Gnetum gnemon L. Seed Hardshell Nanoextract, A Potential Biomaterial for Oral AntiAging through Sirtuin-1 Induction

Marlina Indriastuti; I Ketut Adnyana; Rika Hartati; Heni Rachmawati

doi:10.22146/ijp.21747

Marlina Indriastuti School of Pharmacy, Bandung Institute of Technology, Bandung, 40132, Indonesia; https://orcid.org/0000-0001-8953-5770
I Ketut Adnyana School of Pharmacy, Bandung Institute of Technology, Bandung, 40132, Indonesia https://orcid.org/0000-0001-5217-2312
Rika Hartati School of Pharmacy, Bandung Institute of Technology, Bandung, 40132, Indonesia https://orcid.org/0000-0002-9179-8235
Heni Rachmawati School of Pharmacy, Bandung Institute of Technology, Bandung, 40132, Indonesia https://orcid.org/0000-0003-1968-0002

Keywords: nanoextract, G.gnemon, antiaging, SIRT1, acute oral toxicity

Abstract

The seeds of Gnetum gnemon L. widely referred to as melinjo, enclosed within a distinctly tough outer shell, have attracted interest due to their remarkable anti-aging capabilities. Nevertheless, despite this potential, their practical therapeutic use is limited by their naturally low solubility and restricted bioavailability. To tackle these pharmacokinetic issues, the current study utilized an environmentally friendly nanotechnology approach, specifically high-energy ball milling, to create nanoparticles from the hard shell of the seeds. This technique significantly amplifies the surface area of the bioactive particles, thus improving their absorption and efficacy within biological systems. The resulting nanoextracts were comprehensively characterized and subsequently assessed through in vivo anti-aging tests and acute oral toxicity evaluations. UVB-irradiated rats served as a biological model for simulating aging, with nanoextracts administered at doses of 36, 72, and 144 mg/kg over a duration of 12 weeks. The results demonstrated a statistically significant, dose-dependent rise in the expression of SIRT1, a crucial regulatory protein associated with cellular longevity and aging mechanisms. Notably, an acute toxicity evaluation at a dosage of 5000 mg/kg affirmed the safety of the nanoformulation, with no discernible toxic effects noted in the test subjects. These results highlight the promise of G. gnemon seed hardshell nanoparticles as a feasible and safe natural alternative for anti-aging therapies. The implementation of sustainable nanotechnology not only enhances the delivery and effectiveness of phytochemicals but also corresponds with the increasing demand for environmentally friendly biomedical advancements aimed at fostering healthy aging.

