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onsdag 22 januari 2025

Missä farmakologisissa tuotteissa voi piillä gluteenia? Farmakologin vihjelinkki Virginiasta

 https://med.virginia.edu/ginutrition/wp-content/uploads/sites/199/2015/12/PlogstedArticle.pdf

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söndag 19 januari 2025

Serotoniini-hermovälittäjäainejärjestelmän suhde neuronaaliin excitotoksisuuteen ja mitokondriatasoon ?

 https://pmc.ncbi.nlm.nih.gov/articles/PMC6561197/

Mechanistically, the effects of 5-HT were mediated via the 5-HT2A receptor and master modulators of mitochondrial biogenesis, SIRT1 and PGC-1α.

 SIRT1 was required to mediate the effects of 5-HT on Mitochondrial function is also enhanced by 5-HT, increasing cellular respiration and ATP, the energy currency of the cell. 

We found 5-HT reduces cellular reactive oxygen species and exerts potent neuroprotective action in neurons challenged with stress, an effect that requires SIRT1.

 These findings highlight a role for the mitochondrial effects of 5-HT in the facilitation of stress adaptation and identify drug targets to ameliorate mitochondrial dysfunction in neurons.mitochondrial biogenesis and function in cortical neurons. 

In cortical neurons, 5-HT enhanced expression of antioxidant enzymes, decreased cellular reactive oxygen species, and exhibited neuroprotection against excitotoxic and oxidative stress, an effect that required SIRT1. 

 

 

(Kommentti: excitotatiivit  aminohapot aivojen  funktiossa ovat  glutamiinihappo (E) ja aspartaatti (D). 

E ja D ovat  non-essentiellejä aminohappoja, jotka ovat  elämälle välttämättömiä kehon rakenneosia ja joita keho itse muodostaa. Glutamiinihappo muodostaa glutamiinia Q) sitomalla ammoniuma, joka on pienessäkin määrin myrkyllinen aivolle (esim maksakoomasa). Sitruunahapposklin alfaketoglutaarihappo  on lähde josta muodostuu glutamiinhappoa, joka  rikstuu  glutamiiniksi. Palautuessan glutamiini vapauttaa  "ilmaista"  sidosenergiaa energiaa synteeseihin neuroneissa. GABA on  pääteuote nhibitoriosessa neuronissaja  GLU excitatorisessa neuronissa. 

Ilmeisen tärkeä säätelevä osuus serotonergisellä neuronilla näiden perustavien  järjestelmien  takasäätelijänä viitaisi siihen, että ei  ehkä tarpeeksi edes osata suojata serotonergistä  haermojärjestelmää. Esim  huumeiden käytössä purkaantuu serotonergisistä hermoista välittäjäaineita. Niiden uudelleen muodostuminen  kestää aikaa ja vaikuttaa mielialaan ja unensaantiin cirkadiseen järjestelmään. Serotonergisen järjstelmän toipuminen vaatii kuukausia. jo ne vielä ovat  korjattavissa. Yleensä hoidetaan sekundaaisia  seikkoja kuten  unettomuutta tai määritteleätönä  kivuliaisuutta tai  pahaaoloa  (kipufiltterijärjestelmä aivotasossa  heikkenee, jos serotoniinijärjestelmä  on häiriösså. Tavallisen ruoan, raikkaa nilman , huumeita  pidättymisen ja  alkoholin kohtuullisen käytön tai  jopa raittiuden , säännöllisen unen  merkitys on  suuri  tämän  serotonihermosto tukemisessa.


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Miksi tässä yhteydessä  Gluteeni-blogi?

Arvelen että  gluteeni-intolerantikoilla jää kiertelemään  kehoon  haitallisia  antigeenisiä PQQP, QQQP tms pätkiä   pilkkoutumattomia dipeptidejä   tai  vasta.aineita  ja  ne tavalla tai toisella  vahingoittavat niitä elimiä joissa toimii  tämä a-KG-Glu, Gln, Gamma-Aminovoihappo (Gaba),OH-voihappo, meripihakahapposemialdehydi, alfa-ketoglutaarihappo (alfa-KG)- Glu- aineenvaihdunnallinen  sykli. kylkiäisena  tavalliselle  hyvin toiminalle sitruunahapposyklille mitokondriamaailmassa ja  osin sytoplasmassa.   Sellaisia elimiä aivojen lisäksi on Beta-saarekesolu haimassa ja munuainen. 

