbon atoms is saturated. In alpha-linolenic acid (n-3), however, the bond between the C-16 and C-17 carbon atoms is unsaturated. It seems that enzymes of strain ALA2 oxidized the C-12-C-13 and C-16-C-17 double bonds into dihydroxy groups first and then converted them to

  13. Production of Novel Tetrahydroxyfuranyl Fatty Acids from α-Linolenic Acid by Clavibacter sp. Strain ALA2

    PubMed Central

    Hosokawa, Masashi; Hou, Ching T.; Weisleder, David

    2003-01-01

    Previously, it was reported that a newly isolated microbial culture, Clavibacter sp. strain ALA2, produced trihydroxy unsaturated fatty acids, diepxoy bicyclic fatty acids, and tetrahydroxyfuranyl fatty acids (THFAs) from linoleic acid (C. T. Hou, J. Am. Oil Chem. Soc. 73:1359-1362, 1996; C. T. Hou and R. J. Forman III, J. Ind. Microbiol. Biotechnol. 24:275-276, 2000; C. T. Hou, H. Gardner, and W. Brown, J. Am. Oil Chem. Soc. 75:1483-1487, 1998; C. T. Hou, H. W. Gardner, and W. Brown, J. Am. Oil Chem. Soc. 78:1167-1169, 2001). In this study, we found that Clavibacter sp. strain ALA2 produced novel THFAs, including 13,16-dihydroxy-12-THFA, 15-epoxy-9(Z)-octadecenoic acid (13,16-dihydroxy-THFA), and 7,13,16-trihydroxy-12, 15-epoxy-9(Z)-octadecenoic acid (7,13,16-trihydroxy-THFA), from α-linolenic acid (9,12,15-octadecatrienoic acid). The chemical structures of these products were determined by gas chromatography-mass spectrometry and proton and 13C nuclear magnetic resonance analyses. The optimum incubation temperature was 30°C for production of both hydroxy-THFAs. 13,16-Dihydroxy-THFA was detected after 2 days of incubation, and the concentration reached 45 mg/50 ml after 7 days of incubation; 7,13,16-trihydroxy-THFA was not detected after 2 days of incubation, but the concentration reached 9 mg/50 ml after 7 days of incubation. The total yield of both 13,16-dihydroxy-THFA and 7,13,16-trihydroxy-THFA was 67% (wt/wt) after 7 days of incubation at 30°C and 200 rpm. In previous studies, it was reported that Clavibacter sp. strain ALA2 oxidized the C-7, C-12, C-13, C-16, and C-17 positions of linoleic acid (n-6) into hydroxy groups. In this case, the bond between the C-16 and C-17 carbon atoms is saturated. In α-linolenic acid (n-3), however, the bond between the C-16 and C-17 carbon atoms is unsaturated. It seems that enzymes of strain ALA2 oxidized the C-12-C-13 and C-16-C-17 double bonds into dihydroxy groups first and then converted them to hydroxy-THFAs. PMID

  14. Reversal by [D-Ala2,D-Leu5]enkephalin of the dopamine transporter loss caused by methamphetamine.

    PubMed

    Tsao, L I; Cadet, J L; Su, T P

    1999-05-21

    A single administration of 40 mg/kg (i.p.) of methamphetamine caused a loss of dopamine transporter in the striatum of albino Swiss (CD-1) mouse for at least 3 weeks. The administration of a single dose of [D-Ala2,D-Leu5]enkephalin (DADLE) (18 mg/kg, i.p.), given at day 14 after the administration of methamphetamine, caused a significant, transient restoration of dopamine transporter level in the striatum. These results suggest that delta-opioid peptide DADLE is able to reverse the neuronal damage caused by methamphetamine.

  15. Epidemiological, clinical and biochemical characterization of the p.(Ala359Asp) SMPD1 variant causing Niemann-Pick disease type B.

    PubMed

    Acuña, Mariana; Martínez, Pablo; Moraga, Carol; He, Xingxuan; Moraga, Mauricio; Hunter, Bessie; Nuernberg, Peter; Gutiérrez, Rodrigo A; González, Mauricio; Schuchman, Edward H; Santos, José Luis; Miquel, Juan Francisco; Mabe, Paulina; Zanlungo, Silvana

    2016-02-01

    Niemann-Pick disease type B (NPDB) is a rare, inherited lysosomal storage disorder that occurs due to variants in the sphingomyelin phosphodiesterase 1 (SMPD1) gene and the resultant deficiency of acid sphingomyelinase (ASM) activity. While numerous variants causing NPDB have been described, only a small number have been studied in any detail. Herein, we describe the frequency of the p.(Ala359Asp) variant in the healthy Chilean population, and determine the haplotype background of homozygous patients to establish if this variant originated from a common founder. Genomic DNA samples from 1691 healthy individuals were analyzed for the p.(Ala359Asp) variant. The frequency of p.(Ala359Asp) was found to be 1/105.7, predicting a disease incidence of 1/44 960 in Chile, higher than the incidence estimated by the number of confirmed NPDB cases. We also describe the clinical characteristics of 13 patients homozygous for p.(Ala359Asp) and all of them had moderate to severe NPDB disease. In addition, a conserved haplotype and shared 280 Kb region around the SMPD1 gene was observed in the patients analyzed, indicating that the variant originated from a common ancestor. The haplotype frequency and mitochondrial DNA analysis suggest an Amerindian origin for the variant. To assess the effect of the p.(Ala359Asp) variant, we transfected cells with the ASM-p.(Ala359Asp) cDNA and the activity was only 4.2% compared with the wild-type cDNA, definitively demonstrating the causative effect of the variant on ASM function. Information on common variants such as p.(Ala359Asp) is essential to guide the successful implementation for future therapies and benefit to patients.

  16. Association between the Pro12Ala polymorphism of PPAR-γ gene and the polycystic ovary syndrome: a meta-analysis of case-control studies.

    PubMed

    Zhang, Hong; Bi, Yan; Hu, Changjun; Lu, Weiping; Zhu, Dalong

    2012-07-15

    Several studies have been conducted to examine the association between PPAR-γ2 Pro12Ala polymorphism and polycystic ovary syndrome (PCOS), but the results remain inconsistent. To make a more precise estimation of the relationship, a meta-analysis was performed. In the current meta-analysis, a total of 17 case-control studies, including 2176 cases and 2373 controls, were selected. Odds ratios (ORs) and 95% confidence intervals (CIs) for Pro/Ala+Ala/Ala versus Pro/Pro genotype in all population and different nationality groups, and homeostasis model assessment-insulin resistance (HOMA-IR) of different genotype were evaluated. In the overall analysis, significant association between PPAR-γ2 Pro12Ala polymorphism and reduced risk of PCOS was observed (OR=0.75; 95%CI, 0.62-0.91; p=0.003). Stratified analysis showed that significantly strong association was presented only in Europeans (OR=0.74; 95%CI, 0.60-0.90; p=0.003), but not in Asians (OR=0.86; 95%CI, 0.51-1.43; p=0.56). Additionally, carrying the Ala12 allele was not associated with HOMA-IR in PCOS patients (OR=-0.29; 95%CI, -0.82-0.24; p=0.29). This meta-analysis supported that PPAR-γ2 Pro12Ala polymorphism was capable of reducing polycystic ovary syndrome risk in Europeans, but not in Asians. Copyright © 2012 Elsevier B.V. All rights reserved.

