Aim: The opening of mitochondrial permeability transition (mPT) pore is an important event in the execution of mitochondrial-mediated apoptosis. Some bioactive compounds elicit their chemotherapeutic effects against tumor/cancer cells via the induction of mitochondrial-mediated apoptosis. Annona muricata, a medicinal plant, is folklorically used in the treatment of tumors and cancers. This study therefore aimed at investigating the effect of methanol stem bark extract of Annona muricata (MEAM) on apoptosis via mPT pore and estradiol benzoate (EB)-induced proliferative disorder using female Wistar rats. Methodology: Mitochondria were isolated using differential centrifugation. The mPT pore opening, cytochrome c release and mitochondrial ATPase activity were determined spectrophotometrically. The levels of estrogen (E2), luteinizing hormone (LH), follicle stimulating hormone (FSH), malondialdehyde (MDA) and activities of superoxide dismutase (SOD), glutathione peroxidase (GSH), were determined using ELISA technique. Histological and histochemical assessments of the uterine sections were carried out using standard methods. Phytochemical constituents of MEAM were determined using Gas Chromatography-Mass Spectroscopy (GC-MS). Results: The in vitro results showed a significant induction of mPT pore opening, release of cytochrome c and enhancement of mitochondrial ATPase (mATPase) activity in a concentration-dependent manner. However, oral administration of MEAM did not induce rat uterine mPT pore opening, neither any significant release of cytochrome c nor enhancement of mATPase activity at the dosages used. Interestingly, MEAM reversed the EB-induced increase in E2, LH and FSH. The MEAM also improved the antioxidant milleu by reducing MDA level and increasing the SOD and GSH-Px activities in the treatment groups. Administration of EB induced endometrial hyperplasia in the model group which was mitigated by MEAM in the treatment group. The GC-MS analysis of MEAM revealed the presence of some important phytochemicals that are pharmacological relevant in cancer treatment. Conclusions: This study suggests that the methanol stem bark extract of Annona muricata contains bioactive compounds that protect against EB-induced uterine proliferative disorder in female Wistar rats.
Background Inflammation is a protective response of the host to infections and tissue damage and medicinal plants have been used to regulate inflammatory response. The phytochemical contents of the n -hexane fraction of Alstonia boonei and their anti-inflammatory potentials in lipopolysaccharide-induced inflammation were investigated in rat liver. Materials and Methods A quantity of 5 mg/kg lipopolysaccharide (LPS) was used to induce inflammation in twenty-five male Wistar rats, grouped (n = 5) and treated as follows: negative control (10 mL/kg saline), positive control (1 mg/kg ibuprofen); 50, 100 and 20 mg/kg of the n -hexane fraction of Alstonia boonei were administered to test groups. In another experiment, twenty rats (n = 5, without LPS) were administered the same doses of the n -hexane fraction of A. boonei and ibuprofen for seven days. At the end of the experiment, animals were sacrificed, serum was obtained from blood and liver mitochondria isolated in a refrigerated centrifuge. Mitochondrial permeability transition (mPT) pore opening and mitochondrial F 0 F 1 ATPase (mATPase) were determined spectrophotometrically. Serum interleukins 1β, 6 (IL-1β, IL-6), tumour necrosis factor alpha (TNF-α), C-reactive protein (CRP) and creatine kinase (CK), gamma glutamyl transferase (GGT), aspartate and alanine aminotransferases (AST and ALT,) of the animals in which inflammation was induced using LPS but treated with graded doses of n -hexane fraction of A. boonei were determined using the ELISA technique. The phytochemical contents of the n -hexane fraction of A. boonei were determined using ultra performance liquid chromatography-tandem mass spectrometer (UHPLC-MS). Results Calcium induced mPT in 8 fold and LPS induced mPT 14 fold in the negative control while the n -hexane fraction reversed mPT in the treated groups (50, 100 and 200 mg/kg) to 2, 4, 4 folds, respectively. LPS treatment of the negative group enhanced F 0 F 1 mATPase activity, increased CRP, TNF-α, IL-1β, IL-6 levels as well as CK, AST, ALT and GGT activities. These values were significantly reduced by 100 and 200 mg/kg of the n -hexane fraction. UHPLC-MS analysis of the fraction revealed the presence of terpenoids, phenolics and sphingolipids. Conclusion These results showed that bioactive phytochemicals present in the n -hexane fraction of A. boonei were not toxic, have an anti-inflammatory effect and could be used for the treatment of inflammatory diseases.
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.
Objectives Uterine fibroids are benign tumors that develop in many women of reproductive age. Surgery is the main approach to treatment while other options are also associated with adverse effects. Studies have shown that certain bioactive agents present in medicinal plants elicit their anti-tumor activity by induction of mitochondrial permeability transition (mPT) opening. This research therefore aimed at investigating the effect of methanol extract of Annona muricata (MEAM) on mPT pore opening in normal and monosodium glutamate-induced uterine hyperplasia using female Wistar rats. Methods Mitochondria, isolated from rat liver were exposed to different concentrations (20, 60, 100, 140 and 180 μg/mL) of MEAM. The mPT pore opening, cytochrome c release, mitochondrial ATPase (mATPase) activity and the percentage lipid peroxidation were assessed spectrophotometrically. Histological effects of MEAM on the liver, brain and uterus of normal and MSG-treated rats were investigated. Results The in vitro results showed a significant induction of mPT pore opening by 2.4, 4.2 and 6.4 folds, release of cytochrome c and enhancement of mATPase activity at 100,140 and 180 μg/mL, respectively. However, oral administration of MEAM did not induce mPT pore opening, neither any significant release of cytochrome c nor enhancement of mATPase activity at all the dosages used. However, histological assay revealed the presence of MSG-induced cellular damage and uterine hyperplasia which was ameliorated by MEAM co-administration. Conclusions These findings suggest that MEAM contains phytochemicals that can ameliorate MSG-induced damage and uterine hyperplasia in rats; however, the mechanism might not be via upregulation of mitochondrial-mediated apoptosis.
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