Potential Contribution to Antidiabetic Treatments of Epstein-Barr Virus Proteins LMP1 and EBNA1

Yıl 2018, Cilt: 2 Sayı: 3, 146 - 155, 21.12.2018

Serkan Şen , Merve Şen , Mustafa Altındiş , Sefa Çelik , Korhan Altunbaş , İbrahim Hakkı Ciğerci

Öz

The prevalence and incidence of diabetes is a
global healthcare-management problem that is increasing almost every day. The
high numbers of complications make the diagnosis and treatment of diabetes
extremely important. Nowadays, it is believed that a large number of diseases,
including diabetes, are related to the Endoplasmic Reticulum (ER)
stress-induced apoptosis. Proliferative activity of Epstein-Barr Virus (EBV)
proteins occurs via two
mediators Epstein-Barr Nuclear Antigen-1 (EBNA1) and Latent Membrane Protein-1
(LMP1). In this study, it was aimed to investigate the reversal of pancreatic
cell loss by applying recombinant viral EBV proteins. It has also been
investigated how related proteins can effect DNA damage, ER stress, and
contribute to insulin synthesis-release. For these targets, it has been decided
to use doses of 0.1 ppm and 0.5 ppm of commercially obtained recombinant EBNA1
and LMP1 proteins. The possible effects of these proteins on mRNA expression
levels of genes known to be responsible for the specified proliferation have
been investigated. In the study, DNA damage was analyzed by Comet Assay, and
Endoplasmic Reticulum stress was analyzed by Real Time RT-PCR. In RT-PCR
studies, mRNA expression levels of cell proliferation markers including PDX 1,
WNT 4, FoxO1, TCF7L2 and beta catenin genes in the EBNA1 group were increased
by 6.48, 4.25, 2.37, 3.8 and 1.4 times, respectively compared with control
group. At the end of the study; EBV recombinant proteins LMP1 and EBNA1 have
been shown to increase the expression levels of genes responsible for
proliferation. It has also been shown that related proteins may be advantageous
in reversing beta cell losses by suppressing the expression levels of ER
stress-inducing genes.  It has been thought
that the use of viro-therapeutic agents in antidiabetic treatments may be
appropriate if supported by higher-level studies in this regard.

Anahtar Kelimeler

Epstein Barr Virus, EBNA1, LMP1, Diabetes

Epstein-Barr Virus Proteinleri LMP1 ve EBNA1’in Antidiyabetik Tedavilere Potensiyel Katkısı

Öz

Diyabet prevalansı ve insidansı her geçen gün artmaya devam eden global
bir sağlık problemidir. Diyabetik komplikasyonların sıklığı diyabet tanı ve
tedavisini önemli kılmaktadır. Günümüzde, diyabet de dahil olmak üzere çok
sayıda hastalığın Endoplazmik Retikülüm (ER) stres kaynaklı apoptoz ile
ilişkili olduğuna inanılmaktadır. Epstein-Barr virusun proliferatif etkinliği; Epstein-Barr Nuclear
Antigen-1 (EBNA1) ve Latent Membrane Protein-1 (LMP1) adlı iki mediatör protein
aracılığıyla olmaktadır.  Bu çalışmada;
pankreatik beta hücre kayıplarının bertarafında 
iligili EBV proteinlerinin kullanılması amaçlanmıştır. Ayrıca ilgili
proteinlerin ER stresi, insulin sentez ve salınımı ve DNA hasarı üzerine
etkilerinin araştırılması hedeflenmiştir. Bu hedefler için, 0,1 ppm ve 0,5 ppm
dozlarında ticari olarak elde edilen rekombinant EBNA1 ve LMP1 proteinleri
kullanılmıştır. Bu proteinlerin proliferasyondan sorumlu olduğu bilinen
genlerin mRNA ekspresyon seviyeleri üzerindeki olası etkileri araştırılmıştır.
Çalışmada DNA hasarı Comet Assay ile, proliferasyon düzeyleri Real Time RT-PCR
ile analiz edilmiştir. RT-PCR çalışmasında, hücre proliferasyonundan sorumlu
oldukları bilinen PDX 1,WNT 4, FoxO1, TCF7L2 ve 
beta katenin genlerinin mRNA ekpresyon düzeyleri control grubana nazaran
EBNA 1 grubunda sırasıyla 6.48, 4.25, 2.37, 3.8 ve 1.4 kat arttığı tespit
edilmiştir. Aynı zamanda ilgili proteinlerin ER stres kaynaklı genlerin
ekspresyon seviyelerini bastırarak beta hücre kayıplarını tersine çevirmek
açısından avantajlı olabileceği gösterilmiştir. Bu proteinlerin antidiyabetik
tedavilerde viro-terapötik ajan olarak kullanılması bu konuda daha üst düzey
çalışmalarla desteklenmeye muhtaçtır.

Anahtar Kelimeler

Epstein Barr Virus, EBNA1, LMP1, Diyabet

Kaynakça

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