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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 9  |  Issue : 2  |  Page : 236-243

Antiproliferative and apoptosis-inducing properties of selected medicinal plants of Assam, India


1 Department of Zoology, Bodoland University, Kokrajhar, Assam, India
2 Department of Zoology, Cotton University, Guwahati, Assam, India

Date of Submission14-Sep-2021
Date of Decision28-Oct-2021
Date of Acceptance30-Oct-2021
Date of Web Publication29-Dec-2021

Correspondence Address:
Dr. Ananta Swargiary
Department of Zoology, Bodoland University, Kokrajhar, Assam
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/amhs.amhs_210_21

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  Abstract 


Background and Aim: Ethnomedicine is a common practice of disease treatment among tribal communities of India. The present study investigated the antiproliferative and apoptosis-inducing activities of seven medicinal plants traditionally used by the Bodo tribe of Assam. Materials and Methods: The phytochemical and antioxidant activities of plants were investigated following standard protocols. Antiproliferative and apoptosis-inducing activities were evaluated in Dalton's lymphoma (DL) cells. Plant extract-treated cells were stained with acridine orange/ethidium bromide solutions to see the antiproliferative and apoptosis-inducing properties of plants. Results: The study showed high phenolic and flavonoid contents in all the plants. Phlogacanthus tubiflorus displayed the strongest antioxidant activity. Plant extracts showed concentration-dependent antiproliferative activity. Hydrocotyle sibthorpioides showed the strongest antiproliferative and apoptosis-inducing activities. DL cells treated with plant extracts displayed apoptotic features. Furthermore, docking study revealed 2-methyl-5-(1-adamantyl) pentan the best binding affinity with anti-apoptotic proteins. Conclusion: The present study revealed potential antiproliferative and apoptosis-inducing properties in H. sibthorpioides. However, further study needs to be carried out to investigate bioactive compounds responsible for their pharmacological properties.

Keywords: Anticancer, antioxidant, docking, Kokrajhar, medicinal plants


How to cite this article:
Roy MK, Swargiary A, Verma AK. Antiproliferative and apoptosis-inducing properties of selected medicinal plants of Assam, India. Arch Med Health Sci 2021;9:236-43

How to cite this URL:
Roy MK, Swargiary A, Verma AK. Antiproliferative and apoptosis-inducing properties of selected medicinal plants of Assam, India. Arch Med Health Sci [serial online] 2021 [cited 2022 Aug 19];9:236-43. Available from: https://www.amhsjournal.org/text.asp?2021/9/2/236/334009




  Introduction Top


Cancer is a group of diseases that can start at any organ of the body from an abnormal cell division and invade adjoining parts, spreading the disease to the whole body. According to the WHO, the global burden of cancer has increased up to 18.1 million by 2018, accounting for 9.6 million deaths. Approximately 70% of deaths are from low- and middle-income countries.[1] Today, one of the six deaths is due to cancer. Lung, prostate, colorectal, stomach, and liver cancer are the most common types of cancer in men, while breast, colorectal, lung, cervical, and thyroid cancers are the most common among women.[2] Despite significant improvement in healthcare facilities, the cancer burden continues to grow to cause tremendous financial strain. At the same time, poor accessibility of quality medicines, high cost, and severity of the side effects remain a challenge to cancer treatment. In this regard, exploring anticancer phytochemicals from medicinal plants would be a good option because of their easy availability and less side effects.[3]

Plant and plant-derived compounds serve as a promising source of pharmaceuticals for several ailments. The use of natural products, including medicinal plants and marine organisms, remains an important target of pharmaceutical drug discovery. Today, plant-derived compounds account for more than 60% of the approved anticancer drugs.[4] According to a recent study, 64.9% of approved anticancer drugs from 1940s to 2020 were either derived from natural products or are natural product mimics.[5] Several intrinsic and extrinsic factors are linked to the pathogenesis of cancer. However, the avoidance of cells from normal apoptotic death and the transformation of cells leading to low apoptosis rate or resistance to apoptotic mechanisms is vital in carcinogenesis.[6]

