doktorska disertacija
Eva Brglez Mojzer (Avtor), Urban Bren (Mentor)

Povzetek

Dasiravno obdobje intenzivnega preučevanja raka traja že dobro stoletje, nam še vedno ni obrodilo odgovorov na številna ključna vprašanja o nastanku raka (karcinogenezi), dejavnikih, ki vplivajo na njegovo napredovanje; in seveda kako ga uspešno zdraviti brez ali s kar najmanj stranskimi učinki. Vsled navedega nam ni manjkalo povodov, da se lotimo preučevanja raka s povsem drugačnim, sodobnejšim in varnejšim pristopom. Preučevanja karcinogeneze oziroma njenih molekularnih mehanizmov smo se v doktorskem delu lotili s pomočjo računalniških metod osnovanih na kvantni kemiji oziroma kvantni mehaniki. In silico pristop k preučevanju molekularnih mehanizmov za razliko od številnih drugih namreč ne predstavlja zdravstvenega tveganja. Najprej smo izvedli simulacije reakcije alkilacije in acilacije karcinogena β-propiolaktona z genetskim materialom oziroma posameznimi DNK bazami (adeninom, citozinom, gvaninom in timinom). Uporaba posameznih baz nam je olajšala in pospešila izračune ter omogočila, da smo spoznali, katera so ranljivejša mesta našega dednega materiala in najverjetnejša tarča kemijskih karcinogenov. Za širši in podrobnejši vpogled v molekularne mehanizme karcinogeneze smo preučili tudi mehanizme reakcij karcinogena akrilonitrila z DNK bazami. Kasneje smo z enakimi metodami izvedli tudi reakcije karcinogena β-propiolaktona s snovmi z antikancerogenim delovanjem kamor spadajo glutation (telesu naravni lovilec) in nekatere polifenolne spojine, ki bi glutation lahko potencialno nadomestile in tako preprečile karcinogenezo. Tako smo pokazali, da lahko z računalniškimi metodami na temeljih kvantne kemije ne le preučujemo karcinogenezo, ampak tudi iščemo potencialne kandidate za njeno preprečevanje in celo zdravljenje. V disertaciji smo obsežno predstavili številne naravne spojine skupaj z njihovimi odkritimi biološkimi mehanizmi antikancerogenega delovanja in prednostmi njihovega zaužitja, med katerimi so številni polifenoli, kakor tudi nekatere naravne spojine iz hmelja, čigar uporaba sega ne samo stoletja, temveč celo tisočletje nazaj. Dandanes pa se počasi oživlja uporaba hmelja tudi v zdravstvene namene in ne zgolj v prehranske. Nenazadnje pa nas je zanimalo tudi ali lahko s pomočjo simulacij molekulske dinamike, ki prav tako spadajo med računalniške metode parametrizirane na kvantni mehaniki, preučujemo tudi posledice karcinogeneze, v našem primeru polimorfizmov posameznega nukleotida. Za razliko od večine znanstvene srenje smo hodili po manj raziskanem terenu, saj smo se odločili preučiti vpliv regulatornega polimorfizma posameznega nukleotida (rSNP-ja) iz nekodirajočega področja genoma na vezavo transkripcijskega faktorja vpletenega v ekspresijo specifičnega gena oziroma na regulacijo genske ekspresije tega gena. Nekodirajoči del genoma je še vedno zelo slabo raziskan, čeprav tudi asociacijske študije na celotnem genomu (GWAS) nakazujejo na to, da so tudi polimorfizmi locirani na nekodirajočem delu genoma povezani s povečanim tveganjem za nastanek raka. Dokazali smo, da je s tovrstnim pristopom mogoče preučevati rSNP-je in osvetlili številne ovire na poti k uspešnejšemu in vsestranskemu preučevanju raka, ki lahko v bodoče postanejo nove priložnosti in nova področja raziskav o raku. Doktorsko delo tako zaobjema vse faze raka od njegovega preprečevanja, preko karcinogeneze (nastanka) in preučevanja njenih posledic, vse do zaviranja karcinogeneze ter nenazadnje naravnega zdravljenja raka. S preučevanjem mehanizmov nastanka raka se lahko bolje seznanimo s samo boleznijo in jo posledično, če že ne preprečimo, lahko vsaj ustrezneje zdravimo. Utiramo torej pot k uspešnejšemu preprečevanju in zdravljenju raka z manj ali celo brez stranskih učinkov.

