INTRODUCTION:

In recent years, research has expanded our understanding of the physiology of mPTP in cellular functions. mPTP has its own significant position in the regulаtion аnd control of cellulаr processes^1,2. For example, in Ca²⁺ transport³, in the generation and transmission of cerebrospinal fluid signals⁴, in the lifespan of cells⁵ and in cellular metabolism⁶ mPTP transition to the open state is observed.

Therefore, changes in mPTP conformation and its transition to a dysfunctional state are factors that cause cell deаth in the form of арoрtosis^7,8. Even small changes in mPTP conformation can affect the cellular metabolism.

The structure and subunits of mPTP (VDAC (voltage-dependent anion channel, ANT, CypD, TSPO, Bcl-2) are of great importance for understanding the mechanisms of mitochondrial development and their correction under the influence of biologically active substances in pathological processes^11,12,13.

However, scientific research in recent years has revealed information that mPTP function can be controlled under the influence of certain pharmacological modulators in pathological conditions^14,15,16. These data proved that mPTP is an important object not only in biology but also in medicine and pharmacology.^14,17. Strategies for targeting mitochondrial dysfunction with drugs offer new opportunities for further study of mitochondrial function and therapeutic treatment of various diseases. ^17,18. The activity of cyclosporine A, which is considered an mPTP inhibitor, is a clear confirmation of our point of view¹⁹. Cyclosporine A acts on cyclophilin D, a subunit of mPTP, influencing the entry of Ca2+ ions into mitochondria²⁰ and inhibits the opening of mPTP by preventing its conformational changes. Thus, cyclosporine A is a pharmacological regulator of mPTP ¹⁹. Today, in addition to Cyclosporine A, several other mPTP inhibitors are known in science.^21,22. It is also known that adenine nucleotides ATF and ADF²³, oligomycin²⁴ actively inhibit the opening of mPTP²⁵. Ubiquinone, buterol, bongcreat, sodium hydrosulfide, progesterone, and doxorubicin are also considered pharmacological modulators of mPTP.^26,27.

Recent scientific research in medicine and biology has proven that there are a number of pharmacological agents that inhibit the opening of mPTP and prevent its dysfunctional state. This served as the basis for introducing the term "mitochondrial therapy" or "mitochondrial pharmacology" into science^16,28. In this regard, the leading scientific direction is considered to be the fact that mitochondria and their functional activity can be pharmacologically controlled under the influence of bioactive substances isolated from plants. The soft therapeutic effect of plant bioactive substances on the body in various pathologies, low-toxicity action allows them to be used as pharmacological agents. Thus, the molecular structure and dysfunction of mPTP serve as the goals of the strategy in the development of new types of drugs^29,³⁰^,31.

Pharmacological treatment of mPTP dysfunction with plant bioactive substances has attracted the attention of pharmacologists, medicine and biologists. The number of scientific studies conducted in this direction is increasing every day. For example, studies have shown that some bioactive substances hаvе аn inhibitory effect on thе statе of mPTP, while others exhibit the opposite (activator) properties^26,27,32.

Plant organs and their extracts contain many types of biologically active substances: alkaloids, flavonoids, polyphenols and tannins³³. Among them, polyphenols and tannins are substances with a wide pharmacological spectrum and exhibit a strong inhibitory effect on mPTP ^26,27,32. Рolурhеnols аnd flаvonoids аrе considered powerful antioxidants due to the ability of their hydroxyl groups to donate hydrogen, as well as their ability to donate electrons to stop the formation of free radicals due to oxidative stress³⁴. Рolурhеnols imрrovе mitochondriаl functions, еsрeciаlly electron transport activity, modulate the redox state and inhibit the apoptotic system²¹. Polyphenols can directly or indirectly affect mitochondria. Some of them can affect electron transport in the mitochondrial respiratory chain and ATP sуnthеsis. Currently, polyphenols (rutan, quercetin, slimarin, resveratrol, curcumin, epigallocatechin-3-gallate, quercetin) are considered the most effective plant bioactive substances^37,38,39,40. Therefore, many scientists are interested in the possibility of controlling cellular metabolic processes by regulating mPTP dysfunction under the influence of bioactive substances. Such approaches are of great importance for studying adaptation mechanisms of cells in extreme conditions and prevention of apoptosis. The search for pharmacological modulators of mPTP conformation is considered relevant, and effective treatment of diseases under their influence is promising in pharmacotherapy^28,29,45,46.

Mitochondrial effects of compounds should be studied deeply in order to predict the negative or positive effects of extracts and herbal preparations. This is because, current topics include research on the detection and correction of mPTP dysfunction, as well as the identification of mechanisms of action at the molecular, mitochondrial and cellular levels.

Materials and research methods:

Biological active cubstances studied in this article isolated by PhD Rahimov R. N, Phd Makhmudov R. R, Lutpillayev G’. X, Madrahimova S. D who are senior researchers and doctoral students of Academy of Sciences of Uzbekistan Institute of Bioorganic chemistry.