  17. Association between PPAR-γ2 Pro12Ala genotype and insulin resistance is modified by circulating lipids in Mexican children

    PubMed Central

    Stryjecki, Carolina; Peralta-Romero, Jesus; Alyass, Akram; Karam-Araujo, Roberto; Suarez, Fernando; Gomez-Zamudio, Jaime; Burguete-Garcia, Ana; Cruz, Miguel; Meyre, David

    2016-01-01

    The Pro12Ala (rs1801282) polymorphism in peroxisome proliferator-activated receptor-γ2 (PPAR-γ2) has been convincingly associated with insulin resistance (IR) and type 2 diabetes (T2D) among Europeans, in interaction with a high-fat diet. Mexico is disproportionally affected by obesity and T2D however, whether the Pro12Ala polymorphism is associated with early metabolic complications in this population is unknown. We assessed the association of PPAR-γ2 Pro12Ala with metabolic traits in 1457 Mexican children using linear regression models. Interactions between PPAR-γ2 Pro12Ala and circulating lipids on metabolic traits were determined by adding an interaction term to regression models. We observed a high prevalence of overweight/obesity (49.2%), dyslipidemia (34.9%) and IR (11.1%). We detected nominally significant/significant interactions between lipids (total cholesterol, HDL-cholesterol, LDL-cholesterol), the PPAR-γ2 Pro12Ala genotype and waist-to-hip ratio, fasting insulin, HOMA-IR and IR (9.30 × 10−4  ≤ Pinteraction ≤ 0.04). Post-hoc subgroup analyses evidenced that the association between the PPAR-γ2 Pro12Ala genotype and fasting insulin, HOMA-IR and IR was restricted to children with total cholesterol or LDL-cholesterol values higher than the median (0.02 ≤ P ≤ 0.03). Our data support an association of the Pro12Ala polymorphism with IR in Mexican children and suggest that this relationship is modified by dyslipidemia. PMID:27075119

  18. Pro12Ala variant of the PPARG2 gene increases body mass index: An updated meta-analysis encompassing 49,092 subjects.

    PubMed

    Galbete, C; Toledo, E; Martínez-González, M A; Martínez, J A; Guillén-Grima, F; Marti, A

    2013-07-01

    The peroxisome proliferator-activated receptor gamma 2 (PPARG2) gene has been intensively studied with relation to obesity and metabolic disorders. Indeed, a large number of studies assessing the association between the PPARG2 polymorphism Pro12Ala (rs1801282) and body mass index (BMI) have been published with some controversial results. In this meta-analysis, the effects of Pro12Ala polymorphism of the PPARG2 gene on BMI were investigated. Externally published data were collected and we included our own novel data from a study in the elderly participants (>55 years) of a Mediterranean cohort, the SUN ("Seguimiento Universidad de Navarra") Project (n = 972). A total of 75 independent studies with 49,092 subjects (39,806 with the genotype Pro12Pro and 9,286 carrier subjects of the Ala allele) were included. The meta-analysis revealed a higher BMI with an overall estimation of +0.065 kg/m(2) (95%CI = 0.026-0.103, P = 0.001) for homo-/heterozygous carriers of the Ala allele of the PPARG2 gene in comparison to non-carriers. The analysis also showed that there was heterogeneity (P for heterogeneity <0.001), but funnel plots did not suggest apparent publication bias. Furthermore, the association between the Pro12Ala polymorphism of the PPARG2 gene and increased BMI was stronger in Caucasian. Thus, carriers of the Ala allele had significantly higher BMI than non-carriers in a subsample of 6,528 Caucasian male subjects (standardized mean difference = 0.090, 95%CI=0.032-0.148, P = 0.002, P for heterogeneity = 0.121). This updated meta-analysis showed that carriers of the Ala12 allele of the PPARG2 gene had a higher average BMI. Copyright © 2012 The Obesity Society.

  19. Association between PRO12ALA polymorphism of the PPAR-γ2 gene and type 2 diabetes mellitus in Iranian patients

    PubMed Central

    Motavallian, Azadeh; Andalib, Sasan; Vaseghi, Golnaz; Mirmohammad-Sadeghi, Hamid; Amini, Masoud

    2013-01-01

    BACKGROUND: Peroxisome proliferator-activated receptor (PPARs) have been identified as ligand-activated transcription factors that belong to the nuclear receptor superfamily. It has been shown that an association exists between Proline 12 alanine (Pro12Ala) polymorphism of PPAR-GAMMA2 (PPAR-γ2) gene and increased risk of type 2 diabetes mellitus (T2DM) in different populations. Therefore, the present study was designed to investigate the association between Pro12Ala polymorphism of PPAR-γ2 gene and T2DM in an Iranian population. MATERIALS AND METHODS: Two hundred unrelated people, including 100 healthy controls and 100 diabetic patients were recruited diagnosed based on American Diabetes Association criteria. Blood samples were used for isolation of genomic deoxyribonucleic acid (DNA). Having extracted the genomic DNA from human blood leukocytes by means of High Pure polymerase chain reaction (PCR) Template preparation kit, we carried out polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) on each blood sample. Then, Genomic DNA was digested by BstU-I restriction enzyme. Thereafter, restriction products were analyzed by means of Polyacrylamide gel electrophoresis and stained by Ethidium Bromide. RESULTS: We found that the frequency of Ala allele in healthy subjects was significantly higher than in diabetic subjects (P = 0003). Moreover, the genotype frequency of Ala/Ala in healthy subjects was significantly higher than in diabetic subjects (P < 0.001). However, the genotype frequency of Ala/Pro in diabetic subjects was significantly higher than in healthy subjects (P < 0.001). CONCLUSION: The present study suggests that polymorphism of PPAR-γ2 gene is associated with T2DM. Furthermore, Ala allele is significantly found in non-diabetic individual’s Iranian population. PMID:24019628

  20. Association between PPAR-γ2 Pro12Ala genotype and insulin resistance is modified by circulating lipids in Mexican children.

    PubMed

    Stryjecki, Carolina; Peralta-Romero, Jesus; Alyass, Akram; Karam-Araujo, Roberto; Suarez, Fernando; Gomez-Zamudio, Jaime; Burguete-Garcia, Ana; Cruz, Miguel; Meyre, David

    2016-04-14

    The Pro12Ala (rs1801282) polymorphism in peroxisome proliferator-activated receptor-γ2 (PPAR-γ2) has been convincingly associated with insulin resistance (IR) and type 2 diabetes (T2D) among Europeans, in interaction with a high-fat diet. Mexico is disproportionally affected by obesity and T2D however, whether the Pro12Ala polymorphism is associated with early metabolic complications in this population is unknown. We assessed the association of PPAR-γ2 Pro12Ala with metabolic traits in 1457 Mexican children using linear regression models. Interactions between PPAR-γ2 Pro12Ala and circulating lipids on metabolic traits were determined by adding an interaction term to regression models. We observed a high prevalence of overweight/obesity (49.2%), dyslipidemia (34.9%) and IR (11.1%). We detected nominally significant/significant interactions between lipids (total cholesterol, HDL-cholesterol, LDL-cholesterol), the PPAR-γ2 Pro12Ala genotype and waist-to-hip ratio, fasting insulin, HOMA-IR and IR (9.30 × 10(-4)  ≤ Pinteraction ≤ 0.04). Post-hoc subgroup analyses evidenced that the association between the PPAR-γ2 Pro12Ala genotype and fasting insulin, HOMA-IR and IR was restricted to children with total cholesterol or LDL-cholesterol values higher than the median (0.02 ≤ P ≤ 0.03). Our data support an association of the Pro12Ala polymorphism with IR in Mexican children and suggest that this relationship is modified by dyslipidemia.