Plants and plant-derived phytochemicals possess several biological properties. Several studies have reported having potential anticancer activity of plants and their isolated phytochemicals.[7],[8] Recent studies showed that several plants from the Kokrajhar district of Assam exhibit substantial antiproliferative properties.[9],[10] Isolated phytocompounds, paclitaxel, etoposide, camptothecin, vinblastine, vincristine, uvaribonin, 22-epicalamistrin, and chalcone possess considerable anticancer activity.[11],[12] Because of their ethnomedicinal importance, the present study investigated the antiproliferative and apoptosis-inducing properties of seven medicinal plants of Kokrajhar district of India.


  Materials and Methods Top


Collection and identification plants

Seven commonly used ethnomedicinal plants, namely Clerodendrum viscosum L., Hydrocotyle sibthorpioides Lam., Musa balbisiana Colla, Oroxylum indicum (L.) Kurz, Paspalum fimbriatum Kunth., Phlogacanthus tubiflorus Nees., and Rauvolfia tetraphylla L. used by Bodo tribe of Kokrajhar district of Assam were collected from the Kokrajhar locality. The plants were identified in the Department of Botany, Bodoland University. The name of the plants, families, identification numbers, and parts used are shown in [Table 1].
Table 1: Scientific names and identification details of the seven medicinal plants of Kokrajhar, India

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Preparation of methanolic extract of plants

Fresh plant parts were collected and processed for methanolic crude extraction following the Soxhlet method. Briefly, collected plant parts were washed in distilled water, chopped into small pieces, and allowed to dry completely in a hot-air oven at 40³C–45³C. Dried plants were grounded into powdered form using a mechanical grinder. Dry plant powder was subjected to Soxhlet extraction using 70% methanol for 6 h. The extract was then concentrated in a rotary evaporator at 60³C–65³C. The dry, semi-solid crude extract obtained was stored at −20³C till further use.

Antioxidant study

Total phenolic content

Total phenolic content (TPC) was estimated using Folin-ciocalteu reagent.[13] TPC was calculated using a standard curve of gallic acid (y = 0.0203x − 0.0141, R2 = 0.9997) and results were expressed as μg gallic acid equivalent/mg of plant extract.

Total flavonoid content

Total flavonoid content (TFC) was determined following Ordonez et al.[14] TFC was calculated using a standard curve of quercetin (y = 0.0162x − 0.0268, R2 = 0.9999), and the values were expressed as μg quercetin equivalent/mg of plant extract.

Ferric Reducing Antioxidant Power Assay

Ferric reducing antioxidant power (FRAP) assay was performed following Iloki-Assanga et al.[15] The FRAP activity of extracts was compared with the standard ascorbic acid (y = 0.266x, R2 = 0.9998), and values were expressed as μg Fe2 + equivalent (FE)/mg of plant extract.

2,2-Diphenyl-1-Picrylhydrazyl radical scavenging activity

2,2-Diphenyl-1-Picrylhydrazyl (DPPH) free radical scavenging activity of plant extracts was estimated using DPPH radical.[16] Briefly, 2 mL DPPH reagent (0.135 mM, prepared in methanol) was added to 1 mL of ascorbic acid and plant extracts (25–500 μg/mL). After 30 min incubation at 37³C, color developed was read at 517 nm in a spectrophotometer. The scavenging activity of plant extract was calculated using the formula:



  • Abs control, assay mixture without sample/standard
  • Abs sample, assay mixture with sample/standard.


Cytotoxicity study

Cell line and dose preparation

The antiproliferative activity of plant extracts was studied for 24 h using malignant Dalton's lymphoma (DL) cell line. The cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum, gentamycin (20 mg/mL), streptomycin (100 mg/mL), and penicillin (100 IU) in a CO2 incubator at 37³C with 5% CO2; 80% confluent of exponentially growing cells was subcultured and used in the experiments. The different dosages (10, 25, 50, 100, and 200 mg/mL) of plant extracts were prepared freshly by dissolving in phosphate-buffered saline (pH 7.4) during the experiment.

