Endopeptiaasivajeen korvausyritys ainakin syödyssä ravinnossa

 

Editorial

 

. 2024 Jul 14;30(26):3201-3205.

 doi: 10.3748/wjg.v30.i26.3201.

Digesting gluten with oral endopeptidases to improve the management of celiac disease

Katelin Durham 1, Mirac Nedim Ince 2

Affiliations 

• PMID: 39086640
 
• PMCID: PMC11287399
 
• DOI: 10.3748/wjg.v30.i26.3201

Abstract

In our editorial, we want to comment on the article by Stefanolo et al titled "Effect of Aspergillus niger prolyl endopeptidase in patients with celiac disease on a long-term gluten-free diet". Celiac disease is an immune-mediated disorder triggered by dietary gluten in genetically predisposed individuals. Although avoiding gluten can permit patients to live symptom-free, ongoing voluntary or involuntary exposure to gluten is common and associated with persistent villous atrophy in small bowel mucosa. As villous atrophy predisposes patients to life threatening complications, such as osteoporotic fractures or malignancies, therapeutic adjuncts to gluten-free diet become important to improve patients' quality of life and, if these adjuncts can be shown to improve villous atrophy, avoid complications. Oral administration of enzyme preparations, such as endopeptidases that digest gluten and mitigate its antigenicity to trigger inflammation, is one clinical strategy under investigation. The article is about the utility of one endopeptidase isolated from Aspergillus niger. We critique findings of this clinical trial and also summarize endopeptidase-based as well as other strategies and how they can complement gluten-free diet in the management of celiac disease.

Keywords: Adjunct therapy; Aspergillus niger; Celiac disease; Endopeptidase; Gluten-free diet; Villous atrophy.

©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.

PubMed Disclaimer

Conflict of inte

UBD

 

• This gene encodes a protein which contains two ubiquitin-like domains and appears to have similar function to ubiquitin. Through covalent attachment, the encoded protein targets other proteins for 26S proteasome degradation. This protein has been implicated to function in many cellular processes, including caspase-dependent apoptosis, formation of aggresomes, mitotic regulation, and dendritic cell maturation. Upregulation of this gene may promote inflammation in chronic kidney disease and has been observed in many cancer types. [provided by RefSeq, Aug 2017]

• UBD (Ubiquitin Like Modifier D) is a Protein Coding gene. Diseases associated with UBD include Kidney Disease and Chronic Kidney Disease. Among its related pathways are Metabolism of proteins and BRCA1 Pathway. Gene Ontology (GO) annotations related to this gene include proteasome binding. An important paralog of this gene is RPS27A.

• Ubiquitin-like protein modifier which can be covalently attached to target proteins and subsequently leads to their degradation by the 26S proteasome, in a NUB1-dependent manner (PubMed:15831455, 16707496, 19166848). Conjugation to the target protein is activated by UBA6 via adenylation of its C-terminal glycine (PubMed:17889673, 35970836). Promotes the expression of the proteasome subunit beta type-9 (PSMB9/LMP2). Regulates TNF-alpha-induced and LPS-mediated activation of the central mediator of innate immunity NF-kappa-B by promoting TNF-alpha-mediated proteasomal degradation of ubiquitinated-I-kappa-B-alpha (PubMed:19959714). Required for TNF-alpha-induced p65 nuclear translocation in renal tubular epithelial cells (RTECs). May be involved in dendritic cell (DC) maturation, the process by which immature dendritic cells differentiate into fully competent antigen-presenting cells that initiate T-cell responses (PubMed:19028597). Mediates mitotic non-disjunction and chromosome instability, in long-term in vitro culture and cancers, by abbreviating mitotic phase and impairing the kinetochore localization of MAD2L1 during the prometaphase stage of the cell cycle (PubMed:16495226). May be involved in the formation of aggresomes when proteasome is saturated or impaired (PubMed:19033385). Mediates apoptosis in a caspase-dependent manner, especially in renal epithelium and tubular cells during renal diseases such as polycystic kidney disease and Human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) (PubMed:16495380). ( UBD_HUMAN,O15205 )

