近年奈米物質已被廣泛應用於許多領域當中，其因多樣物化特性和大量的應用引發諸多安全性疑慮，而這些奈米質中，奈米銀 (Silver nanoparticles , AgNPs) 是其中一種備受關注的奈米材料。然而奈米銀已被報導會藉由產生多種細胞毒性機轉，如:過量氧化壓力而導致顯著急性毒性反應。然而長期產生過量氧化壓力將可能進一步導致長期毒性，如壽命的下降。氧化壓力和抗氧氧化路徑平衡是其中一個重要的老化指標，在腸道當中，氧化壓力會藉由誘發幹細胞過度增生進而加速個體和功能性老化。但是目前對於奈米銀所誘發之氧化壓力是否在動物體中介導不良反應及其是否誘發長期毒性仍不清楚。因此本研究以果蠅與斑馬魚胚胎早期暴露作為動物模式，探討奈米銀誘發之氧化壓力於急性和慢性不良反應中之角色，並且本研究也進一步探討奈米銀之物化特性-粒徑大小對於急性毒性的影響。結果顯示奈米銀會累積於果蠅和斑馬魚胚胎當中，且依照粒徑大小和濃度依存效應導致果嚴重不良反應，包含死亡率增加、發育遲緩和畸形。針對毒性機轉而言，奈米銀於果蠅與斑馬魚胚胎皆會誘發氧化壓力和細胞凋亡現象。並且透過給予抗氧化劑和氧化壓力誘導劑證實奈米銀藉由氧化壓力介導急性不良反應。針對慢性毒性而言，我們於果蠅模式當中發現早期暴露的奈米銀會自幼年時期持續殘留至老年時期，這些長期累積的奈米銀會以劑量依存關係減少果蠅壽命，並且會加速功能性老化，包含對於壓力刺激的抵抗能力降低和腸道通透率增加。我們進一步探討氧化壓力平衡對於奈米銀所導致的壽命下降與功能性老化所扮演的角色，老年時奈米銀會使得果蠅無法活化抗氧化路徑因而難以抵抗氧化壓力的侵害，而氧化還原無法維持平衡會進一步導致腸道幹細胞的增生。重要的是我們發現白藜蘆醇的結構相似物紫檀芪 (Pterostilbene) 能夠藉由活化抗氧化路徑來降低氧化壓力，減緩奈米銀所導致的個體老化及功能性老化，綜上所述，本研究證實奈米銀會依照粒徑大小和濃度依存效應導致氧化壓力介導的急性毒性，對於慢性毒性而言，終身蓄積的奈米銀能夠藉由抑制抗氧化路徑加速個體及功能性老化，而紫檀芪能預防奈米銀所誘發的不良反應。本研究對於奈米銀所導致的急性毒性和長期毒性提供更深層的了解，這能夠協助建立奈米材料在科學上的基礎和其使用的安全性。

Engineered nanoparticles (NPs) have been introduced to various fields and raised potential safety and health concerns due to their high volume manufacturing and different physicochemical properties. Among them, silver nanoparticles (AgNPs) are one of the most important and high-profile NPs. Previous studies have shown that AgNPs exert acute adverse effects by inducing reactive oxygen species (ROS) burden. Abundant evidence has demonstrated that long-term ROS burden leads to longstanding toxic effects, such as lifespan shortening. Excessive ROS generation is an essential hallmark of aging and it drives premature aging and functional decline in intestine with dramatic stem cells hyperplasia. However, the molecular mechanisms by which AgNPs exert severe adverse effects and long-term toxicity, particularly in vivo, have remained elusive. Therefore, we have used Drosophila and zebrafish embryos as in vivo models to study how AgNPs induce acute and long-term toxic effects. Moreover, we explored the effects of particle size, one of the important physicochemical properties, on AgNPs-induced adverse effects. We found that early life exposure of AgNPs strongly increases animal lethality, developmental retardation and teratogenicity in dose- and size-dependent manner. Mechanistically, AgNPs elevated cytotoxicity and ROS in vivo models. We further found that ROS mediate AgNPs-induced acute toxicity by conducting animal experiments using antioxidants and ROS inducers. Regarding long-term toxicity, early life exposure to AgNPs led to lifetime bioaccumulation and induced negative effects on lifespan and functional aging such as disruptive intestinal integrity. Furthermore, animals responded to AgNPs by activating antioxidant pathways during young age. However, AgNPs inactivated antioxidant pathways in old animals with increasing susceptibility to ROS stress. The imbalance of the redox system in the intestine consequently gave rise to overperliferation of intestinal stem cells. Importantly, pterostilbene (PT), a structure analog of resveratrol, prevented AgNP-induced adverse effects through elevating antioxidant capacity. Taken together, AgNPs-induced disruption of ROS/antioxidant homeostasis causes acute and long-lasting toxic effects, and PT ameliorates these effects. Our current study provides profound insights into the AgNPs-induced toxic mechanisms and contributes to establishing a scientific foundation and risk assessment.

