scholarly journals New Properties and Mitochondrial Targets of Polyphenol Agrimoniin as a Natural Anticancer and Preventive Agent

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2089
Author(s):  
Tatiana A. Fedotcheva ◽  
Olga P. Sheichenko ◽  
Nadezhda I. Fedotcheva
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Liver Mitochondria ◽  
Rat Liver Mitochondria ◽  
Dependent Manner ◽  
Anticancer Activities ◽  
Concentration Dependent Manner ◽  
Succinate Oxidation ◽  
Mitochondrial Functions

Agrimoniin is a polyphenol from the group of tannins with antioxidant and anticancer activities. It is assumed that the anticancer action of agrimoniin is associated with the activation of mitochondria-dependent apoptosis, but its mitochondrial targets have not been estimated. We examined the direct influence of agrimoniin on different mitochondrial functions, including the induction of the mitochondrial permeability transition pore (MPTP) as the primary mechanism of mitochondria-dependent apoptosis. Agrimoniin was isolated from Agrimonia pilosa Ledeb by multistep purification. The content of agrimoniin in the resulting substance reached 80%, as determined by NMR spectroscopy. The cytotoxic effect of purified agrimoniin was confirmed on the cultures of K562 and HeLa cancer cells by the MTT assay. When tested on isolated rat liver mitochondria, agrimoniin at a low concentration (10 µM) induced the low-amplitude swelling, which was inhibited by the MPTP inhibitors ADP and cyclosporine A, activated the opening of MPTP by calcium ions and stimulated the respiration supported by succinate oxidation. Also, agrimoniin reduced the electron acceptor DCPIP in a concentration-dependent manner and chelated iron ions. Owing to all these properties, agrimoniin can stimulate apoptosis or activate mitochondrial functions, which can be helpful in the prevention and elimination of stagnant pathological states.

scholarly journals Bisindolylpyrrole triggers transient mitochondrial permeability transitions to cause apoptosis in a VDAC1/2 and cyclophilin D-dependent manner via the ANT-associated pore

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Masami Koushi ◽  
Yasunori Aoyama ◽  
Yoshiko Kamei ◽  
Rei Asakai
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Liver Mitochondria ◽  
Rat Liver Mitochondria ◽  
Dependent Manner ◽  
Cyclophilin D ◽  
Cytoprotective Effect ◽  
Mitochondrial Permeability ◽  
Sirna Knockdown ◽  
Pkc Activation

Abstract Bisindolylpyrrole at 0.1 μM is cytoprotective in 2% FBS that is counteracted by cyclosporin-A (CsA), an inhibitor of cyclophilin-D (CypD). We hypothesized that the cytoprotective effect might be due to transient mitochondrial permeability transition (tPT). This study tested the hypothesis that bisindolylpyrrole can trigger tPT extensively, thereby leading to cell death under certain conditions. Indeed, CsA-sensitive tPT-mediated apoptosis could be induced by bisindolylpyrrole at > 5 μM in HeLa cells cultured in 0.1% FBS, depending on CypD and VDAC1/2, as shown by siRNA knockdown experiments. Rat liver mitochondria also underwent swelling in response to bisindolylpyrrole, which proceeded at a slower rate than Ca2+-induced swelling, and which was blocked by the VDAC inhibitor tubulin and the ANT inhibitor bongkrekate, indicating the involvement of the ANT-associated, smaller pore. We examined why 0.1% FBS is a prerequisite for apoptosis and found that apoptosis is blocked by PKC activation, which is counteracted by the overexpressed defective PKCε. In mitochondrial suspensions, bisindolylpyrrole triggered CsA-sensitive swelling, which was suppressed selectively by pretreatment with PKCε, but not in the co-presence of tubulin. These data suggest that upon PKC inactivation the cytoprotective compound bisindolylpyrrole can induce prolonged tPT causing apoptosis in a CypD-dependent manner through the VDAC1/2-regulated ANT-associated pore.

scholarly journals Mitochondria Permeabilization by a Novel Polycation Peptide BTM-P1

2005 ◽  
Vol 280 (16) ◽  
pp. 15579-15586 ◽  
Author(s):  
Victor V. Lemeshko ◽  
Mauricio Arias ◽  
Sergio Orduz
Keyword(s):  
Membrane Potential ◽  
Cyclosporin A ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Liver Mitochondria ◽  
Peptide Sequence ◽  
Rat Liver Mitochondria ◽  
Tryptophan Residue ◽  
Inner Membrane