• GeneCards Symbol: UBD 2 
• Ubiquitin Like Modifier D 2 3
• Ubiquitin D 2 3 4 5
• FAT10 2 3 4 5
• HLA-F Adjacent Transcript 10 2 3
• Ubiquitin-Like Protein FAT10 3 4
• Diubiquitin 3 4
• UBD-3 3

Function:

• Ubiquitin-like protein modifier which can be covalently attached to target proteins and subsequently leads to their degradation by the 26S proteasome, in a NUB1-dependent manner (PubMed:15831455, 16707496, 19166848).
  Conjugation to the target protein is activated by UBA6 via adenylation of its C-terminal glycine (PubMed:17889673, 35970836).
  Promotes the expression of the proteasome subunit beta type-9 (PSMB9/LMP2).
  Regulates TNF-alpha-induced and LPS-mediated activation of the central mediator of innate immunity NF-kappa-B by promoting TNF-alpha-mediated proteasomal degradation of ubiquitinated-I-kappa-B-alpha (PubMed:19959714).
  Required for TNF-alpha-induced p65 nuclear translocation in renal tubular epithelial cells (RTECs).
  May be involved in dendritic cell (DC) maturation, the process by which immature dendritic cells differentiate into fully competent antigen-presenting cells that initiate T-cell responses (PubMed:19028597).
  Mediates mitotic non-disjunction and chromosome instability, in long-term in vitro culture and cancers, by abbreviating mitotic phase and impairing the kinetochore localization of MAD2L1 during the prometaphase stage of the cell cycle (PubMed:16495226).
  May be involved in the formation of aggresomes when proteasome is saturated or impaired (PubMed:19033385).
  Mediates apoptosis in a caspase-dependent manner, especially in renal epithelium and tubular cells during renal diseases such as polycystic kidney disease and Human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) (PubMed:16495380). UBD_HUMAN,O15205

Induction:

• Rapidly degraded by the proteasome.
  Cell-cycle regulation with highest expression during the S-phase (at protein level).
  Induced during dendritic cell maturation.
  Negatively regulated by p53/TP53.
  High levels in various gastrointestinal and gynecological cancer cells.
  Induced in RTECs in common renal diseases including diabetic nephropathy (DN), IgA nephropathy (IgAN), and hypertensive nephrosclerosis (HN), as well as in hepatocellular carcinoma (HCC) and during HIVAN.
  Inducible by the pro-inflammatory cytokines IFNG/IFN-gamma and TNF in cancers of liver and colon.
  Repressed by NUB1 (at protein level). UBD_HUMAN,O15205

Proteosomaalinen dysfunktio alkaa olla celiakiatutkimuksessa polttopisteessä

 https://allergenbureau.net/event/international-celiac-disease-symposium-2026/

A regulatory single nucleotide polymorphism in the ubiquitin D gene associated with celiac disease

• October 2009
• Human Immunology 71(1):96-9

DOI:10.1016/j.humimm.2009.09.359

• Source
• PubMed
  

  Abstract

  An aberrant immune response triggered by dietary gluten is the main driving force underlying celiac disease (CD), but other biologic pathways that are dysregulated also participate in disease development. Genetic variation within these pathways might influence expression, contributing to susceptibility to CD. We have investigated the implication of ubiquitin D (UBD), a member of the ubiquitin–proteasome system that is strongly upregulated in the intestinal mucosa of active CD. Reverse transcriptase-polymerase chain reaction analysis of intestinal biopsy sample pairs (at diagnosis vs treated) from 30 CD patients confirmed overexpression of UBD in active disease tissue (fold change = 8.3; p = 0.0022). In silico prediction tools identified rs11724 as a putative regulatory single nucleotide polymorphism and association analysis of 468 CD patients and 459 controls revealed that the minor rs11724*C allele was more frequent among patients (minor allele frequency = 0.44 vs 0.39; odds ratio [OR] = 1.23; p = 0.028) and suggested a dominant allele effect (OR = 1.49; p = 0.0045). Correlation of the rs11724 genotype and UBD mRNA levels (OR = 0.76; p = 0.0021) further supports its implication in disease development.
  Introduction