Cell proliferation and apoptosis assay

After plant extracts, treatment cell proliferation was measured by 3- [4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay in DL and peripheral blood mononuclear cells used as a normal cell.[17] In brief, the cells were treated with different doses (10, 25, 50, 100, and 200 mg/mL) of plant extracts for 24 h in a 96-well plate(s) tissue. Next, 10 μl of MTT reagent (5 mg/ml in PBS) was added to each well. Then, the treated plates were incubated for 4 h under 5% CO2 and 95% air at 37³C, followed by adding 100 μl DMSO into each well and shaken gently. The plate was checked for complete solubilization of crystal, and then the absorbance was recorded at 570 nm using Elisa Microplate Reader (Rapid Diagnostics; SKU, LISA-R, India). The control and treated cells were stained with acridine orange/ethidium bromide (AO/Eb) for 5 min in a dark, cold room for the apoptosis study.[18] The cells were then thoroughly examined for three replicates under a fluorescence microscope and photographed (Medlab Lx400 FLR Fluorescence Microscope). About 1000 cells were counted, and the percentage of the apoptotic nucleus was determined based on the differential staining pattern (red/green) of the nucleus.

Molecular docking

To further elucidate the antiproliferative activity of the plant, molecular docking was carried out with four compounds; namely, 1-cyclohexyl-2-methyl (C1), 2-methyl-5-(1-adamantyl) pentan (C2), 5-hepten-3-one (C3), and propanoic acid (C4) reported from H. sibthorpioides[19] with six anti-apoptotic proteins, BCL-2 (1YSW), BCL-XL (4QVX), MCL-1 (5KU9), BCL-W (2Y6W), BCL-B (4B4S), and BCL-A1/Bfl-1 (5UUK). The 3D structures of proteins and ligands were retrieved from RCSB-PDB (https://www.rcsb.org/) and PubChem databases (https://pubchem.ncbi.nlm.nih.gov/). Docking was carried out in AutoDock vina software (Molecular Graphics Laboratory, The Scripps Research Institute, San Diego, California).[20] The grid parameters for docking were set as x, y, and z size coordinate, and grid box center coordinate, i.e., 14.496, −3.140, 1.690 and 46, 82, 58 for BCL-2, −15.653, 19.048, 0.789 and 30, 48, 40 for BCL-W, −6.783, 9.665, 2.169 and 38, 38, 30 for BCL-B, 0.308, −21.586, 11.404 and 74, 54, 52 for BCL-XL, −2.209, −10.161, 24.412 and 54, 42, 52 for MCL-1, and-2.219, 20.505, −4.937, and 36, 44, 44 for BCL-A1/Bfl-1 proteins, respectively. Docking was performed in triplicate (n = 3), and the best docking output was visualized in Discovery studio software.

Statistical analysis

All the statistical calculations were carried out in Microsoft excel. IC50 calculation and correlation study was carried out using OriginPro-8.5 software. Data were represented as mean ± standard deviation. One-way analysis of variance was used to calculate the significance of differences, n = 3 at the P ≤ 0.05.


  Results Top


Phytochemical and antioxidant study

The TPC and TFC values of plants are presented in [Figure 1]. The TPC of plants ranged from 10.73 ± 0.097 to 123.68 ± 2.95 μgAAE/mg. The highest TPC was observed in P. tubiflorus and lowest in M. balbisiana. Similarly, the highest TFC was observed in P. tubiflorus (45.85 ± 1.26 μgFE/mg) and lowest in M. balbisiana (4.72 ± 0.33 μgFE/mg). The results also showed a significant difference between the TPC and TFC of the plants at P ≤ 0.05 level. Similarly, the Pearson correlation study revealed a positive and significant correlation between the phenolic and flavonoid contents of the plants (Pearson correlation, 0.588).
Figure 1: Total phenolic and flavonoid contents of the plants. Values are represented as mean ± standard deviation, three replicates, n = 3