Niisä kohdissa kehoa, missä on huippu-nanotekniikan maailman tapahtumia, saadaan  sidosenergian purkautumisesta Gln glutamiinsita  Glu lutamaatiksi se tarvitava  reaktioenergia. Siis Glu ja Gln niiden täytyy pystyä toimiaan  erillisinä,  integroituina   eikä klimmeinä, jotia aggrekaatit ja vasa-aineet  haittaavat.  Tässä on avuksi  vähentää  gluteenin syömistä, kaikkien, ei vain niiden jotaka kuolisivat gluteeniin. Sen takai gluteeniton dieeti  tarjotaanusein mahdollisuutena  monenlaisen vaivan  hhoitoon, kun ei  selvää  hoitokohdemolekyyliä tai järjestelmää edes tunneta.  Asia ei anna heti  imitään tulsota muta  joissain viikoissa, kuukausisa tai vuosissa  voi havaita tapahtuvan  jotain  kohentumista kehon rakenteissa.  esim iho saatta  olla tervempi, haavat paraneva nopeammin,  suoli on joostavampi,  hmm-  tähän menisi kai aika jos kaikkea  kohenemista  gfd-dieetistä kertoo. 

Veri pysyy paremmin koossa, verisuonet eivät itsestään pirstoudu mustelmille. ym ym.

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Toiset muunta vehnän gliadiinigeeniä, toiset taas vehnän excitatorisen aminohapon Glu (E/Q) rakennetta . Toiset tekevät vahvempaa gluteenia, rehua.

