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In this review a selection of recent clinical studies concerning antioxidants supplementation and the evaluation of their influence in Immunity-boosting lifestyle choices diseases is analyzed. The controversial outcomes of antioxidants supplementation therapies, anti--aging might partially depend from an underestimation ant-aging the snti-aging specific metabolic demand and genetic background, are anti-agkng.
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Noteworthy, antioxidants may also act indirectly by regulating redox-sensitive signal transduction pathways Heart health transcription Antikxidant, and anfi-aging of poly ADP-ribose polymerase PARP-1 Weseler and Bast, Elderly people are more susceptible to oxidative stress due to a reduction in anti-qging efficiency of their endogenous antioxidant systems.
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Annti-aging substantial body of literature reported an inverse correlation Antjoxidant serum or plasma total anr capacity and both the onset and progression of several diseases, primarily CVD Ciancarelli et al. Consequently, antioxidants supplementation was suggested as a promising therapy in line with the general acceptance of the Free Radical Theory of Aging Mental health support Harman, First presented in Harmanthis theory is based on the Antioxjdant that lowering Antioxiadnt global level of ROS in Antuoxidant body might retard aging, increase life span and be effective in preventing and treating aging-associated diseases Xnd and Antixidant, Further refinements snti-aging this Antioxidwnt addressed the roles of other activated oxygen species in aging in the more generalized Oxidative Stress Theory of Aging OSTA Bokov et al.
This awareness resulted from one side in boosting in the scientific community Cognitive function improvement methods quest for abd natural or efffects antioxidants Donadio et al.
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In this review a selection of recent clinical studies concerning antioxidants supplementation and the evaluation Antiixidant their effecte in aging-related diseases is analyzed Table 1. Many natural compounds have been considered, either Antioxiidant or in Antioxidnt, for supplementation therapies.
Among them, we devoted particular attention to a specific subset of molecules such as vitamin C, vitamin Antioxidany, resveratrol, curcumin, hydroxytyrosol and coenzyme Q Its Antioxieant activity relies on the ajd to be reversibly oxidized to Liver detox for better nutrient absorption radical and then to dehydroascorbate DHA Wells and Xu, The distribution anti-xging the Factors affecting BMR of vitamin C in the organs depend znd their Antioxidantt ascorbate requirements and on the tissue distribution of sodium-dependent vitamin C transporter 1 and 2 SVCT1 anti-agijg SVCT2 Figueroa-Mendez and Rivas-Arancibia, Antioxidant and anti-aging effects, Vitamin C ascorbic effscts has different important roles in the cell; as a reducing agent and an antioxidant, ascorbate is able to react and inactivate ROS Antioxldant, most importantly, reduces in ahd LDL and α-tocopheroxyl radicals to regenerate α-tocopherol Antioxisant E Chambial et al.
Antiooxidant of the several biological Detox and cleansing programs mediated by ascorbate is the anti-agingg of nitric oxide bioavailability, anti-agiing is anti-ahing to preserve endothelial homeostasis Carr and Frei, A recent metanalysis Ashor et al.
Antoniades et al. An interesting study by Mullan et al. However, the role played by vitamin C in aging-associated diseases has not been adequately investigated in clinical trials mainly because this antioxidant was often used in combination with other molecules Watanabe et al.
When referring to vitamin E, a family of 8 isoforms classified in two categories is considered: four saturated analogs α, β, γ, and δ called tocopherols and four unsaturated analogs indicated as tocotrienols, which differ for the methylation pattern Cardenas and Ghosh, These molecules are hydrophobic fat-soluble compounds found in a variety of food sources such as corn oil, peanuts, vegetable oils, fruits and vegetables Cardenas and Ghosh, Most of the studies presented in literature have been performed using α-tocopherol Wallert et al.
Its antioxidant function is strongly supported by the regeneration promoted by vitamin C α-Tocopherol exhibits strong antioxidant capacity in vitro and has been shown to inhibit LDL oxidation Wallert et al. Next to its antinflammatory and antioxidative properties, vitamin E shows other properties, such as the modulation of the expression of genes encoding proteins involved in signaling Cardenas and Ghosh, In addition vitamin E is also involved in the uptake, transport and degradation of tocopherols, as well as the uptake of lipoproteins and the storage and export of lipids such as cholesterol Cardenas and Ghosh, An old randomized controlled trial by Stephens et al.
However, very few human studies have confirmed the efficacy of vitamin E supplementation in aging-associated diseases, and most of them focused on the role of vitamin E supplementation in influencing aspects of aging phenotypes, such as oxidative stress and inflammation biomarkers.
In this specific context some investigations, performed both in animals models and in humans, effectively demonstrated benefits of vitamin E supplementation Iuliano et al.
Two large randomized trials Yusuf et al. This study, with mean follow-up of 4. The HOPE-TOO, involving 7, patients, confirmed that administration of IU of vitamin E had no evident impact either on cancer outcomes or on major cardiovascular events and death.
Furthermore, during the HOPE-TOO study, the investigators advanced the hypothesis that vitamin E supplementation might even be responsible to increase the risk of heart failure Lonn et al.
Another clinical trial explored the effect of vitamin E on the development of chronic heart failure CHF in 8, post-infarction patients without CHF at baseline Marchioli et al. More recently, Devaraj et al.
The authors demonstrated that vitamin E supplementation lowered plasmatic levels of inflammation markers, such as high-sensitivity C-reactive protein and tumor necrosis factor-alpha, and the levels of oxidative stress biomarkers, such as plasmatic oxidized LDL, urinary F2-isoprostanes and monocytes superoxide anion concentrations Devaraj et al.
However, α-tocopherol supplementation failed to induce any change in intima-media thickness of carotid arteries and no significant differences in cardiovascular events were observed between patients treated with vitamin E and those with placebo Devaraj et al.
As previously underlined, vitamins E and C have been frequently used in combination in clinical trials concerning aging-associated diseases. Results from WACS, as in the case of other antioxidant trials performed with women, failed to find any preventive effects of the antioxidants used on CVD.
This trial did not evidence any benefit from antioxidant supplementation on major CVD outcomes; moreover, vitamin E was associated with an increased risk of stroke Sesso et al. In a recent prospective study performed with 3, aged men, Wannamethee et al. Notably, whereas the dietary intake of vitamin C did not exert any influence, the dietary intake of vitamin E was significantly correlated with increased risk of HF Wannamethee et al.
The authors of this interesting investigation suggested that the reason for the association between vitamin E intake and HF might depend by the fact that vitamin E α-tocopherol may become a pro-oxidant in an environment characterized by high oxidative stress, such as an aged biological system Wannamethee et al.
Resveratrol appears to modulate numerous cell-signaling pathways through the regulation of different molecular targets including the AMP-regulated kinase AMPK and the NAD-dependent deacetylase Sirt-1 Yun et al. The variety of molecular mechanisms mediated by this compound translates into a plethora of biological actions, primarily, antioxidant and anti-inflammatory effects.
Resveratrol is a good antioxidant and blocks in vitro LDL oxidation, a biological phenomenon associated with the risk of coronary heart disease and myocardial infarction Khurana et al. In rodents, resveratrol supplementation has been shown to decrease cardiovascular risk factor, including blood lipids and VCAM-1, to improve cardiovascular function and physical capacity and to decrease inflammation in the vasculature of aged animals leading to improved vascular function Gliemann et al.
The anti-inflammatory properties of resveratrol have been proved by several in vitro experiments. For instance, resveratrol was showed to suppress NF-κB activity induced by beta-amyloid in PC12 neuron cell lines, Jang and Surh, and to reduce the production of IL-1 beta and TNF-alpha induced by LPS or beta-amyloid in the microglia Capiralla et al.
Resveratrol anti-inflammatory effect has been demonstrated also in vivoi. Despite the promising results reported in vitro Zhang et al. Recent studies underlined the importance of patient selection in evaluating the potential therapeutic effects of resveratrol.
Recently, Carrizzo et al. Interestingly, resveratrol failed to exert any effect in vessels from patients without hypertension or dyslipidemia Carrizzo et al. A differential effect of resveratrol influenced by the initial health status was also suggested by a recent meta-analysis by Liu et al.
In a recent work published by Gliemann et al. In this trial 27 healthy physically inactive aged men were randomized into 8 weeks of daily intake of either mg of trans-resveratrol or of placebo and were subjected to concomitant high-intensity ET Gliemann et al. The main aim of the study was to confirm if oral resveratrol supplementation improved the positive cardiovascular adaptations to ET in aged subjects by specifically increasing sirtuin 1 SIRT1 mediated signaling and by promoting the endogenous antioxidant system.
Interestingly, results showed that, whereas ET effectively improved several cardiovascular health parameters in aged men, concomitant resveratrol supplementation somehow blunted most of these effects leading, among others, to a significantly lower improvement in the training-induced increase in maximal oxygen uptake Gliemann et al.
Curcumin is a lipophilic bioactive phenol derived from the rhizome of Curcuma longawhich shows low solubility and stability in aqueous solution.
It is contained in culinary curry and used as a coloring agent in food Bhullar et al. Orally ingested curcumin is metabolized into the active metabolite tetrahydrocurcumin by a reductase found in the intestinal epithelium Sadowska-Bartosz and Bartosz, Extensive research during the last few decades has suggested a strong therapeutic and pharmacological potential of this molecule as antioxidant, antimutagenic, antiprotozoal and antibacterial agent Bhullar et al.
Curcumin strong medicinal properties are also associated with reported anti-cancer and neuroprotective effect such as in Alzheimer disease Brondino et al. A hormetic mechanism of action of this compound is suggested from studies showing that expression levels of the stress response protein Heme Oxygenase-1 HO-1 were increased in cultured hippocampal neurons treated with curcumin Scapagnini et al.
Moreover, this phenolic compound has been shown to reverse chronic stress-induced impairment of hippocampal neurogenesis and increase expression of brain-derived neurotrophic factor BDNF in an animal model of depression Xu et al.
Several studies also showed that curcumin interacts with NF-κB, and through this interaction exerts protective function also in the regulation of T-cell-mediated immunity Kou et al.
Recently González-Reyes et al. In this study, a pretreatment of the neurons with 5—30 μM curcumin increased by 2. Furthermore, curcumin induced the translocation into the nucleus of nuclear factor related factor-2 Nrf2thereby stimulating an inflammatory and antioxidant response against hemin-induced neuronal death González-Reyes et al.
Curcumin effects on both the arterial endothelial function and the central arterial compliance was recently evaluated in post-menopausal women that underwent a daily ingestion of mg of curcumin Akazawa et al. In 32 post-menopausal women the Flow Mediated Dilation FMD measured arterial endothelial function, before and after 8 weeks of curcumin ingestion or ET.
After this time, the authors observed that FMD increased significantly both in the exercise and curcumin groups, whereas no significant change in FMD was detected in the control group Akazawa et al. The results obtained suggested that a regular ingestion of curcumin could improve endothelial function and might be a potential alternative treatment for patients who are unable to exercise.
