Research Article | Volume: 14, Issue: 1, January, 2024

Delphinidin-3-glucoside prolongs lifespan and healthspan in Caenorhabditis elegans with and without environmental stress

John Sylvester B. Nas Paul Mark B. Medina   

Open Access   

Published:  Jan 04, 2024

DOI: 10.7324/JAPS.2024.141494
Abstract

The beneficial effects of crude anthocyanin extracts against ageing, cancer, and bacterial infections are widely documented in the literature. Delphinidin-3-glucoside (D3G) is a class of anthocyanin pigment in fruits and vegetables. Although there are in vitro studies on the bio-functional activities of D3G, none are in vivo. Thus, we examined the effects of D3G on the lifespan of Caenorhabditis elegans (C. elegans) and measured the healthspan indicators like egg-laying ability and pharyngeal pumping during its normal state and in the presence of stressors, such as heat, ultraviolet (UVA) light, and hydrogen peroxide (H2O2). We found out that D3G prolongs the lifespan and improves its health span without stress. These same effects were observed with oxidative stress but not heat and UVA stressors. D3G partially reverses the adverse effects of H2O2 by prolonging the lifespan and augmenting the pharyngeal pumping of treated C. elegans, albeit lower than untreated. Overall, our findings suggest that D3G is capable of extending the lifespan and improving health through its antioxidant properties.


Keyword:     Delphinidin-3-glucoside anthocyanin aging lifespan healthspan Caenorhabditis elegans


Citation:

Nas JSB, Medina PMB. Delphinidin-3-glucoside prolongs lifespan and healthspan in Caenorhabditis elegans with and without environmental stress. J Appl Pharm Sci, 2024; 14(01):108–113. http://doi.org/10.7324/JAPS.2024.141494

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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INTRODUCTION

Numerous studies have investigated the antioxidant, antimicrobial, anti-inflammatory, and anticancer properties of crude anthocyanin extracts from various plant sources [13]. Some of these studies have highlighted the potential of anthocyanin to attenuate aging and reduce aging-associated diseases [4,5]. Delphinidin is one of the most common classes of anthocyanin, but only a few studies have explored its potential as a pure compound, such as delphinidin-3-glucoside (D3G).

Previous research has identified D3G in various berries, grapes, eggplants, and beans. Studies have demonstrated that this compound can inhibit platelet activation and thrombosis [6], suppress breast cancer via the Akt pathway [7], and attenuate lipid accumulation in HepG2 cells [8]. Despite these findings, more research is necessary to understand the effects of D3G on the aging process of multicellular organisms. To the best of our knowledge, there is no study that has investigated the impact of D3G on the lifespan, healthspan, and stress tolerance of a multicellular organism.

Therefore, our study aimed to investigate the effects of D3G on lifespan extension and health indicators such as egg-laying ability and pharyngeal pumping rate. First, we observed that heat, ultraviolet (UVA), and oxidative stress could impact the lifespan of Caenorhabditis elegans (C. elegans). We then assessed the effects of D3G on the lifespan and health indicators of C. elegans under heat, UVA, and oxidative stress.


MATERIALS AND METHODS

Procurement and storage of the compounds

We purchased D3G (>97%) and coenzyme Q10 (coQ10) (>98%) from AS polyphenols (Sandnes, Norway) and ApexBio (TX, USA), respectively. We used freshly prepared D3G and CoQ10 (positive control) solutions by reconstituting these compounds to the desired concentration with distilled water. We stored the freshly prepared solutions at 4°C until used.

Preparation of nematode growth medium and maintenance of the nematode

We followed the protocol described in Nas et al. [9] to prepare the nematode growth medium (NGM) and maintain the C. elegans. To prepare the NGM, we dissolved 750 mg NaCl, 4.5 g bacteriological agar, and 625 mg peptone in 250 ml distilled water, and autoclaved the mixture at 121°C for 15 minutes. After the mixture cooled, we added 125 μl each of 1 M CaCl2, 1 M MgSO4, and 5 mg/ml cholesterol in absolute ethanol, and then added 3.125 ml of 1 M KPO4 before pouring the mixture into small Petri plates. We seeded each plate with 100 μl of Escherichia coli (E. coli) strain OP50 to serve as a food source for the C. elegans N2 strain obtained from the Caenorhabditis Genetic Center (MN, USA).