References

REFERENCES
Abed, S. N., Deb, P. K., Surchi, H. S., Kokaz, S. F., Jamal, S. M., Bandopadhyay, S., & Tekade, R. K. (2019). Nanocarriers in Different Preclinical and Clinical Stages. Academic Press. https://doi.org/10.1016/B978-0-12-817909-3.00017-0
Alqarni, M. H., Foudah, A. I., Muharram, M. M., & Labrou, N. E. (2021). The Pleiotropic Function of Human Sirtuins as Modulators of Metabolic Pathways and Viral Infections. Cells, 10, 460. https://doi.org/10.3390/CELLS10020460
Arora, S., Kumar, G., & Shukla, R. (2020). Nanotechnology for Bioactive Compound Delivery in Food: A Critical Overview. Food Chem, 323, 126871. https://doi.org/10.1016/j.foodchem.2020.126871
Barua, C. C., & Haloi, P. I. C. (2015). Barua Gnetum Gnemon Linn.: A Comprehensive Review on Its Biological. Pharmacological and Pharmacognostical Potentials, IJPPR, 7531–7539.
Bonomi, S., Armenise, V., Accorsi, G., Colella, S., Rizzo, A., Fracassi, F., Malavasi, L., & Listorti, A. (2020). The Effect of Extended Ball-Milling upon Three-Dimensional and Two-Dimensional Perovskite Crystals Properties. Appl. Sci, 10, 4775. https://doi.org/10.3390/app10144775
BPOM. (n.d.). Uji Toksisitas Praklinik Secara In Vivo. Uji Toksisitas Akut Oral. https://doi.org/10/2022
Chang, H.-C., & Guarente, L. (2014). SIRT1 and other sirtuins in metabolism. TEM, 25, 138–145. https://doi.org/10.1016/J.TEM.2013.12.001
Chang, N., Li, J., Lin, S., Zhang, J., Zeng, W., Ma, G., & Wang, Y. (2024). Emerging roles of SIRT1 activator, SRT2104, in disease treatment. Sci. Rep, 14, 5521. https://doi.org/10.1038/s41598-024-55923-8
Covarrubias, A. J., Perrone, R., Grozio, A., & Verdin, E. (2021). NAD+ metabolism and its roles in cellular processes during ageing. Nat. Rev. Mol. Cell Biol, 22, 119–141. https://doi.org/10.1038/s41580-020-00313-x
Cunha-Santos, J., Duarte-Neves, J., Carmona, V., Almeida, L. P., Cavadas, C., & Guarente, L. (2016). Caloric restriction blocks neuropathology and motor deficits in Machado-Joseph disease mouse models through SIRT1 pathway. Nat. Commun, 7. https://doi.org/10.1038/ncomms11445
Davis, B., Son, D. J., Jung, J. C., Choi, Y. M., Ryu, H. Y., & Lee, S. (2020). Wheat Extract Oil (WEO) Attenuates UVB-Induced Photoaging via Collagen Synthesis in Human Keratinocytes and Hairless Mice, Curr. Dev. Dutr, 4, 387. https://doi.org/10.1093/cdn/nzaa045
Gigliobianco, M. R., Casadidio, C., Censi, R., & Martino. (2021). Nanocrystals of poorly soluble drugs. Drug Bioavailability and Physicochemical Stability, armaceutics.10, 1–29.
Grootaert, M., & Bennett, M. R. (2022). Sirtuins in atherosclerosis: Guardians of healthspan and therapeutic targets. Nat. Rev. Cardiol, 19, 668–683. https://doi.org/10.1038/s41569-022-00685-x
Honda, M., Kageyama, H., Zhang, Y., Hibino, T., & Goto, M. (2022). Oral Supplementation with Z-Isomer-Rich Astaxanthin Inhibits Ultraviolet Light-Induced Skin Damage in Guinea Pigs. Marine Drug, 20, 414. https://doi.org/10.3390/md20070414
Huang, Y., Lu, J., Zhan, L., Wang, M., Shi, R., Yuan, X., Gao, X., Liu, X., Zang, J., & W. (2021). Liu Yao X Resveratrol-induced Sirt1 phosphorylation by LKB1 mediates mitochondrial metabolism. JBC, 297. https://doi.org/10.1016/j.jbc.2021.100929
Imokawa, G., & Ishida, K. (2015). Biological mechanisms underlying the ultraviolet radiation-induced formation of skin wrinkling and sagging I: reduced skin elasticity, highly associated with enhanced dermal elastase activity, triggers wrinkling and sagging. Int. J. Mol. Sci, 16, 7753–7775. https://doi.org/10.3390/ijms16047753
Indriastuti, M., Adnyana, I. K., Hartati, R., & Rachmawati, H. (2024). Particle Size Optimization of Melinjo (Gnetum gnemon L.) Seed Hardshell: A Potential Antioxidant Alternative. J. Math. Fund. Sci, 56, 18–29. https://doi.org/10.5614/j.math.fund.sci.2024.56.1.2
Jarvis, M., Krishnan, V., & Mitragotri, S. (2020). Nanocrystals for translational research and clinical applications: Toxicity concerns. BioTM, 5, 5–16.
Khelfa, T., Mhadhbi, M., Khitouni, N., Bachagga, T., Sunol, J. J., & Khitouni, M. (2024). Effect of High-Energy Ball Milling on the Structural and Magnetic Behavior of Fe60Al40 Alloy. J. Mater. Eng. Perform, 33, 7838–7848. https://doi.org/10.1007/s11665-023-08438-8