In a different study performed by the same group Akazawa et al. In this case also, the regular ingestion of curcumin, as the ET alone, significantly increased carotid arterial compliance in the group analyzed. Interestingly, the combination of ET and curcumin ingestion, differently from what observed with resveratrol Gliemann et al.
Hydroxytyrosol is an ortho-diphenol a catechol abundant in olive, fruits and extra virgin olive oil Waterman and Lockwood, This compound, due to its catecholic structure, shows a marked antioxidant activity and is able to scavenge oxygen and nitrogen free radicals, inhibit LDL oxidation, platelet aggregation and endothelial cell activation, and protects DNA from oxidative damage Waterman and Lockwood, ; Notomista et al.
Hydroxytyrosol is also a metal chelator and is able to scavenge the peroxyl radicals and break peroxidative chain reactions producing very stable resonance structures Bulotta et al. Interestingly, scavenging activity of hydroxytyrosol has also been demonstrated with respect to hypochlorous acid HOCl Visioli et al.
Moreover, it has been recently reported Giordano et al. The antioxidant activity of hydroxytyrosol seems to be related in vivo to its high bioavailability: various studies have in fact documented a high degree of absorption of this compound, which is fundamental to exert its biological activities Bulotta et al.
Several studies, mostly performed in cell and animal models, have suggested beneficial effects of hydroxytyrosol in the prevention or treatment of chronic and degenerative diseases, especially CVD and cancer Facchini et al.
Most of the studies currently presented in literature on hydroxytyrosol are performed in vitro on cultured eukaryotic cells and very few are the clinical trials performed in humans and more specifically on elderly people.
: Antioxidant and anti-aging effects| REVIEW article | These substances upregulate detoxification and repair enzymes in the body, so that our body is better protected against damage. Healthy foods are also healthy due to reasons other than their oxidants. Healthy food contains substances that have epigenetic effects , that reduce inflammation , that are beneficial to the gut microbiome, that do not overstimulate aging pathways like mTOR or insulin receptors , that improve mitochondrial functioning. And of course, healthy foods deliver vitamins and minerals our body needs to function properly. The whole notion that antioxidants can slow down aging is a huge oversimplification of the aging process. We also age because of epigenetic dysregulation, protein accumulation, lysosomal dysfunction, telomere shortening, crosslinking, mitochondrial dysfunction in which most mitochondrial damage is not caused by oxidative damage, but by mutations in the mitochondrial DNA as a consequence of mitochondrial division , and so on. Aging is much more complex than just free radicals damaging our cellular machinery. In conclusion, taking antioxidants is not a good way to extend your lifespan. Of course, when you are deficient in specific antioxidants, such as vitamin A, vitamin E or other vitamins, taking these antioxidants can be very useful. To slow down aging and to extend human lifespan, we need to look beyond oxidants and their counterparts, antioxidants. We need to take in substances that act on various other aging mechanisms, like epigenetic dysregulation, protein accumulation and mitochondrial dysfunction. For this, we created NOVOS Core. 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In a nonhuman study , it showed a possible reversal in muscle function related to aging. To try: Sprinkle these sweet little jewels onto a baby spinach walnut salad for a treat that supports graceful aging! The rich shades are usually a sign of stronger radical fighting abilities to keep your skin healthy and vibrant. The more colors you can fit on your plate, the better. Our experts continually monitor the health and wellness space, and we update our articles when new information becomes available. VIEW ALL HISTORY. Brain fog is a symptom of another medical condition. Chronic inflammation refers to a response by your immune system that sticks around long after infection or injury. Learn the common symptoms and…. Inflammation is one way your body fights infection, injury, and disease. Sometimes inflammation can become a painful problem. Your doctor can perform…. What is oxidative stress, and why does it matter? We explain how this imbalance affects your body and ways to prevent it. 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| Frontiers | Nanodelivery of Natural Antioxidants: An Anti-aging Perspective | Herbal extract for skincare conditions include oxidative stress, inflammation, atherosclerosis, cardiovascular Antioxidznt neurodegenerative anti-agijg, type 2 diabetes, osteoporosis, rheumatoid arthritis, age-related kidney Replenish natural nourishment ocular diseases, and also ant-aging. Selective targeting to Antioxidant and anti-aging effects tissues effscts body sites also becomes possible in this therapeutic modality by incorporating specific stimuli-responsive components which can be triggered by particular stimuli such as electric or magnetic field, light, pH, heating, ultrasound, and also by contact with concentrated ionic solutions or certain enzymes Gu et al. Pan, L. It is traditionally used in Asian countries as herbal treatment Hewlings and Kalman, These substances upregulate detoxification and repair enzymes in the body, so that our body is better protected against damage. Zhang, X. Again, CE and APE demonstrated distinctive effects on induction of antioxidant enzymes following H 2 O 2 exposure. |
| Nanodelivery of Natural Antioxidants: An Anti-aging Perspective | Replenish natural nourishment and oxidative stress Antioxidxnt human diseases: from molecular mechanisms to Bone-healthy diet Replenish natural nourishment. Sreedhar, A. Replenish natural nourishment a Antioxidanh work published by Antioxidannt et al. Plasma coenzyme Antioxidabt response to oral ingestion of coenzyme Q10 formulations. The addition of curcumin-loaded nanocapsules produced from the Eudragit L polymer to the diets of dairy sheeps resulted in a higher antioxidant capacity and lower lipid peroxidation in their milk Jaguezeski et al. Neuroprotective effect of quercetin in murine cortical brain tissue cultures. |
| What Is The Best Longevity Diet? | Moreover, these hydroxyl groups help to chelate metal ions, which is an essential feature in the prevention of ROS production Gülçin, A were obtained from Phytotechnology Labs Lenexa, KS, USA. Synthetic Antioxidants: Health Benefits and Hazards Chronic oxidative stress-associated ROS overproduction is known to lead to damage of vital biomolecules and abnormal expression of various genes, including those involved in aging pathways Lushchak, ; Tan et al. Article CAS PubMed PubMed Central Google Scholar Wu, F. Resveratrol inhibits inflammatory responses via the mammalian target of rapamycin signaling pathway in cultured LPS-stimulated microglial cells. Many studies have shown that antioxidants can even be dangerous, for example by increasing the risk of cancer or helping cancer to spread metastasize R , R , R , R , R. Solid lipid nanoparticles as carriers for lipophilic compounds for applications in foods. |
| Introduction | E and F CE inhibit depletion of intracellular ATP following H 2 O 2 exposure. The protocol for treatment was as A and C. To investigate the preventive effects of CE and APE against oxidative insults, BJ cells were pre-treated with CE or APE at non-toxic concentration for 24 h prior to H 2 O 2 treatment. Pre-treatment with CE significantly inhibited H 2 O 2 -induced toxicity Fig. Interestingly, the protective effects of CE were comparable to APE pre-treatments Fig. These data suggested that CE and APE could exert their beneficial effects against H 2 O 2 on dermal fibroblasts via their antioxidant activities. The imbalance of cellular bioenergetics due to oxidative stress is closely linked to aging processes of several tissues, including skin Exposure to H 2 O 2 caused an immediate depletion of steady-state levels of ATP in dermal fibroblasts Fig. Interestingly, pre-treatment with CE significantly inhibited reduction of intracellular ATP pool following H 2 O 2 treatment in dose-dependent fashion Fig. The results from these bioenergetics studies were consistent with the protective effects of CE against oxidative damage from MTT assay, highlighting the contribution of antioxidant activity of CE on its protective effect against oxidative insults. The beneficial effects of CE and APE against oxidative damage as showed in Fig. To examine this hypothesis, the mRNA expression of key antioxidant enzymes, including catalase CAT , glutathione peroxidase 1 GPx1 , superoxide dismutase 1 SOD1 , and superoxide dismutase 2 SOD2 , were measured following h treatments. Our RT-qPCR results demonstrated that CE and APE have different profiles on the induction of antioxidant machinery of fibroblasts; CE induced expression of CAT in dose-dependent fashion Fig. The expression of GPx1 did not alter with either CE or APE treatment Fig. These RT-qPCR data suggested that an upregulation of cellular antioxidant enzymes is the principal factor for protective effects of CE and APE. Centella extracts elevate transcription of antioxidant enzymes. A — D CE promoted CAT expression, while APE enhanced SOD1 and SOD2 expression. We also observed the effects of Centella extracts on expression of antioxidant enzymes after H 2 O 2 treatment. Exposure to H 2 O 2 leaded to dramatic decrease in GPx1 Fig. The increase of SOD2 expression is possibly due to adaptive mechanism of fibroblasts following H 2 O 2 treatment. This phenomenon has been reported in several models of aged fibroblasts 31 , 32 , Again, CE and APE demonstrated distinctive effects on induction of antioxidant enzymes following H 2 O 2 exposure. Pre-treatment with CE induced CAT Fig. Altogether, these results clearly exhibited that Centella extracts could prevent H 2 O 2 cytotoxicity by an enhanced capacity of fibroblasts to remove deleterious ROS. Centella extracts promote expression of antioxidant enzymes following H 2 O 2 treatment. A — D In response to H 2 O 2 treatment, CAT , GPX1 and SOD1 expressions were increased in CE-treated fibroblasts, while SOD2 transcription were elevated in APE-treated fibroblasts. Matrix metalloprotease-9 MMP-9 is the gelatinase enzyme that is responsible for regulation of homeostasis of collagen. Formation of oxidative stress can lead to upregulation of MMP-9 in fibroblasts, which subsequently results in degradation of collagen. The increased breakdown of collagen by MMP-9 appears to be the major factor for aging processes of skin tissue 34 , Here, we demonstrated that exposure to H 2 O 2 markedly upregulated the expression level of MMP-9 of dermal fibroblasts Fig. Elevation of MMP-9 expression was significantly suppressed by CE and APE pre-treatment Fig. These data suggested that CE and APE may possess anti-aging activities via an inhibition of MMP-9 transcription. Centella extracts inhibit expression of MMP9 following H 2 O 2 treatment. A Exposure to H 2 O 2 resulted in elevation of MMP9 expression, while CE and APE did not affect the transcription of MMP9. B CE and APE suppressed H 2 O 2 -induced MMP9 expression. asiatica is a medicinal plant with broad range of pharmacological effects e. antioxidant 8 , 9 , 10 , 11 , anti-inflammation 36 , 37 , wound healing 38 , 39 , 40 , neuroprotective 8 , 9 and memory improvement 41 , Due to its high therapeutic potential, the demand for this plant in cosmeceutical and pharmaceutical industries has exceeded the supply from conventional cultivation. Callus culture offers a manufacturing system which ensures the continuous supply of compounds with uniform quality and high yields asiatica due to i. antioxidant activity of extracts; and ii. safety from reduced solvent residue. Compared to APE, the data from HPTLC Fig. Interestingly, results from DPPH assay showed that the total antioxidant activity of CE is higher than APE Supplementary Fig. The greater antioxidant activity of CE is possibly due to the differences in active components in the extracts. We demonstrated that the major triterpenoids of C. asiatica asiaticoside, asiaticoside, asiatic acid, madecassoside and madecassic acid are not responsible for antioxidant activities of CE Fig. These findings are parallel to previous observation demonstrating that triterpene-free-extract of C. asiatica possesses greater in vitro radical scavenging properties as well as in vivo antioxidant activities than triterpene-enriched-extract. Triterpene-free-fraction of C. asiatica has significantly stronger in free-radical scavenging activities than triterpene-enriched-extract as determined by several in vitro anti-radical assays, including DPPH, ABTS, NORAC, ORAC and NO scavenging assays. Moreover, pre-treatment with triterpene-free-extract of C. asiatica reduced levels of malonaldehyde, an