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مدلسازی ریاضی جهت تعیین تنظیمکنندههای کلیدی اثر هیپوکسی بر تولید سوکسینات در چرخ کربس | ||
| فصلنامه علمی زیست شناسی جانوری تجربی | ||
| دوره 14، شماره 1 - شماره پیاپی 53، شهریور 1404، صفحه 11-21 اصل مقاله (1.06 M) | ||
| نوع مقاله: مقاله پژوهشی | ||
| شناسه دیجیتال (DOI): 10.30473/eab.2025.75818.2009 | ||
| نویسندگان | ||
| جابر هاشم زاده1؛ رضا حاجی حسینی* 1؛ صداقت شهمراد مغانلو* 2 | ||
| 1گروه بیوشیمی، دانشکده بیولوژی، دانشگاه پیام نور تهران شرق، تهران، ایران | ||
| 2گروه ریاضی، دانشکده ریاضی و آمار، دانشگاه تبریز، تبریز، ایران | ||
| چکیده | ||
| در تومورهای جامد، هیپوکسی میتواند باعث بیان نابهنجار بر روی فاکتورها و ژنهای رونویسی شود و در نتیجه باعث عملکردهای بیولوژیکی غیر طبیعی مانند تغییر مسیرهای انرژی در سلولهای سرطانی گردد. مقدمه: هیپوکسی میتواند باعث بیان نابهنجار بر روی فاکتورهای رونویسی و ژنها شود که منجر به عملکردهای بیولوژیکی غیر طبیعی مانند تغییر مسیرهای انرژی در سلولهای سرطانی میگردد. چرخه کربس در متابولیسم گلوکز بهعنوان بخش مهمی از این پدیده است که در شرایط هیپوکسی، با تغییراتی در میزان بیان متابولیتها و آنزیم های دخیل در این مسیر از جمله تجمع برخی متابولیتها مانند سوکسینات و نیز ایجاد تغییر در ترکیب ریزمحیط تومور، میتواند منجر به تهاجم بیشتر و متاستاز سلولهای سرطانی گردد. مطالعه حاضر برای اولین بار با استفاده از مدلسازی محاسباتی، با هدف بررسی اثرات ناشی از هیپوکسی (HIF-1) بر روی میزان بیان عملکردی همه آنزیمها و متابولیتهای درگیر با چرخه کربس انجام شد. در نتیجه، تعیین دقیق مکانیسم و بررسی اثر تغییرات غلظت اکسیژن بر چرخه کربس، که در ارتباط با هم عمل میکنند، ضروری میباشد. روش کار: در مطالعه حاضر برای اولین بار با استفاده از مدلسازی محاسباتی، اثرات ناشی از هیپوکسی (HIF-1) بر روی میزان بیان عملکردی همه آنزیمها و متابولیتهای درگیر با چرخه کربس بررسی شد. بدین منظور یک دستگاه معادلات متشکل از 16 معادله طراحی شد که تمامی اجزای چرخه کربس را به همدیگر و به هیپوکسی ارتباط میدهد. هدف اصلی مطالعه حاضر ایجاد یک رابطه کمی بین شدت هیپوکسی با سطوح متابولیتهای داخل سلولی و نیز تعیین تنظیمکنندههای کلیدی چرخه کربس میباشد. در واقع هدف ما تعیین کمّی اثر تغییرات غلظت اکسیژن بر چرخه کربس در تولید سوکسینات در درون سلول از منظر زیستشناسی سامانه ای مولکولی میباشد. بهعلاوه کاهش اکسیژن در مدل پیشنهادی پیشبینی کرد که آنزیم سوکسینات دهیدروژناز ممکن است مهمترین نقش را در تنظیم چرخه کربس ایفا کند. یافتهها: نتایج حاصل از مطالعه بیانگر رابطه مستقیم بین شدت هیپوکسی و افزایش تولید سوکسینات، بهعنوان عامل مهم پیشبرنده متاستاز، میباشد. بنابراین براساس مطالعه آنالیز حساسیت، مدل پیشنهادی ما پیشبینی کرد که در شرایط کاهش اکسیژن آنزیم سوکسینات دهیدروژناز ممکن است مهمترین نقش را در تنظیم چرخه کربس ایفا کند. | ||
| کلیدواژهها | ||
| چرخه کربس؛ سوکسینات؛ مدلسازی ریاضی؛ هیپوکسی | ||
| عنوان مقاله [English] | ||
| Determination of key metastasis promoters in krebs cycle using mathematical modeling | ||
| نویسندگان [English] | ||
| Jaber Hashemzadeh1؛ Reza Hajihosseini1؛ Sedaghat Shahmorad Moganlu2 | ||
| 1Department of Biochemistry, Faculty of Biology, Payame Noor University, Tehran, Iran | ||
| 2Faculty of Mathmatical Sciences, Tabriz University, Tabriz, Iran | ||
| چکیده [English] | ||
| Introduction: Hypoxia can cause aberrant expression of transcription factors and genes, resulting in which leads to abnormal biological functions such as altered energy pathways in cancer cells. The Krebs cycle in glucose metabolism is an important part of this phenomenon, which can lead to increased invasion and metastasis of cancer cells by changes in the expression of metabolites and enzymes involved in this pathway, including the accumulation of some metabolites such as succinate, as well as changes in the composition of the tumor microenvironment, which under hypoxic conditions, changes in the expression levels of metabolites and enzymes involved in this pathway, including the accumulation of some metabolites such as succinate, as well as changes in the composition of the tumor microenvironment, can lead to increased invasion and metastasis of cancer cells. The present study was conducted for the first time using computational modeling, aiming to investigate the effects of hypoxia (HIF-1) on the functional expression levels of all enzymes and metabolites involved in the Krebs cycle. Consequently, it is essential to determine the precise mechanism and investigate the effect of changes in oxygen concentration on the Krebs cycle, which act in conjunction with each other. Method: In this study, for the first time, using computational modeling, the effects of hypoxia (HIF-1) on the functional expression levels of all enzymes and metabolites involved in the Krebs cycle have been investigated. For this purpose, a system of equations consisting of 16 equations was designed that relates all components of the Krebs cycle to each other and to hypoxia. The main objective The main goal of the present study is to establish a quantitative relationship between the severity of hypoxia and the levels of intracellular metabolites and identify key regulators of the Krebs cycle, as well as to identify key regulators of the Krebs cycle. In fact, our goal is to quantify the effect of changes in oxygen concentration on the Krebs cycle in the production of succinate inside the cell from a molecular systems biology perspective. Also, the oxygen reduction in the proposed model predicted that the enzyme succinate dehydrogenase may play the most important role in regulating the Krebs cycle. Result: The results of the study indicate a direct relationship between the severity of hypoxia and increased succinate production, as an important factor driving metastasis. Consequently, based on a sensitivity analysis study, Our proposed model predicts that the succinate dehydrogenase enzyme probably plays the most important role in regulating the Krebs cycle under hypoxia conditions. | ||
| کلیدواژهها [English] | ||
| Hypoxia, Mathematical modeling, Metastasis, Succinate | ||
| مراجع | ||
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