  1. Peroxisome proliferator-activated receptor γ polymorphism Pro12Ala Is associated with nephropathy in type 2 diabetes: evidence from meta-analysis of 18 studies.

    PubMed

    Zhang, Hui; Zhu, Shimiao; Chen, Jing; Tang, Yang; Hu, Hailong; Mohan, Viswanathan; Venkatesan, Radha; Wang, Jianmin; Chen, Haiping

    2012-06-01

    Insulin resistance plays a part in diabetic nephropathy (DN). The association between the peroxisome proliferator-activated receptor γ Pro to Ala alteration at codon 12 (Pro12Ala) polymorphism and the risk of insulin resistance has been confirmed. The association between the polymorphism and DN risk has also been widely studied recently, but no consensus was available up to now. A systematic search of electronic databases (MEDLINE, Embase, and China National Knowledge Infrastructure) and reference lists of relevant articles was carried out, and then 18 case-control studies involving 3,361 DN cases and 5,825 control subjects were identified. In the overall analysis, the Ala12 variant was observed to be significantly associated with decreased DN risk (odds ratio 0.76 [95% CI 0.61-0.93]). Some evidence of heterogeneity among the included studies was detected, which could be explained by the difference of ethnicity and stage of DN. Subgroup analyses stratified by ethnicity and stage of DN were performed, and results indicated the Pro12Ala polymorphism was associated with the risk of DN in Caucasians but no similar association was observed in Asians. Additionally, we observed that Ala12 was associated with decreased risk of albuminuria. With only a few of subjects were available, we failed to detect statistically significant association between the polymorphism and end-stage renal disease (ESRD). Our results indicated that the Ala12 variant is a significantly protective factor for DN. Future research should focus on the effect of Pro12Ala polymorphism on ESRD and gathering data of Africans.

  2. Cephalometrically assessing the validity of superior, middle and inferior tragus points on ala-tragus line while establishing the occlusal plane in edentulous patient

    PubMed Central

    Thombare, Ram

    2013-01-01

    PURPOSE The purpose of this study was to decide the most appropriate point on tragus to be used as a reference point at time of marking ala tragus line while establishing occlusal plane. MATERIALS AND METHODS The data was collected in two groups of subjects: 1) Dentulous 2) Edentulous group having sample size of 30 for each group with equal gender distribution (15 males, 15 females each). Downs analysis was used for base value. Lateral cephalographs were taken for all selected subjects. Three points were marked on tragus as Superior (S), Middle (M), and Inferior (I) and were joined with ala (A) of the nose to form ala-tragus lines. The angle formed by each line (SA plane, MA plane, IA plane) with Frankfort Horizontal (FH) plane was measured by using custom made device and modified protractor in all dentulous and edentulous subjects. Also, in dentulous subjects angle between Frankfort Horizontal plane and natural occlusal plane was measured. The measurements obtained were subjected to the following statistical tests; descriptive analysis, Student's unpaired t-test and Pearson's correlation coefficient. RESULTS The results demonstrated, the mean angle COO (cant of occlusal plane) as 9.76°, inferior point on tragus had given the mean angular value of IFH [Angle between IA plane (plane formed by joining inferior point-I on tragus and ala of nose- A) and FH plane) as 10.40° and 10.56° in dentulous and edentulous subjects respectively which was the closest value to the angle COO and was comparable with the values of angle COO value in Downs analysis. Angulations of ala-tragus line marked from inferior point with occlusal plane in dentulous subject had given the smallest value 2.46° which showed that this ala-tragus line was nearly parallel to occlusal plane. CONCLUSION The inferior point marked on tragus is the most appropriate point for marking ala-tragus line. PMID:23508068

  3. Epidemiological, clinical and biochemical characterization of the p.(Ala359Asp) SMPD1 variant causing Niemann–Pick disease type B

    PubMed Central

    Acuña, Mariana; Martínez, Pablo; Moraga, Carol; He, Xingxuan; Moraga, Mauricio; Hunter, Bessie; Nuernberg, Peter; Gutiérrez, Rodrigo A; González, Mauricio; Schuchman, Edward H; Luis Santos, José; Miquel, Juan Francisco; Mabe, Paulina; Zanlungo, Silvana

    2016-01-01

    Niemann–Pick disease type B (NPDB) is a rare, inherited lysosomal storage disorder that occurs due to variants in the sphingomyelin phosphodiesterase 1 (SMPD1) gene and the resultant deficiency of acid sphingomyelinase (ASM) activity. While numerous variants causing NPDB have been described, only a small number have been studied in any detail. Herein, we describe the frequency of the p.(Ala359Asp) variant in the healthy Chilean population, and determine the haplotype background of homozygous patients to establish if this variant originated from a common founder. Genomic DNA samples from 1691 healthy individuals were analyzed for the p.(Ala359Asp) variant. The frequency of p.(Ala359Asp) was found to be 1/105.7, predicting a disease incidence of 1/44 960 in Chile, higher than the incidence estimated by the number of confirmed NPDB cases. We also describe the clinical characteristics of 13 patients homozygous for p.(Ala359Asp) and all of them had moderate to severe NPDB disease. In addition, a conserved haplotype and shared 280 Kb region around the SMPD1 gene was observed in the patients analyzed, indicating that the variant originated from a common ancestor. The haplotype frequency and mitochondrial DNA analysis suggest an Amerindian origin for the variant. To assess the effect of the p.(Ala359Asp) variant, we transfected cells with the ASM-p.(Ala359Asp) cDNA and the activity was only 4.2% compared with the wild-type cDNA, definitively demonstrating the causative effect of the variant on ASM function. Information on common variants such as p.(Ala359Asp) is essential to guide the successful implementation for future therapies and benefit to patients. PMID:25920558

  4. IFN-γ and IL-2 Responses to Recombinant AlaDH against ESAT-6/CFP-10 Fusion Antigens in the Diagnosis of Latent versus Active Tuberculosis Infection

    PubMed Central

    Movahedi, Bahram; Mokarram, Pooneh; Hemmati, Mina; Mosavari, Nader; Zare, Razie; Ardekani, Leila Safaee; Mostafavi-Pour, Zohreh

    2017-01-01

    Background: Discriminating latent tuberculosis infection (LTBI) from active TBI may be challenging. The objective of this study was to produce the recombinant L-alanine dehydrogenase (AlaDH) antigen and evaluate individuals with LTBI, those with active TBI, and uninfected individuals by enzyme-linked immunospot assay (ELISPOT) in order to distinguish LTBI from active TBI. Methods: This exploratory study was performed in the Iranian city of Shiraz from 2014 to 2015. The study population (N=99) was divided into 3 groups: individuals with newly diagnosed active TBI (n=33), their household contacts (n=33), and controls (n=33). AlaDH was produced through PCR and cloning methods. The diagnostic characteristics of AlaDH vs. ESAT-6/CFP-10 were evaluated in responses to interferon-γ (IFN-γ) and interleukin-2 (IL-2) with ELISPOT. Differences between the groups were assessed with the Kruskal–Wallis and Mann–Whitney tests for nonparametric data analysis. The statistical analyses were performed with SPSS, version 16. Results: IFN-γ responses to both ESAT-6/CFP-10 (P=0.81) and AlaDH (P=0.18) revealed that there were no significant differences between the individuals with LTBI and those with active TBI. The same results were determined for IL-2 responses to ESAT-6/CFP-10 between the 2 groups, while significantly higher IL-2 responses to AlaDH were observed in LTBI than in active TBI. According to the ROC curve analysis, a cutoff value of 275 SFC showed sensitivity of 75.8% and specificity of 78.8% for distinguishing LTBI from active TBI by IL-2 responses to AlaDH. Conclusion: The current study suggests that it may be possible to discriminate LTBI from active TBI by IL-2 responses to AlaDH. PMID:28533576