Abdal Dayem A, Hossain MK, Lee SB, Kim K, Saha SK, Yang GM, et al. The role of reactive oxygen species (ros) in the biological activities of metallic nanoparticles. Int J Mol Sci 18:120. 2017.
Acharya JD, Ghaskadbi SS. Protective effect of pterostilbene against free radical mediated oxidative damage. BMC complementary and alternative medicine 13:238. 2013.
Adedokun SA, Olojede OC. Optimizing gastrointestinal integrity in poultry: The role of nutrients and feed additives. Front Vet Sci 5:348. 2018.
Agrawal M. Natural polyphenols based new therapeutic avenues for advanced biomedical applications. Drug Metab Rev 47:420-430. 2015.
Ahamed M, Alsalhi MS, Siddiqui MK. Silver nanoparticle applications and human health. Clinica chimica acta; international journal of clinical chemistry 411:1841-1848. 2010.
Akter M, Sikder MT, Rahman MM, Ullah A, Hossain KFB, Banik S, et al. A systematic review on silver nanoparticles-induced cytotoxicity: Physicochemical properties and perspectives. Journal of advanced research 9:1-16. 2018.
Antell DE, Taczanowski EM. How environment and lifestyle choices influence the aging process. Annals of plastic surgery 43:585-588. 1999.
Arab-Nozari M, Zamani E, Latifi A, Shaki F. Mitochondrial toxicity of aluminium nanoparticles in comparison to its ionic form on isolated rat brain mitochondria. Bratislavske lekarske listy 120:516-522. 2019.
Arora S, Jain J, Rajwade JM, Paknikar KM. Cellular responses induced by silver nanoparticles: In vitro studies. Toxicol Lett 179:93-100. 2008.
Asharani PV, Lianwu Y, Gong Z, Valiyaveettil S. Comparison of the toxicity of silver, gold and platinum nanoparticles in developing zebrafish embryos. Nanotoxicology 5:43-54. 2011.
Bar-Ilan O, Chuang CC, Schwahn DJ, Yang S, Joshi S, Pedersen JA, et al. Tio2 nanoparticle exposure and illumination during zebrafish development: Mortality at parts per billion concentrations. Environ Sci Technol 47:4726-4733. 2013.
Bass TM, Weinkove D, Houthoofd K, Gems D, Partridge L. Effects of resveratrol on lifespan in drosophila melanogaster and caenorhabditis elegans. Mechanisms of ageing and development 128:546-552. 2007.
Bayda S, Adeel M, Tuccinardi T, Cordani M, Rizzolio F. The history of nanoscience and nanotechnology: From chemical-physical applications to nanomedicine. Molecules 25:112. 2019.
Bhakkiyalakshmi E, Sireesh D, Sakthivadivel M, Sivasubramanian S, Gunasekaran P, Ramkumar KM. Anti-hyperlipidemic and anti-peroxidative role of pterostilbene via nrf2 signaling in experimental diabetes. European journal of pharmacology 777:9-16. 2016.
Boudreau MD, Imam MS, Paredes AM, Bryant MS, Cunningham CK, Felton RP, et al. Differential effects of silver nanoparticles and silver ions on tissue accumulation, distribution, and toxicity in the sprague dawley rat following daily oral gavage administration for 13 weeks. Toxicol Sci 150:131-160. 2016.
Browning LM, Lee KJ, Nallathamby PD, Xu XH. Silver nanoparticles incite size- and dose-dependent developmental phenotypes and nanotoxicity in zebrafish embryos. Chemical research in toxicology 26:1503-1513. 2013.
Brun NR, Lenz M, Wehrli B, Fent K. Comparative effects of zinc oxide nanoparticles and dissolved zinc on zebrafish embryos and eleuthero-embryos: Importance of zinc ions. The Science of the total environment 476-477:657-666. 2014.