To age-synchronize the C. elegans, we collected the eggs laid by an adult worm after 1 hour of egg-laying on the NGM plate. We assumed that the age difference of each nematode was ± 1 hour. We maintained the nematodes at a constant temperature of 20°C and replenished their food source with freshly prepared E. coli OP50 and treatment solutions on the NGM plates.

Lifespan and healthspan assay without stress

We followed the protocol of Nas et al. [10] and Park et al. [11] with slight modifications for our assay. Briefly, we placed 30 L4-stage C. elegans on freshly prepared NGM plates containing E. coli OP50 coated with either coQ10 (175 μM) or D3G (0, 25, 50, and 100 μM). We monitored the number of live, dead, and missing worms daily using a bright-field stereomicroscope. We classified the nematodes as alive if they responded to a light poke with a nichrome wire. We also counted the number of eggs laid on the plates daily and divided this by the total number of alive individuals to determine egg-laying capacity [12].

To measure the pharyngeal pumping rate, we counted the number of pumps per minute and recorded it daily using an Amscope MD500 camera (7.5 fps, 35 mm, 1080p HD) (Amscope, CA, USA) and stereomicroscope. We transferred each nematode daily to new NGM plates to avoid bacterial depletion. This assay was performed thrice, using a different set of worms in each trial.

Lifespan and healthspan assay with stressors

We conducted an experiment to test the effects of coQ10 (175 μM) or D3G (0, 25, 50, or 100 μM) on 30 L4 nematodes exposed to daily stressors such as heat, UVA, or oxidative stress, following the published protocol of Nas et al. [13]. Each stressor was applied to a different set of nematodes throughout the assay.

To induce heat stress, we placed the live worms in an incubator at a constant temperature of 30°C for 30 minutes daily. For UV stress, we exposed the nematodes to ultraviolet (UVA) light (1,300 μW/cm 2 intensity) at 365 nm for 2 minutes every day using a UV-GL-58 handheld lamp (Analytik Jena, CA, USA), which was positioned 3 inches above the base of the plates. To induce oxidative stress, we followed a modified protocol [14] and administered 100 μM of freshly prepared hydrogen peroxide (H2O2) solution (PHILUSA Corp., Philippines) to the live worms by dispensing about 0.2 μl of the solution to their head. We then placed the worms on NGM plates filled with water to remove the H2O2 solution from their body before transferring them to a newly prepared NGM plate containing the different treatments. We repeated all assays three times, using different sets of worms in each trial.

Statistical analysis

We conducted all experiments using two independent trials and presented the data as mean ± SEM. To analyze the lifespan data, we used OASIS 2 (https://sbi.postech.ac.kr/oasis2) and performed the log-rank test. For the analysis of free radical scavenging activity, EC50, the mean number of eggs laid, and average pharyngeal pumping rate of C. elegans, we used GraphPad Prism version 7 (GraphPad Software, CA, USA) and performed one-way analysis of variance with post-hoc Tukey’s multiple comparisons tests. We considered results statistically significant at a ≤ 0.05.


RESULTS

D3G enhances the lifespan and pharyngeal pumping of C. elegans

We found that supplementation with 100 μM of D3G led to a significant 23.4% increase (p ≤ 0.05) in the mean lifespan of C. elegans, as illustrated in Figure 1A and B. This increase is comparable to the effect observed with coQ10 supplementation. However, D3G and coQ10 intake did not affect the average number of eggs laid by the nematode, as shown in Figure 1C and D. Moreover, C. elegans supplemented with 100 μM of D3G exhibited an average pharyngeal pumping rate approximately 8.5% higher (p ≤ 0.05) than the control group receiving only distilled water, but this effect was similar to that observed with coQ10 supplementation, as shown in Figure 1E and F.

D3G does not improve the tolerance of C. elegans against heat stress

We disrupted the normal physiology of C. elegans by subjecting them to elevated temperatures for a short period every day. While we observed significant increases in the mean lifespan and pharyngeal pumping rate of C. elegans supplemented with D3G under normal conditions, we did not observe similar effects under heat stress conditions. Specifically, we did not find significant changes (p >0.05) in the lifespan, number of eggs laid, or pharyngeal pumping rate of C. elegans exposed to heat stress, as shown in Figure 2A–F.