  Celiac disease (CD# OMIM 212750) is a chronic, immune-mediated enteropathy caused by intolerance to ingested gluten that develops in genetically susceptible individuals. It is one of the most common lifelong disorders affecting Caucasians. Recent studies have estimated a prevalence of CD close to 1:120 [1]. The major genetic determinant of CD maps to the human leukocyte antigen (HLA) class II region on the major histocompatibility complex (MHC) located on 6p21, and more than 90% of celiac patients carry at least one copy of the HLA-DQ2 heterodimer or, less frequently (∼6%), the HLA-DQ8 molecule. HLA alone has proven insufficient to explain all of the genetic susceptibility to CD [2] and much effort has been put into the discovery of additional susceptibility determinants in recent years, with numerous candidate gene association studies and several whole genome linkage analyses performed by different groups. The turnover of such strategies has been limited and results have very often been inconsistent across studies [3]. More recently, as a result of the Genome-Wide Association Study (GWAS), a handful of novel celiac risk variants that are moderately (odds ratio [OR] < 1.5) but robustly associated with CD have been identified and the majority of the associated single nucleotide polymorphisms (SNPs) are in the vicinity of immune response-related genes that could be functionally implicated in development of the disease. However, linkage disequilibrium association mapping is unable either to define the actual genes that are involved in disease susceptibility or to explain the way in which associated DNA polymorphisms may influence the function of these genes [4], [5], so that putative candidates around each association peak must be independently studied in detail before causative variants can be confirmed. An alternative to the GWAS strategy is to focus on genes and pathways that have been shown to be functionally disrupted in the affected tissue and perform association analyses in selected DNA variants that might explain the changes observed. We have previously employed a gene selection strategy combining expression profiling and results from linkage studies with limited success [6] and now focus on altered genes that are important in disease-related pathways to identify potential candidates.

  The ubiquitin–proteasome system is an important biologic route in CD because it plays a central role in the selective degradation of intracellular proteins, including those involved in antigen presentation, nuclear factor-κB (NF-κB)-mediated inflammatory processes, cell cycle regulation, and cytokine gene expression [7]. Results from our previous gliadin-challenged microarray experiments indicated an overall upregulation of the ubiquitin–proteasome system pathway in intestinal mucosa from active celiac patients [6], [8]. Among the genes in the pathway, the most pronounced overexpression was observed for ubiquitin D (UBD) (p value = 2.52 × 10−8, FDR = 0.0009, and fold change = 14.14), a protein that is particularly interesting because it behaves as a ubiquitin-like modifier for rapid degradation of substrate proteins through the proteasome [9]. In addition, UBD is a good CD susceptibility candidate because it participates in the activation of the NF-κB pathway and has been shown to cause apoptosis in a caspase-dependent manner [10], two key events in disease development and progression. Moreover, the gene is located in the extended MHC region, where evidence for the presence of additional minor CD susceptibility loci has accumulated [11]. The aim of the present study was to investigate the potential implication of UBD in the pathogenesis of CD.
  
  
  

Ruokaresepti. aamupala ja välipala, gluteenitonta

 

08:00

Aamukahvi, jossa laktoositonta maitoa.(Cafe Cream kahvikoneesta, jauhetui pavuista)

 Ciabatta-leipää , välissä kasvisperäistä margariinia
(Naturli Bredbart med raps, chea, kokos & mandel)10;30  välipala:

Myös hieman sulatejuustoliuskoja ripoteltuna  leivänpalojen väliin)

Aamulääkkeet  verenpainetta vastaan ja hypotyreoosiin),veden kanssa. 