Isolation of polyphenol extracts:

Extracts from the aerial parts of Karelinia caspia and Cydonia oblonga were extracted as follows: To remove lipophilic compounds, 1000g of plant material was extracted with chloroform (grinding degree 8-10mm), (ratio 1:6, by volume) at a temperature of 45^oC for 2 hours, in a water bath with reflux, repeated 3 times. The extracts were filtered and the crude material was dried at room temperature until the odor of chloroform disappeared (48hours). Then the raw material was extracted 3 times in 70% aqueous acetone (ratio 1:6, by volume) at 45^oC for 2 hours. The extracts were filtered, and the aqueous part was separated by distilling off acetone under vacuum at a temperature of 35-40^oC. The aqueous fraction was extracted with ethyl acetate (1:4, v/v) to obtain the ethyl acetate fraction. This fraction was dried over anhydrous Na₂SO₄ salt, filtered and rotary evaporated to obtain a concentrate with ethyl acetate. By precipitating the concentrate with chloroform in a ratio of 1:4, 5.9% of polyphenols were isolated in terms of the dry weight of the plant.

Isolation of mitochondria:

Rat liver mitochondria were isolated by differential centrifugation⁴⁷. The composition of the excrасtion medium is as follows: 250mM sucrose, 10mM Tris-HCl, 1mM EDTA, pH 7.4. The rat liver was homogenized in a pre-prepared frozen exctraction medium and centrifuged in two stages. The resulting mitochondrial pellet was stored in a 10:1 solution of 250mM sucrose and 10mM Tris-HCl in a container on ice. Mitochondrial protein is found according to the Peterson modification according to the Lowry method⁴⁸.

Measurement of mitochondrial swelling:

The kinetics of mitochondrial swelling was 0.3-0.4 mg/ml. The optical density of the mitochondrial suspension was determined in a UV-5000 spectrophotometer at 540nm⁴⁹ in an open cell (volume 3 ml) at 26°C and constant stirring according to change. To determine mPTP and mitochondrial permeability, the following incubation medium (IM) was used: 200mM sucrose, 20μM EGTA, 5μM succinate, 2μM rotenone, 1 μg/ml oligomycin, 20mM Tris, 20mM HEPES, and 1 mM KH₂PO₄, pH 7.4⁴⁹.

RESULTS:

Some endogenous factors (Ca²⁺, adenine nucleotides, nitric oxide, ROS, pyrimidine and thiol redox states, Bcl2 proteins) have an inducing effect on mPTP permeability and transfer it to an open state⁴⁵. The use of fixed concentrations of Ca²⁺ ions is generally considered by some researchers to be one of the most effective methods for searching for pharmacological modulators of mPTP and has become an experimental tradition. ^{32, 50}. Therefore, we used Ca²⁺ ions as an inducer of mPTP induction. In the initial screening experiments, the addition of 10μM Ca²⁺ ions to IM had an inducing effect on mPTP at time (t-5) and increased its permeability. The obtained results were taken as a control for comparing the indices of the experimental groups and were taken as 100%.

Screening experiments to study the biological activity of the extracts were first carried out on the polyphenol extract PF-1 isolated from Karelinia caspia. In the experiments, the addition of the polyphenol extract PF-1 (from 1μg/ml to15μg/ml) to the incubation medium had an inhibitory effect on mPTP. The addition of 1μg/ml of the PF-1 extract to the incubation medium led to an increase in the mitochondrial density by 66,2±2,8 times and inhibition of mPTP permeability by (33,8%) compared to the control. Different concentrations of PF-1 were added to the incubation medium during the experiment. That is, the number of mitochondria in the amount of 5μg/ml PF-1 was 52.9±2.4, in the amount of 10μg/ml – 34,3±1,7, and in the amount of 15μg/ml – 18,7±1,4 and the permeability of mPTP was inhibited (by 47,1%, 65,7%, 81,3%) compared to the control, respectively. (Figure 1).

Figure 1. А) UV-5000 spectrophotometer image recorded at 540 nm wavelength, B) The effect of PF-1 polyphenol extract isolated from oqbosh (Karelinia caspia) on rat liver mitochondria mРТР.

Explanation:

On the ordinate axis – mPTP conductance in mitochondria is expressed as %; the abscissa axis shows the amount of PF-1 polyphenol extract in the incubation medium. *Р<0.05; **Р<0.01; ***Р<0.001; n=7.

Changing the technologies of extracting biologically active substances at modern pharmaceutical enterprises allows changing the pharmacokinetic parameters of pharmacological modulators in a certain range. In the process of extracting biologically active substances from plants, in some cases this gives positive results, in others - negative. These indicators allow giving an objective characteristic of the substance, as well as increasing scientific information about the substance being studied. ^51,52.