  5. Association of MHTFR Ala222Val (rs1801133) polymorphism and breast cancer susceptibility: An update meta-analysis based on 51 research studies

    PubMed Central

    2012-01-01

    Background The association between MHTFR Ala222Val polymorphism and breast cancer (BC) risk are inconclusive. To derive a more precise estimation of the relationship, a systematic review and meta-analysis was performed. Methods A comprehensive search was conducted through researching MEDLINE, EMBASE, PubMed, Web of Science, Chinese Biomedical Literature database (CBM) and China National Knowledge Infrastructure (CNKI) databases before August 2012. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of the association. Results A total of 51 studies including 20,907 cases and 23,905 controls were involved in this meta-analysis. Overall, significant associations were found between MTHFR Ala222Val polymorphism and BC risk when all studies pooled into the meta-analysis (Ala/Ala vs Val/Val: OR=0.870, 95%CI=0.789–0.958,P=0.005; Ala/Val vs Val/Val: OR=0.895, 95%CI=0.821–0.976, P=0.012; dominant model: OR=0.882, 95%CI=0.808–0.963, P=0.005; and recessive model: OR = 0.944, 95%CI=0.898–0.993, P=0.026; Ala allele vs Val allele: OR = 0.935, 95%CI=0.887–0.986, P=0.013). In the subgroup analysis by ethnicity, the same results were found in Asian populations, while no significant associations were found for all comparison models in other Ethnicity populations. Conclusion In conclusion, our meta-analysis provides the evidence that MTHFR Ala222Val gene polymorphisms contributed to the breast cancer development. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1966146911851976 PMID:23217001

  6. ALA-PpIX variability quantitatively imaged in A431 epidermoid tumors using in vivo ultrasound fluorescence tomography and ex vivo assay

    NASA Astrophysics Data System (ADS)

    DSouza, Alisha V.; Flynn, Brendan P.; Gunn, Jason R.; Samkoe, Kimberley S.; Anand, Sanjay; Maytin, Edward V.; Hasan, Tayyaba; Pogue, Brian W.

    2014-03-01

    Treatment monitoring of Aminolevunilic-acid (ALA) - Photodynamic Therapy (PDT) of basal-cell carcinoma (BCC) calls for superficial and subsurface imaging techniques. While superficial imagers exist for this purpose, their ability to assess PpIX levels in thick lesions is poor; additionally few treatment centers have the capability to measure ALA-induced PpIX production. An area of active research is to improve treatments to deeper and nodular BCCs, because treatment is least effective in these. The goal of this work was to understand the logistics and technical capabilities to quantify PpIX at depths over 1mm, using a novel hybrid ultrasound-guided, fiber-based fluorescence molecular spectroscopictomography system. This system utilizes a 633nm excitation laser and detection using filtered spectrometers. Source and detection fibers are collinear so that their imaging plane matches that of ultrasound transducer. Validation with phantoms and tumor-simulating fluorescent inclusions in mice showed sensitivity to fluorophore concentrations as low as 0.025μg/ml at 4mm depth from surface, as presented in previous years. Image-guided quantification of ALA-induced PpIX production was completed in subcutaneous xenograft epidermoid cancer tumor model A431 in nude mice. A total of 32 animals were imaged in-vivo, using several time points, including pre-ALA, 4-hours post-ALA, and 24-hours post-ALA administration. On average, PpIX production in tumors increased by over 10-fold, 4-hours post-ALA. Statistical analysis of PpIX fluorescence showed significant difference among all groups; p<0.05. Results were validated by exvivo imaging of resected tumors. Details of imaging, analysis and results will be presented to illustrate variability and the potential for imaging these values at depth.

  7. The Pro12Ala variant at the peroxisome proliferator-activated receptor γ gene and change in obesity-related traits in the Diabetes Prevention Program

    PubMed Central

    Franks, P. W.; Jablonski, K. A.; Delahanty, L.; Hanson, R. L.; Kahn, S. E.; Altshuler, D.; Knowler, W. C.; Florez, J. C.

    2008-01-01

    Aims/hypothesis Peroxisome proliferator-activated receptor γ (PPARγ), encoded by the PPARG gene, regulates insulin sensitivity and adipogenesis, and may bind polyunsaturated fatty acids (PUFA) and thiazolidinediones in a ligand-dependent manner. The PPARG proline for alanine substitution at position 12 (Pro12Ala polymorphism) has been related with obesity directly and via interaction with PUFA. Methods We tested the effect-modifying role of Pro12Ala on the 1 year change in obesity-related traits in a randomized clinical trial of treatment with metformin (n=989), troglita-zone (n=363) or lifestyle modification (n=1,004) vs placebo (n=1,000) for diabetes prevention in high-risk individuals. Results At baseline, Ala12 carriers had larger waists (p<0.001) and, in a subset, more subcutaneous adipose tissue (SAT; lumbar 2/3; p=0.04) than Pro12 homozygotes. There was a genotype-by-intervention interaction on 1-year weight change (p=0.01); in the placebo arm, Pro12 homozygotes gained weight and Ala12 carriers lost weight (p=0.001). In the metformin and lifestyle arms, weight loss occurred across genotypes, but was greatest in Ala12 carriers (p<0.05). Troglitazone treatment induced weight gain, which tended to be greater in Ala12 carriers (p=0.08). In the placebo group, SAT (lumbar 2/3, lumbar 4/5) decreased in Ala12 allele carriers, but was unchanged in Pro12 homozygotes (p≤0.005). With metformin treatment, SAT decreased independently of genotype. In the lifestyle arm, SAT (lumbar 2/3) reductions occurred across genotypes, but were greater in Ala12 carriers (p=0.03). A genotype-by-PUFA intake interaction on reduction in visceral fat (lumbar 4/5; p=0.04) was also observed, which was most evident with metformin treatment (p<0.001). Conclusions /interpretation Within the Diabetes Prevention Program, the Ala12 allele influences central obesity, an effect which may differ by treatment group and dietary PUFA intake (ClinicalTrials.gov ID no: NCT00004992). PMID:17898990

  8. Downregulation of ALAS1 by nicarbazin treatment underlies the reduced synthesis of protoporphyrin IX in shell gland of laying hens.

    PubMed

    Samiullah, Sami; Roberts, Juliet; Wu, Shu-Biao

    2017-07-24

    Shell colour is an important trait for eggs and an understanding of pigment deposition will assist potential management of egg shell colour loss. We demonstrated that nicarbazin feeding down-regulated ALAS1 and reduced protoporphyrin IX (PP IX) in both shell gland and eggshell, indicating the role of nicarbazin in inhibiting the synthesis of PP IX. Additionally, the expression levels of the genes did not show sequential upregulation in the same order of diurnal time-points (TP) during egg formation. The gene SLC25A38, responsible for transporting glycine from cytoplasm to mitochondria, and the gene ALAS1, encoding rate-limiting enzyme (delta-aminolevulinic acid synthase 1), had higher expression at 15 hr, as compared with 2, 5 and 23.5 hrs postoviposition. Interestingly, ABCB6, a gene encoding an enzyme responsible for transporting coproporphyrinogen III, showed higher expression level at 2 and 5 hrs. However, the expression of CPOX that converts coproporphyrinogen III to protoporphyrinogen III, and ABCG2 that transports PP IX out from mitochondria did not alter. Nevertheless, mitochondrial count per cell did not show consistent change in response to time-points postoviposition and nicarbazin feeding. The information obtained in the study sheds light on how nicarbazin disrupts the synthesis of PP IX.