10.30

Riisipuffeja (AXA Vårgårda RIS) kaksi kourallista 

mantelimaidon kera, +  1 rkl luumuhilloa , kulhossa. 

 

Kalanmaksaöljyä  1 rkl.

Ginger/lemon/turnips shot  1 rkl.

Zinc citrat  1 tabl.

Gluteeni molekyyli- mikä siinä on toisilla ongelmana

 Toisilla ei ole  entsyymejä,  genomissaan valmiina, niin että  ehtisi  lyhyen  ruoansulatustoiminnan aikana saada pilkottua tuota mammuttimolekyyliä. Se jää  antigeenisiksi pätkiksi, joita sitten immuunivaste yrittää sahata ja  hakata paloiksi toisin keinoin, josta taas immuunivasteen resurssit väsähtävät ja ihminenkinlopulta väsyy ja on  kipeää.   Ihan kuin  tarjoaisi  hampaattomalle koiralle sitkeän  kanan syötäväksi, joka kerta joka ateriassa. 

...Gluten is not a single molecule but a complex of proteins, primarily gliadin and glutenin, found in grains like wheat, barley, and rye. Gliadin proteins are more soluble and contribute to viscosity, while higher-molecular-weight glutenins provide elasticity. Together, they form a cohesive, viscoelastic network when combined with water, which is responsible for dough's ability to stretch and hold gas. 

GLUTEENIA sisältäviä elinarvikkeita, mitä kaikki keliakikot eivät luonnostaan tiedä

 

 DURUM VEHNÄ

 ei tarkoita että tämä on  järkiperäistä gluteenitonta vehnää.vaan: 

vehnälaji, jota käytetään   pastatuotteissa hyvän keitonkestävyyden vuoksi. Sisältää gluteenia. ( Termi"kotimaiset viljat" on harhaan johtava. Gluteenipitoisuuteen ei vaikuta maaperän maantieteellinen sijainti, vaan  viljalaadun   geeni ja lopuksi myös viljan käsittely, sillä jyviä voi  tulla eri viljoista  jauhoon ja muodostaa  gluteenikontaminaatiolähteen) 

 

KAMUT-VEHNÄ

vehnän lajike. Sisältää gluteenia.

 

MALTAAT

sisältävät gluteenia.

 

OLUT osa olueista on tutkimuksen mukaan gluteenittoman rajan (0.3%) alapuolella. Sisältää gluteenia.

(On  nykyään olutta, joka on  gluteenittomaksi  asti käsitltyä. ) 

 

SAHTI ja KOTIKALJA

eivät sovi keliaakikolle. isältävät gluteenia.  ( henkilökohtaisesti minulla oli  stabiili aversio suomalaista kaljaa , jopa sen tuoksua kohtaan, jota  kasvuympäristössä aikuisille tehtiin maidon rinnalle juotavaksi päivittäinkin).

 

SPELT-VEHNÄ

alkuvehnän muoto. Sisältää gluteenia.

 

OHRATÄRKKELYS(Ohrakas)

Sisältää gluteenia.

 

Taxonomia POOIDAE

  he Pooideae are the largest subfamily of the grass family Poaceae, with about 4,000 species in 15 tribes and roughly 200 genera. They include some major cereals such as wheat, barley, oat, rye and many lawn and pasture grasses. They are often referred to as cool-season grasses, because they are distributed in temperate climates.^[1] All of them use the C₃ photosynthetic pathway.

GLUTEENIA VAI EI? Lista gluteenittomia elintarvikkeita. Kysymyksiä herättäviä lisäaineita! www.sci.fi lähteestä

 Lähde selittää näitä elintarvikkeita, Henkilökohtaisesti  taas en käyttäisi vehnäperäistä öljyä edes sen oraita periaatteerssa immunologisen tason  mahdollisten vaikutusten takia. 

