Effects of sesquiterpene lactones on mitochondrial oxidative phosphorylation

Narasimhan, T.R.; Kim, H.L.; Safe, Stephen

doi:10.1016/0306-3623(89)90107-9

Cited by 13 publications

(6 citation statements)

References 20 publications

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“…The inhibition of mitochondrial oxidative phosphorylation by sesquiterpene lactones isolated from G. aspera has been demonstrated previously (Narasimhan, Kim & Safe 1989; Van Aswegen, Vermeulen & Potgieter 1979). Decreased enzyme activities (such as mitochondrial succinate dehydrogenase involved in mitochondrial electron transfer chain reactions) as a result of mitochondrial damage have been linked to reduced ATP synthesis, which is crucial for metabolic functions and growth of cells (Schulze-Osthoff et al 1992).…”

Section: Discussionsupporting

confidence: 56%

Geigerin-induced cytotoxicity in a murine myoblast cell line (C2C12)

Botha

Clift

Ferreira

et al. 2017

Onderstepoort j. vet. res.

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Geigeria poisoning in sheep, locally known as ‘vermeersiekte’, is an economically important plant poisoning in southern Africa. The toxic principles contained by the toxic plants are believed to be several sesquiterpene lactones, such as geigerin, vermeeric acid and vermeerin, which cause striated muscle lesions in small stock. Because of ethical issues surrounding the use of live animals in toxicity studies, there is currently a dire need to establish an in vitro model that can be used to replace traditional animal experimentation. The objective of this study was to determine the cytotoxicity of geigerin in a murine myoblast cell line (C2C12) using methyl-thiazol-tetrazolium (MTT) and lactate dehydrogenase (LDH) assays, annexin V and propidium iodide (PI) flow cytometry and transmission electron microscopy (TEM). Mouse myoblasts were exposed to 2.0 mM, 2.5 mM and 5.0 mM geigerin for 24, 48 and 72 h. A concentration-dependent cytotoxic response was observed. Apoptosis was detected by means of annexin V flow cytometry during the first 24 h and apoptotic bodies were also visible on TEM. According to the LDH and PI flow cytometry results, myoblast cell membranes were not injured. We concluded that the murine myoblast cell line (C2C12) is a suitable model for future studies planned to evaluate the cytotoxicity of other and combinations of sesquiterpene lactones, with and without metabolic activation, implicated in ‘vermeersiekte’ and to elucidate the subcellular effects of these myotoxins on cultured myoblasts.

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Section: Discussionsupporting

confidence: 56%

Geigerin-induced cytotoxicity in a murine myoblast cell line (C2C12)

Botha

Clift

Ferreira

et al. 2017

Onderstepoort j. vet. res.

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“…It is of interest that the hepatic mitochondrial GSH was induced only in the higher EQ diet group while the difference in tissue GSH and EQ residue levels of high-and low-EQ diet groups was insignificant. The hepatic mitochondria isolated from mice that received a diet containing 0.5% EQ HCI for 7-10 d tolerated more toxicants known to deplete hepatic GSH (Narasimhan et al, 1989). Since mitochondrial GSH is important in protecting and possibly regulating many cellular functions (Reed, 1990), the induction of mitochondrial GSH by dietary EQ may contribute to various cellular functions.…”

Section: Resultsmentioning

confidence: 99%

Accumulation of ethoxyquin in the tissue

Kim

1991

Journal of Toxicology and Environmental Health

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Ethoxyquin (EQ) residue levels in the mouse tissue were determined by the HPLC-fluorometric detection method. Mice were given powdered feed containing 0, 0.125, and 0.5% EQ HCl and the EQ residue levels in liver, kidney, lung, and brain tissues were determined after 2, 4, 6, 10, and 14 wk (4 mice/group). The tissue samples were homogenized in 10 volumes (w/v) of acetonitrile-water (7:3, v/v), centrifuged, and the supernatants were stored in a freezer for 2-3 h or until the two layers separated; then the clear upper layers were analyzed. The mean EQ residue levels in the tissue ranged 0.84-4.58 micrograms EQ/g liver and 0.11-0.92 micrograms EQ/g brain. The relative weight of the liver (5.21-7.07% body weight) and the hepatic glutathione level (5.99-7.83 microM GSH/g tissue) of mice that received EQ were significantly higher than those of the controls (4.67-5.05% body weight and 4.30-5.78 microM GSH/g tissue, respectively). The mean hepatic mitochondrial glutathione level of the higher EQ feeding group, following dietary administration of EQ for 14 wk, was approximately twofold (1.68 nM GSH/mg protein) of both the control and the lower EQ feeding groups (0.83 and 0.74 nM GSH/mg protein, respectively).

