@phdthesis{
author = "Vasić, Marija",
year = "2024",
abstract = "Multipla skleroza (MS) je autoimunska bolest, nepredvidivog toka, sa zonama inflamacije i demijelinizacije u centralnom nervnom sistemu. Cilj istraživanja je bio da se utvrdi klinički značaj oksidativnog stresa (OS) i kinureninskog puta (KP) metabolizma triptofana u nastanku i razvoju relapsno-remitentne multiple skleroze (RRMS) u populaciji Srbije, kao i efekti terapije koja menja prirodni tok bolesti (DMT). Dodatno, cilj je bio da se ispita uticaj sredinskih faktora (duvanski dim, izlaganje suncu i konzumiranje kravljeg mleka) na nastanak i razvoj MS.Istraživanje je obuhvatilo 175 RRMS pacijenata (76 muškaraca i 99 žena) i 254 zdravih osoba (81 muškarac i 173 žene). Za procenu progresije bolesti korišćen je Multiple Sclerosis Severity Score (MSSS). OS je procenjen na osnovu ukupnog antioksidativnog i oksidativnog statusa i oksidativnog indeksa u serumu (TAS, TOS, OSI) i 8-okso-7,8-dihidro-2´-deoksiguanozina (8-oksodG/kreatinin) u urinu. Analiziran je polimorfizam gena za enzim 8-oksoguanin-glikozilazu 1, OGG1 rs1052133 (Ser326Cys). U serumu pacijenata su praćeni laki lanci neurofilamenata (sNfL), sfingozin-1-fosfat (S1P), kinureninska (KA) i hinolinska (QA) kiselina.Rezultati ovog istraživanja su pokazali da OS utiče na nastanak i razvoj MS u populaciji Srbije. Porast OSI, porast 8-oksodG/kreatinina i pasivno pušenje su identifikovani kao nezavisni prediktori za nastanak MS. Dodatno, kod pacijenata sa težim oblikom MS, nivo OS povezanog sa pušenjem bio je veći kod žena, što ukazuje na veće potrebe uključivanja antioksidativne terapije kod žena koje su već obolele od MS, kako bi se prevenirao dalji nepovoljan tok bolesti. Primena TAS, TOS, OSI i 8-oksodG/kreatinina ima potencijalni značaj u proceni rizika od razvoja OS i praćenju efikasnosti antioksidativne terapije. Viši 8-oksodG/kreatinin kod nosilaca C alela rs1052133 u odnosu na GG homozigote bio je povezan sa pojavom MS, što ukazuje na povećanu izloženost sistemskim efektima OS kod nosioca određenog alela genetičke varijante OGG1 rs1052133, ali i na efikasnost sistema reparacije oksidativno modifikovane dezoksiribonukleinske kiseline (DNK). S druge strane, prisustvo C alela kod pacijenata-pušača je bilo povezano sa višim 8-oksodG/kreatinin indeksom u odnosu na nepušače, što ukazuje na moguću genotip-fenotip interakciju u razvoju OS. Dalje, rezultati ove studije ukazuju na zaštitni efekat DMT terapije od pojave OS, međutim, kod žena efekti terapije na prevenciju OS i pojavu teškog oblika MS su bili ograničeni, što ukazuje na neophodnost uvođenja antioksidativne terapije kod žena. Osim toga što su žene, generalno imale viši nivo sNfL, ova studija je pokazala da žene-nosioci G alela rs1052133 imaju viši sNfL u odnosu na žene-homozigote CC, kao i u odnosu na muškarce-nosioce G alela. Dodatno, žene su nakon šestomesečne DMT terapije imale značajno veći porast sNfL u odnosu na muškarce, što može ukazati da njihova veća osetljivost na oštećenje aksona zahteva duži vremenski period za postizanje pozitivnih efekata terapije. Povećana produkcija hinolinske kiseline bila je povezana sa rizikom od progresije MS kod žena, što ukazuje da hronična aktivacija KP povećava rizik od neurodegeneracije. Nakon šestomesečne DMT terapije, kod oba pola uočen je značajan pad indeksa QA/KA, što ukazuje na njen zaštitni efekat od nakupljanja neurotoksičnih metabolita i ovaj indeks bi mogao da bude koristan za procenu rizika od progresije MS..., Multiple sclerosis (MS) is an autoimmune disease with an unpredictable course, with zones of inflammation and demyelination in the central nervous system. The aim of the research was to determine the clinical significance of oxidative stress (OS) and the kynurenine pathway (KP) of