scholarly journals In vitro and in vivo effect of 3-Para-fluorobenzoyl-propionic acid on rat liver mitochondrial permeability transition pore opening and lipid peroxidation

2020 ◽  
Vol 5 (1) ◽  
pp. 39-44 ◽  
Author(s):  
Adeola O. Olowofolahan ◽  
Omosola L. Bolarin ◽  
Olufunso O. Olorunsogo
Keyword(s):  
Lipid Peroxidation ◽  
Cytochrome C ◽  
Propionic Acid ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Mitochondrial Atpase ◽  
Cytochrome C Release ◽  
Mitochondrial Permeability ◽  
Pore Opening

AbstractThe opening of mitochondrial permeability transition (mPT) pore is a well recognized important event in the execution of mitochondrial-mediated apoptosis. Some bioactive compounds induce apoptosis in tumour cells via the induction of mPT pore opening. This study therefore investigated the effect of 3-Para-fluorobenzoyl-propionic acid (3PFBPA), a metabolite of haloperidol on mPT pore, mitochondrial ATPase activity (mATPase), mitochondrial lipid peroxidation (mLPO) and cytochrome c release (CCR). Thirty-two male Wistar rats, were acclimatized for 14 days in clean cages. After 30 days of treatment, they were sacrificed and the liver mitochondria isolated using differential centrifugation. The mPT pore, mATPase, mLPO and CCR were determined by standard methods using a spectrophotometer. The mPT pore opening was induced by 3PFBPA by 1.4, 3.6, 5.6, 6.6 and 7.4 folds, when compared with the control. Also, there was release of cytochrome c and enhancement of mATPase activity by 3PFBPA. The results also show that 3PFBPA reduced lipid peroxidation. However, oral administration of 3PFBPA at 50, 100 and 200 mg/kg did not have any effect on mPT pore opening and mATPase activity when compared with the control but there was inhibition of mLPO. These findings suggested the pharmacological potential of 3PFBPA against the pathological processes related to insufficient apoptosis (based on the in vitro data) and oxidative stress due to its anti-lipidperoxidative effect.

scholarly journals Metformin induces apoptosis via uterus mitochondrial permeability transition pore opening and protects against estradiol benzoate-induced uterine defect and associated pathophysiological disorder in female Wistar rats

2021 ◽  
Vol 45 (1) ◽  
Author(s):  
Adeola Oluwakemi Olowofolahan ◽  
Obinna Matthew Paulinus ◽  
Heritage Mojisola Dare ◽  
Olufunso Olabode Olorunsogo
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Estradiol Benzoate ◽  
Histological Evaluation ◽  
Mitochondrial Atpase ◽  
Rat Uterus ◽  
Mitochondrial Permeability ◽  
Pore Opening

Abstract Background Some antitumor or anticancer agents have been shown to execute cell death by induction of mitochondrial permeability transition (mPT) pore opening in order to elicit their chemotherapeutic effect. Therefore, this study investigated the effect of metformin on cell death via rat uterus mPT pore and estradiol benzoate-induced uterine defect and associated pathophysiological disorder in female rat. Mitochondria were isolated using differential centrifugation. The mPT pore opening, cytochrome c release and mitochondrial ATPase activity were determined spectrophotometrically. Caspases 9 and 3 activities, MDA and estradiol levels and SOD, GSH activities, were determined using ELISA technique. Histological and histochemical assessments of the uterine section were carried out using standard methods. Results Metformin at concentrations 10–90 μg/mL, showed no significant effect on mPT pore opening, mATPase activity and release of cytochrome c. However, oral administration of metformin caused mPT pore opening, enhancement of mATPase activity and activation of caspases 9 and 3 significantly at 300 and 400 mg/kg. Metformin protected against estradiol benzoate (EB)-induced uterine defect and other associated pathophysiological disorder. It also improved the antioxidant defense system. The histological evaluation revealed the protective effect of metformin on the cellular architecture of the uterus while the histochemical examination showed severe hyperplasia in the uterine section of EB-treated rats, remarkably reversed by metformin co-treatment. Conclusion This study suggests that metformin at high doses induces apoptosis via rat uterus mPT pore opening and protects against EB-induced uterine defect (hyperplasia) and associated pathophysiological disorder.

scholarly journals Toxic Effects of Unripe Carica papaya (Linn) Fruit Extract on Healthy Rat Liver Mitochondria