D3G does not enhance the tolerance of C. elegans against UVA-induced stress

We examined the effects of D3G supplementation in C. elegans exposed to UVA light for a short period every day. Our results, as depicted in Figure 3A and B, show that the mean lifespan of C. elegans fed with varying concentrations of D3G was not significantly different (p > 0.05) from that of untreated worms. Moreover, we did not observe any significant changes (p > 0.05) in the number of eggs laid or the pharyngeal pumping rate of C. elegans supplemented with D3G, as shown in Figure 3C and F.

Figure 1. D3G prolongs the lifespan and enhances the pharyngeal pumping in C. elegans without stress. We nourished the nematodes with varying concentrations of D3G (0, 25, 50, and 100 μM) and we used coQ10 (175 μM) as the positive control. We measured the A – Daily survival rate, B – Mean lifespan, C – Daily eggs laid, D – Mean number of eggs laid, E – Daily pharyngeal pumping rate, and F – Average pharyngeal pumping rate of the nematodes. Each column represents mean ± SEM from three independent trials. Significance was set at p ≤ 0.05 represented by *.

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Figure 2. D3G did not affect the lifespan and health indicators of C. elegans under heat stress. We supplemented the nematodes with varying concentrations of D3G (0, 25, 50, and 100 μM) and we used coQ10 (175 μM) as the positive control. We incubated the C. elegans at 30°C for 30 minutes every day. We measured the A – Daily survival rate, B – Mean lifespan, C – Daily eggs laid, D – Mean number of eggs laid, E – Daily pharyngeal pumping rate, and F – Average pharyngeal pumping rate of the nematodes. Each column represents mean ± SEM from three independent trials. Significance was set at p≤0.05 represented by *.

[Click here to view]

D3G enhances lifespan and pharyngeal pumping of C. elegans under H2O2-induced stress

We determined that H2O2 at concentrations greater than 100 μM is toxic to C. elegans. To evaluate the protective effects of D3G, we supplemented the nematodes with D3G and exposed them to 100 μM of H2O2 daily. Our findings shown in Figure 4A and B demonstrate that 100 μM D3G extended the lifespan and increased the mean lifespan of C. elegans by 32.5% (p≤0.05). Similarly, the pharyngeal pumping rate of C. elegans supplemented with 100 μM D3G under oxidative stress was also enhanced by 8.13% (p≤0.05), as shown in Figure 4E–F. However, the number of eggs laid by the nematodes was still unaffected, as shown in Figure 4C and D. The observed increase in the mean lifespan and average pharyngeal pumping rate were all comparable to coQ10.

Figure 3. D3G did not affect the lifespan and health indicators of C. elegans treated with UVA. We fed the nematodes with varying concentrations of D3G (0, 25, 50, and 100 μM) and we used coQ10 (175 μM) as the positive control. We measured the A – Daily survival rate, B – Mean lifespan, C – Daily eggs laid, D – Mean number of eggs laid, E – Daily pharyngeal pumping rate, and F – Average pharyngeal pumping rate of the nematodes. Each column represents mean ± SEM from three independent trials. Significance was set at p≤0.05 represented by *.

[Click here to view]
Figure 4. D3G increased the mean lifespan and pharyngeal pumping rate of C. elegans fed with H2O2. We nourished the nematodes with varying concentrations of D3G (0, 25, 50, and 100 μM) and we used coQ10 (175 μM) as the positive control. We measured the A – Daily survival rate, B – Mean lifespan, C – Daily eggs laid, D – Mean number of eggs laid, E – Daily pharyngeal pumping rate, and F – Average pharyngeal pumping rate of the nematodes. Each column represents mean ± SEM from three independent trials. Significance was set at p < 0.05 represented by *.

[Click here to view]

DISCUSSION

The findings of our study suggest that D3G supplementation could promote healthy aging and improve physiological function in C. elegans. Specifically, our results showed that D3G was able to increase the mean lifespan of the nematodes by a significant amount, which is a promising result for the potential use of D3G as an anti-aging supplement. The observed increase in lifespan was comparable to that seen with coQ10, a well-known antioxidant and anti-aging supplement. Our findings align with previous research demonstrating the lifespan-extending effects of anthocyanin extracts from various sources such as purple wheat, blueberry, and acai berry [1517].