Kong, Y. K., Lee, K. S., & Kim, D. M. (2013). Biomechanical Evaluation of the Pinch Test in Hand Dexterity and Rehabilitation. J. Hand. Ther, 26, 31–39. https://doi.org/10.1016/j.jht.2012.09.002
Kumar, S., Sharma, A., & Pandey, A. (2019). Influence of Milling on the Particle Size and Content of Bioactive Compounds in Medicinal Plants. J. Herb. Med, 19, 100287. https://doi.org/10.1016/j.hermed.2019.100287
Lalatsa, A., & Butt, A. M. (2018). Physiology of the Blood Brain Barrier and Mechanism of Transport Across the BBB. NBDDS, 49–74. https://doi.org/10.1016/b978-0-12-812218-1.00003-8.
Lalatsa, A., Leite, D. M., Figueiredo, M. F., & O’Connor, M. (2018). NBDDS (pp. 111-145,). DOI: 10.1016/b978-0-12-812218-1.0000-1
Law, M., Wang, P.-C., Zhou, Z.-Y., & Wang, Y. (2024). From Microcirculation to Aging-Related Diseases: A Focus on Endothelial SIRT1. Pharm, 17. https://doi.org/10.3390/ph17111495
Lee, H., Kim, Y., & Shin, Y. (2019). Polyphenol-induced SIRT1 activation improves cellular function and reduces risk of degenerative diseases. J. Funct. Foods, 54, 200–210.
Lee, S. H., Choi, J. W., & Kim, Y. H. (2017). Effect of Particle Size Reduction on the Bioavailability and Bioefficacy of Phytochemicals. Food Chem, 221, 30–38. https://doi.org/10.1016/j.jff.2019.103680
Lee, S. H., Lee, J. H., Lee, H. Y., & Min, K. J. (2019). Sirtuin signaling in cellular senescence and aging. BMB Rep, 52, 24–34. https://doi.org/10.5483/BMBRep.2019.52.1.290
Li, X., Zhang, L., & Chen, R. (2020). Stability of Bioactive Compounds during Mechanical Milling: Degradation and Loss Analysis. J. Food Eng, 276, 109859. https://doi.org/10.1016/j.jfoodeng.2020.109859
Li, Z., & Gu, L. (2011). Effects of mass ratio, pH, temperature, and reaction time on fabrication of partially purified pomegranate ellagitanninegelatin nanoparticles. J. Agric. Food Chem, 59(8), 4225–4231.
Li, Z., Jiang, H., Xu, C., & Gu, L. (2015). A review: Using nanoparticles to enhance absorption and bioavailability of phenolic phytochemicals. Food Hydrocoll, 43, 153–164.
Malerba, M. E., Malerba, M. E., & Marshall, D. J. (2021). Larger cells have relatively smaller nuclei across the Tree of Life. Evolution Letters, 5(4), 306–314. https://doi.org/10.1002/EVL3.243
Masruriati, E., Adnyana, I. K., Mudhakir, D., Mahmudah, R., & Rachmawati, H. (2024). Development of controlled release particulate system of Melinjo (Gnetum Gnemon L.) seed shell extract and effectivity on the hyperuricemic rat model. J. Appl. Pharm. Sci, 14, 159–169. https://doi.org/10.7324/JAPS.2024.146973
Miao, C., Jia, P., Luo, C., Pang, J., Xiao, L., Zhang, T., Duan, J., Li, Y., & Sun, Z. (2024). The size-dependent in vivo toxicity of amorphous silica nanoparticles: A systematic review. Ecotoxicol. Environ. Saf, 271, 115910–115910. https://doi.org/10.1016/j.ecoenv.2023.115910
Morris, B. J. (2021). Sirtuins in Aging. In D. Gu & M. E. Dupre (Eds.), Encyclopedia of Gerontology and Population Aging Sirtuins in Aging. https://doi.org/10.1007/978-3-030-22009-9_1037
Okoye, U. C., Arhewoh, M. I., & Okhamafe, A. (2022). Synthesis, Characterization, and Applications of Nanoparticles,. IJPSRR, 14–20. https://doi.org/10.47583/ijpsrr.2022.v77i01.003
Oliveira, V. S., Converti, A., & Lima, A. A. N. (2023). Microparticles in the development and improvement of pharmaceutical formulations: An analysis of in vitro and in vivo studies. Front. Int. J. Mol. Sci, 24, 5441.
Panda, B. P. (2017). Current Trends in Design and Development of Nanopharmaceutical Dosage Forms. Bioequiv & Bioavailab Int J, 1(1). https://doi.org/10.23880/BEBA-16000104
Price, N. L., Gomes, A. P., & Sinclair, D. A. (2021). Resveratrol Increases SIRT1 Activity and Mimics Caloric Restriction to Promote Antiaging Effects Nat. Rev. Mol. Cell Biol, 22, 192–210. https://doi.org/10.1038/s41580-021-00332-x
Prusty, A., & Padhi, S. (2024). Nanomaterials Marvels: Transformative Advancements in Biomedicine, Drug Delivery, and Pharmaceutical Analysis. FABAD Journal of Pharmaceutical Sciences. https://doi.org/10.55262/fabadeczacilik.1520564
Pu, S.-Y., Huang, Y.-L., Pu, C.-M., Kang, Y.-N., Hoang, K. D., Chen, K.-H., & Chen, C. (2023). Effects of Oral Collagen for Skin Anti-Aging: A Systematic Review and Meta-Analysis. Nutrients, 15. https://doi.org/10.3390/nu15092080