 Glu  in gluten

19 results

Enhancing growth, liver health, and bile acid metabolism of tilapia (Oreochromis niloticus) through combined cholesterol and bile acid supplementation in plant-based diets.
Jiang J, Lu X, Dong L, Tian J, Zhang J, Guo Z, Luo Y, Cui Z, Wen H, Jiang M. Anim Nutr. 2024 Mar 8;17:335-346. doi: 10.1016/j.aninu.2024.03.001. eCollection 2024 Jun. PMID: 38800736 Free PMC article.
The isonitrogenous (321 g/kg crude protein) and isolipidic (76 g/kg crude fat) diets (Con diet) were based on plant protein sources, which included corn gluten meal, soybean meal, cottonseed meal and rapeseed meal. The Con diet was supplemented with 12 g/kg cholesterol (CH …
Absence of Dx2 at Glu-D1 Locus Weakens Gluten Quality Potentially Regulated by Expression of Nitrogen Metabolism Enzymes and Glutenin-Related Genes in Wheat.
Song L, Li L, Zhao L, Liu Z, Xie T, Li X. Int J Mol Sci. 2020 Feb 18;21(4):1383. doi: 10.3390/ijms21041383. PMID: 32085665 Free PMC article.
Absence of high-molecular-weight glutenin subunit (HMW-GS) Dx2 weakens the gluten quality, but it is unclear how the absence of Dx2 has these effects. Thus, we investigated the gluten quality in terms of cytological, physicochemical, and transcriptional characterist …
Wheat Gluten Amino Acid Analysis by High-Performance Anion-Exchange Chromatography with Integrated Pulsed Amperometric Detection.
Rombouts I, Lagrain B, Lamberts L, Celus I, Brijs K, Delcour JA. Methods Mol Biol. 2019;2030:381-394. doi: 10.1007/978-1-4939-9639-1_28. PMID: 31347132
The present chapter describes an accurate and user-friendly method for determining amino acid composition of wheat gluten proteins and their gliadin and glutenin fractions. The method consists of hydrolysis of the peptide bonds in 6.0 M hydrochloric acid (HCl …
Deletion of the low-molecular-weight glutenin subunit allele Glu-A3a of wheat (Triticum aestivum L.) significantly reduces dough strength and breadmaking quality.
Zhen S, Han C, Ma C, Gu A, Zhang M, Shen X, Li X, Yan Y. BMC Plant Biol. 2014 Dec 19;14:367. doi: 10.1186/s12870-014-0367-3. PMID: 25524150 Free PMC article.
The Glu-A3a-encoded B-subunit showed a higher expression level and accumulation rate during grain development. These characteristics of the Glu-A3a allele could contribute to achieving superior gluten quality and demonstrate its potential application t …
Whey protein delays gastric emptying and suppresses plasma fatty acids and their metabolites compared to casein, gluten, and fish protein.
Stanstrup J, Schou SS, Holmer-Jensen J, Hermansen K, Dragsted LO. J Proteome Res. 2014 May 2;13(5):2396-408. doi: 10.1021/pr401214w. Epub 2014 Apr 21. PMID: 24708224 Clinical Trial.
In contrast to previous studies, the WI meal caused a decreased rate of gastric emptying compared to the other test meals. The WI meal also caused elevated levels of a number of amino acids, possibly stimulating insulin release leading to reduced plasma glucose. The …
Wheat gluten amino acid analysis by high-performance anion-exchange chromatography with integrated pulsed amperometric detection.
Rombouts I, Lagrain B, Lamberts L, Celus I, Brijs K, Delcour JA. Methods Mol Biol. 2012;828:329-37. doi: 10.1007/978-1-61779-445-2_26. PMID: 22125156
This chapter describes an accurate and user-friendly method for determining amino acid composition of wheat gluten proteins and their gliadin and glutenin fractions. The method consists of hydrolysis of the peptide bonds in 6.0 M hydrochloric acid solution at …
Wheat gluten amino acid composition analysis by high-performance anion-exchange chromatography with integrated pulsed amperometric detection.
Rombouts I, Lamberts L, Celus I, Lagrain B, Brijs K, Delcour JA. J Chromatogr A. 2009 Jul 17;1216(29):5557-62. doi: 10.1016/j.chroma.2009.05.066. Epub 2009 Jun 3. PMID: 19523641
Gradient conditions including an extra eluent (0.1M acetic acid solution) allowed multiple sequential sample analyses without risk of Glu contamination on the anion-exchange column. While gluten amino acid compositions by the present method were mostly …
Characterization of novel LMW-GS genes at Glu-D3 locus on chromosome 1D in Aegilops tauschii.
Zhao X, Yang Y, He Z, Lei Z, Ma W, Sun Q, Xia X. Hereditas. 2008 Oct;145(5):238-50. doi: 10.1111/j.1601-5223.2008.02046.x. PMID: 19076692 Free article.
The objectives of this study were to clarify the relationship between LMW-GS Glu-D3 gene of Ae. tauschii registered in GenBank and the six Glu-D3 genes including 12 allelic variants of common wheat characterized in our previous studies, and identify novel Glu …
Plant promoter driven heterologous expression of HMW glutenin gene(s) subunit in E. coli.
Pandey R, Mishra A, Garg GK. Mol Biol Rep. 2008 Jun;35(2):153-62. doi: 10.1007/s11033-007-9065-7. Epub 2007 Mar 23. PMID: 17380427
Probable secondary structure of HMW glutenin protein was predicted using online ExPASy server. HMW glu Dx5 and Dy10 gave significant similarity (more than 90%) to the available database but, 1Ax1 didn't show significant similarity. ...The transcription was confirmed by Rev …
Novel DNA variations to characterize low molecular weight glutenin Glu-D3 genes and develop STS markers in common wheat.
Zhao XL, Xia XC, He ZH, Lei ZS, Appels R, Yang Y, Sun QX, Ma W. Theor Appl Genet. 2007 Feb;114(3):451-60. doi: 10.1007/s00122-006-0445-5. Epub 2006 Nov 15. PMID: 17106734
The objectives of this study were to characterize Glu-D3 subunit coding genes and to develop molecular markers for identifying Glu-D3 gene haplotypes. ...These markers will be useful to identify the Glu-D3 gene haplotypes in wheat breeding programs....
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Haku "Hordein antibodies". Hordein on ohran prolamiini ja ohra taas kuuluu gluteeni muodostaviin viljoihin.

 