Bacillus thuringiensissubsp.medellinis known to produce the Cry11Bb protein of 94 kDa, which is toxic for mosquito larvae due to permeabilization of the plasma membrane of midgut epithelial cells. Earlier we found that a 2.8-kDa novel peptide BTM-P1, which was artificially synthesized taking into account the primary structure of Cry11Bb endotoxin, is active against several species of bacteria. In this work we show that BTM-P1 induces cyclosporin A-insensitive swelling of rat liver mitochondria in various salt solutions but not in the sucrose medium. Inorganic phosphate and Ca2+significantly increased this effect of the peptide. The uncoupling action of BTM-P1 on oxidative phosphorylation was stronger in the potassium-containing media and correlated with a decrease of the inner membrane potential of mitochondria. In isotonic KNO3, KCl, or NH4NO3media, a complete drop of the inner membrane potential was observed at 1–2 μg/ml of the peptide. The peptide-induced swelling was increased by energization of mitochondria in the potassium-containing media, but it was inhibited in the NaNO3, NH4NO3, and Tris-NO3media. All mitochondrial effects of the peptide were completely prevented by adding a single N-terminal tryptophan residue to the peptide sequence. We suggest a mechanism of membrane permeabilization that includes a transmembrane- and surface potential-dependent insertion of the polycation peptide into the lipid bilayer and its oligomerization leading to formation of ion channels and also to the mitochondrial permeability transition pore opening in a cyclosporin A-insensitive manner.

scholarly journals The Effects of PK11195 and Protoporphyrin IX Can Modulate Chronic Alcohol Intoxication in Rat Liver Mitochondria under the Opening of the Mitochondrial Permeability Transition Pore

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1774
Author(s):  
Yulia Baburina ◽  
Irina Odinokova ◽  
Olga Krestinina
Keyword(s):  
Rat Liver ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Alcohol Exposure ◽  
Liver Mitochondria ◽  
Rat Liver Mitochondria ◽  
Chronic Alcohol ◽  
Mitochondrial Permeability

Decades of active research have shown that mitochondrial dysfunction, the associated oxidative stress, impaired anti-stress defense mechanisms, and the activation of the proapoptotic signaling pathways underlie pathological changes in organs and tissues. Pathologies caused by alcohol primarily affect the liver. Alcohol abuse is the cause of many liver diseases, such as steatosis, alcoholic steatohepatitis, fibrosis, cirrhosis, and, potentially, hepatocellular cancer. In this study, the effect of chronic alcohol exposure on rat liver mitochondria was investigated. We observed an ethanol-induced increase in sensitivity to calcium, changes in the level of protein kinase Akt and GSK-3β phosphorylation, an induction of the mitochondrial permeability transition pore (mPTP), and strong alterations in the expression of mPTP regulators. Moreover, we also showed an enhanced effect of PK11195 and PPIX, on the parameters of the mPTP opening in rat liver mitochondria (RLM) isolated from ethanol-treated rats compared to the RLM from control rats. We suggest that the results of this study could help elucidate the mechanisms of chronic ethanol action on the mitochondria and contribute to the development of new therapeutic strategies for treating the effects of ethanol-related diseases.

scholarly journals Fractions of Adenopus breviflorus Extract Modulate Calcium-induced Mitochondrial Permeability Transition Pore Opening in Rat Liver

2018 ◽  
Vol 3 (1) ◽  
pp. 21-27
Author(s):  
Tolulope A. Oyedeji ◽  
Chibuzor I. Akobi ◽  
Daniel O. Onireti ◽  
Olufunso O. Olorunsogo
Keyword(s):  
Rat Liver ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Rat Liver Mitochondria ◽  
Mitochondrial Atpase ◽  
Dependent Manner ◽  
Mitochondrial Permeability ◽  
Pore Opening