 

 FIBREX

gluteeniton kuituvalmiste sokerijuurikkaasta, rödbeta , Red beet (selek adom) (Beta vulgaris, B. esculenta, B. altissima Chenopodiaceae)

 

GLUTAMIINIHAPPO, (aminohappo Glu, E, glutamate, glutamic acid),  on kehon muodostama nonessentielli aminohappo, muta käytetään mös elintarvikelisänä). Gluteeniton. 

 

KAURA (Avena sativa) 

Kaura, havre, oat,  (Avena sativa)   (Shibbolet Shual,  "ketuntähkä" villikaurana, wild oat , arab. Khafur)

Nykyopetuksen mukaan Pohjoismaissa  sekä lapsi-että aikuiskeliaakikot voivat käyttää kauraa ruokavalionsa lisänä. Henkilökohtaisesti vältän kauraa. On kauralaatuja, joista on poistettu  gluteiinikontaminaatio, joka tulee muista kotimaisista viljoista   viljelysmailla. "Gluteenitonta kauraa".

 

LAKRITSIUUTE,ärtväxt  lakritsrot  extract  (Glycyrrhiza glabra) 

lakritsin makuinen aromiaine.Papukasveihin kuuluvan  lakristijuuren   kuivatuista  juurista    Gly cyrrhiza glabra,Common lecorice, hebr. Shush keireiach , arab. Irk e-sus    Gluteeniton. 

 

MALLASUUTE ja -JAUHE (mallas= malt, 

maunvahvenne, sisältää häviävän pienen määrän gluteenia. Murot, joissa on mallasuutetta käytännössä gluteenittomia, mainitsee  www.sci.fi lähde, mutta henkiolökohtaisesti tarkistan ovatko  esim maissimurot  tehty maissimallasuutteella (malted maize, Indian corn,liltot  tiras) vai ohramallasuutteella  ( malted barley, hebr. letet,liltot sheora),   kun paketissa lukee  Gluteenittomia Corn Flakes hiutaleita. 

  

MALTOPDEKSTRIINI  (pilkkoutuu esiin tärkkelyksestä, spjälkningsprodukt av stärkelse)  

maissi- tai ohratärkkelyksen eräs muoto. Alkuperä ilmoitettava jos kyseessä on yliherkkyyttä  aiheuttava aine, esim "maltodekstriini ohrasta".  Tällainen tuote katsotaan tässä lähteessä kuitenkin gluteenittomaksi, mutta " tieto voi olla tärkeä herkälle allergikolle" on  lisä tietona. 

 

NATRIUMGLUTAMAATTI

sromivahvenne, gluteenitont. Aminohappo glutamiinihapon natrium-suola.

Na-salt av glutamat, Sodium salt of glutamate

 

OLUTHIIVA , bryggerijäst, brewery yeast

 hiivasolukko inaktivoitu, ei aiheuta käymistä. Gluteeniton 

 

PROTEIINIHYDROLYSAATTI

aromivahvenne,. Alkuperä ilmoitettava, jos kyseessä on yliherkkyyttä aiheuttava aine, esim. "vehnäproteiinihydrolysaatti".  Lähteen mukaan tällainen tuote  sanotaan kuitenkin gluteenittomaksi. Tieto voi olla tärkeä herkälle allergikolle, koska  gluteeni tunnistuu  heillä immuunisolujen tasolla.  En itse käytä ns. (gluteenitonta vehnätärkkelystä", koskma englantilaisen tiedon mukaan  se tunnistuu T-soluilla ja vaikutata ajan mittaan verekuvaan. 

 

QUINOAKinua, kvinoa 

Heimo:	Revonhäntäkasvit Amaranthaceae
Alaheimo:	Chenopodioideae
Suku:	Savikat Chenopodium
Laji:	quinoa

gluteeniton riisinkaltainen viljakasvi. Kvinoa eli kinua (Chenopodium quinoa) on eteläamerikkalainen hiilihydraattipitoinen ruokakasvi. Se ei ole heinäkasvi kuten viljat, mutta sen siemeniä käytetään ruoanvalmistuksessa viljojen tapaan. Lisäksi sen lehtiä voidaan syödä lehtivihanneksen tapaan. 