Ključne besede

rak;karcinogeneza;kvantna mehanika;molekulska dinamika;polifenoli;hmelj;doktorske disertacije;

Podatki

Jezik: Slovenski jezik
Leto izida:
Tipologija: 2.08 - Doktorska disertacija
Organizacija: UM FKKT - Fakulteta za kemijo in kemijsko tehnologijo
Založnik: [E. Španinger]
UDK: 576.385.5:663.791(043.3)
COBISS: 132751363 Povezava se bo odprla v novem oknu
Št. ogledov: 18
Št. prenosov: 7
Ocena: 0 (0 glasov)
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Ostali podatki

Sekundarni jezik: Angleški jezik
Sekundarni naslov: Quantum mechanical study of molecular mechanisms of carcinogenesis and their prevention with natural compounds
Sekundarni povzetek: Even though a period of thorough studies in the field of cancer research durates more than a century, several crucial answers about carcinogenesis, factors that impact cancer's progression, and about the most successful way of treating cancer with the least or even without side effects have not yet been answered. Therefore, we needed no additional reasons to study cancer, with an entirely different state-of-the-art and safer approach. In this thesis, we have chosen to study the carcinogenesis, respectively its molecular mechanisms with computation methods based on quantum chemistry, hence using quantum mechanics. Unlike many others, the in silico approach for studying the molecular mechanisms of cancer does not pose any health risks. First, we performed alkylation and acylation reactions of carcinogen β-propiolactone with the genetic material, more precisely with each DNA base (adenine, cytosine, guanine, and thymine) separately. The separate reactions of DNA bases have simplified and accelerated our calculations and enabled us to uncover the more voulnerable parts of our genetic material and thereby the most likely targets of chemical carcinogens. For a wider and more detailed insight into the molecular mechanisms of carcinogenesis, we have studied also the mechanisms of reactions between the chemical carcinogen acrylonitrile and the DNA bases. Next, using identical methods, we have additionally studied the reactions between the chemicalcarcinogen β-propiolactone and the anticarcinogenic agents, namely glutathione (organism's scavenger molecule) and several polyphenolic substances that carry a potential for replacing glutathione and could therefore prevent carcinogenesis. All in all, we have shown that with the use of computational methods based on quantum chemistry we can not only study the carcinogenesis but additionally search for potential candidate molecules for its prevention and even cancer treatment. Moreover, the thesis provides a thorough review of numerous natural substances, like several polyphenols and various hop compounds, together with their known biological mechanisms of anticarcinogenic action and the advantages of their indigestion. The use of hops and its compounds dates back at least centuries or even a millennium. Currently, its part in the treatment of various diseases instead of only for dietary use is gradually raising. Last but not least, we aimed to uncover whether we can study the consequences of carcinogenesis, in our case single nucleotide polymorphisms, with the use of computational methods parametrized on quantum mechanics more precisely with the molecular dynamics simulations as well. Unlike the vast majority of the scientific community, we have chosen to study a less uncovered part of the genome – its noncoding part-by studying the effect of a regulatory single nucleotide polymorphism (rSNP) on the binding of a transcription factor essential for the expression of a specific gene on the regulation of this gene's expression. Even though genome-wide association studies (GWAS) imply that polymorphisms located in the noncoding part of the genome are linked with a higher risk for cancer, the noncoding part of the genome remains very poorly studied. We have proven that our approach can be used for studying the rSNPs and discovered numerous hindrances on the way to a successful and widespread cancer research that can be overcome and transformed into new opportunities and novel fields of cancer research. The thesis, therefore, encompasses all the cancer stages from its prevention through carcinogenesis and studies of its consequences, all the way to the prevention of carcinogenesis and non the least a natural approach to the healing of cancer. Studies of the mechanisms of carcinogenesis enable us to get better acquainted with cancer and consequentially to prevent it or even to more appropriately treat it. We are therefore pawing the way to the more successful cancer prevention and its treatm
Sekundarne ključne besede: cancer;carcinogenesis;quantum mechanics;molecular dynamics;polyphenols;hops;
Vrsta dela (COBISS): Doktorsko delo/naloga
Komentar na gradivo: Univ. v Mariboru, Fak. za kemijo in kemijsko tehnologijo
Strani: 217 str.
ID: 16461503