2021 ◽  
Author(s):  
Olubukola T. Oyebode ◽  
Adeola O. Olowofolahan ◽  
Olufunso O. Olorunsogo
Keyword(s):  
Lipid Peroxidation ◽  
Cytochrome C ◽  
Atpase Activity ◽  
Carica Papaya ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Fruit Extract ◽  
Mitochondrial Permeability ◽  
Pore Opening ◽  
Mitochondrial Lipid

The opening of the mitochondrial Permeability Transition (mPT) pore proceeds the activation of programmed cell death (apoptosis) and its functional status serves as marker of mitochondrial health. Unripe fruits of Carica papaya are used in the traditional treatment of several diseases. There is paucity of information on the level of safety of the consumption of the plant. The effects of crude Methanol Extract of Carica papaya (MECP) on the status of the mPT pore in healthy rat liver was investigated in this study. Mitochondrial FOF1 ATPase activity, mitochondrial permeability transition and mitochondrial lipid peroxidation as well as the release of cytochrome c were evaluated spectrophotometrically using standard methods. The MECP activated mPT pore opening in the absence of calcium in a concentration-dependent fashion.  Specifically, induction folds of 3.1, 6.0, 9.1, 11.9 and 14.3 were recorded at 20, 60,100, 140and 180 µg/ml, respectively. In addition, MECP potentiated calcium-induced pore opening of the mPT pore in a concentration-dependent style by   22.5, 24.1, 25.0, 25.1 and 25.5 folds, respectively at 20, 60, 100, 140 and 180 µg/mL. Furthermore, mitochondrial ATPase activity was significantly (p < 0.001) stimulated at pH (7.4) while the extent of cytochrome c release increased by 5 and 7 folds respectively at the highest concentrations tested. Interestingly, Fe2+-induced mitochondrial lipid peroxidation was inhibited by varying concentrations of MECP.  Specifically, significant (p < 0.001) reduction in levels of mitochondrial lipid peroxides were observed at 50, 100, 200, 300, 600 µg/ml MECP by 10, 22, 53, 74, 112 %, respectively. These findings indicate that unripe Carica papaya fruit extract contains bioactive compounds that cause mitochondrial injury via activation of the mitochondrial permeability transition pore opening in healthy liver cells. Hence, its use in the management of diseases should be approached with caution.

scholarly journals Investigating the Modulatory Effect of Methanol Extract of Daniellia oliveri (ROLFE) Leaves on Mitochondrial Membrane Permeability Transition (MPT) Pore

2020 ◽  
pp. 40-51
Author(s):  
Jonah Achem ◽  
Cosmos Ifeanyi Onyiba ◽  
Mobolaji T. Akinwole ◽  
Jemimah M. Malgwi ◽  
Omosola L. Bolarin ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Methanol Extract ◽  
Permeability Transition ◽  
Mitochondrial Atpase ◽  
Cytochrome C Release ◽  
Methanol Fraction ◽  
Pore Opening ◽  
Daniellia Oliveri ◽  
Crude Methanol Extract

Background: Mitochondrial-mediated cell death begins with opening of mitochondrial membrane permeability transition (mPT) pore and medicinal plants contain phytochemicals that modulate the mPT pore. Hypothesis and Purpose: We investigated the modulatory effects of crude methanol extract of Daniellia oliveri leaves (CMDO) on mPT pore in vitro. Study Design and Methods: Phytochemical screening and antioxidant activities of crude methanol extract of Daniellia oliveri leaves (CMDO) were evaluated according to standard procedures. CMDO was partitioned into chloroform fraction (CFDO), ethyl acetate fraction (EFDO) and methanol fraction (MFDO) by Vacuum liquid chromatography (VLC). Effects of CMDO, CFDO, EFDO and MFDO on mPT pore were assessed by spectrophotometry. Effects of the most potent fraction on mitochondrial ATPase, Fe-induced lipid peroxidation and cytochrome c release were assessed by spectrophotometry. CMDO was subjected to GC-MS analysis to identify the bioactive compounds present. Results: CMDO contains phytochemicals and showed appreciable total flavonoid content (0.483±0.02 QE mg/100g), total phenolic content (0.886±0.12 GAE mg/100g), total antioxidant capacity (0.039±0.001 AE mg/100 g), ferric antioxidant reducing power (IC50=350 µg/ml) and 2, 2-diphenyl-1 picrylhydrazyl (DPPH) radical scavenging activity (IC50=166 µg/ml). The maximum induction of mPT pore opening in the absence and presence of calcium, respectively, were as follows: CMDO (10.11 folds, 5.18 folds), CFDO (19.9 folds, 16.3 folds), EFDO (7.5 folds, 23.2 folds), MFDO (22.2 folds, 31.3 folds). The most potent mPT pore-opening fraction (MFDO) enhanced mitochondrial ATPase activity, inhibited Fe-induced lipid peroxidation and caused cytochrome c release. GC-MS analysis of CMDO revealed the presence of bioactive compounds including methyl propanamide, Dibutyl phthalate, saturated and unsaturated fatty acids. Conclusion: Methanol fraction (MFDO) of CMDO most potently induced mPT pore opening via enhancement of mitochondrial ATPase activity, which was substantiated by the release of cytochrome c (in vitro). This includes MFDO as a candidate pharmacologic remedy for diseases associated with insufficient apoptosis.