2,907 results

A randomized, double-blind, placebo-controlled, multiple dose, parallel study to investigate the effects of a cathepsin S inhibitor in celiac disease.
Bentley D, Mannino M, Manchester M, Teixeira PC, Reis B, Boyce M, Nagel S. Clin Transl Sci. 2025 Jan;18(1):e13901. doi: 10.1111/cts.13901. PMID: 39739628 Free PMC article. Clinical Trial.
Few participants had an increase in gliadin-specific, IFNgamma-secreting T cells, and the antigen-specific responses (anti-tTG and anti-DGP antibodies) were weaker than expected in both arms. Therefore, the primary end point was not met, although the study was underpowered …
What is the Role of Measuring Urinary Gluten Immunogenic Peptides in Clinical Practice in Patients with Coeliac Disease?
Raju SA, Ingham KE, Green O, Johnson CM, Shiha MG, Nandi N, Trott N, Penny HA, Hadjivassiliou M, Wild G, Sanders DS. J Gastrointestin Liver Dis. 2024 Dec 28;33(4):482-487. doi: 10.15403/jgld-5659. PMID: 39733322 Free article.
In our retrospective study, the results of the urinary gluten immunogenic peptide test collected within 7 days, self-reported adherence to a gluten free diet reported within 3 months, serology collected within 7 days (immunoglobulin A - tissue transglutaminase and endomysial a …
Anxiety and Depression Among Adults and Children With Celiac Disease: A Meta-Analysis of Different Psychiatry Scales.
Moawad MH, Serag I, Shalaby MM, Aissani MS, Sadeq MA, Hendi NI, Elawfi B, Ghorab RMF, Mostafa N, Ibrahim N, Abdelrhem HAH, Rady AHA, Alkasaby M. Psychiatr Res Clin Pract. 2024 Jul 12;6(4):124-133. doi: 10.1176/appi.prcp.20230076. eCollection 2024 Winter. PMID: 39669540 Free PMC article. Review.
BACKGROUND: Celiac disease (CD) is an autoimmune disorder in which genetically susceptible individuals cannot digest gluten (wheat) and its homologs such as Scalin (rye) and Hordein (barley). AIM: This systematic review and meta-analysis aimed to investigate the measures o …
[Assessment of tolerance of a new product (gluten-free grain snack) in children with food allergy to gluten].
Revyakina VA, Serba EM, Mukhortykh VA, Larkova IA, Kuvshinova ED, Dolzhenkova VG, Sharikov AY, Amelyakina MV. Vopr Pitan. 2024;93(4):104-111. doi: 10.33029/0042-8833-2024-93-4-104-111. Epub 2024 Jul 15. PMID: 39396221 Russian.
Clinical safety parameters were assessed based on the dynamics of complete blood count and blood immunological parameters (total IgE, specific IgE, and IgG4 antibodies to the studied allergens) at the beginning and end of the consumption period. ...In the results of clinic …
Detection of gluten peptides in human duodenal fluids with immuno-liquid chromatography-mass spectrometry.
Dayon L, Núñez Galindo A, Chevalier J, Aquarius M, Otten B, Troost FJ, Duncan P, Affolter M. Anal Methods. 2024 Oct 17;16(40):6819-6828. doi: 10.1039/d4ay00852a. PMID: 39264106
Thus, an initial immunoprecipitation (IP) step was included. Several antibodies were tested, and one proved reliable for the enrichment of the 33-mer gluten peptide as well as a few additional gluten peptides. ...
CRISPR/Cas9-mediated multiplex gene editing of gamma and omega gliadins: paving the way for gliadin-free wheat.
Sánchez-León S, Marín-Sanz M, Guzmán-López MH, Gavilán-Camacho M, Simón E, Barro F. J Exp Bot. 2024 Dec 4;75(22):7079-7095. doi: 10.1093/jxb/erae376. PMID: 39238167 Free PMC article.
The mutations were transmitted to the offspring, and the analysis of homozygous derived lines by reverse-phase HPLC and monoclonal antibodies showed a 97.7% reduction in gluten content. Crossing these lines with other CRISPR/Cas lines deficient in the alpha-gliadins allowe …
Gastrointestinal dysfunction in Parkinson's Disease: absence of anti-gliadin antibodies.
Sahbaz G, Tekol SD, Barut BO. Asia Pac J Clin Nutr. 2024 Dec;33(4):490-495. doi: 10.6133/apjcn.202412_33(4).0003. PMID: 39209358 Free PMC article.
BACKGROUND AND OBJECTIVES: Parkinson disease (PD), which is a neurodegenerative disorder, includes several gastrointestinal symptoms that are similar to those of Celiac disease (CD). However, the presence of celiac antibodies in PD patients has not yet been studied. Our ai …
2,907 results
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lördag 23 november 2024

Lasten diagnosoimattomasta tai hoitamattomasta keliakiasta tulevaista ongelmaa

  Hakusana: Gene  behind NALFD? ( Yksinkertainen oire NAFLD taudista, nonalkoholiesta rasvamaksataudista, on rasvaripuli (steatorrhea) , kelluvat  ulosteet ja ulosteioden  epätavallinen väri ja  hajukin riippuen  suolistn biomin  tilasta ja  maksantoiminansta.  Aikuisten NAFLD Review PubMed lätheessä antaa yli 10 100 artikkelia ja uusimmat ovat aivan tältä kuulta vuonna 2024.

. 2022 Nov 11;20(1):440.
doi: 10.1186/s12916-022-02635-3.

Intestinal gluconeogenesis is downregulated in pediatric patients with celiac disease

Olof Karlson  1 , Henrik Arnell  2   3 , Audur H Gudjonsdottir  4 , Daniel Agardh  5 , Åsa Torinsson Naluai  6
Affiliations
Abstract

Background: Untreated celiac disease (CD) patients have increased levels of blood glutamine and a lower duodenal expression of glutaminase (GLS). Intestinal gluconeogenesis (IGN) is a process through which glutamine is turned into glucose in the small intestine, for which GLS is crucial. Animal studies suggest impaired IGN may have long-term effects on metabolic control and be associated with the development of type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). The aim of this study was to thoroughly investigate IGN at the gene expression level in children with untreated celiac disease.