  9. Thermodynamic and structural characterization of Asn and Ala residues in the disallowed II' region of the Ramachandran plot.

    PubMed

    Vega, M C; Martínez, J C; Serrano, L

    2000-12-01

    Residue Asn47 at position L1 of a type II' beta-turn of the alpha-spectrin SH3 domain is located in a disallowed region of the Ramachandran plot (phi = 56 +/- 12, psi = -118 +/- 17). Therefore, it is expected that replacement of Asn47 by Gly should result in a considerable stabilization of the protein. Thermodynamic analysis of the N47G and N47A mutants shows that the change in free energy is small (approximately 0.7 kcal/mol; approximately 3 kJ/mol) and comparable to that found when mutating a Gly to Ala in a alpha-helix or beta-sheet. X-ray structural analysis of these mutants shows that the conformation of the beta-turn does not change upon mutation and, therefore, that there is no relaxation of the structure, nor is there any gain or loss of interactions that could explain the small energy change. Our results indicate that the energetic definition of II' region of the Ramachandran plot (phi = 60 +/- 30, psi = -115 +/- 15) should be revised for at least Ala and Asn in structure validation and protein design.

  10. Phototoxic effects of zinc oxide nanowires (ZnO NWs) complexed with 5-ALA in RD cell line

    NASA Astrophysics Data System (ADS)

    Fakhar-e-Alam, M.; Ali, S. M. U.; Ibupoto, Z. H.; Atif, M.; Willander, M.

    2011-12-01

    In this current study, we have manifested the photosensitizing effects of zinc oxide nanowires (ZnO NWs) in dark as well as under ultra violet light exposure with 240 nm of UV region, using human muscle cancer (Rhybdomyosarcoma cells, RD) as in vitro experimental model. We have fabricated ZnO-NWs on the tip of borosilicate glass capillaries (0.5 μm diameter) and were conjugated using 5-aminolevulinic acid (ALA) for the efficient intracellular drug delivery. When ZnO NWs were applied on tumor localizing drugs with non ionizing illumination, then excited drug liberates reactive oxygen species (ROS), effecting mitochondria and nucleus resulting in cell necrosis within few minutes. During investigations, we observed that when ZnO-NWs grown on intracellular tip was excited by using 240 nm of UV light, as a resultant 625 nm of emitted red light were used as appetizer in the presence of 5-ALA for chemical reaction, which produces singlet oxygen, responsible for cell necrosis. Morphological changes of necrosed cells were examined under microscopy. Moreover, Viability of controlled and treated RD cells with optimum dose of light (UV-Visible) has been assessed by MTT assay as well as reactive oxygen species (ROS) detection.

  11. A novel presenilin 1 mutation (Ala275Val) as cause of early-onset familial Alzheimer disease.

    PubMed

    Luedecke, Daniel; Becktepe, Jos S; Lehmbeck, Jan T; Finckh, Ulrich; Yamamoto, Raina; Jahn, Holger; Boelmans, Kai

    2014-04-30

    Mutations in the presenilin 1 (PS1) gene (PSEN1) are associated with familial Alzheimer disease (FAD). Here, we report on a 50-year-old patient presenting with progressive deterioration of his short-term memory and a family history of early-onset dementia. Diagnostic workup included a neuropsychological examination, structural magnetic resonance (MR) imaging, cerebrospinal fluid (CSF) biomarkers including total tau, phosphorylated tau, and Aβ42 levels, as well as sequencing relevant fragments of the genes PSEN1, PSEN2, and APP. Additionally, we were able to obtain archival paraffin-embedded cerebellar tissue from the patient's father for cosegregation analysis. Clinical, neuropsychological and MR imaging data were indicative of early-onset Alzheimer disease. Furthermore, CSF biomarkers showed a typical pattern for Alzheimer disease. DNA sequencing revealed a heterozygous nucleotide transition (c.824C>T) in exon 8 of PSEN1, leading to an amino acid change from alanine to valine at codon 275 (Ala275Val). The same mutation was found in an archival brain specimen of the patient's demented father, but not in a blood sample of the non-demented mother. This mutation alters a conserved residue in the large hydrophilic loop of PS1, suggesting pathogenic relevance. Cosegregegation analysis and the structural as well as the presumed functional role of the mutated and highly conserved residue suggest FAD causing characteristics of the novel PSEN1 mutation Ala275Val.

  12. The Synonymous Ala87 Mutation of Estrogen Receptor Alpha Modifies Transcriptional Activation Through Both ERE and AP1 Sites.

    PubMed

    Fernández-Calero, Tamara; Flouriot, Gilles; Marín, Mónica

    2016-01-01

    Estrogen receptor α (ERα) exerts regulatory actions through genomic mechanisms. In the classical pathway, ligand-activated ERα binds directly to DNA through estrogen response elements (ERE) located in the promoter of target genes. ERα can also exert indirect regulation of transcription via protein-protein interaction with other transcription factors such as AP-1.S everal ERα synonymous polymorphisms have been identified and efforts to understand their implications have been made. Nevertheless effects of synonymous polymorphisms are still neglected. This chapter focuses on the experimental procedure employed in order to characterize the transcriptional activity of a synonymous polymorphism of the ERα (rs746432) called Alanine 87 (Ala87). Activity of both WT and Ala87 ERα isoforms on transcriptional pathways can be analyzed in transiently transfected cells using different reporter constructs. ERα efficiency on the classical genomic pathway can be analyzed by determining its transactivation activity on an ERE-driven thymidine kinase (TK) promoter controlling the expression of the luciferase reporter gene. Transcriptional activity through the indirect genomic pathway can be analyzed by employing an AP-1 DNA response element-driven promoter also controlling the expression of luciferase reporter gene.

  13. Electronic structures of non-half-metallic antiferromagnetic double perovskites ALaVMoO6 (A = Ca, Sr, and Ba)

    NASA Astrophysics Data System (ADS)

    Kim, I. G.; Park, M. S.

    2005-03-01

    Recently, double perovskites ALaVMoO6 (A= Ca and Sr) of the Fm3m space group were proposed experimentally to be half-metallic antiferromagnets.ootnotetextUehara, Yamada, and Kimishima, Solid St. Commun. 129, 385 (2004). The electronic structures and magnetism of the double perovskites ALaVMoO6 (A= Ca, Sr, and Ba) were determined within the generalized gradient approximation to density functional theory using the all-electron full-potential linearized augmented plane wave (FLAPW) method.ootnotetextWimmer, Krakauer, Weinert, and Freeman, PRB 24, 864 (1981). The A= Ca case shows metallic ferrimagnetism as the most stable phase, with magnetic moments of 1.15;μB for V and -0.53;μB for Mo, whereas the Sr and Ba cases are calculated to be almost non-magnetic metals. Comparing the calculated density of states, we find that the heavier A implies stronger hybridization between the divalent atom sp states and the transition metal atom d states. The stronger sp-d hybridization is considered to be responsible for the suppression of magnetism for the Sr and Ba cases. These results, at least for the Fm3m space group, are in contrast with the recent experimental result proposing half-metallic antiferromagnetism for A= Ca and Sr.