Carvalho PM, Felício MR, Santos NC, Gonçalves S, Domingues MM. Application of light scattering techniques to nanoparticle characterization and development. Front Chem 6:237. 2018.
Castillo-Quan JI, Li L, Kinghorn KJ, Ivanov DK, Tain LS, Slack C, et al. Lithium promotes longevity through gsk3/nrf2-dependent hormesis. Cell reports 15:638-650. 2016.
Chakkalakal JV, Jones KM, Basson MA, Brack AS. The aged niche disrupts muscle stem cell quiescence. Nature 490:355-360. 2012.
Chelakkot C, Ghim J, Ryu SH. Mechanisms regulating intestinal barrier integrity and its pathological implications. Exp Mol Med 50:1-9. 2018.
Chen B, Chai Q, Xu S, Li Q, Wu T, Chen S, et al. Silver nanoparticle-activated cox2/pge2 axis involves alteration of lung cellular senescence in vitro and in vivo. Ecotoxicology and environmental safety 204:111070. 2020.
Chen D, Zhang D, Yu JC, Chan KM. Effects of cu2o nanoparticle and cucl2 on zebrafish larvae and a liver cell-line. Aquatic toxicology (Amsterdam, Netherlands) 105:344-354. 2011.
Chen RJ, Kuo HC, Cheng LH, Lee YH, Chang WT, Wang BJ, et al. Apoptotic and nonapoptotic activities of pterostilbene against cancer. Int J Mol Sci 19. 2018.
Chen RJ, Chen YY, Liao MY, Lee YH, Chen ZY, Yan SJ, et al. The current understanding of autophagy in nanomaterial toxicity and its implementation in safety assessment-related alternative testing strategies. Int J Mol Sci 21. 2020.
Chen Y, Wang M, Zhang T, Du E, Liu Y, Qi S, et al. Autophagic effects and mechanisms of silver nanoparticles in renal cells under low dose exposure. Ecotoxicology and environmental safety 166:71-77. 2018.
Chen ZY, Li NJ, Cheng FY, Hsueh JF, Huang CC, Lu FI, et al. The effect of the chorion on size-dependent acute toxicity and underlying mechanisms of amine-modified silver nanoparticles in zebrafish embryos. International journal of molecular sciences 21. 2020.
Chiu CT, Chuang DM. Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of cns disorders. Pharmacol Ther 128:281-304. 2010.
Choi JR, Shin DM, Song H, Lee D, Kim K. Current achievements of nanoparticle applications in developing optical sensing and imaging techniques. Nano Converg 3:30. 2016.
Collin F. Chemical basis of reactive oxygen species reactivity and involvement in neurodegenerative diseases. Int J Mol Sci 20:2407. 2019.
Cone RA. Barrier properties of mucus. Adv Drug Deliv Rev 61:75-85. 2009.
Contado C. Nanomaterials in consumer products: A challenging analytical problem. Front Chem 3. 2015.
Contreras EQ, Puppala HL, Escalera G, Zhong W, Colvin VL. Size-dependent impacts of silver nanoparticles on the lifespan, fertility, growth, and locomotion of caenorhabditis elegans. Environ Toxicol Chem 33:2716-2723. 2014.
Davalli P, Mitic T, Caporali A, Lauriola A, D'Arca D. Ros, cell senescence, and novel molecular mechanisms in aging and age-related diseases. Oxid Med Cell Longev 2016:3565127. 2016.
Di Ciaula A, Portincasa P. The environment as a determinant of successful aging or frailty. Mechanisms of ageing and development 188:111244. 2020.
Dumic I, Nordin T, Jecmenica M, Stojkovic Lalosevic M, Milosavljevic T, Milovanovic T. Gastrointestinal tract disorders in older age. Can J Gastroenterol Hepatol 2019:6757524. 2019.
Dziendzikowska K, Gromadzka-Ostrowska J, Lankoff A, Oczkowski M, Krawczyńska A, Chwastowska J, et al. Time-dependent biodistribution and excretion of silver nanoparticles in male wistar rats. J Appl Toxicol 32:920-928. 2012.
El Chakhtoura NG, Bonomo RA, Jump RLP. Influence of aging and environment on presentation of infection in older adults. Infect Dis Clin North Am 31:593-608. 2017.
Farhadi A, Banan A, Fields J, Keshavarzian A. Intestinal barrier: An interface between health and disease. J Gastroenterol Hepatol 18:479-497. 2003.