Methods: Quantitative polymerase chain reaction (qPCR) was used to quantify the expression of 11 target genes related to IGN using the delta-delta Ct method with three reference genes (GUSB, IPO8, and YWHAZ) in duodenal biopsies collected from 84 children with untreated celiac disease and 58 disease controls.

Results: Significantly lower expression of nine target genes involved in IGN was seen in duodenal biopsies from CD patients compared with controls: FBP1, G6PC, GLS, GPT1, PCK1, PPARGC1A, SLC2A2, SLC5A1, and SLC6A19. No significant difference in the expression was observed for G6PC3 or GOT1.

Conclusions: Children with untreated celiac disease have lower expression of genes important for IGN. Further studies are warranted to disentangle whether this is a consequence of intestinal inflammation or due to an impaired metabolic pathway shared with other chronic metabolic diseases. Impaired IGN could be a mechanism behind the increased risk of NAFLD seen in CD patients.

Keywords: Celiac disease; Gluten; Non-alcoholic fatty liver disease; intestinal gluconeogenesis.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no competing interests.

 


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måndag 12 juni 2023

Katson geeneistä PREP ja PREPL jotain niiden vaikutuksista.

Tämä on vasta bulk-alkuhakua. Katson ajan mittaan vähän vähemmäksi tämän artikkelin  sisällön. Kyse on prolyyliä pilkkova entsyymi. se pilkkoo oligopeptidin C_terminaalista. PREPL ei pilko   arginiinin tai lysiinin jälkeen (R tai K)  ja se on muutenkin  erilainen hieman rakennepiirteiltään, kuten esim  sisältää runsaasti  cysteinejä (C) ihan  riittäisi sinkkisormeksikin ja rakenne on miltei  puolipropellinen.  Toimivatkohan nuo peräkanaa?

 

(*) TÄSTÄ KIRJOITTAA DUODECIM  11/23

Katson GENECARDS lähteestä : “PREP” ja sen jälkeen PREP

Tekstit mainitsevat että se jollain tavalla osallistuu inositolin aineenvaihduntaan, joten katson tarkemmin. Lisäksi se puuttuu QPPAQP etc. sisältävien peptidien pilkkoutumiseen. Joita uodostuss gluteenipitoisesta ravinnosta. Huomaan että se on selektiivisesstio peptidien C-terminaalisen proliinin pilkkoja ja tuotaa oligopeptidilopputuotteita eikä esim. erillisiä proliineja tai erillisiäaminohappoja. Sen rakenteessa ei näy tavallisia Znf sinkkisormimahdollisuuksia. Se on aika järjestäytynyt beetanauhojensa ja alfahelixiensä suhteen.Se ei vaikuta suoraan sigannlivälittäjään IP3 itse vaan sen kinaasisäätelyjärjestelmään, joka on saateaa olla laaja. Siitä tietoisuus on kasvanut nyt vuosituhannen vaihteen jälkeen.

* HAKU GENE CARDS “PREP Showing 25 of 2,755 results for PREP Search Time: 0 ms.

PREP (6q21).  Prolyl oligoendopeptidases                    GENECARDS haku 12.6. 2023 .

Aliases for PREP Gene

  • GeneCards Symbol: PREP 2

  • Prolyl Endopeptidase 2 3 4 5

  • Post-Proline Cleaving Enzyme 3 4

  • Prolyl Oligopeptidase 2 3

  • EC 3.4.21.26 4 48

  • PEP 3 4

  • PE 3 4

  • DJ355L5.1 (Prolyl Endopeptidase) 3

The protein encoded by this gene is a cytosolic prolyl endopeptidase that cleaves peptide bonds on the C-terminal side of prolyl residues within peptides that are up to approximately 30 amino acids long. Prolyl endopeptidases have been reported to be involved in the maturation and degradation of peptide hormones and neuropeptides. [provided by RefSeq, Jul 2008]

GeneCards Summary for PREP Gene: PREP (Prolyl Endopeptidase) is a Protein Coding gene. Diseases associated with PREP include Amnestic Disorder and Post-Traumatic Stress Disorder. Gene Ontology (GO) annotations related to this gene include serine-type endopeptidase activity and serine-type exopeptidase activity. An important paralog of this gene is PREPL. 