Interestingly, D3G supplementation did not affect the average number of eggs laid by the nematodes. This finding suggests that D3G may not directly impact the deterioration of the muscles involved in egg laying in C. elegans. Further studies are needed to investigate the underlying mechanisms behind this observation.

Our study also demonstrated that D3G supplementation could increase the average pharyngeal pumping rate of C. elegans, an indicator of physiological function. In a study on blueberry polyphenols, Wilson et al. [17] reported that the extract enhanced pharyngeal pumping in C. elegans. This result is significant, as it suggests that D3G supplementation could improve the overall healthspan of the nematodes, possibly by enhancing their ability to maintain proper nutrient uptake and digestion.

However, our results also indicate that the protective effects of D3G were not observed in C. elegans exposed to heat stress or UVA radiation. These findings suggest that the effects of D3G may be context-dependent, and its potential benefits may vary in different physiological contexts. Further research is needed to fully understand the mechanisms underlying the effects of D3G and its potential applications.

The results of our study suggest that D3G has a protective effect on C. elegans under oxidative stress induced by H2O2. This is evidenced by the significant increase in mean lifespan and average pharyngeal pumping rate of the nematodes supplemented with 100 μM of D3G, compared to the control group exposed to H2O2 only. Interestingly, the protective effect of D3G on mean lifespan and pharyngeal pumping rate was similar to that observed with coQ10 supplementation, a well-known antioxidant with reported anti-aging properties. However, it is important to note that while the supplementation of D3G showed positive effects under oxidative stress, it was not sufficient to fully reverse the detrimental impact of H2O2. Despite the administration of D3G supplementation, the mean lifespan and average pharyngeal pumping of the nematodes did not exhibit a comparable outcome to those worms that did not receive H2O2 treatment.

It is worth noting that the average number of eggs laid by C. elegans was not affected by D3G supplementation under oxidative stress, indicating that the protective effects of D3G may be specific to certain physiological functions. Further studies are needed to explore the underlying mechanisms of D3G’s protective effects and to determine its potential as an anti-aging supplement.

Overall, our study provides evidence for the potential use of D3G as a protective agent against oxidative stress and highlights its comparable effectiveness to coQ10 in improving lifespan and pharyngeal pumping rate in C. elegans. These findings may have implications for developing new therapeutic strategies for age-related diseases and improving human healthspan.

It is worth noting that previous studies on the effects of crude anthocyanins on the survival of C. elegans have presented conflicting claims. For example, the study on blueberry polyphenols suggested that this extract could not defend C. elegans from paraquat and H2O2 [17]. On the other hand, other studies demonstrated that anthocyanins from acai, bilberry, and mulberry attenuated reactive oxygen species (ROS) and protected C. elegans from oxidative damage [16,1820]. These inconsistencies may be due to differences in the types and concentrations of anthocyanins used and the specific stress conditions applied in each study.

Oxidative damage is a well-established contributor to the aging process and age-related diseases. Our findings revealed that D3G exhibited the ability to slow down aging and mitigate the functional decline observed in the nematodes exposed to oxidative stress. This suggests that D3G may hold potential benefits for promoting healthy aging by reducing oxidative damage. Although the exact mechanism by which D3G confers these benefits is yet to be fully understood, we have put forth several hypotheses. It is possible that D3G acts by neutralizing ROS, which are known to cause oxidative damage. By scavenging ROS, D3G may prevent their harmful effects on cellular components. Furthermore, D3G might activate inherent antioxidant defense pathways, enhancing the cellular antioxidant capacity. This can help counteract the detrimental effects of oxidative stress and contribute to maintaining cellular health and function. Additionally, D3G may stimulate genes involved in cellular repair and maintenance, potentially aiding in the restoration of damaged cellular components and promoting longevity. By reducing oxidative damage, D3G has the potential to confer benefits to cellular health and function, which are critical factors for healthy aging. Further research is warranted to elucidate the specific mechanisms through which D3G exerts its effects and to explore its potential applications for promoting healthy aging in diverse model systems and human studies.