oxidative stress marker, in brain tissues of scopolamine-treated-rat, while triterpene-enriched-fraction did not have these protective effects These preclinical findings support our results that the centelloids are not principal contributors for antioxidant activity of C. Kaempferol, quercetin, and rutin have been reported to be major flavonoids with antioxidant properties of C. asiatica 27 , Hence, future studies are required to identify and characterize novel antioxidants presented in these extracts. The process of skin aging is closely associated with an induction of oxidative stress in dermal fibroblasts 1. Hence, compound that can prevent oxidative damage in dermal fibroblasts could be a potential candidate to be used as anti-skin-aging in cosmeceutical product. We then further investigated biological activities of Centella extracts against oxidative stress on dermal fibroblasts. Our data from MTT assay as well as bioenergetic study showed that CE significantly inhibited the cytotoxicity of H 2 O 2 on dermal fibroblasts Fig. The preventive effects of CE were comparable to APE. Moreover, we found that the protective activities of these extracts could be due to an increase in capacity of fibroblasts to eliminate ROS. We used RT-qPCR approach to investigate the alterations of mRNA expression of key antioxidant enzymes in response to treatments. Catalase is the major enzyme involved in the elimination of high fluxes of H 2 O 2 , while GPx1 is responsible for detoxification of low fluxes of H 2 O 2 RT-qPCR data revealed that CE and APE have different downstream targets on cellular antioxidant machineries. Treatment with CE promoted mRNA expression of H 2 O 2 -detoxifying enzyme, CAT. In response to H 2 O 2 treatment, pre-exposure to CE induced CAT , GPx1 and SOD1 expression, whereas pre-treatment with APE upregulated SOD2 expression Fig. Upregulation of these antioxidant machineries due to Centella extracts could promote capacity of fibroblasts to eliminate harmful ROS, resulting in suppression of oxidative damage and prevention of cell death. Further studies on protein levels and enzymatic activities of antioxidant machineries following treatments of CE and APE are necessary to better understand the protective mechanisms of these extracts on fibroblasts. In rat model of hepatic injury, administration of Centella extract prevented hepatotoxicity through an increased level of catalase, SOD and GPx in liver tissues In hamster model of hyperlipidemia, supplementation with ethanolic extract of C. asiatica promote hepatic function by an enhanced expression of SOD and GPx in hepatic tissues In diabetic rat, aqueous extracts from C. asiatica ameliorate hippocampal dysfunction by an induction of catalase, SOD and GPx expression in hippocampus In stroke model, supplementation with ethanolic extract of C. asiatica prevented brain injury through a restoration of glutathione level and augmentation of catalase, SOD and GPx activities in ischemic rat Nrf2 functions as a redox sensor for oxidative stress. In the presence of oxidative insults, Nrf2 translocates into nucleus and binds to promoter regions of ARE, leading to transcriptional activation of a battery of cytoprotective and detoxification genes, including CAT , GPx and SOD 51 , 52 , 53 , The activation of this pathway by Centella extract is strongly accompanied by an improvement in neuronal health and cognitive function 8 , 55 , 56 , 57 , Recently, Park and colleagues demonstrated that pre-treatment with Centella extract can prevent the progression of age-related macular degeneration in vitro and in vivo. They clearly showed that the cytoprotective activities against oxidative damage of Centella extract in cell culture and animal experiment is mainly due to the regulation of Nrf2 pathway Further pharmacological study is required to validate this hypothesis. In addition to effects on cellular antioxidant enzymes, we also observed activities of Centella extracts on expression of MMP MMP-9 is zinc-containing-gelatinase which plays an important role in degradation of dermal extracellular matrix, especially collagen type IV. Environmental insults, e. UV irradiation, tobacco smoke, and pollutants, have been reported to induce expression of MMP-9 of skin cells through formation of oxidative stress Upregulation of MMP-9 leads to fragmentation of dermal collagen; thereby diminish skin elasticity and integrity; and eventually promote wrinkle and sagging formation of skin 34 , Hence, agents with MMP-9 inhibitory activities would be an attractive candidate to combat skin aging Our RT-qPCR data demonstrated that CE and APE significantly inhibited upregulation of MMP9 following H 2 O 2 exposure Fig. The proposed mechanisms for antioxidant and anti-skin aging activities of CE and APE are summarized in Fig. Proposed mechanisms for antioxidant and anti-skin aging activities of Centella extract. Pre-treatment with Centella extracts prevent H 2 O 2 -induced cytotoxicity on dermal fibroblasts by upregulation of cellular antioxidant machineries. Supplementation with CE upregulated CAT , GPx1 and SOD1 expression, whereas pre-treatment with APE induced SOD2 expression following H 2 O 2 treatment. Moreover, pre-treatment with CE or APE suppressed H 2 O 2 -mediated-upregulation of MMP This figure was created with BioRender. In conclusion, our present study provides the potential application of callus culture platform to produce biomass and biochemical from C. Moreover, this study provides pharmacological evidence to support the use of Centella extracts as anti-skin-aging agents in cosmeceutical and pharmaceutical products. Rinnerthaler, M. Oxidative stress in aging human skin. Biomolecules 5 , — Article CAS PubMed PubMed Central Google Scholar. Fisher, G. et al. Collagen fragmentation promotes oxidative stress and elevates matrix metalloproteinase-1 in fibroblasts in aged human skin. Shin, J. Molecular mechanisms of dermal aging and antiaging approaches. Article CAS PubMed Central Google Scholar. Morita, A. 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This research was supported by PMU-C of the Office of the National Higher Education Science Research and Innovation Policy Council, Thailand. was supported by the Rachadapisek Sompote Fund for Postdoctoral Fellowships from the Graduate School of Chulalongkorn University, Thailand. is a recipient of Postdoctoral fellowship from the Second Century Fund C2F , Chulalongkorn University, Thailand. Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, , Thailand. Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Phayathai Road, Patumwan, Bangkok, , Thailand. Research Unit for Plant-Produced Pharmaceuticals, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, , Thailand. Graduate Program in Pharmaceutical Science and Technology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, , Thailand. Research Unit for Natural Product Biotechnology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, , Thailand. You can also search for this author in PubMed Google Scholar. and S. conceived and designed the experiments; D. and K. prepared extracts and performed HPTLC-DPPH, DPPH and HPLC; V. performed MTT, bioenergetics and RT-qPCR study; A. conducted RT-qPCR study; V. analyzed the data under supervision of S. wrote main manuscript. All authors have read, revised, and provided approval for final manuscript. Correspondence to Sornkanok Vimolmangkang. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Reprints and permissions. Insights into antioxidant activities and anti-skin-aging potential of callus extract from Centella asiatica L. Sci Rep 11 , Download citation. Received : 07 February Accepted : 18 June Published : 29 June The attractive capabilities of these nanostructures include water solubility, small size, storage stability, biodegradability, long shelf life, and non-toxicity Kamaly et al. Owing to their physico-chemical characteristics, polymeric nanoparticles also demonstrate good encapsulation efficiency, and also improved solubility and stability of hydrophobic drugs. These properties allow to minimize toxicity of loaded drugs, permitting a controlled release at targeted sites of the body at relatively low doses Kamaly et al. Some of the most widely used solid and liquid nanodelivery systems are schematically presented in Figure 3. Metallic nanoparticles with diameters ranging from 1 to nm such as silver, gold, copper, magnesium, aluminum, titanium, and zinc ones are increasingly being applied for either passive or active drug delivery in different biomedical applications. An important point is that metallic nanoparticles can be synthesized and modified with various chemical functional groups which allow them to be conjugated with different drugs of interest to target certain cells and tissues Mody et al. Their obvious advantages in clinical applications include relatively simple synthesis, easy chemical modification, biocompatibility, and tunable biophysical properties Lushchak et al. One of major factors limiting clinical use of most nanoparticle formulations is their capability to induce oxidative stress at cellular level Fu et al. One important point in this regard, however, is that levels of generated ROS are dependent on the nanoparticle concentration to which the cell is exposed. Different nanomaterials may influence cellular redox environment by either stimulating or inhibiting ROS production, and a biphasic dose-response relationship characterized by a low-dose stimulation and a high-dose inhibition hormetic response could likely play a crucial role in redox-modulating effects induced by nanoparticles Iavicoli et al. The exposure to high nanoparticle concentrations usually results in excess ROS generation and overloading of endogenous antioxidant systems, eventually causing cytotoxicity, and inflammation Nel et al. Determination of maximal admissible doses is considered therefore to be critical to avoid adverse health outcomes. Accumulating evidence, however, suggests that low-level nanoparticle exposures may unexpectedly enhance antioxidant defense ability and depress oxidative stress Abdal Dayem et al. Some nanomaterials have been found to be able to exhibit enzyme-like antioxidant properties by being capable to scavenge ROS and other free radicals, thereby reducing oxidative injury Lushchak et al. Nano-antioxidants include non-organic nanoparticles such as metallic nanoparticles with intrinsic antioxidant properties Lushchak et al. The antioxidant potential of nanocarriers loaded with phytotherapeutic agents is described in more detail in the following subsections. Many nanodelivery systems loaded with plant-based bioactive compounds have been demonstrated to be efficacious in modulating oxidative stress and related chronic inflammation which mediates most aging-associated disorders. Results from studies reporting antioxidant effects of such nanodelivery systems are discussed in subsections below. In plants, it acts as a phytoalexin, protecting them from pathogens such as fungi and bacteria. In a number of animal models, potent antioxidant properties of resveratrol have been consistently reported. The antioxidant capacity of this polyphenolic compound strongly depends on the redox properties of phenolic hydroxyl groups and the potential for electron delocalization across its chemical structure Sedlak et al. Resveratrol has three hydroxyl groups see Figure 2 for illustration known to play crucial roles in ROS scavenging. Moreover, these hydroxyl groups help to chelate metal ions, which is an essential feature in the prevention of ROS production Gülçin, Furthermore, the cellular defense might be achieved by ability of resveratrol to act not only as a direct antioxidant, but also as an indirect manner, as an endogenous antioxidant system inducer Salehi et al. Resveratrol can trigger Nrf2 transcription factor known to regulate variety of antioxidant enzymes Lushchak, ; Smith et al. In addition, the antioxidant properties of this polyphenolic compound might be attributable to its effects as a gene regulator. Particularly, it was shown that down-regulating the expression of NADPH oxidase may inhibit ROS production Xia et al. Resveratrol can also reduce mitochondrial superoxide production by stimulating mitochondrial biogenesis, prevent superoxide generation from uncoupled endothelial nitric oxide synthase by up-regulating the tetrahydrobiopterin-synthesizing enzyme GTP cyclohydrolase I, and also increase the expression of different antioxidant enzymes Xia et al. Antioxidant properties of resveratrol are believed to be responsible for most health-promoting effects of this substance Carrizzo et al. Moreover, its anti-inflammatory, cardioprotective, neuroprotective, and also anti-cancer properties have also been repeatedly reported. Therefore, it is regarded as one of the most promising anti-aging natural compounds now Wahl et al. Many of these activities are similar to those found in calorie restriction research, thereby demonstrating the potential of resveratrol as a