  UniProtKB/Swiss-Prot Summary for PREP Gene: Cleaves peptide bonds on the C-terminal side of prolyl residues within peptides that are up to approximately 30 amino acids long. ( PPCE_HUMAN,P48147 )

Show:



Symbol

Description

Category

UniProt ID

GIFtS

GC id

Score ▼

1

PREP

Prolyl Endopeptidase

Protein Coding

P48147

49

GC06M105277

43.35
  • Header
  • Symbol: PREP
    • Publications (5/19) See All
    • Prolyl oligopeptidase enhances α-synuclein...protein-protein interaction. (PMID: 25555914)
      Abstract:
      ...oligopeptidase (PREP) accelerates the aggregation of α-synuclein (aSyn)...of Parkinson disease and other synucleinopathies. PREP inhibitors reduce aSyn aggregation, but the mechanism...microscale thermophoresis in parallel to show that PREP interacts directly with aSyn in both intact cells...split luciferase-based PCA, we first showed that PREP enhances the formation of soluble aSyn dimers in live Neuro-2A neuroblastoma cells. A PREP inhibitor, KYP-2047, reduced aSyn dimerization in PREP-expressing cells but not in cells lacking PREP expression. aSyn dimerization was also enhanced by PREP(S554A), an enzymatically inactive PREP mutant, but this was not affected by KYP-2047. PCA...thermophoresis studies showed that aSyn interacts with both PREP and PREP...
    • Prolyl oligopeptidase inhibition reduces...phosphatase 2A. (PMID: 33838285)
      Abstract:
      ...oligopeptidase (PREP) is a serine protease that is linked to neurodegeneration, as endogenous PREP inhibits autophagy and induces the accumulation of...detrimental protein aggregates. As such, inhibition of PREP by a small-molecular inhibitor has provided neuroprotection...models of neurodegenerative diseases. In addition, PREP inhibition has been shown to reduce production of...reactive oxygen species (ROS) and the absence of PREP blocks stress-induced ROS production. However, the mechanism behind PREP-related ROS regulation is not known. As we recently discovered PREP's physiological role as a protein phosphatase 2A (PP2A) regulator, we wanted to characterize PREP inhibition as an approach to reduce OS. We studied the impact of a PREP inhibitor, KYP-2047, on hydrogen peroxide and ferrous...and SH-SY5Y cells. In addition, we used HEK-2...
    • Distribution of prolyl oligopeptidase in...colorectal tumors. (PMID: 22740343)
      Abstract:
      ...oligopeptidase (PREP) is a serine protease that hydrolyzes peptides shorter...multiple physiological and pathological conditions. PREP has been mostly studied in the brain, but significant PREP activities have been measured in peripheral tissues. Moreover, increased PREP activities have been found in tumors. In this study...authors studied the immunohistochemical distribution of PREP protein in human peripheral tissues and in ovarian and colorectal tumors. PREP was found to be widely distributed in human peripheral...and specifically in certain cells. The most intense PREP expression was seen in the testis, ovaries, liver...some parts of the skin. At the cellular level, high PREP levels were seen as a rule in secreting epithelial...cells and cells involved in reproduction. Increased PREP expression was seen in most of the tumors studied. PREP expression was high...
    • (x) Prolyl oligopeptidase inhibition activates...phosphatase 2A. (PMID: 31759088)
      Abstract:

    • Prolyl endopeptidase is involved in cellular...SH-SY5Y cells. (PMID: 21487212)
      Abstract:
      Prolyl endopeptidase (PREP), probably acting through the inositol cycle, has been implicated in memory and learning. However, the physiological role of PREP is unknown. It has been shown that PREP expression, regulated in cerebellar granule cells...report the levels and subcellular distribution of PREP in human neuroblastoma SH-SY5Y cells in proliferating conditions and under differentiation induced by retinoic acid (RA). We analysed the levels of cell signalling intermediates, growth behavior and gene expression, and differentiation morphology changes, upon PREP inhibition. After induction of differentiation,PREP activity was found decreased in the nucleus but increased to high levels in the cytoplasm, due in part to increased PREP transcription. The levels of inositol (1,4,5)-trisphosphate revealed no correlation with PREP activity, but phosphorylated extracellular signal-regulated kinases 1 and 2 were decreased by PREP inhibition during early stages of differentiation. Morphological evaluation indicated that PREP inhibition retarded the onset of differentiation. PREP activity regulated gene expression of protein synthesis machinery, intracellular transport and kinase complexes. We conclude that PREP is a regulatory target and a regulatory element in cell signalling. This is the first report of a direct influence of a cell signalling molecule, RA, on PREP expression.
    Function
    Phenotypes (5/10) See All
    • homeostasis/metabolism phenotype: Alleles: Prep PrepGt(RRM213)Byg / Prep Preptm1b(KOMP)Wtsi - MP:0005376
    • behavior/neurological phenotype: Alleles: Prep Preptm1b(KOMP)Wtsi / Prep Preptm1Dgen - MP:0005386
    • renal/urinary system phenotype: Alleles: Prep PrepGt(RRM213)Byg - MP:0005367
    • liver/biliary system phenotype: Alleles: Prep PrepGt(RRM213)Byg - MP:0005370
    • adipose tissue phenotype: Alleles: Prep PrepGt(RRM213)Byg - MP:0005375