  14. Effects of Lys2 to Ala2 substitutions on the structure and potency of ω-conotoxins MVIIA and CVID.

    PubMed

    Schroeder, Christina I; Nielsen, Katherine J; Adams, Denise A; Loughnan, Marion; Thomas, Linda; Alewood, Paul F; Lewis, Richard J; Craik, David J

    2012-01-01

    Lys2 has previously been implicated as a residue important in binding interactions between omega-conotoxins and the N-type calcium channel. To further assess the importance of this residue, Lys2 to Ala2 derivatives of omega-conotoxins MVIIA and CVID were synthesized and their structures and binding potencies determined. A comparison of the 3D structures of the Ala2 mutants with the parent peptides suggest there are significant structural differences brought about by this substitution. In particular, stabilizing interactions between Lys2 and loop 2 of the omega-conotoxins are removed, leading to greater flexibility in loop 2, which contains Tyr13, a crucial residue for omega-conotoxin binding to the N- and P/Q-type voltage-gated calcium channel (VGCC). The significant drop in binding potencies resulting from replacement of Lys2 thus appears to relate more to entropic factors than to any direct interaction of Lys2 with the VGCC. This has significant implications for the development of a pharmacophore binding model for omega-conotoxins, as removal of Lys2 from consideration suggests that the omega-conotoxins residues that interact with the N-type VGCC reside in loop 2 and 4, and thus cover a significantly smaller and more defined area of the surface of omega-conotoxin than previously thought.

  15. Effect of sodium benzoate preservative on micronucleus induction, chromosome break, and Ala40Thr superoxide dismutase gene mutation in lymphocytes.

    PubMed

    Pongsavee, Malinee

    2015-01-01

    Sodium benzoate is food preservative that inhibits microbial growth. The effects of sodium benzoate preservative on micronucleus induction, chromosome break, and Ala40Thr superoxide dismutase gene mutation in lymphocytes were studied. Sodium benzoate concentrations of 0.5, 1.0, 1.5, and 2.0 mg/mL were treated in lymphocyte cell line for 24 and 48 hrs, respectively. Micronucleus test, standard chromosome culture technique, PCR, and automated sequencing technique were done to detect micronucleus, chromosome break, and gene mutation. The results showed that, at 24- and 48-hour. incubation time, sodium benzoate concentrations of 1.0, 1.5, and 2.0 mg/mL increased micronucleus formation when comparing with the control group (P < 0.05). At 24- and 48-hour. incubation time, sodium benzoate concentrations of 2.0 mg/mL increased chromosome break when comparing with the control group (P < 0.05). Sodium benzoate did not cause Ala40Thr (GCG→ACG) in superoxide dismutase gene. Sodium benzoate had the mutagenic and cytotoxic toxicity in lymphocytes caused by micronucleus formation and chromosome break.

  16. Prostaglandin analogue-induced pigmentation of the skin of the nasal septum and nasal alae in a glaucoma patient.

    PubMed

    Holló, Gábor; Kóthy, Péter

    2015-05-25

    To present a case of topical prostaglandin analogue-induced skin pigmentation in a location previously never reported, with a differential diagnostic significance. An 83-year-old man successfully treated for primary open-angle glaucoma of both eyes with the bimatoprost/timolol fixed combination for 6 years reported increased pigmentation of the skin of the nasal septum and alae. According to his report, the darkened skin area was not present when he was a young or middle-aged man. The patient had noted periocular pigmentation and deepening of the upper lid sulcus on both sides, which developed during the years of his bimatoprost/timolol treatment. Dermatology consultation excluded any nevus, malignancy, or other pathology as a cause of the pigmentation. The otorhinolaryngology consultation failed to identify any pathologic condition in the nasal cavity, but described mild chronic senile rhinitis. The acquired pigmentation of the skin of the nasal septum and alae in our patient represents a new form of cutaneous pigmentation induced by topical prostaglandin analogue therapy, which may have differential diagnostic significance in clinical practice. We speculate that the senile rhinitis of the patient increased the exposure of the nasal skin to the prostaglandin analogue solution drained via the nasolacrimal duct, and could therefore play a role in the development of skin pigmentation in this location.

  17. Electron diffraction studies of light-induced conformational changes in the Leu-93 → Ala bacteriorhodopsin mutant

    PubMed Central

    Subramaniam, Sriram; Faruqi, A. R.; Oesterhelt, Dieter; Henderson, Richard

    1997-01-01

    We previously have presented evidence for prominent structural changes in helices F and G of bacteriorhodopsin during the photocycle. These changes were determined by carrying out electron diffraction analysis of illuminated two-dimensional crystals of wild-type bacteriorhodopsin or the Asp-96 → Gly mutant that were trapped at a stage in the photocycle after light-driven proton release, but preceding proton uptake from the aqueous medium. Here, we report structural analysis of the long-lived O intermediate observed in the photocycle of the Leu-93 → Ala mutant, which accumulates after the release and uptake of protons, but before the reisomerization of retinal to its initial all-trans state. Projection Fourier difference maps show that upon illumination of the Leu-93 → Ala mutant, significant structural changes occur in the vicinity of helices C, B, and G, and to a lesser extent near helix F. Our results suggest that (i) all four helices that line the proton channel (B, C, F, and G) participate in structural changes during the late stages of the photocycle, and (ii) completion of the photocycle involves significant conformational changes in addition to those that are associated with steps in proton transport. PMID:9050853

  18. Synthesis and pharmacology of halogenated δ-opioid-selective [d-Ala(2)]deltorphin II peptide analogues.

    PubMed

    Pescatore, Robyn; Marrone, Gina F; Sedberry, Seth; Vinton, Daniel; Finkelstein, Netanel; Katlowitz, Yitzchak E; Pasternak, Gavril W; Wilson, Krista R; Majumdar, Susruta

    2015-06-17

    Deltorphins are naturally occurring peptides produced by the skin of the giant monkey frog (Phyllomedusa bicolor). They are δ-opioid receptor-selective agonists. Herein, we report the design and synthesis of a peptide, Tyr-d-Ala-(pI)Phe-Glu-Ile-Ile-Gly-NH2 3 (GATE3-8), based on the [d-Ala(2)]deltorphin II template, which is δ-selective in in vitro radioligand binding assays over the μ- and κ-opioid receptors. It is a full agonist in [(35)S]GTPγS functional assays and analgesic when administered supraspinally to mice. Analgesia of 3 (GATE3-8) is blocked by the selective δ receptor antagonist naltrindole, indicating that the analgesic action of 3 is mediated by the δ-opioid receptor. We have established a radioligand in which (125)I is incorporated into 3 (GATE3-8). The radioligand has a KD of 0.1 nM in Chinese hamster ovary (CHO) cells expressing the δ receptor. Additionally, a series of peptides based on 3 (GATE3-8) was synthesized by incorporating various halogens in the para position on the aromatic ring of Phe(3). The peptides were characterized for binding affinity at the μ-, δ-, and κ-opioid receptors, which showed a linear correlation between binding affinity and the size of the halogen substituent. These peptides may be interesting tools for probing δ-opioid receptor pharmacology.

  19. Fluorescence behaviour and dural infiltration of meningioma analyzed by 5-ALA based fluorescence: Operating microscope versus mini-spectrometer.