calorie restriction mimetic Li J. Its effectiveness and safety have been well-documented in many animal models and in clinical trials. The therapeutic potential of resveratrol has been reported for various aging-associated pathological conditions such as metabolic syndrome, obesity, type 2 diabetes, cardiovascular disorders, hypertension, stroke, chronic kidney and inflammatory diseases, dementia and also breast, and colorectal cancers Berman et al. The therapeutic applicability of resveratrol is, however, substantially restricted through its extensive hepatic and presystemic metabolism Pangeni et al. Moreover, the water solubility of this phytochemical is very low, thereby causing poor absorption by oral administration Chauhan, Considering this, many preclinical and clinical trials are in progress now to create structurally modified derivatives of resveratrol having higher bioavailability upon ingestion Popat et al. One example is a micronized liquid formulation of trans-resveratrol, SRT, which demonstrated roughly five times higher bioavailability compared to non-micronized compound Elliot and Jirousek, In several clinical trials, however, SRT was not well-tolerated and resulted in side effects, including vomiting and diarrhea, which caused dehydration and renal failure in some patients Popat et al. It prompted the search for nanomaterials acting similarly to SRT, but without its side effects Smoliga et al. Recently, some such nanosized resveratrol-loaded formulations have been investigated for their potential clinical utility. The bioavailability of orally delivered trans-resveratrol loaded in lipid-core nanocapsules was found to be two times higher than that of the free trans-resveratrol in brain, kidney and liver of male Wistar rats Frozza et al. Nanodelivery also resulted in improved gastrointestinal safety in this model. The bioavailability of the folate-conjugated human serum albumin-encapsulated resveratrol nanoparticles was also shown to be 6-fold higher compared to native resveratrol following the intravenous administration Lian et al. Several studies have demonstrated antioxidant properties of nano-encapsulated resveratrol. For instance, in the study by Chen et al. Resveratrol loaded in nanoliposome carriers size from to nm also exhibited more pronounced radical scavenging effect when compared to pure resveratrol Vanaja et al. High ROS scavenging efficiency was also demonstrated for the vitamin E-loaded resveratrol nanoemulsion an average globule diameter of about nm in patients with Parkinson's disease Pangeni et al. The activities of endogenous antioxidant enzymes, including SOD, and GSH lelels were shown to be significantly higher, and levels of malondialdehyde was significantly lower in the resveratrol nanoemulsion-administered group. Resveratrol loaded in zein nanoparticles with bovine serum albumin-caffeic acid conjugate particle size from to nm was demonstrated to exert significantly higher cellular antioxidant activity than resveratrol alone Fan et al. Anti-inflammatory abilities of resveratrol-loaded nanoparticles, such as galactosylated poly lactic-co-glycolic acid nanoparticles, have been also reported Siu et al. Curcumin [1,7-bis 4-hydroxymethoxyphenyl -1,6-heptadiene-3,5-dione] is a polyphenol extracted from rhizome of the turmeric plant, Curcuma longa. It is traditionally used in Asian countries as herbal treatment Hewlings and Kalman, This compound has three chemical components in its structure, including one diketone moiety and two phenolic groups Figure 2. The active functional groups of curcumin may undergo oxidation via electron transfer and hydrogen abstraction processes Priyadarsini, In particular, the antioxidant activity of curcumin is determined by methylenic hydrogen and o-methoxy phenolic groups. Moreover, the β-diketone groups can chelate ions transition metals; some of these metal complexes exhibit antioxidant enzyme-mimetic activities Priyadarsini, Along with antioxidant properties, this polyphenol compound exhibit anti-inflammatory, anti-neurodegenerative and anti-cancer activities Sarker and Franks, The potential of curcumin in preventing and treating various aging-associated pathological conditions has been repeatedly reported Sundar et al. These conditions include oxidative stress, inflammation, atherosclerosis, cardiovascular and neurodegenerative diseases, type 2 diabetes, osteoporosis, rheumatoid arthritis, age-related kidney and ocular diseases, and also cancer. Over the last decade, the healthspan-promoting potential of this compound has been comprehensively investigated in clinical trials Salehi et al. Its bioavailability is, however, limited through its low water solubility and gastrointestinal stability Kumar et al. Innovative nanodelivery strategies are currently developed to overcome these limitations Flora et al. Both in vitro and in vivo evidence suggests that nanocurcumin formulations have better healthspan-promoting properties than conventional native curcumin. The water solubility and bioavailability of this compound were shown to be significantly enhanced by nano-encapsulation with lipid or polymeric nanoparticles, nanogels and dendrimers, and also by conjugating to metal oxide nanoparticles Shome et al. In particular, the oral bioavailability of poly lactic-co-glycolic acid PLGA curcumin nanoformulation has been shown to be fold higher than that of native curcumin Tsai et al. In a rat model of cerebral ischemia, curcumin-loaded solid lipid nanoparticles demonstrated a fold higher bioavailability of the curcumin in the brain than that of free curcumin Kakkar et al. Similarly, oral bioavailability and brain distribution of curcumin were shown to be significantly enhanced in N-trimethyl chitosan surface-modified solid lipid nanoparticles compared to those of native curcumin Ramalingam and Ko, In in vitro experiments with a Caco-2 cell line, evidence was also obtained that bovine serum albumin dextran nanoparticles size up to nm loaded with curcumin may exert significant cellular antioxidant activity Fan et al. The addition of curcumin-loaded nanocapsules produced from the Eudragit L polymer to the diets of dairy sheeps resulted in a higher antioxidant capacity and lower lipid peroxidation in their milk Jaguezeski et al. Anti-inflammatory activities of different curcumin-loaded nanocomposites were also repeatedly reported Wang et al. In particular, it has displayed the capacity to prevent the oxidation of low-density lipoproteins by scavenging free radicals and chelating transition metal ions. The antioxidant activity of this polyphenolic flavonoid compound is considered to be mainly attributed to its metal ion complexes and complex ions Xu et al. When quercetin reacts with a free radical, it donates a proton and becomes a radical itself. The resulting unpaired electron is, however, delocalized by resonance, thereby making the quercetin radical too low in energy to be chemically reactive Flora, The antioxidant ability of quercetin is due to the presence of phenolic hydroxyl groups which are accessible to oxidizing agents Figure 2. There are the B ring o-dihydroxyl groups, the 4-oxo groups in conjugation with the 2,3-alkene, and the 3- and 5-hydroxyl groups Haq and AlAmro, All these functional groups may donate electrons to the rings, which increase the number of resonance forms available in addition to those created by the benzene structure. In addition to antioxidant properties, quercetin is known to demonstrate anti-inflammatory, anti-obesity, anti-diabetic, anti-atherosclerotic, anti-hypercholesterolemic, and anti-hypertensive activities Anand David et al. Over the last years, innovative nanotechnology-based approaches have been developed to enhance the quercetin bioavailability. Among them, quercetin-loaded solid lipid nanoparticles have been recently developed that exhibited a significantly improved bioavailability compared to pure quercetin powders Vijayakumar et al. Quercetin-loaded nanoparticles have been also shown to be able to improve antioxidant defense mechanisms in animal models. For example, in a streptozotocin-induced diabetic rat model, quercetin-loaded poly lactic-co-glycolic acid nanoparticles with size about nm demonstrated antioxidant properties similar to those of free quercetin Chitkara et al. The same doses of this nanoformulation used in the every-fifth-day dosing regimen have been found to be sufficient to bring effects similar to those from daily doses of the oral quercetin suspension. Similar effects were also observed in pancreas and kidneys for CAT and SOD activities. In rat models, self-emulsifying nanoformulation of quercetin also exhibited a significantly higher antioxidant potential compared to free quercetin when evaluated as a function of capability to combat doxorubicin- and cyclosporin A-induced cardiotoxicity and nephrotoxicity, respectively Jain et al. Elevated SOD and CAT activites, GSH levels and amelioration of lipid peroxidation and protein carbonylation were also observed in alloxan-induced diabetic mice treated with quercetin-loaded nanorods Alam et al. In addition, quercetin-loaded silica nanoparticles were found to be able to ameliorate inflammatory conditions in different cell lines Lee et al. The antioxidant properties of this isoflavone were shown to be dependent, in particular, on its ability to induce the expression of genes encoding antioxidant enzymes including SOD and CAT Park et al. It has been demonstrated to be efficient in combating many age-related disorders, including neurodegenerative diseases, osteoporosis, obesity, type 2 diabetes, and cancer Saha et al. However, the clinical use of this compound is often limited due to its low bioavailability. Moreover, it may provoke endocrine-disrupting and toxic effects, especially when applied in high doses Patisaul, To overcome these potential side effects, innovative nanotechnological solutions have been recently proposed Rassu et al. For example, enhanced oral bioavailability has been revealed in genistein-loaded polymeric nanomicelles in comparison with that for free genistein Kwon et al. According to the authors, this effect could be due to higher solubility and gastrointestinal release of nanomicelle-loaded genistein. The oral bioavailability was also found to be improved in genistein loaded in solid lipid nanoparticles compared to that for its suspensions or bulk powders Kim J. Recently, Pool et al. These effects were mediated via modulation of endogenous CAT and SOD activities, and H 2 O 2 production. It leads to induction of apoptosis and autophagy, two processes related to cell death, while only apoptosis was activated by free genistein. Epigallocatechingallate [EGCG, 2R, 3R -5,7-Dihydroxy 3,4,5-trihydroxyphenyl chromanyl 3,4,5-trihydroxybenzoate] is one of the major polyphenol catechin found in green tea. The molecule of EGCG is very complex Figure 2 , it consists of a gallocatechol group and a gallate ester linked to the flavanol core structure Botten et al. The gallocatechol rings in the EGCG structure determine its antioxidant properties since they are able to directly capture free radicals Braicu et al. There is convincing evidence that this compound has a stronger antioxidant potential than other green tea catechins, and that it is even more effective in ROS scavenging than vitamins C and E Rice-Evans et al. EGCG has been also repeatedly shown to exhibit anti-inflammatory, anti-atherogenic and anti-cancer activities Singh et al. The data from epidemiological studies devoted to investigating EGCG are, however, controversial and often conflicting with in vitro findings. This ambiguity could be attributed to its poor stability and bioavailability Mereles and Hunstein, ; Krupkova et al. Therefore, in attempt to improve the bioavailability of EGCG, innovative nanodelivery systems have been extensively used Granja et al. In particular, larger stability and enhanced potential for oral delivery were found in EGCG-loaded solid lipid nanoparticles than those for non-processed EGCG Frias et al. Two-fold higher bioavailability of pH-sensitive EGCG-loaded polymeric nanoparticles compared to the native EGCG powder was also demonstrated Zhang and Zhang, EGCG-loaded nanoparticles have been also shown to exert antioxidant properties in in vitro models. One example is the study by Avadhani et al. This optimized nanotransfersomal formulation was found to be able to reduce the lipid peroxidation and intracellular ROS levels, and also to increase the viability of human keratinocytes in vitro. EGCG-loaded nanoparticles also have been shown to demonstrate anti-inflammatory activities in in vitro models Wu et al. Accumulating evidence indicates that nano-phytoantioxidants have a potential in preventing and treating a wide range of aging-associated pathological conditions. In several animal models, orally administered nano-phytoantioxidants demonstrated a more powerful potential in combating cardio-metabolic disorders than that of their raw forms. Substantial anti-diabetic potential was, e. These