Use of Kinetic Analysis and Mathematical Modeling in the Study of Metabolic Pathways in Vivo

1979 ◽  
Vol 300 (19) ◽  
pp. 1078-1086 ◽  
Author(s):  
Ewart R. Carson ◽  
E. Anthony Jones
Keyword(s):  
Mathematical Modeling ◽  
Kinetic Analysis ◽  
Metabolic Pathways

scholarly journals Integrated multi-omics analysis of RB-loss identifies widespread cellular programming and synthetic weaknesses

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Swetha Rajasekaran ◽  
Jalal Siddiqui ◽  
Jessica Rakijas ◽  
Brandon Nicolay ◽  
Chenyu Lin ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Human Cells ◽  
Cellular Reprogramming ◽  
Hallmarks Of Cancer ◽  
Compensatory Mechanisms ◽  
Response Factors ◽  
Cancer Data ◽  
Cell Stress Response ◽  
Metabolic Output

AbstractInactivation of RB is one of the hallmarks of cancer, however gaps remain in our understanding of how RB-loss changes human cells. Here we show that pRB-depletion results in cellular reprogramming, we quantitatively measured how RB-depletion altered the transcriptional, proteomic and metabolic output of non-tumorigenic RPE1 human cells. These profiles identified widespread changes in metabolic and cell stress response factors previously linked to E2F function. In addition, we find a number of additional pathways that are sensitive to RB-depletion that are not E2F-regulated that may represent compensatory mechanisms to support the growth of RB-depleted cells. To determine whether these molecular changes are also present in RB1−/− tumors, we compared these results to Retinoblastoma and Small Cell Lung Cancer data, and identified widespread conservation of alterations found in RPE1 cells. To define which of these changes contribute to the growth of cells with de-regulated E2F activity, we assayed how inhibiting or depleting these proteins affected the growth of RB1−/− cells and of Drosophila E2f1-RNAi models in vivo. From this analysis, we identify key metabolic pathways that are essential for the growth of pRB-deleted human cells.

OPTIMIZATION AND ASSESSMENT OF THE IN VIVO EFFICACY OF A HEPARIN-REMOVING BIOREACTOR USING MATHEMATICAL MODELING

ASAIO Journal ◽  
1996 ◽  
Vol 42 (2) ◽  
pp. 58
Author(s):  
Youngro Byun ◽  
Tanya Wang ◽  
Jae-Seung Kim ◽  
Victor C. Yang
Keyword(s):  
Mathematical Modeling ◽  
In Vivo Efficacy

Current trends in mathematical modeling of tumor–microenvironment interactions: a survey of tools and applications

2010 ◽  
Vol 235 (4) ◽  
pp. 411-423 ◽  
Author(s):  
Katarzyna A Rejniak ◽  
Lisa J McCawley
Keyword(s):  
Mathematical Modeling ◽  
Protein Interactions ◽  
Computational Models ◽  
Chemical Species ◽  
Tumor Stroma ◽  
Cellular Functions ◽  
Complex Interactions ◽  
Expanding Population

In its simplest description, a tumor is comprised of an expanding population of transformed cells supported by a surrounding microenvironment termed the tumor stroma. The tumor microcroenvironment has a very complex composition, including multiple types of stromal cells, a dense network of various extracellular matrix (ECM) fibers interpenetrated by the interstitial fluid and gradients of several chemical species that either are dissolved in the fluid or are bound to the ECM structure. In order to study experimentally such complex interactions between multiple players, cancer is dissected and considered at different scales of complexity, such as protein interactions, biochemical pathways, cellular functions or whole organism studies. However, the integration of information acquired from these studies into a common description is as difficult as the disease itself. Computational models of cancer can provide cancer researchers with invaluable tools that are capable of integrating the complexity into organizing principles as well as suggesting testable hypotheses. We will focus in this Minireview on mathematical models in which the whole cell is a main modeling unit. We will present a current stage of such cell-focused mathematical modeling incorporating different stromal components and their interactions with growing tumors, and discuss what modeling approaches can be undertaken to complement the in vivo and in vitro experimentation.