CONCLUSION

In conclusion, our study investigated the effects of D3G supplementation on the lifespan and healthspan of C. elegans under various conditions. We found that D3G supplementation significantly increased the mean lifespan and average pharyngeal pumping rate of C. elegans under oxidative stress induced by H2O2. However, supplementation did not significantly affect the nematodes exposed to elevated temperatures or UVA light. Additionally, D3G supplementation did not affect the average number of eggs laid by the nematodes. Our results suggest that D3G has the potential as a protective agent against oxidative stress-induced damage in C. elegans. Further studies are needed to determine the underlying mechanisms of D3G’s protective effects and its potential application as a human dietary supplement.


AUTHOR CONTRIBUTIONS

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. All the authors are eligible to be an author as per the international committee of medical journal editors (ICMJE) requirements/guidelines.


FINANCIAL SUPPORT

This study was funded by the Department of Science and Technology Accelerated Science and Technology Human Resource Development Program (DOST-ASTHRDP), Philippines.


CONFLICTS OF INTEREST

The authors report no financial or any other conflicts of interest in this work.


ETHICAL APPROVALS

This study does not involve experiments on animals or human subjects.


DATA AVAILABILITY

All data generated and analyzed are included in this research article.


PUBLISHER’S NOTE

This journal remains neutral with regard to jurisdictional claims in published institutional affiliation.


REFERENCES

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2. Bowen-Forbes CS, Zhang Y, Nair MG. Anthocyanin content, antioxidant, anti-inflammatory and anticancer properties of blackberry and raspberry fruits. J Food Compos Anal. 2010;23(6):554–60.

3. Cisowska A, Wojnicz D, Hendrich AB. Anthocyanins as antimicrobial agents of natural plant origin. Nat Prod commun. 2011;6(1):1934578X1100600136.

4. Abdellatif AA, Alawadh SH, Bouazzaoui A, Alhowail AH, Mohammed HA. Anthocyanins rich pomegranate cream as a topical formulation with anti-aging activity. J Dermatolog Treat. 2020;4:1–8.

5. Wei J, Zhang G, Zhang X, Xu D, Gao J, Fan J, et al. Anthocyanins from black chokeberry (Aroniamelanocarpa Elliot) delayed aging-related degenerative changes of brain. J Agric Food Chem. 2017;65(29):5973–84.

6. Yang Y, Shi Z, Reheman A, Jin JW, Li C, Wang Y, et al. Plant food delphinidin-3-glucoside significantly inhibits platelet activation and thrombosis: novel protective roles against cardiovascular diseases. PLoS One. 2012;7(5):e37323.

7. Yang X, Luo E, Liu X, Han B, Yu X, Peng X. Delphinidin-3-glucoside suppresses breast carcinogenesis by inactivating the Akt/HOTAIR signaling pathway. BMC Cancer. 2016;16(1):1–8.

8. Harada G, Onoue S, Inoue C, Hanada S, Katakura Y. Delphinidin-3-glucoside suppresses lipid accumulation in HepG2 cells. Cytotechnology. 2018;70(6):1707–12.

9. Nas JS, Roxas CK, Acero RR, Gamit AL, Kim JP, et al. Solanum melongena (Eggplant) crude anthocyanin extract and delphinidin-3-glucoside protects Caenorhabditis elegans against Staphylococcus aureus and Klebsiella pneumoniae. Philippine J Health Res Devel. 2019;23(4):17–24.

10. Nas JS, Dangeros SE, Chen PD, Dimapilis RC, Gonzales DJ, Hamja FJ, Ramos CJ, Villanueva AD. Evaluation of anticancer potential of Eleusine indica methanolic leaf extract through Ras-and Wnt-related pathways using transgenic Caenorhabditis elegans strains. J Pharm Negat Res. 2020;11(1):42.

11. Park HE, Jung Y, Lee SJ. Survival assays using Caenorhabditis elegans. Mol Cells. 2017;40(2):90.

12. Bany IA, Dong MQ, Koelle MR. Genetic and cellular basis for acetylcholine inhibition of Caenorhabditis elegans egg-laying behavior. J Neurosci. 2003;23(22):8060–9.