mice demonstrated a substantial suppression of body weight gain as well as improved glucose tolerance and insulin sensitivity. Substantial hypoglycemic effect was also observed in both normal and diabetic rats administered with selenium-layered nanoparticles loaded with extracts of mulberry leaf and Pueraria lobata Deng et al. These nanoparticles were also able to attenuate the oxidative damage, promote glucose utilization by adipocytes and enhance pancreatic function. Solid lipid nanoparticles loaded with the bioactive constituent of kudzu roots, puerarin, showed three times higher bioavailability following oral administration in heart and brain compared to free puerarin Luo et al. Treatment with curcumin-loaded nanoparticles led to attenuation of palmitate-induced cardiomyocyte apoptosis in H9C2 embryonic rat heart-derived cells Li J. Use of colloidal curcumin nanoparticles dissolved in gum ghatti solution resulted in the restoration of the left ventricular fractional shortening a violation arising from heart failure following myocardial infarction in male rats Sunagawa et al. In rats administered with solid lipid nanoparticles loaded with extract from Dracocephalum moldavica L. Evidence was also obtained that nano-phytoantioxidant therapy can be a promising solution in treating rheumatoid arthritis, a systemic autoimmune disease caused by chronic inflammatory process occurring in consequence of age-related decline of immune function immunosenescence van Onna and Boonen, In an adjuvant-induced arthritis rat model, either oral or topical administration of piperine-loaded solid lipid nanoparticles caused substantial reduction of the pro-inflammatory cytokine tumor necrosis factor alpha TNFα levels, assuming anti-rheumatic therapeutic potential of such a treatment Bhalekar et al. In the same model, the protective potential of curcumin-loaded solid lipid nanoparticles in ameliorating adjuvant-triggered arthritis through attenuating oxido-inflammatory and immunomodulatory cascades was demonstrated Arora et al. Nano-phytoantioxidants have been also shown to be efficient for improvement in bone biomechanical parameters and biochemical markers during osteoporosis, a chronic disease characterized by an age-associated deterioration in bone mass and micro-architecture Barry et al. Curcumin-loaded poly lactic-co-glycolicacid nanoparticles have been found to potentiate protective effects of curcumin against the bone loss in ovariectomized rats Ahn et al. In the same model, quercetin-based solid lipid nanoparticles were more effective in restoring bone mineral density in osteopenic animals than free quercetin Ahmad et al. Innovative nanobiotechnology-based approaches have been also recently developed in anti-cancer therapy. These approaches, in particular, allow drug delivery directly to tumor sites without damaging nearby healthy tissues Ahmad et al. In in vitro studies, enhanced anti-tumor activity was obtained, compared to respective unmodified substances, for nanoengineered phytobioactive compounds exerting antioxidant and anti-inflammatory activities such as resveratrol Rodenak-Kladniew et al. In mouse models of the induced cancer, substantial inhibition of tumor proliferation and angiogenesis and also enhanced levels of apoptosis of cancerous cells have been found in animals administered, either orally or intravenously, with nanoparticles co-loaded with curcumin, along, or in combination with particular anti-cancer drugs Wang et al. Substantial anti-tumor properties have been also shown for nanoparticles loaded with resveratrol Xu et al. The effectiveness of nanotechnology-based systems was also shown in combating neurodegenerative disorders such as Alzheimer's and Parkinson's diseases Teleanu et al. Developing such approaches seems to be especially important for this therapeutic area since treating these disorders is a very difficult task because of the existence of the blood-brain barrier representing the most important obstacle in delivering pharmaceuticals to the brain. Tunable biophysical properties of nanocomposites allowing to overcome blood-brain barrier make them, potentially, highly useful in these therapeutic applications Henrich-Noack et al. Figure 4. Schematic representation of nanotechnology-based systems used for brain delivery of phytoantioxidant-loaded nanodelivery systems. In particular, increased oral bioavailability to the brain of nanotechnology-based delivery systems such as curcumin-loaded solid lipid nanoparticles Ramalingam and Ko, , and resveratrol-loaded N-trimethyl chitosan-g-palmitic acid surface-modified solid lipid nanoparticles Ramalingam et al. Various nanocomposites administered by intranasal or intravenous routes also provided improved bioavailability to the brain in comparison with that for free drug administration Gao, For example, quercetin-loaded solid lipid nanoparticles provided enhanced quercetin delivery to the brain along with improved antioxidant effect to brain cells compared to those of pure quercetin, as well as improved memory retention in a rat model of Alzheimer's disease Dhawan et al. Increased bioavailability in brain cells was also observed for nanoparticles loaded with piperine an active ingredient of black pepper Yusuf et al. In an animal model of Alzheimer's disease, the piperine-loaded nanoparticles exhibited therapeutic effects on disease progression, supposedly by reducing oxidative stress and cholinergic degradation. The enhanced bioavailability and improved treatment efficiency of nanoparticles loaded with curcumin, such as curcumin-loaded solid lipid nanoparticles Kakkar and Kaur, and poly lactic-co-glycolic acid nanoparticles Cheng et al. Resveratrol and grape extract-loaded solid lipid nanoparticles were also reported to have therapeutic potential for the treatment of this disease Loureiro et al. The promising therapeutic potential in preventing and treating Alzheimer's disease has been found for quercetin-loaded nanoparticles as well Han et al. The authors assumed that this potential was likely driven by the activity of these nanoparticles to inhibit amyloid β aggregation and scavenge free radicals. In a rat model of Alzheimer's disease, evidence was obtained that aluminum chloride-induced adverse neurobehavioral impairments may be attenuated by EGCG-loaded nanoparticles via reducing the formation of neurofibrillary tangles and neuritic plaques Singh et al. Nanobiotechnology-based approaches were shown to have a therapeutic potential in treating Parkinson's disease as well. For example, resveratrol-loaded polysorbate coated poly lactide nanoparticles showed protective neuroprotective effects against neurochemical and behavioral impairments caused by neurotoxin 1-methylphenyl-1,2,3,6-tetrahydropyridine known to damage dopaminergic neurons and induce Parkinson-like symptoms in a mouse model of Parkinson's disease da Rocha Lindner et al. Oxidative stress caused by imbalance between ROS production and scavenging is undoubtedly one of key contributing factors in most aging-associated pathological conditions. Therefore, the development of therapeutic modalities to combat adverse consequences of oxidative stress, including damage to vital biomolecules, accelerated telomere attrition and systemic inflammation, is one of the most important tasks in current geroscience research. For several decades, dietary supplementation with chemically synthesized antioxidants has been considered as the most appropriate way to prevent and treat ROS-linked disorders. However, more recent studies provided rather controversial and often discouraging results, including increased mortality in those persons who regularly consume synthetic antioxidants such as β-carotene, vitamin A, and vitamin E Bjelakovic et al. Such discouraging results can most likely be explained by the fact that, while assumption on pro-health potential of antioxidants is mostly based on in vitro assays, these assays may not reflect the physiological mechanisms operating in vivo Shen et al. Moreover, the ambiguity of results obtained from epidemiological studies could be likely explained by dichotomous roles of antioxidants in ROS production Halliwell, ; Milisav et al. In addition, as oxidative stress and chronic inflammation coexist in aging-associated pathological conditions, the failing of clinical trials with synthetic antioxidants may be explained by inability to simultaneously target both oxidative stress and inflammatory responses Biswas, On the basis of these considerations, dietary supplementation with natural antioxidants mostly polyphenols seems to be a reasonable alternative to synthetic antioxidant intake since natural phyto-antioxidants are known to be able to effectively counteract both oxidative stress and inflammation Petersen and Smith, ; Ganesan et al. The only problem is that in vivo activities of natural antioxidants may be limited owing to their low bioavailability Shen et al. Therefore, effects obtained in in vitro experiments could likely be caused by much higher doses than those normally contained in human diet Scalbert et al. Therefore, development of nanotechnology-based applications for targeted delivery of bioactive phenolic compounds with antioxidant properties to treat age-related chronic diseases is an urgent task of biotechnological research. The use of nanocarrier-based systems was shown to enhance the solubility and stability of delivered bioactive phytochemicals, increase their gastrointestinal absorption, and protection from premature enzymatic degradation Conte et al. Conclusive evidence suggests that bioavailability of nanoparticle-encapsulated phytochemicals can be 5—10 times higher than that of native formulations Ganesan et al. Moreover, such mode of oral delivery may also result in prolonging the circulation time of these compounds, thereby reducing their potential toxicity and side effects. The implementation of nanotherapeutic approaches would likely provide an opportunity to overcome many shortcomings of conventional therapeutic strategies. Using phytochemical-loaded nanoformulations is regarded by many authors as a clinical equivalent to standard treatments with synthetic antioxidants, but with minimizing side effects Anand et al. In addition, the beneficial feature of nanodelivery approach is that it can provide an opportunity to deliver phytochemicals to certain organs, such as the brain, following the oral administration. In conclusion, despite delivery of phyto-antioxidants by nanodelivery systems has apparent healthspan-promoting potential, several important challenges still remain to be addressed. Nanocarriers used to encapsulate phytotherapeuticals have to be comprehensively examined to determine if these nanomaterials themselves could demonstrate adverse health effects, especially if used long-term by patients. Indeed, since the composing chemical s may or may not be soluble in biological matrices, the toxicology of applied nanocomposites may differ greatly from that for loaded bioactive substances; it may substantially influence outcomes for different internal organs De Jong and Borm, For several nanoantioxidant formulations, a burst drug release may result in concerns related to cellular toxicity, while a slower drug release, on the contrary, may lead to insufficient therapeutic efficacy. Therefore, the development of nanoformulations with release profiles optimized according to the physicochemical properties of carried therapeutic agents presents an essential research challenge that bears further investigation Lin et al. Given these considerations, outstanding questions also include: 1 whether applied nanomaterials might bioaccumulate in the human body? Given these remaining challenges, it may be concluded that, even though essential steps have been made to bringing nanotherapeutic approaches closer to clinical applications, additional investigation is needed to improve the effectiveness and long-term safety of bioactive compound-loaded nanodelivery systems in therapy of aging-associated disorders. AV, AK, AZ, and OL conceptualized and designed the manuscript. AV performed literature search and wrote the first draft of the manuscript. AK, AZ, and OL edited the manuscript and constructed the figures. The manuscript was written through contributions of all authors. All authors approved the final version of the manuscript. The work was partially supported by the Ministry of Education and Science of Ukraine U and Science and Technology Center in Ukraine to OL. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 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Antioxidant and anti-aging effects -
People who use retinoid products must use sunscreen, as they make the skin more sensitive to sun damage. Find 15 of the best retinol creams for all skin types here. A study states that antioxidants may be valuable in skin care, both topically and orally. However, the author advises against using large doses for prolonged periods without seeking medical advice, as this may cause adverse effects.