Farkas J, Peter H, Christian P, Gallego Urrea JA, Hassellöv M, Tuoriniemi J, et al. Characterization of the effluent from a nanosilver producing washing machine. Environ Int 37:1057-1062. 2011.
Fasano A, Shea-Donohue T. Mechanisms of disease: The role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nat Clin Pract Gastroenterol Hepatol 2:416-422. 2005.
Ferdous Z, Nemmar A. Health impact of silver nanoparticles: A review of the biodistribution and toxicity following various routes of exposure. Int J Mol Sci 21:2375. 2020.
Flatt T. A new definition of aging? Front Genet 3:148. 2012.
Flint HJ, Scott KP, Louis P, Duncan SH. The role of the gut microbiota in nutrition and health. Nat Rev Gastroenterol Hepatol 9:577-589. 2012.
Funk MC, Zhou J, Boutros M. Ageing, metabolism and the intestine. EMBO Rep 21:e50047. 2020.
Giorgio M, Migliaccio E, Orsini F, Paolucci D, Moroni M, Contursi C, et al. Electron transfer between cytochrome c and p66shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell 122:221-233. 2005.
Gladyshev VN. The free radical theory of aging is dead. Long live the damage theory! Antioxid Redox Signal 20:727-731. 2014.
Guerville F, De Souto Barreto P, Ader I, Andrieu S, Casteilla L, Dray C, et al. Revisiting the hallmarks of aging to identify markers of biological age. The journal of prevention of Alzheimer's disease 7:56-64. 2020.
Gupta R, Xie H. Nanoparticles in daily life: Applications, toxicity and regulations. J Environ Pathol Toxicol Oncol 37:209-230. 2018.
Harman D. Aging: A theory based on free radical and radiation chemistry. J Gerontol 11:298-300. 1956.
He Y, Jasper H. Studying aging in drosophila. Methods 68:129-133. 2014.
Hill AJ, Teraoka H, Heideman W, Peterson RE. Zebrafish as a model vertebrate for investigating chemical toxicity. Toxicological sciences : an official journal of the Society of Toxicology 86:6-19. 2005.
Hoshyar N, Gray S, Han H, Bao G. The effect of nanoparticle size on in vivo pharmacokinetics and cellular interaction. Nanomedicine (London, England) 11:673-692. 2016.
Jafari M. Drosophila melanogaster as a model system for the evaluation of anti-aging compounds. Fly 4:253-257. 2010.
Jasper H. Exploring the physiology and pathology of aging in the intestine of drosophila melanogaster. Invertebr Reprod Dev 59:51-58. 2015.
Jasper H. Intestinal stem cell aging: Origins and interventions. Annu Rev Physiol 82:203-226. 2020.
Jeevanandam J, Barhoum A, Chan YS, Dufresne A, Danquah MK. Review on nanoparticles and nanostructured materials: History, sources, toxicity and regulations. Beilstein J Nanotechnol 9:1050-1074. 2018.
Kaegi R, Sinnet B, Zuleeg S, Hagendorfer H, Mueller E, Vonbank R, et al. Release of silver nanoparticles from outdoor facades. Environ Pollut 158:2900-2905. 2010.
Kang K, Jung H, Lim JS. Cell death by polyvinylpyrrolidine-coated silver nanoparticles is mediated by ros-dependent signaling. Biomol Ther (Seoul) 20:399-405. 2012.
Kapetanovic IM, Muzzio M, Huang Z, Thompson TN, McCormick DL. Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats. Cancer Chemother Pharmacol 68:593-601. 2011.
Katz D, Hollander D, Said HM, Dadufalza V. Aging-associated increase in intestinal permeability to polyethylene glycol 900. Dig Dis Sci 32:285-288. 1987.
Khan I, Saeed K, Khan I. Nanoparticles: Properties, applications and toxicities. Arab J Chem 12:908-931. 2019.
Kim KT, Tanguay RL. The role of chorion on toxicity of silver nanoparticles in the embryonic zebrafish assay. Environmental health and toxicology 29:e2014021. 2014.
Kimmel CB, Ballard WW, Kimmel SR, Ullmann B, Schilling TF. Stages of embryonic development of the zebrafish. Developmental dynamics : an official publication of the American Association of Anatomists 203:253-310. 1995.