13. Nas JS, Manalo RV, Medina PM. Peonidin-3-glucoside extends the lifespan of Caenorhabditis elegans and enhances its tolerance to heat, UV, and oxidative stresses. Sci Asia. 2021;47(4):457–65.

14. Bhatla N, Horvitz HR. Light and hydrogen peroxide inhibit C. elegans feeding through gustatory receptor orthologs and pharyngeal neurons. Neuron. 2015;85(4):804–18.

15. Chen W, Mu?ller D, Richling E, Wink M. Anthocyanin-rich purple wheat prolongs the life span of Caenorhabditis elegans probably by activating the DAF-16/FOXO transcription factor. J Agric Food Chem. 2013;61(12):3047–53.

16. Peixoto H, Roxo M, Krstin S, Ro?hrig T, Richling E, Wink M. An anthocyanin-rich extract of acai (Euterpe precatoria Mart.) increases stress resistance and retards aging-related markers in Caenorhabditis elegans. J Agric Food Chem. 2016;64(6):1283–90.

17. Wilson MA, Shukitt-Hale B, Kalt W, Ingram DK, Joseph JA, Wolkow CA. Blueberry polyphenols increase lifespan and thermotolerance in Caenorhabditis elegans. Aging cell. 2006;5(1):59–68.

18. González-Paramás AM, Brighenti V, Bertoni L, Marcelloni L, Ayuda-Durán B, González-Manzano S, et al. Assessment of the in vivo antioxidant activity of an anthocyanin-rich bilberry extract using the Caenorhabditis elegans model. Antioxidants. 2020;9(6):509.

19. Yan F, Chen Y, Azat R, Zheng X. Mulberry anthocyanin extract ameliorates oxidative damage in HepG2 cells and prolongs the lifespan of Caenorhabditis elegans through MAPK and Nrf2 pathways. Oxid Med Cell Longev. 2017;2017:7956158.

20. Zhao X, Zhang X, Tie S, Hou S, Wang H, Song Y, et al. Facile synthesis of nano-nanocarriers from chitosan and pectin with improved stability and biocompatibility for anthocyanins delivery: an in vitro and in vivo study. Food Hydrocoll. 2020;2020:106114.

Reference

1. Bagchi D, Sen CK, Bagchi M, Atalay M. Anti-angiogenic, antioxidant, and anti-carcinogenic properties of a novel anthocyanin-rich berry extract formula. Biochemistry (Moscow). 2004;69(1):75- 80. https://doi.org/10.1023/B:BIRY.0000016355.19999.93

2. Bowen-Forbes CS, Zhang Y, Nair MG. Anthocyanin content, antioxidant, anti-inflammatory and anticancer properties of blackberry and raspberry fruits. J Food Compos Anal. 2010;23(6):554-60. https://doi.org/10.1016/j.jfca.2009.08.012

3. Cisowska A, Wojnicz D, Hendrich AB. Anthocyanins as antimicrobial agents of natural plant origin. Nat Prod commun. 2011;6(1):1934578X1100600136. https://doi.org/10.1177/1934578X1100600136

4. Abdellatif AA, Alawadh SH, Bouazzaoui A, Alhowail AH, Mohammed HA. Anthocyanins rich pomegranate cream as a topical formulation with anti-aging activity. J Dermatolog Treat. 2020;4:1-8. https://doi.org/10.1080/09546634.2020.1721418

5. Wei J, Zhang G, Zhang X, Xu D, Gao J, Fan J, et al. Anthocyanins from black chokeberry (Aroniamelanocarpa Elliot) delayed aging-related degenerative changes of brain. J Agric Food Chem. 2017;65(29):5973-84. https://doi.org/10.1021/acs.jafc.7b02136

6. Yang Y, Shi Z, Reheman A, Jin JW, Li C, Wang Y, et al. Plant food delphinidin-3-glucoside significantly inhibits platelet activation and thrombosis: novel protective roles against cardiovascular diseases. PLoS One. 2012;7(5):e37323. https://doi.org/10.1371/journal.pone.0037323

7. Yang X, Luo E, Liu X, Han B, Yu X, Peng X. Delphinidin-3- glucoside suppresses breast carcinogenesis by inactivating the Akt/ HOTAIR signaling pathway. BMC Cancer. 2016;16(1):1-8. https://doi.org/10.1186/s12885-016-2465-0

