Oleanolic acid from antifilarial triterpene saponins of Dipterocarpus zeylanicus induces oxidative stress and apoptosis in filarial parasite Setaria digitata in vitro

Senathilake, Kanishka; Karunanayake, E.H.; Samarakoon, Sameera Ranganath; Tennekoon, Kamani Hemamala; Silva, E.D. de; Adhikari, Achyut

doi:10.1016/j.exppara.2017.03.007

Cited by 28 publications

(19 citation statements)

References 27 publications

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“…As oxidative stress plays critical roles in the apoptosis triggered by a number of chemical compounds [ 35 , 36 , 37 , 38 , 39 , 40 ], we investigated whether reactive oxygen species (ROS) could be involved in the rhein-induced apoptosis of blastocysts in vitro. Staining with dichlorodihydrofluorescein diacetate (DCFDA) fluorescence dye (which detects intracellular ROS levels) revealed that the rhein-treated group had significantly higher ROS levels compared to the untreated control group ( Figure 5 A,B).…”

Section: Resultsmentioning

confidence: 99%

Rhein Induces Oxidative Stress and Apoptosis in Mouse Blastocysts and Has Immunotoxic Effects during Embryonic Development

Huang

Chan

2017

IJMS

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Rhein, a glucoside chemical compound found in a traditional Chinese medicine derived from the roots of rhubarb, induces cell apoptosis and is considered to have high potential as an antitumor drug. Several previous studies showed that rhein can inhibit cell proliferation and trigger mitochondria-related or endoplasmic reticulum (ER) stress-dependent apoptotic processes. However, the side effects of rhein on pre- and post-implantation embryonic development remain unclear. Here, we show that rhein has cytotoxic effects on blastocyst-stage mouse embryos and induces oxidative stress and immunotoxicity in mouse fetuses. Blastocysts incubated with 5–20 μM rhein showed significant cell apoptosis, as well as decreases in their inner cell mass cell numbers and total cell numbers. An in vitro development assay showed that rhein affected the developmental potentials of both pre- and post-implantation embryos. Incubation of blastocysts with 5–20 μM rhein was associated with increased resorption of post-implantation embryos and decreased fetal weight in an embryo transfer assay. Importantly, in an in vivo model, intravenous injection of dams with rhein (1, 3, and 5 mg/kg body weight/day) for four days resulted in apoptosis of blastocyst-stage embryos, early embryonic developmental injury, and decreased fetal weight. Intravenous injection of dams with 5 mg/kg body weight/day rhein significantly increased the total reactive oxygen species (ROS) content of fetuses and the transcription levels of antioxidant proteins in fetal livers. Additional work showed that rhein induced apoptosis through ROS generation, and that prevention of apoptotic processes effectively rescued the rhein-induced injury effects on embryonic development. Finally, the transcription levels of the innate-immunity related genes, CXCL1, IL-1 β and IL-8, were down-regulated in the fetuses of dams that received intravenous injections of rhein. These results collectively show that rhein has the potential to induce embryonic cytotoxicity and induce oxidative stress and immunotoxicity during the development of mouse embryos.

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Section: Resultsmentioning

confidence: 99%

Rhein Induces Oxidative Stress and Apoptosis in Mouse Blastocysts and Has Immunotoxic Effects during Embryonic Development

Huang

Chan

2017

IJMS

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“…Saponin cytotoxicity was also encountered when analysing active methanolic extracts from seeds, bark and leaves from the Sri Lankan tree Dipterocarpus zeylanicus . All extracts displayed activity against the adult and microfilarial stages of the bovine filarial nematode Setaria digitata [93]. Considering toxicity to human cells, the extract from seeds seemed to have better selectivity (although no more than 2-fold) than extracts from other plant parts, and it was fractionated to identify its active components.…”

Section: Chemical Classes Of Natural Compounds Described As Anthelminmentioning

confidence: 99%

“…[94]), it was considered interesting to hydrolyse the saponins and test the released oleanolate. Senathilake et al [93] measured an EC 50 of ~ 40 µM for inhibition of motility by oleanolic acid, both in microfilariae and adult worms, with selectivity indices > 10-fold relative to cytotoxicity. At concentrations of more than twice the EC 50 , signs of tissue damage in worms were observed, with apoptotic bodies, DNA fragmentation and increased levels of oxidative stress markers, concordant with previously described effects of oleanolate in rapidly growing cells.…”