In our article (Cydonia Oblonga) we would like to dwell on the biologically active substances isolated from quince and their pharmacological properties. Because quince (Cydonia Oblonga) has higher medicinal properties than other types of fruit plants in folk medicine. Bioactive substances (tannins, phenolic compounds, vitamins, macro- and microelements, organic acids) extracted from the fruits and stems of bexi strengthen the human immune system, normalize blood pressure, are of great importance in normalizing brain activity, ensuring the strength of bones and teeth. ^53,54.

Therefore, in our next experiments, we investigated the effect of isolated PF-4 polyphenol extract (Cydonia Oblonga) on mPTP of rat liver mitochondria (Fig. 3). The inhibitory property of PF-4 polyphenol extract was observed depending on the amounts (from 2 μg/ml to 15 μg/ml) added to the incubation medium. However, the inhibitory activity of PF-4 polyphenol extract on mPTP permeability was more active than that of PF-1 polyphenol extract.

Figure 2. A) UV-5000 spectrophotometer image recorded at 540 nm wavelength, B) The effect of PF-4 polyphenol extract isolated from the leaf of quince (Сydonla Оblonga) on rat liver mitochondria mРТР.

Explanation: on the ordinate axis – mPTP conductance in mitochondria is expressed as %; the abscissa axis shows the amount of PF-4 polyphenol extract in the incubation medium. *Р<0.05; **Р<0.01; ***Р<0.001; n=7

In the experiments, the addition of 2μg/ml of PF-4 polyphenol extract to the incubation medium resulted in mitochondrial swelling of 65,4±2,8. These data prove that PF-4 causes inhibition of mPTP permeability (34.6%). When PF-4 (5, 10, 15μg/ml) was added to the incubation medium, mitochondrial swelling was observed under the action of Ca²⁺ ions, 45,1±2,4 at 5 μg/ml, 35 at 10μg/ml, it was 4±1,47 and 16,6±0,8 at 15 μg/ml. According to the obtained results, the polyphenol extract PF-4 inhibited the permeability of mPTP (by 54, 9%, 64,6% and 83,4%). The determined % values prove that the inhibitory activity of the polyphenol extract PF-4 on mPTP permeability is slightly more active than that of the polyphenol extracts PF-1. (Figure 3).

DISCUSSION:

In sources, during pathological processes- cardiovascular, neurodegenerative diseases, hypoxia, oxidative stress and other conditions, the concentration of Ca²⁺ in the mitochondrial matrix is 100-200 nmol/l⁵⁵ an increase in the amount leads to a decrease in the transmembrane potential of mitochondria, which leads to the transition of mPTP to an open conformational state. Exceeding the maximum limit of this state activates caspase enzymes by releasing cytochrome c and similar pro-apoptotic proteins from the intermembrane space into the cell cytosol, increasing permeability for water and dissolved ions in the matrix and activating the apoptosis mechanism. The open conformational state of mPTP, in turn, causes the cessation of ATP synthesis, disruption of the integrity of the outer mitochondrial membrane, cessation of bioenergetic functions, apoptosis or necrotic cell death. Currently, mPTP permeabilization can be controlled by pharmacological agents (cyclosporine A, ubiquinone, buterol, bongcreat, sodium hydrosulfide, progesterone, doxorubicin).^26,27. However, the effect of plant-based bioactive substances on mPTP permeability is multi-effective. According to the literature, polyphenols interact with amino acid residues of the N-terminal helix of VDAC, changing the protein conformation and inhibiting mPTP opening.⁵⁶. We propose that polyphenol extracts have an inhibitory effect on mitochondrial membrane peroxidation due to their strong antioxidant properties, that is, polyphenols can directly interact with mPTP components or modify mPTP protein to inhibit pores²¹.

In this article, the inhibitory effect of polyphenol extracts isolated from plant organs (Karelinia caspia) and (Cydonia oblonga) and polyphenol extracts isolated from rat plants on the permeabilization state of mPTP was studied.

CONCLUSION:

As can be seen from the above experiments, PF-1 and PF-4 extracts isolated from plants (Karelinia caspia) and (Cydonia oblonga) had an inhibitory effect on mPTP permeability induced by Ca²⁺ ions. mPTP mitochondria are a "target" for pharmacological agents, which has been proven once again by scientific research. The results show that PF-1 and PF-4 extracts have inhibitory and corrective properties in relation to mPTP permeabilization. The results allow us to create effective drugs based on PF-1 and PF-4 extracts that have a membrane-active effect in regulating mitochondrial processes in cell physiology.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

The authors would like to thank the Institute of Biophysics and Biochemistry under the State University of Uzbekistan and the Institute of Bioorganic Chemistry of the Academy of Sciences of the Republic of Uzbekistan

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Received on 16.08.2024 Revised on 12.11.2024

Accepted on 18.01.2025 Published on 10.04.2025

Available online from April 12, 2025

Research J. Pharmacy and Technology. 2025;18(4):1825-1830.

DOI: 10.52711/0974-360X.2025.00261

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