tryptophan metabolism in the onset and development of relapsing-remitting multiple sclerosis (RRMS) in the population of Serbia, as well as the effects of therapy that changes the natural course of the disease (DMT). Additionally, the aim was to examine the influence of environmental factors (tobacco smoke, sun exposure and consumption of cow's milk) on the onset and development of MS.The research included 175 RRMS patients (76 men and 99 women) and 254 healthy individuals (81 men and 173 women). The Multiple Sclerosis Severity Score (MSSS) was used to assess the severity of the disease. OS was evaluated based on total antioxidant and oxidative status and oxidative index in serum (TAS, TOS, OSI), and 8-oxo-7,8-dihydro-2´-deoxyguanosine (8-oxodG/creatinine) in urine. The gene polymorphism of the enzyme 8-oxoguanine-glycosylase 1, OGG1 rs1052133 (Ser326Cys) was analyzed. Neurofilament light chains (sNfL), sphingosine-1-phosphate (S1P), kynurenic (KA) and quinolinic (QA) acid were monitored in the patients' serum.The results of this research showed that OS affects the onset and development of MS in the population of Serbia. Increase in OSI, increase in 8-oxodG/creatinine and passive smoking were identified as independent predictors for the development of MS. Additionally, in patients with a more severe form of MS, the level of OS-related to smoking was higher in women, which indicates a greater need to include antioxidant therapy in women already suffering from MS, in order to prevent further adverse course of the disease. The application of TAS, TOS, OSI and 8-oxodG/creatinine has potential importance in assessing the risk of developing OS and monitoring the effectiveness of antioxidant therapy. Higher 8-oxodG/creatinine in rs1052133 C allele carriers compared to GG homozygotes was associated with the occurrence of MS, which indicates increased exposure to systemic effects of OS related to certain allele of genetic variant OGG1 rs1052133, but also the efficiency of the repair system of oxidatively modified DNA. On the other hand, the presence of the rs1052133 C allele in smoking patients was associated with higher 8-oxodG/creatinine compared to non-smokers, indicating a possible genotype-phenotype interaction in the development of OS. Furthermore, the results of this study indicate a protective effect of DMT therapy against the occurrence of OS, however, in women, the effects of the therapy on the prevention of OS and the occurrence of severe MS were limited, which indicates the necessity of introducing antioxidant therapy in women. In addition to women generally having higher sNfL, this study showed that female carriers of the rs1052133 G allele have higher sNfL compared to homozygous CC women, as well as compared to male carriers of the G allele. After six months of DMT therapy, women had a significantly greater increase in sNfL compared to men, which may indicate that their greater sensitivity to axonal damage requires a longer period of time to achieve positive effects of therapy. Increased production of quinolinic acid was associated with the risk of MS progression in women, indicating that chronic KPactivation increases the risk of neurodegeneration. After six months of DMT therapy, a significant decrease in the QA/KA index was observed in both sexes, indicating its protective effect against the accumulation of neurotoxic metabolites, and this index could be useful for assessing the risk of MS progression...",
publisher = "Универзитет у Београду, Фармацеутски факултет",
journal = "Универзитет у Београду",
title = "Značaj oksidativnog stresa i kinureninskog puta metabolizma triptofana u nastanku i razvoju multiple skleroze u populaciji Srbije",
url = "https://hdl.handle.net/21.15107/rcub_nardus_22507"
}