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[Table 2] shows the phytochemical and antioxidant activity of the plants. The DPPH free-radical scavenging activity of the plants ranged from (IC50) 23.34 ± 1.33 μg/mL (P. tubiflorus) to 1.66 ± 0.10 mg/mL (P. fimbriatum). The reference standard gallic acid showed the strongest DPPH radical scavenging activity with IC50, 3.45 ± 0.20 μg/mL. Similarly, for the ferric reducing activity of the plants, O. indicum showed the strongest activity (708.75 ± 23.75 μgFE/mL) while C. viscosum showed the lowest activity (47.93 ± 1.61 μgFE/mL). Statistical analysis and Pearson correlation study showed a significant correlation between TPC, DPPH, and FRAP activity of the plants at P ≤ 0.05 level. Antioxidant properties showed a negative correlation to the antiproliferative and apoptosis-inducing properties of the plants [Table 3].
Table 2: Antioxidant activities and IC50 values of seven medicinal plants of Assam

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Table 3: Pearson correlation analysis of phytochemical contents and antioxidant property of the plants

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Antiproliferative and apoptotic activities of plants

The results of antiproliferative and apoptotic-inducing properties of plant extracts in DL cell lines are presented in [Figure 2]. Methanolic crude extracts of plants showed dose-depended antiproliferative and apoptosis-inducing activity. Increasing the dose of the plant extracts (10–100 mg/mL) increased the percentage of cell mortality. In terms of antiproliferative and apoptotic-inducing activity, H. sibthorpioides showed the most potent activity, followed by P. fimbriatum and M. balbisiana, while O. indicum showed the lowest activity. The percentage mortality of DL cells ranged from 23% to 58.67% in MTT assay (cytotoxicity). In contrast, in the apoptotic assay, the percentage (%) mortality ranged from 16.67% to 42.33% at the highest treatment dose (200 mg/mL). Statistical analysis showed a significant correlation between antiproliferative and apoptotic properties of the plants at P ≤ 0.05 level. Cisplatin, a reference chemical, showed 82% and 64% cell mortality in antiproliferative and apoptotic-inducing activity at 200 mg/mL concentration, respectively. A positive and significant correlation has been seen between antiproliferative and apoptotic properties of the plants.
Figure 2: Antiproliferative and apoptosis-inducing activities of medicinal plants. Values are expressed as mean ± standard deviation. Mortality values are significantly different between cisplatin and plant extract treatment

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Fluorescent microscopy study revealed that plant extract-treated DL cells developed morphological characteristics of apoptosis, including red/orange nuclei, membrane blebbing, chromatin condensation, and formation of apoptotic bodies [Figure 3]. Control DL cells showed green nuclei with intact cell and nuclear membrane structures. Of the seven plants, the extracts of H. sibthorpioides, P. fimbriatum, and M. balbisiana induced more substantial apoptotic implications in DL cells. Apoptotic features of the cell, such as chromosome condensation and membrane blebbing, were prominent in DL cells treated with H. sibthorpioides, P. fimbriatum, and M. balbisiana. Statistical analysis revealed that the antioxidant properties of medicinal plants do not positively correlate to the plants' antiproliferative and apoptosis-inducing properties. Instead, the study found a negative correlation. Similarly, the apoptotic properties of the plants showed a negative but significant correlation to the phenolic content of the plants (P ≤ 0.05 level).
Figure 3: Morphological features of apoptotic and viable cells observed under a fluorescence microscope after AO/Eb staining. Cisplatin treatment showed apoptotic cells (red/orange nucleus), control DL cells showed viable cells (green nucleus), and plant extracts treated groups at different doses showing apoptotic nucleus with membrane damage and chromatin condensation