scholarly journals Metformin inhibits mitochondrial permeability transition and cell death: a pharmacological in vitro study

2004 ◽  
Vol 382 (3) ◽  
pp. 877-884 ◽  
Author(s):  
Bruno GUIGAS ◽  
Dominique DETAILLE ◽  
Christiane CHAUVIN ◽  
Cécile BATANDIER ◽  
Frédéric De OLIVEIRA ◽  
...  
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Cytochrome C Release ◽  
Intact Cells ◽  
Human Carcinoma ◽  
Butyl Hydroperoxide ◽  
Mitochondrial Permeability ◽  
New Findings

Metformin, a drug widely used in the treatment of Type II diabetes, has recently received attention owing to new findings regarding its mitochondrial and cellular effects. In the present study, the effects of metformin on respiration, complex 1 activity, mitochondrial permeability transition, cytochrome c release and cell death were investigated in cultured cells from a human carcinoma-derived cell line (KB cells). Metformin significantly decreased respiration both in intact cells and after permeabilization. This was due to a mild and specific inhibition of the respiratory chain complex 1. In addition, metformin prevented to a significant extent mitochondrial permeability transition both in permeabilized cells, as induced by calcium, and in intact cells, as induced by the glutathione-oxidizing agent t-butyl hydroperoxide. This effect was equivalent to that of cyclosporin A, the reference inhibitor. Finally, metformin impaired the t-butyl hydroperoxide-induced cell death, as judged by Trypan Blue exclusion, propidium iodide staining and cytochrome c release. We propose that metformin prevents the permeability transition-related commitment to cell death in relation to its mild inhibitory effect on complex 1, which is responsible for a decreased probability of mitochondrial permeability transition.

scholarly journals Bax-induced Cytochrome C Release from Mitochondria Is Independent of the Permeability Transition Pore but Highly Dependent on Mg2+ Ions

1998 ◽  
Vol 143 (1) ◽  
pp. 217-224 ◽  
Author(s):  
Robert Eskes ◽  
Bruno Antonsson ◽  
Astrid Osen-Sand ◽  
Sylvie Montessuit ◽  
Christoph Richter ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cyclosporin A ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Cytochrome C Release ◽  
Mitochondrial Permeability ◽  
Isolated Mitochondria ◽  
Mammalian Homologue

Bcl-2 family members either promote or repress programmed cell death. Bax, a death-promoting member, is a pore-forming, mitochondria-associated protein whose mechanism of action is still unknown. During apoptosis, cytochrome C is released from the mitochondria into the cytosol where it binds to APAF-1, a mammalian homologue of Ced-4, and participates in the activation of caspases. The release of cytochrome C has been postulated to be a consequence of the opening of the mitochondrial permeability transition pore (PTP). We now report that Bax is sufficient to trigger the release of cytochrome C from isolated mitochondria. This pathway is distinct from the previously described calcium-inducible, cyclosporin A–sensitive PTP. Rather, the cytochrome C release induced by Bax is facilitated by Mg2+ and cannot be blocked by PTP inhibitors. These results strongly suggest the existence of two distinct mechanisms leading to cytochrome C release: one stimulated by calcium and inhibited by cyclosporin A, the other Bax dependent, Mg2+ sensitive but cyclosporin insensitive.

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