Kirkwood TB, Kowald A. The free-radical theory of ageing--older, wiser and still alive: Modelling positional effects of the primary targets of ros reveals new support. BioEssays : news and reviews in molecular, cellular and developmental biology 34:692-700. 2012.
Kosuru R, Singh S. Pterostilbene ameliorates insulin sensitivity, glycemic control and oxidative stress in fructose-fed diabetic rats. Life sciences 182:112-121. 2017.
López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell 153:1194-1217. 2013.
Lai SK, Wang YY, Hanes J. Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues. Adv Drug Deliv Rev 61:158-171. 2009.
Lee KJ, Browning LM, Nallathamby PD, Desai T, Cherukuri PK, Xu X-HN. In vivo quantitative study of sized-dependent transport and toxicity of single silver nanoparticles using zebrafish embryos. Chemical research in toxicology 25:1029-1046. 2012.
Lee WS, Cho H-J, Kim E, Huh YH, Kim H-J, Kim B, et al. Bioaccumulation of polystyrene nanoplastics and their effect on the toxicity of au ions in zebrafish embryos. Nanoscale. 2019.
Lekamge S, Miranda AF, Abraham A, Li V, Shukla R, Bansal V, et al. The toxicity of silver nanoparticles (agnps) to three freshwater invertebrates with different life strategies: Hydra vulgaris, daphnia carinata, and paratya australiensis. Front environ sci 6:152. 2018.
Li H, Jiang N, Liang B, Liu Q, Zhang E, Peng L, et al. Pterostilbene protects against uvb-induced photo-damage through a phosphatidylinositol-3-kinase-dependent nrf2/are pathway in human keratinocytes. Redox report : communications in free radical research 22:501-507. 2017.
Li YR, Li S, Lin CC. Effect of resveratrol and pterostilbene on aging and longevity. BioFactors (Oxford, England) 44:69-82. 2018.
Liang R, Ghaffari S. Stem cells, redox signaling, and stem cell aging. Antioxid Redox Signal 20:1902-1916. 2014.
Liguori I, Russo G, Curcio F, Bulli G, Aran L, Della-Morte D, et al. Oxidative stress, aging, and diseases. Clin Interv Aging 13:757-772. 2018.
Lin HS, Yue BD, Ho PC. Determination of pterostilbene in rat plasma by a simple hplc-uv method and its application in pre-clinical pharmacokinetic study. Biomed Chromatogr 23:1308-1315. 2009.
Lin J, Miao L, Zhong G, Lin CH, Dargazangy R, Alexander-Katz A. Understanding the synergistic effect of physicochemical properties of nanoparticles and their cellular entry pathways. Commun Biol 3:205-205. 2020.
Lin S, Zhao Y, Nel AE, Lin S. Zebrafish: An in vivo model for nano ehs studies. Small (Weinheim an der Bergstrasse, Germany) 9:1608-1618. 2013.
Liu H, Wang X, Wu YH, Hou J, Zhang S, Zhou N, et al. Toxicity responses of different organs of zebrafish (danio rerio) to silver nanoparticles with different particle sizes and surface coatings. Environ Pollut 246:414-422. 2019.
Loeschner K, Hadrup N, Qvortrup K, Larsen A, Gao X, Vogel U, et al. Distribution of silver in rats following 28 days of repeated oral exposure to silver nanoparticles or silver acetate. Part Fibre Toxicol 8:18. 2011.
Mao BH, Tsai JC, Chen CW, Yan SJ, Wang YJ. Mechanisms of silver nanoparticle-induced toxicity and important role of autophagy. Nanotoxicology 10:1021-1040. 2016.
Mao BH, Chen ZY, Wang YJ, Yan SJ. Silver nanoparticles have lethal and sublethal adverse effects on development and longevity by inducing ros-mediated stress responses. Sci Rep 8:2445. 2018.
McCormack D, McFadden D. A review of pterostilbene antioxidant activity and disease modification. Oxid Med Cell Longev 2013:575482. 2013.
McGillicuddy E, Murray I, Kavanagh S, Morrison L, Fogarty A, Cormican M, et al. Silver nanoparticles in the environment: Sources, detection and ecotoxicology. Sci Total Environ 575:231-246. 2017.
Morris O, Jasper H. Reactive oxygen species in intestinal stem cell metabolism, fate and function. Free Radic Biol Med 166:140-146. 2021.