scholarly journals Dynamics of intraocular temperature during local hypothermia (experimental study and mathematical modeling)

2019 ◽  
pp. 383-388
Author(s):  
Lukyan Anatychuk ◽  
Roman Kobyliansky ◽  
Nataliya Pasyechnikova ◽  
Volodymyr Naumenko ◽  
Oleg Zadorozhnyy ◽  
...  
Keyword(s):  
Mathematical Modeling ◽  
Mathematical Model ◽  
Biological Tissues ◽  
Comsol Multiphysics ◽  
Rabbit Eye ◽  
Local Contact ◽  
Group 2 ◽  
Local Hypothermia ◽  
Group 1

Therapeutic hypothermia currently is successfully in various fields of medicine to protect biological tissues from ischemia. However the issue of changes in intraocular temperature under hypothermia remains poorly understood. Purpose. To study the dynamics of intraocular temperature in conditions of local hypothermia and on the basis of the obtained data to develop a mathematical model of thermophysical processes in the rabbit eye. Materials and methods. An in vivo experiment was performed on 10 rabbits (20 eyes). In group 1 (5 rabbits, 10 eyes), epibulbar and intraocular temperature was measured after local contact hypothermia through closed eyelids, in group 2 (5 rabbits, 10 eyes) after local contact hypothermia directly through the cornea. ока безпосередньо через рогівку. Для гіпотермії застосовувався гелевий акумулятор холоду температурою -10 °С. Для вимірювання температури в різних відділах ока застосовувався термоелектричний пристрій, розроблений Інститутом термоелектрики НАН і МОН України та ДУ «Інститут очних хвороб і тканинної терапії ім. В. П.Філатова НАМН України». Для розробки математичної моделі теплофізичних процесів в оці кролика використано пакет прикладних програм COMSOL Multiphysics. Результати. Температура склоподібного тіла в 1-й і 2-й групі тварин знизилася в порівнянні з вихідними даними відповідно на 2,8 °С і 5,4 °С. Температурний градієнт між зовнішньою поверхнею рогівки і середньою частиною склоподібного тіла ока кролика в 1-й групі становив 7,1 °С, у 2-й групі – 9,2 °С. На підставі отриманих експериментальних даних було розроблено схематичну, математичну та комп’ютерну моделі ока кролика з урахуванням його теплофізичних особливостей, кровообігу, процесів метаболізму і теплообміну. Висновки. У разі локальної контактної гіпотермії очей кролика відбувається зниження епібульбарної температури і температури внутрішньоочних середовищ, як під час охолодження безпосередньо зовнішньої поверхні рогівки, так і під час впливу холоду через закриті повіки. Ключові слова: внутрішньоочна температура, локальна гіпотермія, око кролика, математична модель ока. Для цитування: Анатичук ЛІ, Пасєчнікова НВ, Науменко ВО, Задорожний ОС, Назаретян РЕ, Кобилянський РР, Верешко ЄЮ. Динаміка внутрішньоочної температури в умовах локальної гіпотермії (експериментальне дослідження та математичне моделювання). Журнал Національної академії медичних наук України. 2019;25(4):383–8

scholarly journals In Silico Investigation of Mitragynine and 7-Hydroxymitragynine Metabolism

2019 ◽  
Author(s):  
Taweetham Limpanuparb ◽  
Rattha Noorat ◽  
Yuthana Tantirungrotechai
Keyword(s):  
Gas Phase ◽  
In Silico ◽  
Metabolic Pathways ◽  
Experimental Studies ◽  
Medicinal Uses ◽  
Detection Techniques ◽  
Mass Spectrom ◽  
Gibbs Energies ◽  
In Silico Study