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“…If parthenin was internalized by the parasite, the washing step could have failed to remove the compound; or parthenin could have already compromised the parasite internally so that it appeared morphologically similar to control parasites but was not fully functional when ingested by the mosquito. One possible mechanism of parthenin's action that loses support in this assay is that parthenin inhibits oxidative phosphorylation (25). Male gametes appear to lack mitochondria and have been shown to rely on glycolysis quite heavily for exflagellation (52,53).…”

Section: Discussionmentioning

confidence: 96%

“…Further studies on parthenin have revealed that it has a wide array of potentially useful biological effects and that it has shown activity as a potential herbicide (10,12,13), pesticide (14,15), antiparasitic (16,17), and anticancer compound (18)(19)(20)(21). Parthenin may act through a variety of mechanisms, including directly damaging DNA, inhibiting oxidative phosphorylation, inducing formation of nitric oxide, and promoting apoptotic signaling (18,19,(22)(23)(24)(25). General cytotoxicity of parthenin remains a concern, but its activity varies greatly among different cell lines, as illustrated by 50% inhibitory concentrations (IC 50 s) of 0.061 M and 594 M against Jurkat cells and HeLa cells, respectively (26).…”

mentioning

confidence: 99%

The Nonartemisinin Sesquiterpene Lactones Parthenin and Parthenolide Block Plasmodium falciparum Sexual Stage Transmission

Balaich

Mathias

Torto

et al. 2016

Antimicrob Agents Chemother

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f Parthenin and parthenolide are natural products that are closely related in structure to artemisinin, which is also a sesquiterpene lactone (SQL) and one of the most important antimalarial drugs available. Parthenin, like artemisinin, has an effect on Plasmodium blood stage development. We extended the evaluation of parthenin as a potential therapeutic for the transmissible stages of Plasmodium falciparum as it transitions between human and mosquito, with the aim of gaining potential mechanistic insight into the inhibitory activity of this compound. We posited that if parthenin targets different biological pathways in the parasite, this in turn could pave the way for the development of druggable compounds that could prevent the spread of artemisinin-resistant parasites. We examined parthenin's effect on male gamete activation and the ookinete-to-oocyst transition in the mosquito as well as on stage V gametocytes that are present in peripheral blood. Parthenin arrested parasite development for each of the stages tested. The broad inhibitory properties of parthenin on the evaluated parasite stages may suggest different mechanisms of action between parthenin and artemisinin. Parthenin's cytotoxicity notwithstanding, its demonstrated activity in this study suggests that structurally related SQLs with a better safety profile deserve further exploration. We used our battery of assays to test parthenolide, which has a more compelling safety profile. Parthenolide demonstrated activity nearly identical to that of parthenin against P. falciparum, highlighting its potential as a possible transmission-blocking drug scaffold. We discuss the context of the evidence with respect to the next steps toward expanding the current antimalarial arsenal.A n estimated 198 million cases of malaria and 584,000 deaths, mostly among young children, were reported worldwide in 2013 (1). However, as a result of concerted control efforts since 2000, including antimalarial drugs, mortality has declined by 47%, resulting in an estimated 4.3 million lives saved (1). Artemisinin, delivered with a partnered drug, is one of the fastest acting antimalarial therapies available (2, 3). However, antimalarial resistance in Plasmodium falciparum has been described recently in Southeast Asia (4). This discovery emphasizes the need for novel compounds that are effective against resistant strains, presumably because they act on the parasite differently from artemisinin. Artemisinin was originally isolated from Artemisia annua, or sweet wormwood, a member of the Asteraceae family. We hypothesized that natural product compounds derived from related family members might retain potent activities against Plasmodium while targeting different biological pathways.Parthenin is a sesquiterpene lactone (SQL) derived from Parthenium hysterophorus, which is an invasive, flowering annual weed in the Asteraceae family; it grows to 2 m in height, with small white flowers, and has spread throughout much of the world (5). P. hysterophorus causes millions of dollars in damag...

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Effects of sesquiterpene lactones on mitochondrial oxidative phosphorylation

Cited by 13 publications

References 20 publications

Geigerin-induced cytotoxicity in a murine myoblast cell line (C2C12)

Geigerin-induced cytotoxicity in a murine myoblast cell line (C2C12)

Accumulation of ethoxyquin in the tissue

The Nonartemisinin Sesquiterpene Lactones Parthenin and Parthenolide Block Plasmodium falciparum Sexual Stage Transmission

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