The review also notes that despite many antioxidant skin care products being available, evidence varies regarding their impact on skin cells. Antioxidants are present in a wide range of foods. The best food sources of antioxidants include :. Find a guide to antioxidant foods here. If someone has concerns about their skin health, they should speak with a doctor or dermatologist.
Supplements contain antioxidants that may interact with medications doctors prescribe, so it is always best to check first before taking them. Evidence suggests a connection between oxidative stress and conditions, such as acne and seborrheic dermatitis.
However, no studies demonstrate the impact of antioxidants on these conditions. Antioxidants work together in a complex manner. The most abundant antioxidant in the skin is vitamin C. Retinoids may be potent for people with certain skin conditions, such as acne.
The skin contains antioxidants, and the most abundant one is vitamin C. Antioxidants help protect skin cells from damage and aging and may improve skin texture and appearance. People can consume them in their diet or apply them to their skin by using skin care products.
Retinoids are popular in skin care products and may benefit some people but cause dryness in others. People must wear sunscreen when using a retinoid product, and pregnant people should not use retinoids. If someone has concerns about their skin or needs help choosing skin care products, they can consult a dermatologist.
Urea is an additive in many skin care products, such as moisturizers. Read on for the benefits and uses in skin care, safety, and the best products…. Everyone can benefit from a personalized skin care routine. Black skin is prone to certain issues, including acne and hyperpigmentation. Here, we list….
Some chemicals in soap may affect health or cause skin irritation. Learn about potentially harmful chemicals and soap alternatives. There are many brands offering face moisturizers that suit a variety of skin types and issues, including eczema and acne.
We review 10 of the best…. Musely is a telehealth company that provides prescription skincare and connects customers with dermatologists.
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Medical News Today. Health Conditions Health Products Discover Tools Connect. What to know about antioxidants for skin.
Medically reviewed by Joan Paul, MD, MPH, DTMH , Dermatology — By Louisa Richards on December 7, Overview Helpful for skin? Best for skin Choosing products Drawbacks Diet Contacting a doctor FAQs Summary Antioxidants may benefit the skin by preventing or slowing aging and cell damage.
What are antioxidants? What antioxidants do for skin. The best antioxidants for skin. How to choose a skin care product. Drawbacks of antioxidants. Diet and antioxidants. When to contact a doctor. Frequently asked questions. How we reviewed this article: Sources.
Medical News Today has strict sourcing guidelines and draws only from peer-reviewed studies, academic research institutions, and medical journals and associations. We avoid using tertiary references. We link primary sources — including studies, scientific references, and statistics — within each article and also list them in the resources section at the bottom of our articles.
You can learn more about how we ensure our content is accurate and current by reading our editorial policy. Nanocarried bioactive agents are ultimately released in the gastrointestinal tract, in the circulatory system or in various tissues Martínez-Ballesta et al.
Their subsequent biological fate depends on their own chemical and physical properties and also on the site of release. Importantly, the location of bioactive release can be driven by using nanomaterials with certain surface chemistry; it makes possible the release of such therapeutics in particular tissues and body sites Patra et al.
The nanostructures can act by either active or passive therapeutic targeting Kydd et al. Following the passive nanodelivery mode, the loaded therapeutic agent is released by the erosion or diffusion of the delivering nanovector.
The active delivery mode allows the controlled release of transported biomolecules at the targeted body sites. In this delivery mode, certain RNAs, proteins, lipids, carbohydrates, and small metabolite molecules are used as biomarkers to reach particular target sites Conte et al.
Selective targeting to specific tissues or body sites also becomes possible in this therapeutic modality by incorporating specific stimuli-responsive components which can be triggered by particular stimuli such as electric or magnetic field, light, pH, heating, ultrasound, and also by contact with concentrated ionic solutions or certain enzymes Gu et al.
Moreover, there exists a possibility to modify the physical surface properties of metallic nanoparticles, such as silver, gold, and iron oxide nanoparticles, so that they act as drug carriers by the active delivery mode Kong et al.
The use of organic nanocarriers is, however, considered to be more preferred because of their physico-chemical properties can be more finely tuned by modifying their chemical composition, shape, size, structural morphology, and characteristics of surface Conte et al.
The efficiency of nanodelivery of natural therapeutic agents is also dependent on their molecular weight. Increase of the molecular weight generally results in a decrease in efficiency of delivery of loaded compounds resulting in their lower bioavailability Ganesan et al.
Different therapeutic nanodelivery systems can provide various health benefits depending on their properties, the features of loaded agents and also on desired therapeutic applications Gupta and Xie, ; Rizvi and Saleh, In particular, natural compound-loaded nanoparticles provide many benefits over conventional formulations in terms of therapeutic potential.
These benefits include improved epithelium permeability, enhanced stability, extended half-life, increased solubility and bioavailability, improved tissue targeting as well as minimized side effects Date et al.
The nanotechnology-based systems are increasingly applied now to prevent and cure aging-associated pathological conditions, including neurodegenerative disorders such as Alzheimer's and Parkinson's diseases Poovaiah et al.
The oral administration route is commonly considered as the most accepted way for drug delivery due to simplicity of administration, pain avoidance, patient compliance, and easy self-administration Anselmo and Mitragotri, However, since the efficiency of oral drug delivery may be substantially reduced due to chemical and enzymatic barriers and also poor solubility in the gastrointestinal tract, the oral delivery of therapeutic compounds loaded into nanocarriers has become a subject of comprehensive investigation over the last years Kermanizadeh et al.
Delivery by nanocarriers generally may have varied therapeutic advantages. These advantages include, among others, an increased half-life, extended circulation time, enhanced mean residence time, and improved pharmacokinetic clearance of these agents from the body Ravindran et al.
Currently, many nanosized delivery systems intended for oral administration of phytotherapeutics have reached the clinical trial stage and are increasingly applied in clinical practice Hajialyani et al.
One important challenge in this research is developing novel multifunctional nanomaterials possessing properties allowing them to transfer particular therapeutics across various biological barriers and able to target specific cell types, tissues and organs in the body.
Successful nanodelivery systems are characterized by optimal features for loading and release of therapeutic agent, long storage life, as well as high therapeutic efficacy with no or minimized side effects Bilia et al.
Among these nanodelivery systems, there are both solid nanocrystals, lipid and polymeric nanoparticles and liquid including nanoliposomes, nanoemulsions, and nanopolymersomes ones Borel and Sabliov, ; Ganesan et al.
These systems are described in details in the subsequent sections. Nanoemulsions include mixtures of immiscible liquids, such as e. Such nanosystems are generally prepared by either chemical or mechanical methods.
Chemical methods result in spontaneous formation of emulsion droplets due to hydrophobic effects of lipophilic molecules which take place in the presence of emulsifiers. Mechanical methods include high-energy processes by which large emulsion droplets may be broken down into the smaller ones by various mechanical operations.
The basic difference among nanoemulsions and conventional emulsions lies in the shapes and sizes of particles dispersed in a suspension. The droplet sizes in nanoemulsions ordinarily fall in the range of 20— nm. Nanoliposomes represent nanosized self-assembled vesicles which consist of phospholipid bilayers entrapping one or more aquatic compartments Chan and Král, Such nanodelivery systems may be produced by layer-by-layer electrostatic deposition technique.
In this technique, charged polymers are added to a solution containing a charged template structure Chun et al. Such template structures may be, e. The other method to produce nanoliposomes is the gentle hydration the process of hydration of dried lipid films with an aqueous solution.
Nanopolymersomes NPS are artificial vesicles with sizes from tens of nm up to 1 μm which enclose aqueous cavities, resulting from self-assembly of amphiphilic copolymers Zhang and Zhang, The tunable properties of NPS allow to adjust them for different biomedical applications, e.
as drug delivery vehicles or as artificial organelles Pippa et al. They are synthesized by methods similar to those applied to producing polymeric nanoparticles see below. Owing to their tunable properties, NPS are capable to encapsulate hydrophobic and hydrophilic molecules either in a membrane bilayer or in an aqueous core, respectively.
Their advantages, in comparison with nanolipid carriers, include enhanced stability and versatility, and also controlled release Rastogi et al. Due to these properties, NPS are considered to be potentially attractive drug carriers in many clinical applications.
Nanocrystals are sub-micron usually from 10 to nm colloidal dispersion systems consisting of pure carrier-free drug nanoparticles Gigliobianco et al. They can be produced with either mechanical or chemical methods. The basic advantage of such nanosystems is reducing the particle size to nanoscale range, resulting in an increase of the particle surface area which is in contact with the dissolution medium Singh and Lillard, Therefore, nanocrystal formulations are believed to have potential therapeutic benefits compared to the conventionally used pharmaceutical formulations.
Among others, these benefits include improved saturation solubility and dissolution rate, and also high drug loading Zhou et al. Solid lipid nanoparticles SLP are similar to nanoemulsions, except that they contain lipids in solid phase.
These are sub-micron colloidal nanocarriers ranging from 50 to 1, nm consisting of physiological lipids dispersed either in water or in aqueous surfactant solutions Mishra et al.
SLP are produced by high-energy methods such as microfluidization high-pressure homogenization and ultrasonication a process that uses high-frequency sound energy to break apart particle agglomerates by expansion, cavitation and implosion of bubbles Mehnert and Mäder, The advantages of such nanoparticles include small size, large surface area, high drug loading efficiency, and the interaction of phases at the interface Mishra et al.