Mudshinge SR, Deore AB, Patil S, Bhalgat CM. Nanoparticles: Emerging carriers for drug delivery. Saudi Pharm J 19:129-141. 2011.
Murthy M, Ram JL. Invertebrates as model organisms for research on aging biology. Invertebr Reprod Dev 59:1-4. 2015.
Nagy P, Sándor GO, Juhász G. Autophagy maintains stem cells and intestinal homeostasis in drosophila. Sci Rep 8:4644. 2018.
Najahi-Missaoui W, Arnold RD, Cummings BS. Safe nanoparticles: Are we there yet? Int J Mol Sci 22. 2020.
Nalapareddy K, Zheng Y, Geiger H. Aging of intestinal stem cells. Stem Cell Rep 17:734-740. 2022.
Park EJ, Bae E, Yi J, Kim Y, Choi K, Lee SH, et al. Repeated-dose toxicity and inflammatory responses in mice by oral administration of silver nanoparticles. Environ Toxicol Pharmacol 30:162-168. 2010.
Perde-Schrepler M, Florea A, Brie I, Virag P, Fischer-Fodor Ea, Vâlcan A, et al. Size-dependent cytotoxicity and genotoxicity of silver nanoparticles in cochlear cells <i>in vitro</i>. J Nanomater 2019:6090259. 2019.
Phaniendra A, Jestadi DB, Periyasamy L. Free radicals: Properties, sources, targets, and their implication in various diseases. Indian J Clin Biochem 30:11-26. 2015.
Piao MJ, Kim KC, Choi JY, Choi J, Hyun JW. Silver nanoparticles down-regulate nrf2-mediated 8-oxoguanine DNA glycosylase 1 through inactivation of extracellular regulated kinase and protein kinase b in human chang liver cells. Toxicology letters 207:143-148. 2011.
Piechulek A, von Mikecz A. Life span-resolved nanotoxicology enables identification of age-associated neuromuscular vulnerabilities in the nematode caenorhabditis elegans. Environ Pollut 233:1095-1103. 2018.
Piper MDW, Partridge L. Drosophila as a model for ageing. Biochim Biophys Acta - Mol Basis Dis 1864:2707-2717. 2018.
Queen BL, Tollefsbol TO. Polyphenols and aging. Curr Aging Sci 3:34-42. 2010.
Ragonnaud E, Biragyn A. Gut microbiota as the key controllers of "healthy" aging of elderly people. Immunity & ageing : I & A 18:2. 2021.
Raj A, Shah P, Agrawal N. Sedentary behavior and altered metabolic activity by agnps ingestion in drosophila melanogaster. Sci Rep 7:15617. 2017a.
Raj A, Shah P, Agrawal N. Dose-dependent effect of silver nanoparticles (agnps) on fertility and survival of drosophila: An in-vivo study. PLoS One 12:e0178051. 2017b.
Ravindran S, Suthar JK, Rokade R, Deshpande P, Singh P, Pratinidhi A, et al. Pharmacokinetics, metabolism, distribution and permeability of nanomedicine. Current drug metabolism 19:327-334. 2018.
Ren R, Ocampo A, Liu GH, Izpisua Belmonte JC. Regulation of stem cell aging by metabolism and epigenetics. Cell Metab 26:460-474. 2017.
Riaz Ahmed KB, Nagy AM, Brown RP, Zhang Q, Malghan SG, Goering PL. Silver nanoparticles: Significance of physicochemical properties and assay interference on the interpretation of in vitro cytotoxicity studies. Toxicology in vitro : an international journal published in association with BIBRA 38:179-192. 2017.
Rimando AM, Kalt W, Magee JB, Dewey J, Ballington JR. Resveratrol, pterostilbene, and piceatannol in vaccinium berries. J Agric Food Chem 52:4713-4729. 2004.
Ristow M, Schmeisser S. Extending life span by increasing oxidative stress. Free Radic Biol Med 51:327-336. 2011.
Rodriguez-Fernandez IA, Tauc HM, Jasper H. Hallmarks of aging drosophila intestinal stem cells. Mech Ageing Dev 190:111285. 2020.
Roupe KA, Remsberg CM, Yáñez JA, Davies NM. Pharmacometrics of stilbenes: Seguing towards the clinic. Curr Clin Pharmacol 1:81-101. 2006.
Saffrey MJ. Aging of the mammalian gastrointestinal tract: A complex organ system. Age (Dordr) 36:9603. 2014.