8. Harada G, Onoue S, Inoue C, Hanada S, Katakura Y. Delphinidin- 3-glucoside suppresses lipid accumulation in HepG2 cells. Cytotechnology. 2018;70(6):1707-12. https://doi.org/10.1007/s10616-018-0246-0

9. Nas JS, Roxas CK, Acero RR, Gamit AL, Kim JP, et al. Solanum melongena (Eggplant) crude anthocyanin extract and delphinidin-3- glucoside protects Caenorhabditis elegans against Staphylococcus aureus and Klebsiella pneumoniae. Philippine J Health Res Devel. 2019;23(4):17-24.

10. Nas JS, Dangeros SE, Chen PD, Dimapilis RC, Gonzales DJ, Hamja FJ, Ramos CJ, Villanueva AD. Evaluation of anticancer potential of Eleusine indica methanolic leaf extract through Ras-and Wnt-related pathways using transgenic Caenorhabditis elegans strains. J Pharm Negat Res. 2020;11(1):42. https://doi.org/10.4103/jpnr.JPNR_7_20

11. Park HE, Jung Y, Lee SJ. Survival assays using Caenorhabditis elegans. Mol Cells. 2017;40(2):90. https://doi.org/10.14348/molcells.2017.0017

12. Bany IA, Dong MQ, Koelle MR. Genetic and cellular basis for acetylcholine inhibition of Caenorhabditis elegans egg-laying behavior. J Neurosci. 2003;23(22):8060-9. https://doi.org/10.1523/JNEUROSCI.23-22-08060.2003

13. Nas JS, Manalo RV, Medina PM. Peonidin-3-glucoside extends the lifespan of Caenorhabditis elegans and enhances its tolerance to heat, UV, and oxidative stresses. Sci Asia. 2021;47(4):457-65. https://doi.org/10.2306/scienceasia1513-1874.2021.059

14. Bhatla N, Horvitz HR. Light and hydrogen peroxide inhibit C. elegans feeding through gustatory receptor orthologs and pharyngeal neurons. Neuron. 2015;85(4):804-18. https://doi.org/10.1016/j.neuron.2014.12.061

15. Chen W, Mu?ller D, Richling E, Wink M. Anthocyanin-rich purple wheat prolongs the life span of Caenorhabditis elegans probably by activating the DAF-16/FOXO transcription factor. J Agric Food Chem. 2013;61(12):3047-53. https://doi.org/10.1021/jf3054643

16. Peixoto H, Roxo M, Krstin S, Ro?hrig T, Richling E, Wink M. An anthocyanin-rich extract of acai (Euterpe precatoria Mart.) increases stress resistance and retards aging-related markers in Caenorhabditis elegans. J Agric Food Chem. 2016;64(6):1283-90. https://doi.org/10.1021/acs.jafc.5b05812

17. Wilson MA, Shukitt-Hale B, Kalt W, Ingram DK, Joseph JA, Wolkow CA. Blueberry polyphenols increase lifespan and thermotolerance in Caenorhabditis elegans. Aging cell. 2006;5(1):59-68. https://doi.org/10.1111/j.1474-9726.2006.00192.x

18. González-Paramás AM, Brighenti V, Bertoni L, Marcelloni L, Ayuda-Durán B, González-Manzano S, et al. Assessment of the in vivo antioxidant activity of an anthocyanin-rich bilberry extract using the Caenorhabditis elegans model. Antioxidants. 2020;9(6):509. https://doi.org/10.3390/antiox9060509

19. Yan F, Chen Y, Azat R, Zheng X. Mulberry anthocyanin extract ameliorates oxidative damage in HepG2 cells and prolongs the lifespan of Caenorhabditis elegans through MAPK and Nrf2 pathways. Oxid Med Cell Longev. 2017;2017:7956158. https://doi.org/10.1155/2017/7956158

20. Zhao X, Zhang X, Tie S, Hou S, Wang H, Song Y, et al. Facile synthesis of nano-nanocarriers from chitosan and pectin with improved stability and biocompatibility for anthocyanins delivery: an in vitro and in vivo study. Food Hydrocoll. 2020;2020:106114. https://doi.org/10.1016/j.foodhyd.2020.106114

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