Rachmawati, H., Shaal, L. A., & Müller, R. H. (2013). Keck CM Development of curcumin nanocrystal: Physical aspects. J. Pharm. Sci, 102, 204–214. https://doi.org/10.1002/jps.23335
Saraswaty, V., Adnyana, I. K., Pudjiraharti, P., Mozef, T., Insanu, M., Kurniati, N. F., & Rachmawati, H. (2017). Fractination using adsorptive macroporous resin HPD-600 enhances antioksidant activity of Gnetum Gnemon L. Seed Hard Shell Extract, J. Food Sci. Technol, 54, 3349–3357. https://doi.org/10.1007/S13197-017-2793-3
Saraswaty, V., Suparta, N. W., Setiyanto, H., Rachmawati, H., & Adnyana, I. K. (2019). Transformation of Mlinjo Seed Micropowders into Nanopowders Enhances Extractability of Phenolic Compounds and Tyrosinase Inhibitory Activity. Sains Malaysia, 48, 983–990.
Sarubbo, F., Estebean, S., Miralles, A., & Moranta, D. (2017). Effects of Resveratrol and Other Polyphenols onSIRT1: Relevance to brain Function During Aging, Curr. Neuropharmacol, 16, 126–136. https://doi.org/10.2174/1570159X15666170703113212
Sebastian, J. A., Moore, M. J., Berndl, E. S. L., & Kolios, M. C. (2022a). An image-based flow cytometric approach to the assessment of the nucleus-to-cytoplasm ratio. PLOS One, 16(6). https://doi.org/10.32920/21290967
Sebastian, J. A., Moore, M. J., Berndl, E. S. L., & Kolios, M. C. (2022b). An image-based flow cytometric approach to the assessment of the nucleus-to-cytoplasm ratio. PLOS One, 16(6). https://doi.org/10.1371/JOURNAL.PONE.0253439
Shabatina, T. I., Gromova, Y. A., Vernaya, O. I., Soloviev, A. V., Shabatin, A. V., Morosov, Y., Astashova, I., & Melnikov, M. Y. (2024). Pharmaceutical Nanoparticles Formation and Their Physico-Chemical and Biomedical Properties. Pharmaceuticals. https://doi.org/10.3390/ph17050587
Shin, J., Park, Y., & Jang, S. (2021). Modulation of SIRT1 and Its Role in Cellular Senescence and Aging. Aging Cell, 20.
Sim, W.-J., Kim, J., Baek, K.-S., Lim, W., & Lim, T.-G. (2024). Porcine Placenta Peptide Inhibits UVB-Induced Skin Wrinkle Formation and Dehydration: Insights into MAPK Signaling Pathways from In Vitro and In Vivo Studies. Int. J. Mol. Sci, 25, 83. https://doi.org/10.3390/ijms25010083
Strambeanu, N., Demetrovici, L., Dragos, D., & Lungu, M. (2015). Nanoparticles: Definition, Classification and General Physical Properties. Nanoparticles’ Promises and Risks, 3–8. https://doi.org/10.1007/978-3-319-11728-7_1
Tani, H., Hikami, S., Izuna, S., Yoshimatsu, M., Asama, T., Ota, H., Kimura, Y., Tatefuji, T., Hashimoto, K., & Higaki, K. (2014). Pharmacokinetics and Safety of Resveratrol Derivatives in Humans after Oral After Administration of Mlinjo (Gnetum Gnemon L. Seed Extract Powder, J. Agric. Food Chem, 62. https://doi.org/10.1021/jf4048435
Thapa, R., Moglad, E., Afzal, M., Gupta, G., Bhat, A. A., Almalki, W. H., Kazmi, I., Alzarea, S. I., Pant, K., Singh, T. G., Singh, S. K., & H, A. (2024). The Role of Sirtuin 1 in Ageing and Neurodegenerative Disease: A Molecular Perspective,. Ageing Res. Rev, 102, 102545–102545. https://doi.org/10.1016/j.arr.2024.102545
Titisari, R. S., Herawati, E., & Astirin, O. P. (2023). Oral intake of collagen hydrolysate from mackerel scad (Decapterus macarellus) attenuates skin photoaging by suppressing the UVB-induced expression of MMP-1 and IL-6. J. Chem. Inf. Model, 21, 71–79. https://doi.org/10.1515/jcim-2023-0209
Wang, X., Parvathaneni, V., Shukla, S. K., Kulkarni, N. S., Muth, A., Kunda, N., & Gupta, V. (2020). Inhalable resveratrol-cyclodextrin complex loaded biodegradable nanoparticles for enhanced efficacy against non-small cell lung cancer. Int. J. Biol. Macromol, 164, 638–650. https://doi.org/10.1016/j.ijbiomac.2020.07.124
Zhang, M., Zhou, X., & Wei, Y. (2022). Safety and Toxicity Evaluation of Plant-derived Nanoparticles in Animal Models. NBN, 43, 102371.
Zhang, Y., Wang, L., & Zhao, C. (2021). Impact of Grinding on Particle Characteristics and Functional Properties of Natural Products. Powder Technol, 379, 295–301. https://doi.org/10.1016/j.powtec.2020.10.053
Zhou, Y., Liu, Q., & Lin, Z. (2019). Toxicity Study of Herbal Nanoparticles in High Dose Administration: Effects on Behavior and Organ Health. Front. Pharmacol, 10, 1025.