Schneider G, Decher G. Functional core/shell nanoparticles via layer-by-layer assembly. Investigation of the experimental parameters for controlling particle aggregation and for enhancing dispersion stability. Langmuir 24:1778-1789. 2008.
Sena LA, Chandel NS. Physiological roles of mitochondrial reactive oxygen species. Mol Cell 48:158-167. 2012.
Shaw AC, Joshi S, Greenwood H, Panda A, Lord JM. Aging of the innate immune system. Curr Opin Immunol 22:507-513. 2010.
Shin SH, Ye MK, Kim HS, Kang HS. The effects of nano-silver on the proliferation and cytokine expression by peripheral blood mononuclear cells. Int Immunopharmacol 7:1813-1818. 2007.
Shin SW, Song IH, Um SH. Role of physicochemical properties in nanoparticle toxicity. Nanomaterials (Basel) 5:1351-1365. 2015.
Shukla RK, Badiye A, Vajpayee K, Kapoor N. Genotoxic potential of nanoparticles: Structural and functional modifications in DNA. Front Genet 12:728250. 2021.
Shvedova AA ST, Murray AR, et al. . Critical issues in the evaluation of possible adverse pulmonary effects from airborne nanoparticles. Nanotoxicology, characterization, dosing and health effects. New york and london: Informa healthcare, USA inc; 2007.
Soenen S, Rayner CK, Jones KL, Horowitz M. The ageing gastrointestinal tract. Curr Opin Clin Nutr Metab Care 19:12-18. 2016.
Sofola-Adesakin O, Castillo-Quan JI, Rallis C, Tain LS, Bjedov I, Rogers I, et al. Lithium suppresses aβ pathology by inhibiting translation in an adult drosophila model of alzheimer's disease. Front Aging Neurosci 6:190. 2014.
Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science (New York, NY) 273:59-63. 1996.
Soler AP, Miller RD, Laughlin KV, Carp NZ, Klurfeld DM, Mullin JM. Increased tight junctional permeability is associated with the development of colon cancer. Carcinogenesis 20:1425-1431. 1999.
Somayyeh M, Hammed A, Motallebi A, Anvar A, Jafar R-N, Shokrgozar M. Toxicity study of nanosilver (nanocid®) on osteoblast cancer cell line. Int Nano Lett 1. 2011.
Stadtman ER. Protein oxidation and aging. Science (New York, NY) 257:1220-1224. 1992.
Stark WJ, Stoessel PR, Wohlleben W, Hafner A. Industrial applications of nanoparticles. Chemical Society reviews 44:5793-5805. 2015.
Stenzel A, Wirt H, Patten A, Theodore B, King-Heiden T. Larval exposure to environmentally relevant concentrations of triclosan impairs metamorphosis and reproductive fitness in zebrafish. Reprod Toxicol 87:79-86. 2019.
Su C, Liu Y, Li R, Wu W, Fawcett JP, Gu J. Absorption, distribution, metabolism and excretion of the biomaterials used in nanocarrier drug delivery systems. Adv Drug Deliv Rev 143:97-114. 2019.
Sung JH, Ji JH, Yoon JU, Kim DS, Song MY, Jeong J, et al. Lung function changes in sprague-dawley rats after prolonged inhalation exposure to silver nanoparticles. Inhal Toxicol 20:567-574. 2008.
Tan BL, Norhaizan ME, Liew WP, Sulaiman Rahman H. Antioxidant and oxidative stress: A mutual interplay in age-related diseases. Front Pharmacol 9:1162. 2018.
Tian T, Wang Z, Zhang J. Pathomechanisms of oxidative stress in inflammatory bowel disease and potential antioxidant therapies. Oxid Med Cell Longev 2017:4535194. 2017.
van der Zande M, Vandebriel RJ, Van Doren E, Kramer E, Herrera Rivera Z, Serrano-Rojero CS, et al. Distribution, elimination, and toxicity of silver nanoparticles and silver ions in rats after 28-day oral exposure. ACS Nano 6:7427-7442. 2012.
Vazquez-Munoz R, Borrego B, Juarez-Moreno K, Garcia-Garcia M, Mota Morales JD, Bogdanchikova N, et al. Toxicity of silver nanoparticles in biological systems: Does the complexity of biological systems matter? Toxicology letters 276:11-20. 2017.
Vila L, Marcos R, Hernández A. Long-term effects of silver nanoparticles in caco-2 cells. Nanotoxicology 11:771-780. 2017.