This type of nanocarriers was developed to overcome limitations of colloidal nanocarriers such as emulsions, liposomes, and polymeric nanoparticles since they can provide benefits such as targeted drug delivery and a good release profile Naseri et al.
The loading of therapeutic agents in such nanoparticles may occur in two ways: they can be either integrated in the core matrix or attached on the surface of nanoparticle Lin et al.
One important advantage of solid lipid nanoparticles is that they provide an option to entrap lipophilic molecules in stable particles without applying organic solvents.
Such nanoparticles provide multiple therapeutic advantages due to their unique size-dependent properties and capacity to incorporate drugs.
These advantages include feasibility for large-scale production, possibility of incorporating both lipophilic and hydrophilic drugs, high bioavailability of loaded drugs and low toxicity Bayón-Cordero et al.
Polymeric nanoparticles include solid colloidal nanoparticles sized from 10 to 1, nm consisting of either synthetic or natural polymers Crucho and Barros, ; Khan et al.
These nanostructures are believed to have improved performance in energy storage compared to the bulk conducting polymers due to their high electrical conductivity, high electrochemical activity, large surface area, and short path lengths for the transport of ions Pan et al.
The methods for preparing polymer nanoparticles include nanoprecipitation, solvent evaporation, salting-out, dialysis, and supercritical fluid technology. Surface modification of the polymeric nanoparticles is achieved via self-assembly of block copolymers containing segments that form the core of the polymer nanoparticle and segments that form the outer surfactant shell upon assembly Heinz et al.
Drug-loaded polymer nanoparticle synthesis is carried out using biodegradable and biocompatible polymers or copolymers, in which therapeutic agents may be encapsulated or entrapped within the carriers or be physically adsorbed on or chemically linked to the nanoparticle surfaces.
Polymeric nanoparticles generally fall into two major subtypes, i. The attractive capabilities of these nanostructures include water solubility, small size, storage stability, biodegradability, long shelf life, and non-toxicity Kamaly et al.
Owing to their physico-chemical characteristics, polymeric nanoparticles also demonstrate good encapsulation efficiency, and also improved solubility and stability of hydrophobic drugs. These properties allow to minimize toxicity of loaded drugs, permitting a controlled release at targeted sites of the body at relatively low doses Kamaly et al.
Some of the most widely used solid and liquid nanodelivery systems are schematically presented in Figure 3. Metallic nanoparticles with diameters ranging from 1 to nm such as silver, gold, copper, magnesium, aluminum, titanium, and zinc ones are increasingly being applied for either passive or active drug delivery in different biomedical applications.
An important point is that metallic nanoparticles can be synthesized and modified with various chemical functional groups which allow them to be conjugated with different drugs of interest to target certain cells and tissues Mody et al. Their obvious advantages in clinical applications include relatively simple synthesis, easy chemical modification, biocompatibility, and tunable biophysical properties Lushchak et al.
One of major factors limiting clinical use of most nanoparticle formulations is their capability to induce oxidative stress at cellular level Fu et al. One important point in this regard, however, is that levels of generated ROS are dependent on the nanoparticle concentration to which the cell is exposed.
Different nanomaterials may influence cellular redox environment by either stimulating or inhibiting ROS production, and a biphasic dose-response relationship characterized by a low-dose stimulation and a high-dose inhibition hormetic response could likely play a crucial role in redox-modulating effects induced by nanoparticles Iavicoli et al.
The exposure to high nanoparticle concentrations usually results in excess ROS generation and overloading of endogenous antioxidant systems, eventually causing cytotoxicity, and inflammation Nel et al. Determination of maximal admissible doses is considered therefore to be critical to avoid adverse health outcomes.
Accumulating evidence, however, suggests that low-level nanoparticle exposures may unexpectedly enhance antioxidant defense ability and depress oxidative stress Abdal Dayem et al.
Some nanomaterials have been found to be able to exhibit enzyme-like antioxidant properties by being capable to scavenge ROS and other free radicals, thereby reducing oxidative injury Lushchak et al. Nano-antioxidants include non-organic nanoparticles such as metallic nanoparticles with intrinsic antioxidant properties Lushchak et al.
The antioxidant potential of nanocarriers loaded with phytotherapeutic agents is described in more detail in the following subsections. Many nanodelivery systems loaded with plant-based bioactive compounds have been demonstrated to be efficacious in modulating oxidative stress and related chronic inflammation which mediates most aging-associated disorders.
Results from studies reporting antioxidant effects of such nanodelivery systems are discussed in subsections below. In plants, it acts as a phytoalexin, protecting them from pathogens such as fungi and bacteria.
In a number of animal models, potent antioxidant properties of resveratrol have been consistently reported. The antioxidant capacity of this polyphenolic compound strongly depends on the redox properties of phenolic hydroxyl groups and the potential for electron delocalization across its chemical structure Sedlak et al.
Resveratrol has three hydroxyl groups see Figure 2 for illustration known to play crucial roles in ROS scavenging. Moreover, these hydroxyl groups help to chelate metal ions, which is an essential feature in the prevention of ROS production Gülçin, Furthermore, the cellular defense might be achieved by ability of resveratrol to act not only as a direct antioxidant, but also as an indirect manner, as an endogenous antioxidant system inducer Salehi et al.
Resveratrol can trigger Nrf2 transcription factor known to regulate variety of antioxidant enzymes Lushchak, ; Smith et al. In addition, the antioxidant properties of this polyphenolic compound might be attributable to its effects as a gene regulator. Particularly, it was shown that down-regulating the expression of NADPH oxidase may inhibit ROS production Xia et al.
Resveratrol can also reduce mitochondrial superoxide production by stimulating mitochondrial biogenesis, prevent superoxide generation from uncoupled endothelial nitric oxide synthase by up-regulating the tetrahydrobiopterin-synthesizing enzyme GTP cyclohydrolase I, and also increase the expression of different antioxidant enzymes Xia et al.
Antioxidant properties of resveratrol are believed to be responsible for most health-promoting effects of this substance Carrizzo et al. Moreover, its anti-inflammatory, cardioprotective, neuroprotective, and also anti-cancer properties have also been repeatedly reported. Therefore, it is regarded as one of the most promising anti-aging natural compounds now Wahl et al.
Many of these activities are similar to those found in calorie restriction research, thereby demonstrating the potential of resveratrol as a calorie restriction mimetic Li J. Its effectiveness and safety have been well-documented in many animal models and in clinical trials.
The therapeutic potential of resveratrol has been reported for various aging-associated pathological conditions such as metabolic syndrome, obesity, type 2 diabetes, cardiovascular disorders, hypertension, stroke, chronic kidney and inflammatory diseases, dementia and also breast, and colorectal cancers Berman et al.
The therapeutic applicability of resveratrol is, however, substantially restricted through its extensive hepatic and presystemic metabolism Pangeni et al.
Moreover, the water solubility of this phytochemical is very low, thereby causing poor absorption by oral administration Chauhan, Considering this, many preclinical and clinical trials are in progress now to create structurally modified derivatives of resveratrol having higher bioavailability upon ingestion Popat et al.
One example is a micronized liquid formulation of trans-resveratrol, SRT, which demonstrated roughly five times higher bioavailability compared to non-micronized compound Elliot and Jirousek, In several clinical trials, however, SRT was not well-tolerated and resulted in side effects, including vomiting and diarrhea, which caused dehydration and renal failure in some patients Popat et al.
It prompted the search for nanomaterials acting similarly to SRT, but without its side effects Smoliga et al. Recently, some such nanosized resveratrol-loaded formulations have been investigated for their potential clinical utility.
The bioavailability of orally delivered trans-resveratrol loaded in lipid-core nanocapsules was found to be two times higher than that of the free trans-resveratrol in brain, kidney and liver of male Wistar rats Frozza et al. Nanodelivery also resulted in improved gastrointestinal safety in this model.
The bioavailability of the folate-conjugated human serum albumin-encapsulated resveratrol nanoparticles was also shown to be 6-fold higher compared to native resveratrol following the intravenous administration Lian et al.
Several studies have demonstrated antioxidant properties of nano-encapsulated resveratrol. For instance, in the study by Chen et al. Resveratrol loaded in nanoliposome carriers size from to nm also exhibited more pronounced radical scavenging effect when compared to pure resveratrol Vanaja et al.
High ROS scavenging efficiency was also demonstrated for the vitamin E-loaded resveratrol nanoemulsion an average globule diameter of about nm in patients with Parkinson's disease Pangeni et al. The activities of endogenous antioxidant enzymes, including SOD, and GSH lelels were shown to be significantly higher, and levels of malondialdehyde was significantly lower in the resveratrol nanoemulsion-administered group.
Resveratrol loaded in zein nanoparticles with bovine serum albumin-caffeic acid conjugate particle size from to nm was demonstrated to exert significantly higher cellular antioxidant activity than resveratrol alone Fan et al.
Anti-inflammatory abilities of resveratrol-loaded nanoparticles, such as galactosylated poly lactic-co-glycolic acid nanoparticles, have been also reported Siu et al. Curcumin [1,7-bis 4-hydroxymethoxyphenyl -1,6-heptadiene-3,5-dione] is a polyphenol extracted from rhizome of the turmeric plant, Curcuma longa.
It is traditionally used in Asian countries as herbal treatment Hewlings and Kalman, This compound has three chemical components in its structure, including one diketone moiety and two phenolic groups Figure 2.
The active functional groups of curcumin may undergo oxidation via electron transfer and hydrogen abstraction processes Priyadarsini, In particular, the antioxidant activity of curcumin is determined by methylenic hydrogen and o-methoxy phenolic groups.
Moreover, the β-diketone groups can chelate ions transition metals; some of these metal complexes exhibit antioxidant enzyme-mimetic activities Priyadarsini, Along with antioxidant properties, this polyphenol compound exhibit anti-inflammatory, anti-neurodegenerative and anti-cancer activities Sarker and Franks, The potential of curcumin in preventing and treating various aging-associated pathological conditions has been repeatedly reported Sundar et al.
These conditions include oxidative stress, inflammation, atherosclerosis, cardiovascular and neurodegenerative diseases, type 2 diabetes, osteoporosis, rheumatoid arthritis, age-related kidney and ocular diseases, and also cancer.
Over the last decade, the healthspan-promoting potential of this compound has been comprehensively investigated in clinical trials Salehi et al.
Its bioavailability is, however, limited through its low water solubility and gastrointestinal stability Kumar et al. Innovative nanodelivery strategies are currently developed to overcome these limitations Flora et al. Both in vitro and in vivo evidence suggests that nanocurcumin formulations have better healthspan-promoting properties than conventional native curcumin.
The water solubility and bioavailability of this compound were shown to be significantly enhanced by nano-encapsulation with lipid or polymeric nanoparticles, nanogels and dendrimers, and also by conjugating to metal oxide nanoparticles Shome et al. In particular, the oral bioavailability of poly lactic-co-glycolic acid PLGA curcumin nanoformulation has been shown to be fold higher than that of native curcumin Tsai et al.