    PubMed

    Knipps, Johannes; Beseoglu, Kerim; Kamp, Marcel; Fischer, Igor; Felsberg, Joerg; Neumann, Lisa M; Steiger, Hans-Jakob; Cornelius, Jan F

    2017-08-30

    To compare fluorescence intensity of tumor specimens as measured by a FGS-microscope and a spectrometer, 2.) to evaluate tumor infiltration of dura mater around meningiomas with help of these two different 5-ALA based fluorescence tools and 3.) to correlate fluorescence intensity with histopathological data. In a clinical series menigiomas were resected by 5-ALA fluorescence guided surgery. Fluorescence intensity was semi-quantitatively rated by the surgeon at pre-defined points. Biopsies were harvested and fluorescence intensity measured by a spectrometer and histopathologically analysed. Sampling was realized at the level of the dura in a centrifugal direction. 104 biopsies (n= 13 tumors) were analysed. Specificity and sensitivity of the microscope were 0.96 and 0.53 and of the spectrometer 0.95 and 0.93, respectively. Fluorescence intensity as measured by the spectrometer was correlated to histologically confirmed tumor burden. In a centrifugal direction, tumor burden and fluorescence intensity continuously decreased (along the dural tail). Below a threshold value of 639 arbitrary units no tumor was histologically detectable. At the level of the dura the spectrometer was highly sensitive for detection of meningioma cells. The surgical microscope showed false negative results and missed residual tumor cells in more than half of the cases. The complementary use of both fluorescence tools may improve resection quality. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Association between Pro12Ala, Pvull, Avall, Sstl and ADIPOQ single-nucleotide polymorphisms with lipid and glycemic profiles of patients with Berardinelli-Seip syndrome.

    PubMed

    Baracho, Maria F P; Nunes, Adriana B; Hirata, Mario H; Hirata, Rosario D C; Fajardo, Christina M; Santos, Maria G N; Wajchenberg, Bernardo L; De Marco, Luiz A; Brandão-Neto, José

    2014-01-01

    Berardinelli-Seip syndrome (BSS) is a recessive autosomal genetic disorder characterized by the near loss of adipose tissue with disturbance in lipid metabolism. Biochemical and hormonal parameters and Pro12Ala, Pvull, Avall, Sstl and ADIPOQ polymorphisms in 22 patients with BSS were analyzed and examined for a possible association with lipid profiles. Parental consanguinity, insulin resistance and diabetes mellitus were observed in 63.6, 81.8 and 59.1% of patients, respectively. All individuals presented high triglyceride levels, and 68.1% of patients showed high cholesterol levels. The Pro/Pro genotype of the Pro12Ala polymorphism of the PPARγ2 gene was found in 86.3% of patients; the Ala/Ala variant was not observed in any patient. The PvuII polymorphism of the LPL gene showed a frequency of 50% for the P1P2 variant. The AvaII polymorphism of the LDLR gene showed a similar frequency of 40.9% for both CT and TT variants. The S1S1 genotype of the Sstl polymorphism of the APOC3 gene had a frequency of 86.3%. The CC allele of the ADIPOQ polymorphism of the adiponectin gene was found in 54.6% of patients. No association was found between lipid parameters and the relevant Pvull, Avall and Sstl polymorphisms. However, we did observe an association of the Pro12Ala and ADIPOQ polymorphisms with higher lipid levels, suggesting a close relationship between these factors.

  1. Association between the Pro12Ala polymorphism of PPAR-γ gene and the non-alcoholic fatty liver disease: a meta-analysis.

    PubMed

    Wang, Jun; Guo, Xufeng; Wu, Pengbo; Song, Jia; Ye, Chuncui; Yu, Shijie; Zhang, Jixiang; Dong, Weiguo

    2013-10-10

    Several studies have been conducted to examine the association between PPAR-γ2 Pro12Ala polymorphism and non-alcoholic fatty liver disease (NAFLD), but the results remain inconsistent. In this study, a meta-analysis was performed to assess the association of PPAR-γ Pro12Ala polymorphism with NAFLD risk. A total of 8 case-control studies, including 1697 cases and 2427 controls, were selected. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model. Overall, no evidence has indicated that the Pro12Ala polymorphism was associated with the susceptibility to NAFLD. Besides, stratified analysis with ethnicity also indicated that no significant association between PPAR-γ Pro12Ala and the risk of NAFLD under all for genetic model in both Asian and Caucasian populations was observed. This meta-analysis indicated that the Pro12Ala polymorphism is not associated with NAFLD risk. Large and well-designed studies are warranted to validate our findings. © 2013.

  2. Effect of the Pro12Ala Polymorphism of the Peroxisome Proliferator-activated Receptor γ2 Gene on Lipid Profile and Adipokines Levels in Obese Subjects

    PubMed Central

    Becer, E; Çırakoğlu, A

    2017-01-01

    Abstract Peroxisome proliferator-activated receptor γ (PPARγ) is a key regulator of metabolism, adipokines production and secretion. The aim of this study was to investigate the association between the PPARγ2 gene Pro12Ala polymorphism in obesity in terms of body mass index (BMI), lipid parameters, homeostasis model assessment of insulin resistance (HOMA-IR), serum lipid, leptin, adiponectin, resistin and chemerin levels. The study included 160 obese and 140 non obese subjects. The Pro12Ala polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Serum lipid, leptin, adiponectin, resistin and chemerin levels were measured. No association was found between the Pro12Ala polymorphism and BMI. Strikingly, in the study group, obese subjects with the AA genotype had significantly higher triglycerides (p = 0.046) and resistin (p <0.001) levels than those with the wild-type PP and heterozygous PA genotypes. Serum leptin and chemerin levels were significantly associated with Pro-12Ala poymorphism in the obese and non obese groups (p <0.01). In the obese group, subjects with the homozygous AA genotype had significantly lower adiponectin (p = 0.010) activity than the PP genotype. Our results suggest that the PPARγ2 gene Pro12Ala polymorphism has no direct association with obesity but does have significant influences on lipid profiles and adipokines levels. PMID:28924543

  3. Effect of the Pro12Ala Polymorphism of the Peroxisome Proliferator-activated Receptor γ2 Gene on Lipid Profile and Adipokines Levels in Obese Subjects.

    PubMed

    Becer, E; Çırakoğlu, A

    2017-06-30

    Peroxisome proliferator-activated receptor γ (PPARγ) is a key regulator of metabolism, adipokines production and secretion. The aim of this study was to investigate the association between the PPARγ2 gene Pro12Ala polymorphism in obesity in terms of body mass index (BMI), lipid parameters, homeostasis model assessment of insulin resistance (HOMA-IR), serum lipid, leptin, adiponectin, resistin and chemerin levels. The study included 160 obese and 140 non obese subjects. The Pro12Ala polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Serum lipid, leptin, adiponectin, resistin and chemerin levels were measured. No association was found between the Pro12Ala polymorphism and BMI. Strikingly, in the study group, obese subjects with the AA genotype had significantly higher triglycerides (p = 0.046) and resistin (p <0.001) levels than those with the wild-type PP and heterozygous PA genotypes. Serum leptin and chemerin levels were significantly associated with Pro-12Ala poymorphism in the obese and non obese groups (p <0.01). In the obese group, subjects with the homozygous AA genotype had significantly lower adiponectin (p = 0.010) activity than the PP genotype. Our results suggest that the PPARγ2 gene Pro12Ala polymorphism has no direct association with obesity but does have significant influences on lipid profiles and adipokines levels.

  4. The Pro12Ala Polymorphism of the Peroxisome Proliferator-Activated Receptor Gamma Gene Modifies the Association of Physical Activity and Body Mass Changes in Polish Women.

