Effect of betulin and betulonic acid on isolated rat liver mitochondria and liposomes

Dubinin, Mikhail V.; Semenova, Alena A.; Ilzorkina, Anna I.; Mikheeva, I. B.; Yashin, V. A.; Penkov, Nikita V.; Выдрина, В. А.; Ishmuratov, G. Yu.; Sharapov, Vyacheslav A.; Khoroshavina, E. I.; Gudkov, Sergey V.; Belosludtsev, Konstantin N.

doi:10.1016/j.bbamem.2020.183383

Cited by 34 publications

(28 citation statements)

References 44 publications

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“…The antitumor as well as the cytotoxic effect of betulin and other triterpenoids is due to ROS overproduction and the development of oxidative stress in cells [ 34 ]. It is believed that mitochondria-targeted compounds based on DLCs have a powerful effect on the redox state of cells, contributing, in particular, to an increase in the generation of ROS in mitochondria [ 14 , 15 , 17 ].…”

Section: Resultsmentioning

confidence: 99%

“…We have previously demonstrated that betulin exhibits pronounced membranotropic properties, facilitating the aggregation and permeabilization of biological membranes, including mitochondrial and artificial membranes [ 34 ]. One could assume that F16-betulin conjugate, possessing similar properties, will accumulate in mitochondrial membranes and affect the surface properties of organelles and their components.…”

Section: Resultsmentioning

confidence: 99%

“…This, in turn, may be due to a decrease in the activity of complexes of the electron transport chain of organelles or reversion of the activity of ATP synthase, leading to ADP conservation and maintenance of a high rate of oxygen consumption in state 4 [ 37 ]. We have previously shown that triterpenoids and, in particular, betulin, accumulating in the inner membrane of mitochondria, may significantly affect the redox activity of complexes of the mitochondrial electron transport chain [ 34 ]. The same is observed in the case of hybrids of F16 and betulinic acid, which have a powerful modulating effect on the ETC complexes [ 6 ].…”

Section: Resultsmentioning

confidence: 99%

“…In this case, we studied the effect of the conjugate on the state of organelle membranes and basic parameters reflecting the functional activity of rat liver mitochondria. We have previously shown that native betulin can easily integrate into the lipid bilayer of the membrane, forming domains enriched in triterpenoid and leading to phase separation [ 34 ]. These structural changes presumably contribute to further changes in membrane dynamics, causing loss of their integrity and membrane aggregation/fusion.…”

Section: Discussionmentioning

confidence: 99%

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Effect of F16-Betulin Conjugate on Mitochondrial Membranes and Its Role in Cell Death Initiation

et al. 2021

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This work demonstrates the effects of a newly synthesized conjugate of the plant triterpenoid betulin and the penetrating cation F16 used for mitochondrial targeting. The resulting F16-betulin conjugate revealed a mitochondria-targeted effect, decreasing the mitochondrial potential and inducing superoxide overproduction in rat thymocytes in vitro. It has been suggested that this may cause the cytotoxic effect of the conjugate, which significantly exceeds the effectiveness of its precursors, betulin and F16. Using isolated rat liver mitochondria, we found that the F16-betulin conjugate has a surface-active effect on mitochondrial membranes, causing organelle aggregation. This effect of the derivative resulted in a dose-dependent decrease in mitochondrial transmembrane potential, as well as suppression of respiration and oxidative phosphorylation, especially in the case of nicotinamide adenine dinucleotide (NAD)-fueled organelles. In addition, the F16-betulin conjugate caused an increase in H2O2 generation by mitochondria fueled with glutamate and malate. These effects of the derivative can presumably be due to the powerful suppression of the redox activity of complex I of the mitochondrial electron transport chain. The paper discusses how the mitochondria-targeted effects of the F16-betulin conjugate may be related to its cytotoxic effects.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Effect of F16-Betulin Conjugate on Mitochondrial Membranes and Its Role in Cell Death Initiation

et al. 2021

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“…It should be noted that betulin is capable of affecting metabolism at the cellular level, namely respiration and oxidative phosphorylation of rat liver mitochondria, but only in high concentrations (50 μM) [26]. Moderate concentrations of betulin in the range of 11-20 μM [27,28] demonstrate an ability to selectively suppress tumor growth without affecting the growth of normal cells.…”

Section: Introductionmentioning

confidence: 99%

Supported Silver Nanoparticles as Catalysts for Liquid-Phase Betulin Oxidation

et al. 2021

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Herein, it has been shown that betulin can be transformed into its biologically active oxo-derivatives (betulone, betulinic and betulonic aldehydes) by liquid-phase oxidation over supported silver catalysts under mild conditions. In order to identify the main factors determining the catalytic behavior of nanosilver catalysts in betulin oxidation, silver was deposited on various alumina supports (γ-alumina and boehmite) using deposition–precipitation with NaOH and incipient wetness impregnation methods, followed by treatment in H2 or O2. Silver catalysts and the corresponding supports were characterized by X-ray diffraction, nitrogen physisorption, inductively coupled plasma optical emission spectroscopy, photoelectron spectroscopy and transmission electron microscopy. It was found that the support nature, preparation and treatment methods predetermine not only the average Ag nanoparticles size and their distribution, but also the selectivity of betulin oxidation, and thereby, the catalytic behavior of Ag catalysts. In fact, the support nature had the most considerable effect. Betulin conversion, depending on the support, increased in the following order: Ag/boehmite < Ag/boehmite (calcined) < Ag/γ-alumina. However, in the same order, the share of side reactions catalyzed by strong Lewis acid centers of the support also increased. Poisoning of the latter by NaOH during catalysts preparation can reduce side reactions. Additionally, it was revealed that the betulin oxidation catalyzed by nanosilver catalysts is a structure-sensitive reaction.

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Transformations of pentacyclic triterpenoids as a route to the future medicines

Baltina¹,

Komissarova²

2023

Studies in Natural Products Chemistry

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Effect of betulin and betulonic acid on isolated rat liver mitochondria and liposomes

Cited by 34 publications

References 44 publications

Effect of F16-Betulin Conjugate on Mitochondrial Membranes and Its Role in Cell Death Initiation

Effect of F16-Betulin Conjugate on Mitochondrial Membranes and Its Role in Cell Death Initiation

Supported Silver Nanoparticles as Catalysts for Liquid-Phase Betulin Oxidation

Transformations of pentacyclic triterpenoids as a route to the future medicines

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