    (x)  Pharmacol Res

    • 2020 Jan;151:104558. doi: 10.1016/j.phrs.2019.104558. Epub 2019 Nov 20.Prolyl oligopeptidase inhibition activates autophagy via protein phosphatase 2A Reinis Svarcbahs  1 , Maria Jäntti  1 , Tommi Kilpeläinen  1 , Ulrika H Julku  1 , Lauri Urvas  1 , Saara Kivioja  1 , Susanna Norrbacka  1 , Timo T Myöhänen  DOI: 10.1016/j.phrs.2019.104558 
    • Abstract. Prolyl oligopeptidase (PREP) is a serine protease that has been studied particularly in the context of neurodegenerative diseases for decades but its physiological function has remained unclear. We have previously found that PREP negatively regulates beclin1-mediated macroautophagy (autophagy), and that PREP inhibition by a small-molecule inhibitor induces clearance of protein aggregates in Parkinson's disease models. Since autophagy induction has been suggested as a potential therapy for several diseases, we wanted to further characterize how PREP regulates autophagy. We measured the levels of various kinases and proteins regulating beclin1-autophagy in HEK-293 and SH-SY5Y cell cultures after PREP inhibition, PREP deletion, and PREP overexpression and restoration, and verified the results in vivo by using PREP knock-out and wild-type mouse tissue where PREP was restored or overexpressed, respectively. We found that PREP regulates autophagy by interacting with protein phosphatase 2A (PP2A) and its endogenous inhibitor, protein phosphatase methylesterase 1 (PME1), and activator (protein phosphatase 2 phosphatase activator, PTPA), thus adjusting its activity and the levels of PP2A in the intracellular pool. PREP inhibition and deletion increased PP2A activity, leading to activation of death-associated protein kinase 1 (DAPK1), beclin1 phosphorylation and induced autophagy while PREP overexpression reduced this. Lowered activity of PP2A is connected to several neurodegenerative disorders and cancers, and PP2A activators would have enormous potential as drug therapy but development of such compounds has been a challenge. The concept of PREP inhibition has been proved safe, and therefore, our study supports the further development of PREP inhibitors as PP2A activators.Keywords: Alzheimer’s disease; Bafilomycin A1 (PubChem CID: 6436223); FTY-720 (fingolimod, PubChem CID: 107970); KYP-2047 (PubChem CID: 11198569); Neurodegeneration; Okadaic acid (PubChem CID: 446512); PP242 (PubChem CID: 135565635); Parkinson’s disease; Protein phosphatase 2 phosphatase activator; Protein phosphatase methylesterase 1; Rapamycin (sirolimus, PubChem CID: 5284616); Serine protease. Copyright © 2019 Elsevier Ltd. All rights reserved.

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    The strategy for interpreting the role of autophagy on the basis of evidence obtained through autophagic inhibition sounds logical, but is beset with practical constraints. The knock down of autophagy-related (ATG) gene(s) or blockage of class III PI3-Kinase are the most common approaches for inhibiting autophagy. However, during stressful conditions, autophagy may operate in synchrony with other processes such as apoptosis; autophagy-related genes, unlike what their name implies, exert their regulation on apoptosis as well. Knocking down such genes not only blocks autophagy but also renders apoptosis defective, making the interpretation of autophagic roles unreliable. Similarly, class III PI3-Kinase aids in initiating autophagy but it is not a quintessential autophagic regulator. Class III PI3-Kinase also has a role in regulating almost all membrane transport in cells. Blocking it not only inhibits autophagy, but also hampers all the membrane trades, including endosomal transport. The pharmacological inhibitors used to block autophagy by blocking class III PI3-Kinase further compound these limitations with their off-target effects. Knowing the limitations involved in blocking a target or using an autophagy-blocking tool is a prerequisite for designing the experiments meant for analyzing autophagic functions. This review attempts to provide a detailed overview about the practical constraints involved in using autophagic inhibition as a strategy to understand autophagy.Keywords: 3-Methyladenine; 3-Methyladenine (PubChem CID: 1673); Ammonium chloride (PubChem CID: 25517); Apoptosis; Atg5; Autophagy; Bafilomycin A1 (PubChem CID: 6436223); Beclin1; Chloroquine (PubChem CID: 2719); E64d (PubChem CID: 393035); KU55933 (PubChem CID: 5278396); Monensin (PubChem CID: 28263); Wortmannin (PubChem CID: 312145). Copyright © 2014 Elsevier Ltd. All rights reserved.