Abstract Objective: Mitragynine is the main active compound of Mitragyna speciose (Kratom in Thai). The understanding of mitragynine derivative metabolism in human body is required to develop effective detection techniques in case of drug abuse or establish an appropriate dosage in case of medicinal uses. This in silico study is based upon in vivo results in rat and human by Philipp et al. (J. Mass Spectrom., 2009, 44, 1249.) Results: The gas-phase structures of mitragynine, 7-hydroxymitragynine and their metabolites were obtained by quantum chemical method at B3LYP/6-311++G(d,p) level. Results in terms of standard Gibbs energies of reaction for all metabolic pathways are reported with solvation energy from SMD model. We found that 7-hydroxy substitution leads to changes in reactivity in comparison to mitragynine: position 17 is more reactive towards demethylation and conjugation to a glucuronide and position 9 is less reactive towards conjugation to a glucuronide. Despite the changes, position 9 is the most reactive for demethylation and position 17 is the most reactive for conjugation to a glucuronide for both mitragynine and 7-hydroxymitragynine. Our results suggest that 7-hydroxy substitution could lead to different metabolic pathways and raise an important question for further experimental studies of this more potent derivative.

scholarly journals Interactions Between Ephedra sinica and Prunus armeniaca: From Stereoselectivity to Deamination as a Metabolic Detoxification Mechanism of Amygdalin

2021 ◽  
Vol 12 ◽  
Author(s):  
Yan Qin ◽  
Shanshan Wang ◽  
Qiuyu Wen ◽  
Quan Xia ◽  
Sheng Wang ◽  
...  
Keyword(s):  
Rat Liver ◽  
Metabolic Pathways ◽  
Liver Microsomes ◽  
Prunus Armeniaca ◽  
Rat Liver Microsomes ◽  
Microbial Enzymes ◽  
Ephedra Sinica ◽  
Metabolic Detoxification ◽  
Detoxification Pathway

Mahuang–Xingren (MX, Ephedra sinica Stapf-Prunus armeniaca L.) is a classic herb pair used in traditional Chinese medicine. This combined preparation reduces the toxicity of Xingren through the stereoselective metabolism of its main active ingredient amygdalin. However, whether stereoselectivity is important in the pharmacokinetic properties of amygdalin either in the traditional decoction or in the dispensing granules is unclear. Amygdalin is hydrolyzed to its metabolite, prunasin, which produces hydrogen cyanide by degradation of the cyano group. A comprehensive study of the metabolic pathway of amygdalin is essential to better understand the detoxification process. In this article, the potential detoxification pathway of MX is further discussed with regard to herb interactions. In this study, the pharmacokinetic parameters and metabolism of amygdalin and prunasin were investigated by comparing the traditional decoction and the dispensing granule preparations. In addition, several potential metabolites were characterized in an incubation system with rat liver microsomes or gut microbial enzymes. The combination of Xingren with Mahuang reduces exposure to D-amygdalin in vivo and contributes to its detoxification, a process that can be further facilitated in the traditional decoction. From the in vitro co-incubation model, 15 metabolites were identified and classified into cyanogenesis and non-cyanogenesis metabolic pathways, and of these, 10 metabolites were described for the first time. The level of detoxified metabolites in the MX traditional decoction was higher than that in the dispensing granules. The metabolism of amygdalin by the gut microbial enzymes occurred more rapidly than that by the rat liver microsomes. These results indicated that combined boiling both herbs during the preparation of the traditional decoction may induce several chemical changes that will influence drug metabolism in vivo. The gut microbiota may play a critical role in amygdalin metabolism. In conclusion, detoxification of MX may result 1) during the preparation of the decoction, in the boiling phase, and 2) from the metabolic pathways activated in vivo. Stereoselective pharmacokinetics and deamination metabolism have been proposed as the detoxification pathway underlying the compatibility of MX. Metabolic detoxification of amygdalin was quite different between the two combinations, which indicates that the MX decoctions should not be completely replaced by their dispensing granules.

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