Wahab A, Gao K, Jia C, Zhang F, Tian G, Murtaza G, et al. Significance of resveratrol in clinical management of chronic diseases. Molecules 22. 2017.
Wang B, Liu H, Yue L, Li X, Zhao L, Yang X, et al. Neuroprotective effects of pterostilbene against oxidative stress injury: Involvement of nuclear factor erythroid 2-related factor 2 pathway. Brain research 1643:70-79. 2016.
Wang C, Wheeler CT, Alberico T, Sun X, Seeberger J, Laslo M, et al. The effect of resveratrol on lifespan depends on both gender and dietary nutrient composition in drosophila melanogaster. Age (Dordrecht, Netherlands) 35:69-81. 2013.
Wang YY, Lai SK, So C, Schneider C, Cone R, Hanes J. Mucoadhesive nanoparticles may disrupt the protective human mucus barrier by altering its microstructure. PloS one 6:e21547. 2011.
Weil M, Meissner T, Busch W, Springer A, Kuhnel D, Schulz R, et al. The oxidized state of the nanocomposite carbo-iron(r) causes no adverse effects on growth, survival and differential gene expression in zebrafish. The Science of the total environment 530-531:198-208. 2015.
Wen H, Dan M, Yang Y, Lyu J, Shao A, Cheng X, et al. Acute toxicity and genotoxicity of silver nanoparticle in rats. PLoS One 12:e0185554. 2017.
Wickens AP. Ageing and the free radical theory. Respiration physiology 128:379-391. 2001.
Wu M, Luo Q, Nie R, Yang X, Tang Z, Chen H. Potential implications of polyphenols on aging considering oxidative stress, inflammation, autophagy, and gut microbiota. Critical reviews in food science and nutrition:1-19. 2020.
Xue EX, Lin JP, Zhang Y, Sheng SR, Liu HX, Zhou YL, et al. Pterostilbene inhibits inflammation and ros production in chondrocytes by activating nrf2 pathway. Oncotarget 8:41988-42000. 2017.
Yang HJ, Ratnapriya R, Cogliati T, Kim JW, Swaroop A. Vision from next generation sequencing: Multi-dimensional genome-wide analysis for producing gene regulatory networks underlying retinal development, aging and disease. Prog Retin Eye Res 46:1-30. 2015.
Yang Y, Fan C, Wang B, Ma Z, Wang D, Gong B, et al. Pterostilbene attenuates high glucose-induced oxidative injury in hippocampal neuronal cells by activating nuclear factor erythroid 2-related factor 2. Biochimica et biophysica acta Molecular basis of disease 1863:827-837. 2017.
Yu Z, Li Q, Wang J, Yu Y, Wang Y, Zhou Q, et al. Reactive oxygen species-related nanoparticle toxicity in the biomedical field. Nanoscale research letters 15:115-115. 2020.
Yue MS, Peterson RE, Heideman W. Dioxin inhibition of swim bladder development in zebrafish: Is it secondary to heart failure? Aquat Toxicol 162:10-17. 2015.
Zarse K, Schmeisser S, Groth M, Priebe S, Beuster G, Kuhlow D, et al. Impaired insulin/igf1 signaling extends life span by promoting mitochondrial l-proline catabolism to induce a transient ros signal. Cell Metab 15:451-465. 2012.
Zhang J, Wang X, Vikash V, Ye Q, Wu D, Liu Y, et al. Ros and ros-mediated cellular signaling. Oxidative medicine and cellular longevity 2016:4350965-4350965. 2016.
Zhao MJ, Yuan S, Zi H, Gu JM, Fang C, Zeng XT. Oxidative stress links aging-associated cardiovascular diseases and prostatic diseases. Oxid Med Cell Longev 2021:5896136. 2021.
Zhou J, Ci X, Ma X, Yu Q, Cui Y, Zhen Y, et al. Pterostilbene activates the nrf2-dependent antioxidant response to ameliorate arsenic-induced intracellular damage and apoptosis in human keratinocytes. Front Pharmacol 10:497. 2019.
Ziehm M, Piper MD, Thornton JM. Analysing variation in drosophila aging across independent experimental studies: A meta-analysis of survival data. Aging cell 12:917-922. 2013.
Ziehm M, Thornton JM. Unlocking the potential of survival data for model organisms through a new database and online analysis platform: Survcurv. Aging cell 12:910-916. 2013.