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Molecular docking

Of all the four compounds, compound C2 showed the strongest binding affinity with all the six anti-apoptotic proteins. The binding energies of all four compounds and the anti-apoptotic proteins are shown in [Table 4]. BCL-2 and BCL-W showed the best binding affinity, followed by MCL-1, BCL-A1/bfl-1, BCL-B, and BCL-W. The 2D display of the best binding ligand with proteins is shown in [Figure 4]. Docking studies revealed that the compound C2 interacted with nine amino acids residues of BCL-2, from which five amino acid residues Thr93, Gln96, Asp100, Tyr105, and Phe193 showed Van der Waals (VDW) interactions, Ala97 showed hydrogen bonding, Val145, and Ala97 showed alkyl bonding, and Phe101, Tyr199 showed Pi-alkyl interaction with C2 [Figure 4]. Similarly, C2 interacted with seven amino acid residues of BCL-W, Leu96 residue made VDW interaction, Leu134, Arg95, and Ala98 made alkyl bonding, Trp137 made Pi-sigma bonding, and Tyr129 and Phe99 showed Pi-alkyl bonding. The interaction between BCL-B and C2 involved seven residues, Ile48 showed VDW interaction, Phe159 H-bonding, and Val87, Leu45, Arg44, and Ala41 showed alkyl interaction, whereas Phe163 and Phe159 showed Pi-alkyl interaction. Similarly, BCL-XL and C2 complex showed three types of interactions, VDW interaction (Ser145, Phe146, Asp107, Arg132, and Glu129), alkyl (Leu108, Leu130, Arg102, and Ala142), and Pi-alkyl interactions (Phe97, and Phe105). An unfavorable acceptor-acceptor interaction was observed in Ser106 residue. For MCL-1 protein, the C2 interacted with seven amino acids; Gln221 showed convention H-bonding, Glu225, Leu232, His277, and Gln229 showed VDW interaction, Lys276 showed unfavorable donor-donor interaction, Phe273 showed Pi-sigma and Pi-alkyl interaction, and Arg222 and Lys276 showed alkyl bond interaction. In BCL-1A/Bfl1 protein, Lys46 showed conventional H-bonding with C2, while Glu49, Lys102, Asp57, and Lys101 showed VDW interaction, and Lue56, Ile98, Lys53, and Lys50 residues showed alkyl interaction.
Table 4: Binding energies (kcal/mol) of chemicals with anti-apoptotic proteins

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Figure 4: Binding of 2-methyl-5-(1-adamantyl) pentan (C2) with anti-apoptotic proteins, (a) BCL-2, (b) BCL-A1B/Bfl-1, (c) BCL-B, (d) BCL-W, (e) BCL-XL, and (f) MCL-1

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  Discussion Top


Plants and natural products remain the focal point of drug discovery because of their rich phytochemicals. The bioactive compounds and other phytochemicals show diverse biological functions such as antioxidants, anti-diabetes, anti-inflammatory, anticancer, and antimicrobial. There are several reasons for cancer, and free radicals are one of the crucial agents. Broad ranges of human diseases are associated with excess free radicals in the body. Reactive oxygen species are critical free radicals crucial for determining several fates of cells, while the imbalance in its concentration causes several pathological conditions, including cancer.[21] Plants have the natural ability to generate antioxidant molecules and therefore possess considerable therapeutic potential.[22] The present study revealed that all plants possess a considerable amount of phenolics and flavonoid content. Phenolics and flavonoids are important secondary metabolites of plants having several medicinal values. The antioxidant properties of a plant are attributed to the presence of phenolic content.[23] The present study found a positive and significant correlation (P ≤ 0.05 level) between the phenolic content and antioxidant property. Similarly, a study done by Kumar et al. found that the extracts of Lantana camara (Verbenaceae) leave showed a strong correlation between the phenolic content and antioxidant activities.[24] The present study observed a negative correlation between antioxidant and antiproliferative and apoptosis-inducing properties of the plants. Similarly, our earlier studies observed an insignificant correlation between the antioxidant and antiproliferative activities of the plants.[9],[10] Similarly, several studies have revealed a positive correlation between the phenolic and flavonoid contents and antioxidants, while the antiproliferative and apoptotic properties of plants showed negative correlations.[25],[26] Jiménez-Estrada et al. investigated six plants, Krameria erecta, Struthanthus palmeri, Phoradendron californicum, Senna covesii and Stegnosperma halimifolium, on HeLa and L929 cell lines. They observed an insignificant correlation between antioxidant and antiproliferative activities of the plants.[27] Different solvent extracts of Artemisia nilagirica were also reported to possess an insignificant correlation between the antioxidant and antiproliferative activities of the extracts.[28]