    PubMed

    Zarebska, Aleksandra; Jastrzebski, Zbigniew; Cieszczyk, Pawel; Leonska-Duniec, Agata; Kotarska, Katarzyna; Kaczmarczyk, Mariusz; Sawczuk, Marek; Maciejewska-Karlowska, Agnieszka

    2014-01-01

    Peroxisome proliferator-activated receptor γ is a key regulator of adipogenesis, responsible for fatty acid storage and maintaining energy balance in the human body. Studies on the functional importance of the PPARG Pro12Ala polymorphic variants indicated that the observed alleles may influence body mass measurements; however, obtained results were inconsistent. We have decided to check if body mass changes observed in physically active participants will be modulated by the PPARG Pro12Ala genotype. The genotype distribution of the PPARG Pro12Ala allele was examined in a group of 201 Polish women measured for selected body mass variables before and after the completion of a 12-week training program. The results of our experiment suggest that PPARG genotype can modulate training-induced body mass measurements changes: after completion of the training program, Pro12/Pro12 homozygotes were characterised by a greater decrease of body fat mass measurements in comparison with 12Ala allele carriers. These results indicate that the PPARG 12Ala variant may impair the training-induced positive effects on body mass measurements; however, the detailed mechanism of such interaction remained unclear and observed correlation between PPARG genotype and body mass differential effects should be interpreted with caution.

  5. Peroxisome proliferator-activated receptor γ Pro12Ala polymorphism decrease the risk of diabetic nephropathy in type 2 diabetes: a meta analysis.

    PubMed

    Ding, Jiarong; Zhu, Chao; Mei, Xiaobin; Zhou, Yangyang; Feng, Bing; Guo, Zhiyong

    2015-01-01

    The association between peroxisome proliferators-activated receptor γ (PPARγ) Pro12Ala polymorphism and T2DN risk is inconclusive and contradictory. Therefore, we performed a meta-analysis. All relevant studies were searched by using the PubMed and EMBASE. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated. Effect model selection was on the basis of heterogeneity test. A total of 20 case-control studies with 9357 subjects were included in this meta-analysis. We found that PPARγ Pro12Ala polymorphism significantly associated with decreased T2DN risk (OR = 0.74; 95% CI 0.59-0.94; P = 0.01). In the subgroup analysis by race, Caucasian with PPARγ Pro12Ala polymorphism showed decreased T2DN risk (OR = 0.63; 95% CI 0.46-0.88; P = 0.006). But Asian with PPARγ Pro12Ala polymorphism did not show decreased T2DN risk (OR = 0.87; 95% CI 0.62-1.22; P = 0.41). In conclusion, our meta-analysis study confirmed that PPARγ Pro12Ala polymorphism might contribute to the risk for T2DN.

  6. Peroxisome proliferator-activated receptor γ Pro12Ala polymorphism decrease the risk of diabetic nephropathy in type 2 diabetes: a meta analysis

    PubMed Central

    Ding, Jiarong; Zhu, Chao; Mei, Xiaobin; Zhou, Yangyang; Feng, Bing; Guo, Zhiyong

    2015-01-01

    Background: The association between peroxisome proliferators-activated receptor γ (PPARγ) Pro12Ala polymorphism and T2DN risk is inconclusive and contradictory. Therefore, we performed a meta-analysis. Methods: All relevant studies were searched by using the PubMed and EMBASE. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated. Effect model selection was on the basis of heterogeneity test. Results: A total of 20 case-control studies with 9357 subjects were included in this meta-analysis. We found that PPARγ Pro12Ala polymorphism significantly associated with decreased T2DN risk (OR = 0.74; 95% CI 0.59-0.94; P = 0.01). In the subgroup analysis by race, Caucasian with PPARγ Pro12Ala polymorphism showed decreased T2DN risk (OR = 0.63; 95% CI 0.46-0.88; P = 0.006). But Asian with PPARγ Pro12Ala polymorphism did not show decreased T2DN risk (OR = 0.87; 95% CI 0.62-1.22; P = 0.41). Conclusions: In conclusion, our meta-analysis study confirmed that PPARγ Pro12Ala polymorphism might contribute to the risk for T2DN. PMID:26221313

  7. Revisiting the ALA/N (alpha-lipoic acid/low-dose naltrexone) protocol for people with metastatic and nonmetastatic pancreatic cancer: a report of 3 new cases.

    PubMed

    Berkson, Burton M; Rubin, Daniel M; Berkson, Arthur J

    2009-12-01

    The authors, in a previous article, described the long-term survival of a man with pancreatic cancer and metastases to the liver, treated with intravenous alpha-lipoic acid and oral low-dose naltrexone (ALA/N) without any adverse effects. He is alive and well 78 months after initial presentation. Three additional pancreatic cancer case studies are presented in this article. At the time of this writing, the first patient, GB, is alive and well 39 months after presenting with adenocarcinoma of the pancreas with metastases to the liver. The second patient, JK, who presented to the clinic with the same diagnosis was treated with the ALA/N protocol and after 5 months of therapy, PET scan demonstrated no evidence of disease. The third patient, RC, in addition to his pancreatic cancer with liver and retroperitoneal metastases, has a history of B-cell lymphoma and prostate adenocarcinoma. After 4 months of the ALA/N protocol his PET scan demonstrated no signs of cancer. In this article, the authors discuss the poly activity of ALA: as an agent that reduces oxidative stress, its ability to stabilize NF(k)B, its ability to stimulate pro-oxidant apoptosic activity, and its discriminative ability to discourage the proliferation of malignant cells. In addition, the ability of lowdose naltrexone to modulate an endogenous immune response is discussed. This is the second article published on the ALA/N protocol and the authors believe the protocol warrants clinical trial.

  8. Delta-ALA-D inhibitory potential and protective action of Syzygium jambos and Solanum guaraniticum leaf extracts on oxidatively stressed erythrocytes.

    PubMed

    Bonfanti, Gabriela; Bona, Karine Santos De; Lucca, Leidiane de; Jantsch, Leticia; Pigatto, Aline Schirmer; Boligon, Aline A; Athayde, Margareth L; Moretto, Maria Beatriz; Gonçalves, Thissiane de Lima

    2014-09-01

    This study aimed to investigate the effect of the leaf extracts of Syzygium jambos and Solanum guaraniticum on the δ-aminolevulinate dehydratase (δ-ALA-D) activity, their antioxidant activity and potential protective action on oxidatively stressed erythrocytes, in order to demonstrate the safety or toxicity of the plant. In erythrocyte samples, the effect of both extracts on δ-ALA-D activity, H2O2-induced oxidative stress, and 2,2'azobis (2-amidinopropane) (AAPH)-induced hemolysis was evaluated, as well as some antioxidant mechanisms. Both extracts inhibited δ-ALA-D activity (S. guaraniticum > S. jambos), and an involvement of the zinc ion of the δ-ALA-D structure on the inhibition of enzyme activity was verified. S. jambos leaf extract showed marked efficiency in countering H2O2-induced lipid peroxidation and in maintaining cellular integrity against AAPH-induced hemolysis. Furthermore, S. jambos exhibited greater H2O2 scavenging activity and stronger reduction power than S. guaraniticum. Both extracts bear potent antioxidant property as an important beneficial effect. However, the inhibition of δ-ALA-D activity suggests a possible harmful effect of these vegetal preparations and indicates the need for further investigation regarding their toxicological properties. All together, these data represent a significant contribution to the knowledge of these plants, both to the scientific community and t