Section: Chemical Classes Of Natural Compounds Described As Anthelminmentioning

confidence: 99%

An appraisal of natural products active against parasitic nematodes of animals

Garcia-Bustos

Sleebs

2019

Parasites Vectors

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Here, the scientific and patent literature on the activities of purified natural compounds has been reviewed, with the aim of assessing their suitability as anthelmintic drug discovery starting points. Only compounds described as active against parasitic nematodes of animals or against the model nematode Caenorhabditis elegans have been analysed. Scientific articles published since 2010 and patents granted from 2000, both inclusive, have been included in this analysis. The results show a scarcity of novel chemical structures, a limited follow-up of compounds disclosed before 2010 and a bias towards the screening of plant products, almost to the exclusion of other sources, when microbial extracts have, historically, provided most starting points for anti-infective drugs. All plant products published in this period were previously known, alerting to the high re-discovery rates of a limited number of chemical classes from this source. The most promising compounds described in the literature reviewed here, namely the linear nemadectin-derivatives, are novel and of bacterial origin. Patented but otherwise unpublished spiroketal structures also appear as interesting scaffolds for future development. The patent literature confirmed that it is possible to patent derivatives of previously known products, making them valid starting points for translational research.

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“…Our previous investigations on the antifilarial efficacy of phytochemicals showed the involvement of oxidative damages as a major player behind inducing worm mortality [14, 29]. Herein, shrinkage and damage in EECs treated worms (Fig 2C) suggested that there may be an involvement of oxidative damage.…”

Section: Resultsmentioning

confidence: 71%

“…Cells were incubated at 37°C for 24 h in a humidified, 5% CO 2 environment. The safety of extracts was determined in terms of the selectivity index (SI) which was defined as CC 50 / IC 50 (SI = CC 50 / IC 50 , where SI >1 = more toxic to parasites than to Mϕ, SI <1 = more toxic to Mϕ than to parasites) [29].…”

Section: Methodsmentioning

confidence: 99%

Polyphenol enriched ethanolic extract of Cajanus scarabaeoides (L.) Thouars exerts potential antifilarial activity by inducing oxidative stress and programmed cell death

et al. 2018

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Development of antifilarial drug from the natural sources is considered as one of the most efficacious, safe, and affordable approaches. In this study, we report the antifilarial activity of a leguminous plant Cajanus scarabaeoides (L.) Thouars. The polyphenol-rich ethanolic extract obtained from the stem part of the plant C. scarabaeoides (EECs) was found to be efficient in killing the filarial nematode Setaria cervi in all the three developmental stages viz. oocytes, microfilariae (Mf) and adults with LD50 values of 2.5, 10 and 35 μg/ml, respectively. While studying the molecular mechanism of action, we found that induction of oxidative stress plays the key role in inducing the mortality in S. cervi. The redox imbalance finally results in activation of the nematode CED pathway that executes the death of the parasite. Intriguingly, EECs was found to be selectively active against the worm and absolutely non-toxic to the mammalian cells and tissues. Taken together, our experimental data demonstrate that C. scarabaeoides can be chosen as an affordable natural therapeutic for treating filarial infection in the future with high efficacy and less toxicity.

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Oleanolic acid from antifilarial triterpene saponins of Dipterocarpus zeylanicus induces oxidative stress and apoptosis in filarial parasite Setaria digitata in vitro

Cited by 28 publications

References 27 publications

Rhein Induces Oxidative Stress and Apoptosis in Mouse Blastocysts and Has Immunotoxic Effects during Embryonic Development

Rhein Induces Oxidative Stress and Apoptosis in Mouse Blastocysts and Has Immunotoxic Effects during Embryonic Development

An appraisal of natural products active against parasitic nematodes of animals

Polyphenol enriched ethanolic extract of Cajanus scarabaeoides (L.) Thouars exerts potential antifilarial activity by inducing oxidative stress and programmed cell death

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