AbstractMitochondrial dysfunction (MD) and impaired apoptotic pathways cause irreversible opening of the Mitochondrial Permeability Transition (MPT) pore, resulting in several pathological conditions e.g. cancer, ageing and neurodegenerative diseases. Many bioactive compounds from plants have been identified as modulators of the MPT pore which makes them possible drugs for the management of MD associated diseases. Adenopus breviflorus (A.breviflorus) is a tropical medicinal plant used in folkore medicine as an abortifacient and in treating gonorrhoea. In this study, the effects of ethylacetate and methanol fractions of A.breviflorus were assessed on rat liver MPT pore and Mitochondrial ATPase (mATPase). The fruit of A.breviflorus was extracted with water to obtain the aqueous Extract (AEAB), which was fractionated using vacuum liquid chromatography (VLC) to obtain ethylacetate and methanol fractions of A.breviflorus (EFAB, and MFAB). The extent of MPT pore opening and mATPase by EFAB and MFAB were assayed spectrophotometrically. The results obtained showed that EFAB and MFAB have no significant inductive effect on the MPT pore in the absence of Ca2+. However, in the presence of Ca2+, EFAB inhibited calcium-induced MPT pore opening in a non-concentration dependent manner. Maximum inhibition of MPT pore opening was 57.1% at 50 μg/ml. Interestingly, MFAB potentiated calcium ion effect by opening the pore further. Specifically, MFAB opened the MPT pore by 11, 10, 17 and 9% at 50, 150, 250 and 350 μg/ml, respectively. Furthermore, EFAB and MFAB inhibited mATPase activity in rat liver mitochondria at 62.5, 187.5, 312.5 and 437.5 μg/ml by 2.6, 18.8, 37.3, 52.6% and 41.8, 6.8, 24.3, 8.4%, respectively. The ethylacetate and methanol fractions of Adenopus breviflorus possess potential phytochemicals that can modulate opening of the mitochondrial permeability transition pore and inhibit mitochondrial ATPase activity in rat liver. These fractions may find use in drug development against diseases where excessive apoptosis takes place.

scholarly journals Factors Affecting the Function of the Mitochondrial Membrane Permeability Transition Pore and Their Role in Evaluation of Calcium Retention Capacity Values

2020 ◽  
pp. 491-499
Author(s):  
Z DRAHOTA ◽  
R ENDLICHER ◽  
O KUČERA ◽  
D RYCHTRMOC ◽  
Z ČERVINKOVÁ
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Liver Mitochondria ◽  
Rat Liver Mitochondria ◽  
Experimental Conditions ◽  
Protein Ratio ◽  
Retention Capacity ◽  
Calcium Retention ◽  
Calcium Retention Capacity

Values of the calcium retention capacity (CRC) of rat liver mitochondria are highly dependent on the experimental conditions used. When increasing amounts of added calcium chloride are used (1.25-10 nmol), the values of the CRC increase 3-fold. When calcium is added in 75 s intervals, the CRC values increase by 30 % compared with 150 s interval additions. CRC values are not dependent on the calcium/protein ratio in the measured sample in our experimental design. We also show that a more detailed evaluation of the fluorescence curves can provide new information about mitochondrial permeability transition pore opening after calcium is added.

scholarly journals Age-Dependent Changes in the Function of Mitochondrial Membrane Permeability Transition Pore in Rat Liver Mitochondria

2021 ◽  
pp. 905-911
Author(s):  
R. Endlicher ◽  
Z. Drahota ◽  
O. Kučera ◽  
Z. Červinková
Keyword(s):  
Rat Liver ◽  
Mitochondrial Membrane ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Liver Mitochondria ◽  
Cell Aging ◽  
Rat Liver Mitochondria ◽  
Age Related ◽  
Old Rats

Mitochondria play an important role in the cell aging process. Changes in calcium homeostasis and/or increased reactive oxygen species (ROS) production lead to the opening of mitochondrial permeability transition pore (MPTP), depolarization of the inner mitochondrial membrane, and decrease of ATP production. Our work aimed to monitor age-related changes in the Ca2+ ion effect on MPTP and the ability of isolated rat liver mitochondria to accumulate calcium. The mitochondrial calcium retention capacity (CRC) was found to be significantly affected by the age of rats. Measurement of CRC values of the rat liver mitochondria showed two periods when 3 to17-week old rats were tested. 3-week and 17-week old rats showed lower CRC values than 7-week old animals. Similar changes were observed while testing calcium-induced swelling of rat liver mitochondria. These findings indicate that the mitochondrial energy production system is more resistant to calcium-induced MPTP opening accompanied by the damaging effect of ROS in adult rats than in young and aged animals.

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