Unregulated cell division and growth leading to the tumor formation and avoidance of cells to cellular apoptosis is one of the leading causes of cancer.[29] Apoptosis is a cellular mechanism that causes normal cell death. Because of its cellular importance, apoptosis-inducing drugs are the center of new anticancer therapy. Several studies were carried out to study the antiproliferative and apoptosis-inducing potentials of medicinal plants.[30] Phytochemicals and bioactive compounds isolated from plants were also investigated for anticancer activity in numerous cell lines.[31] In the present study, H. sibthorpioides and P. fimbriatum showed better antiproliferative and apoptosis-inducing properties than other plants. Both the plants showed more than 50% cell mortality at the highest dose of treatment. The synergistic effect of phytocompounds present in the plant extracts may be attributed to the antiproliferative and apoptotic activities of the plants. Cisplatin, a well-established antiproliferative agent, showed a significant difference (at P ≤ 0.05 level) in both antiproliferative and apoptotic-inducing capacity compared to the plant extracts.[32] Many studies reported that the crude extracts of plants show lesser biological activity than isolated compounds. Crude extracts of plants contain several phytocompounds. The weaker apoptotic and antiproliferative activities of plants may be attributed to phytocompounds present in the plants. Because of its pure form, cisplatin has better bioactivity compared to crude plant extracts. Several studies have revealed a positive correlation between the phenolic and flavonoid contents and antioxidant, antiproliferative, and apoptotic properties of plants.[33] Similarly, Verma and Sweta also reported stronger apoptotic and antiproliferative activity of cisplatin compared to plant extracts.[34]

Molecular docking is a crucial bioinformatics tool to study molecular interactions between ligands and proteins. The binding of a chemical to the protein may be exploited to design therapeutic inhibitors. The present study also investigated the binding affinity of four compounds reported from the aerial parts of H. sibthorpioides with the main anti-apoptotic proteins. BCL-2 family proteins are crucial in regulating programmed cell death or apoptosis, consisting of pro-apoptotic and anti-apoptotic proteins.[35] Pro-apoptotic proteins help in the apoptosis process, while anti-apoptotic proteins help in the prevention of apoptosis. One of the main hallmarks of cancer is the dysfunction of apoptotic pathways leading to the survival and proliferation of cells. Anti-apoptotic proteins such as BCL-2, BCL-XL, MCL-1, BCL-W, BCL-B, and BCL-A1/Bfl-1 are among the critical chemotherapeutic targets of cancer treatment.[36] In the present study, 2-methyl-5-(1-adamantyl) pentan showed the strongest binding affinity among the four chemicals reported from H. sibthorpioides. BCL-2 and BCL-XL have been the best binding anti-apoptotic proteins with 2-methyl-5-(1-adamantyl) pentan. Therefore, the substantial in-vitro antiproliferative property and molecular docking analysis suggest that the extracts of H. sibthorpioides could be a potential source of anticancer agents.


  Conclusion Top


The present study investigated the antioxidant, antiproliferative, and apoptotic activity of the crude extracts of the medicinal plants. H. sibthorpioides induced the most potent antiproliferative and apoptotic activity on DL cell. It is also worth mentioning that H. sibthorpioides is a prevalent wild edible plant having several ethnomedicinal values. However, less work is reported regarding the anticancer activity in this plant. Further investigation regarding the phytochemical isolation and molecular mode of action needs to be carried out.

Acknowledgment

Authors would like to thank the traditional healer and older people for providing ethnomedicinal information. We also acknowledge Dr. Sanjib Baruah, Department of Botany, for helping in scientific validation of the plants.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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