 Quinoa (Chenopodium quinoa), med det rekommenderade svenska namnet mjölmålla^[1][a] och även kallad rismålla^[1], är en ört som växer vilt i Sydamerika. Den beskrevs av den tyske botanikern Carl Ludwig Willdenow 1798.

 

SAKEUTTAMISAINEET

elintarviketeollisuuden  käyttämät rakenteen parantajat. Esim. tärkkelyksen johdannaiset (vehnä- ja ohratärkkelys on mainitava pakkausmerkinnöissä);  liivate,pektiini sekä erilaiset kasvikumit, alginaatit, guarkumi, karboksimetyyliselluloossa (CMC). Gluteenittomia.  

 

SINAPPIJAUHE    Sinappi,Senap,Mustard,  Chardal,  Khardal haSade (Sinapis arvensis,

 Sinapinsiemen; dardar haKhardal, seed of mustard plant;  .Mustard is a condiment made from the seeds of a mustard plant

Jauhettua sinapinsiementä. Gluteeniton.  

 

SOIJA,

soijajauhon raaka-aine. Gluteeniton. 

Soija kuuluu papukasveihin ja on luonostaan gluteeniton.The soybean, soy bean, or soya bean (Glycine max)[3] is a species of legume native to East Asia, widely grown for its edible bean. Soy is a staple crop, the world's most grown legume, and an important animal feed.[4]
Soy is a key source of food, useful both for its protein and oil content. Soybean oil is widely used in cooking, as well as in industry. Traditional unfermented food uses of soybeans include edamame, as well as soy milk, from which tofu and tofu skin are made. Fermented soy foods include soy sauce, fermented bean paste, nattō, and tempeh. Fat-free (defatted) soybean meal is a significant and cheap source of protein for animal feeds and many packaged meals.[4] For example, soybean products, such as textured vegetable protein (TVP), are ingredients in many meat and dairy substitutes.[4][5] Soy based foods are traditionally associated with East Asian cuisines, and still constitute a major part of East Asian diets, but processed soy products are increasingly used in Western cuisines.  

 

SOIJALESITIINI

soijaperäinen teollisuuden käyttämä emulgointiaine. Gluteniton. Fosfatidyylikoliini  fosfolipidi(PC). 

 

TÄRKKELYSSIIRAPPI

makeisteollisuuden käyttämä muotoilu- ja täyteaine. Valmistetaan perunasta ja ohrasta. Alkuperä ilmoitettava, jos kyseessä yliherkkyyttä aiheuttava aine, esim. "ohratärkkelyssiirappi" . valmistusprosessissa gluteeni poistuu, eli tuote on gluteeniton. Tieto alkuperästä voi olla tärkeä allergikolle. 

 

VEHNÄNALKIOÖLJY

luontaistuote, valmistetaan puristamalla rasva vehnänalkiosta. Gluteeniton. (Tämä on hyvin E-vitamiinipitoista, mutta henkilöklohtaisesti  koetan saada E-vitamiinin muista kasvisöljyistä ja kalanmaksaöljystä) 

 

VEHNÄN ORAS

vehnän siemenen annetaan itää ja kasvaa iduksi, oraaksi. oras käyttää siemenen proteiinin kasvuunsa. Gluteeniton. (Henkilökohtaisesti en ole tällaista koskaan kokeillut).  (Mainitsen tässä että vanhempieni  herkku oli KRUSKA, jonka valmistamiseen kului päiviä  liinoin haudotussa kattilassa. Varmaan joukossa oli tällaista vehnäitua. En koskaan  ainakaan tietoisesti  syönyt kruskaa.https://sv.wikipedia.org/wiki/Kruska)

 

 

VEHNÄNORASMEHU 

huolella tehtynä gluteeniton ( siementä ei saa päästää mukaan). Tällaista en ole koskaan kokeillut henkilökohtaisesti.