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    (*) Toinen HAKU “PREPL”(2p21)

    Selected DME Specific Peptides for PREP Gene

    P48147:
    • KQHFEWL
    • LCAEFPDEPKWMGGAELSDDGRYVLLSI
    • TNEGTVFTFKTNR
    • VFREVTVKGIDA
    • AYGLSASGSDWVTIKFMKVDGAKEL
    • TKIPMFI
    • IYHCDLTKEELEP
    • NQRPDLF
    • RGGGEYG
    • GGSNGGLL
    • GILKWVKLIDNFEGEYDY
    • FKKGKRYFYFYNTGLQNQRVLYVQDSLEGEARV
    • QDYHGHK
    • EIFYQFTSFLSPG
    • TIGHAWTTDYGCSD
    • AAEYLIKE
    • YPQQDGKSDGTETSTNLHQKL
    • YHGHKICDPY
    • TGALLKTFPL
    • YGGFNIS
    • KYSPLHNVKLPEADDIQYPSMLLLTADHDDRVVPLHS
    • VGVMDML
    • See less «

     

    b) ( PARALOG GENE Tässä paralogissa on useita cysteiinejä, rakenne on puoli propellimainen verattuna edelliseen ja se katsotaan solunsisäiseksi, osallistu retrogradisen suunnan liikutteluun. Endosomi Golgi, Golgi PM, ja lopulta Ja lopulta mm synaptisen vesikkelin erityksiin)

    Aliases for PREPL Gene 2p21.

    • GeneCards Symbol: PREPL 2

    • Prolyl Endopeptidase Like 2 3 5

    • Prolyl Endopeptidase-Like 2 3 4

    • KIAA0436 2 4 5

    • Putative Prolyl Oligopeptidase 3

    • Prolylendopeptidase-Like 4

    • EC 3.4.21.83 48

    • EC 3.4.21.- 4

    • EC 3.4.21 48

    • CMS22 3

    Gene Families for PREPL Gene

    IUPHAR :S9: Prolyl oligopeptidase

    Human Protein Atlas (HPA):

    • Disease related genes

    • Enzymes

    • Human disease related genes

    • Potential drug targets

    • Predicted intracellular proteins

    Protein Domains for PREPL Gene

    InterPro:

    Blocks:

    • Prolyl oligopeptidase serine protease (S9A) signature

    Suggested Antigen Peptide Sequences for PREPL Gene

    GenScript: Design optimal peptide antigens:

    • Prolylendopeptidase-like (PPCEL_HUMAN)

      Graphical View of Domain Structure for InterPro EntryQ4J6C6 UniProtKB/Swiss-Prot:PPCEL_HUMAN :

    • Belongs to the peptidase S9A family.

    Molecular function for PREPL Gene according to UniProtKB/Swiss-Prot

    Function:

    • Serine peptidase whose precise substrate specificity remains unclear (PubMed:16143824, 16385448, 28726805).
      Does not cleave peptides after a arginine (R)  or lysine (K) residue (PubMed:16143824).
      Regulates trans-Golgi network morphology and sorting by regulating the membrane binding of the AP-1 complex (PubMed:23321636).
      May play a role in the regulation of synaptic vesicle exocytosis (PubMed:24610330). PPCEL_HUMAN,Q4J6C6

    EnzymeRegulation:

    • Inhibited by PMSF and Prefabloc, as well as leupeptin at high concentrations (PubMed:16385448).
      Partially inhibited by TPCK, a chymotrypsin inhibitor and E64, a cysteine protease inhibitor (PubMed:16385448).
      Not affected by 4-amidinophenyl-methanesulfonyl fluoride (APMSF), pepstatin or EDTA (PubMed:16385448).
      Inhibited by 1-isobutyl-3-oxo-3,5,6,7-tetrahydro-2H-cyclopenta[c]pyridine-4-carbonitrile (PubMed:28726805). PPCEL_HUMAN,Q4J6C6

    Phenotypes for PREPL Gene MGI mutant phenotypes for PREPL:



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