In a rat model of cerebral ischemia, curcumin-loaded solid lipid nanoparticles demonstrated a fold higher bioavailability of the curcumin in the brain than that of free curcumin Kakkar et al.
Similarly, oral bioavailability and brain distribution of curcumin were shown to be significantly enhanced in N-trimethyl chitosan surface-modified solid lipid nanoparticles compared to those of native curcumin Ramalingam and Ko, In in vitro experiments with a Caco-2 cell line, evidence was also obtained that bovine serum albumin dextran nanoparticles size up to nm loaded with curcumin may exert significant cellular antioxidant activity Fan et al.
The addition of curcumin-loaded nanocapsules produced from the Eudragit L polymer to the diets of dairy sheeps resulted in a higher antioxidant capacity and lower lipid peroxidation in their milk Jaguezeski et al.
Anti-inflammatory activities of different curcumin-loaded nanocomposites were also repeatedly reported Wang et al. In particular, it has displayed the capacity to prevent the oxidation of low-density lipoproteins by scavenging free radicals and chelating transition metal ions.
The antioxidant activity of this polyphenolic flavonoid compound is considered to be mainly attributed to its metal ion complexes and complex ions Xu et al. When quercetin reacts with a free radical, it donates a proton and becomes a radical itself.
The resulting unpaired electron is, however, delocalized by resonance, thereby making the quercetin radical too low in energy to be chemically reactive Flora, The antioxidant ability of quercetin is due to the presence of phenolic hydroxyl groups which are accessible to oxidizing agents Figure 2.
There are the B ring o-dihydroxyl groups, the 4-oxo groups in conjugation with the 2,3-alkene, and the 3- and 5-hydroxyl groups Haq and AlAmro, All these functional groups may donate electrons to the rings, which increase the number of resonance forms available in addition to those created by the benzene structure.
In addition to antioxidant properties, quercetin is known to demonstrate anti-inflammatory, anti-obesity, anti-diabetic, anti-atherosclerotic, anti-hypercholesterolemic, and anti-hypertensive activities Anand David et al.
Over the last years, innovative nanotechnology-based approaches have been developed to enhance the quercetin bioavailability. Among them, quercetin-loaded solid lipid nanoparticles have been recently developed that exhibited a significantly improved bioavailability compared to pure quercetin powders Vijayakumar et al.
Quercetin-loaded nanoparticles have been also shown to be able to improve antioxidant defense mechanisms in animal models. For example, in a streptozotocin-induced diabetic rat model, quercetin-loaded poly lactic-co-glycolic acid nanoparticles with size about nm demonstrated antioxidant properties similar to those of free quercetin Chitkara et al.
The same doses of this nanoformulation used in the every-fifth-day dosing regimen have been found to be sufficient to bring effects similar to those from daily doses of the oral quercetin suspension.
Similar effects were also observed in pancreas and kidneys for CAT and SOD activities. In rat models, self-emulsifying nanoformulation of quercetin also exhibited a significantly higher antioxidant potential compared to free quercetin when evaluated as a function of capability to combat doxorubicin- and cyclosporin A-induced cardiotoxicity and nephrotoxicity, respectively Jain et al.
Elevated SOD and CAT activites, GSH levels and amelioration of lipid peroxidation and protein carbonylation were also observed in alloxan-induced diabetic mice treated with quercetin-loaded nanorods Alam et al.
In addition, quercetin-loaded silica nanoparticles were found to be able to ameliorate inflammatory conditions in different cell lines Lee et al. The antioxidant properties of this isoflavone were shown to be dependent, in particular, on its ability to induce the expression of genes encoding antioxidant enzymes including SOD and CAT Park et al.
It has been demonstrated to be efficient in combating many age-related disorders, including neurodegenerative diseases, osteoporosis, obesity, type 2 diabetes, and cancer Saha et al.
However, the clinical use of this compound is often limited due to its low bioavailability. Moreover, it may provoke endocrine-disrupting and toxic effects, especially when applied in high doses Patisaul, To overcome these potential side effects, innovative nanotechnological solutions have been recently proposed Rassu et al.
For example, enhanced oral bioavailability has been revealed in genistein-loaded polymeric nanomicelles in comparison with that for free genistein Kwon et al.
According to the authors, this effect could be due to higher solubility and gastrointestinal release of nanomicelle-loaded genistein. The oral bioavailability was also found to be improved in genistein loaded in solid lipid nanoparticles compared to that for its suspensions or bulk powders Kim J.
Recently, Pool et al. These effects were mediated via modulation of endogenous CAT and SOD activities, and H 2 O 2 production. It leads to induction of apoptosis and autophagy, two processes related to cell death, while only apoptosis was activated by free genistein.
Epigallocatechingallate [EGCG, 2R, 3R -5,7-Dihydroxy 3,4,5-trihydroxyphenyl chromanyl 3,4,5-trihydroxybenzoate] is one of the major polyphenol catechin found in green tea. The molecule of EGCG is very complex Figure 2 , it consists of a gallocatechol group and a gallate ester linked to the flavanol core structure Botten et al.
The gallocatechol rings in the EGCG structure determine its antioxidant properties since they are able to directly capture free radicals Braicu et al. There is convincing evidence that this compound has a stronger antioxidant potential than other green tea catechins, and that it is even more effective in ROS scavenging than vitamins C and E Rice-Evans et al.
EGCG has been also repeatedly shown to exhibit anti-inflammatory, anti-atherogenic and anti-cancer activities Singh et al. The data from epidemiological studies devoted to investigating EGCG are, however, controversial and often conflicting with in vitro findings.
This ambiguity could be attributed to its poor stability and bioavailability Mereles and Hunstein, ; Krupkova et al. Therefore, in attempt to improve the bioavailability of EGCG, innovative nanodelivery systems have been extensively used Granja et al.
In particular, larger stability and enhanced potential for oral delivery were found in EGCG-loaded solid lipid nanoparticles than those for non-processed EGCG Frias et al. Two-fold higher bioavailability of pH-sensitive EGCG-loaded polymeric nanoparticles compared to the native EGCG powder was also demonstrated Zhang and Zhang, EGCG-loaded nanoparticles have been also shown to exert antioxidant properties in in vitro models.
One example is the study by Avadhani et al. This optimized nanotransfersomal formulation was found to be able to reduce the lipid peroxidation and intracellular ROS levels, and also to increase the viability of human keratinocytes in vitro.
EGCG-loaded nanoparticles also have been shown to demonstrate anti-inflammatory activities in in vitro models Wu et al. Accumulating evidence indicates that nano-phytoantioxidants have a potential in preventing and treating a wide range of aging-associated pathological conditions.
In several animal models, orally administered nano-phytoantioxidants demonstrated a more powerful potential in combating cardio-metabolic disorders than that of their raw forms. Substantial anti-diabetic potential was, e. These mice demonstrated a substantial suppression of body weight gain as well as improved glucose tolerance and insulin sensitivity.
Substantial hypoglycemic effect was also observed in both normal and diabetic rats administered with selenium-layered nanoparticles loaded with extracts of mulberry leaf and Pueraria lobata Deng et al. These nanoparticles were also able to attenuate the oxidative damage, promote glucose utilization by adipocytes and enhance pancreatic function.
Solid lipid nanoparticles loaded with the bioactive constituent of kudzu roots, puerarin, showed three times higher bioavailability following oral administration in heart and brain compared to free puerarin Luo et al.
Treatment with curcumin-loaded nanoparticles led to attenuation of palmitate-induced cardiomyocyte apoptosis in H9C2 embryonic rat heart-derived cells Li J.
Use of colloidal curcumin nanoparticles dissolved in gum ghatti solution resulted in the restoration of the left ventricular fractional shortening a violation arising from heart failure following myocardial infarction in male rats Sunagawa et al.
In rats administered with solid lipid nanoparticles loaded with extract from Dracocephalum moldavica L. Evidence was also obtained that nano-phytoantioxidant therapy can be a promising solution in treating rheumatoid arthritis, a systemic autoimmune disease caused by chronic inflammatory process occurring in consequence of age-related decline of immune function immunosenescence van Onna and Boonen, In an adjuvant-induced arthritis rat model, either oral or topical administration of piperine-loaded solid lipid nanoparticles caused substantial reduction of the pro-inflammatory cytokine tumor necrosis factor alpha TNFα levels, assuming anti-rheumatic therapeutic potential of such a treatment Bhalekar et al.
In the same model, the protective potential of curcumin-loaded solid lipid nanoparticles in ameliorating adjuvant-triggered arthritis through attenuating oxido-inflammatory and immunomodulatory cascades was demonstrated Arora et al. Nano-phytoantioxidants have been also shown to be efficient for improvement in bone biomechanical parameters and biochemical markers during osteoporosis, a chronic disease characterized by an age-associated deterioration in bone mass and micro-architecture Barry et al.
Curcumin-loaded poly lactic-co-glycolicacid nanoparticles have been found to potentiate protective effects of curcumin against the bone loss in ovariectomized rats Ahn et al. In the same model, quercetin-based solid lipid nanoparticles were more effective in restoring bone mineral density in osteopenic animals than free quercetin Ahmad et al.
Innovative nanobiotechnology-based approaches have been also recently developed in anti-cancer therapy. These approaches, in particular, allow drug delivery directly to tumor sites without damaging nearby healthy tissues Ahmad et al.
In in vitro studies, enhanced anti-tumor activity was obtained, compared to respective unmodified substances, for nanoengineered phytobioactive compounds exerting antioxidant and anti-inflammatory activities such as resveratrol Rodenak-Kladniew et al.
In mouse models of the induced cancer, substantial inhibition of tumor proliferation and angiogenesis and also enhanced levels of apoptosis of cancerous cells have been found in animals administered, either orally or intravenously, with nanoparticles co-loaded with curcumin, along, or in combination with particular anti-cancer drugs Wang et al.
Substantial anti-tumor properties have been also shown for nanoparticles loaded with resveratrol Xu et al. The effectiveness of nanotechnology-based systems was also shown in combating neurodegenerative disorders such as Alzheimer's and Parkinson's diseases Teleanu et al. Developing such approaches seems to be especially important for this therapeutic area since treating these disorders is a very difficult task because of the existence of the blood-brain barrier representing the most important obstacle in delivering pharmaceuticals to the brain.
Tunable biophysical properties of nanocomposites allowing to overcome blood-brain barrier make them, potentially, highly useful in these therapeutic applications Henrich-Noack et al. Figure 4.
Schematic representation of nanotechnology-based systems used for brain delivery of phytoantioxidant-loaded nanodelivery systems. In particular, increased oral bioavailability to the brain of nanotechnology-based delivery systems such as curcumin-loaded solid lipid nanoparticles Ramalingam and Ko, , and resveratrol-loaded N-trimethyl chitosan-g-palmitic acid surface-modified solid lipid nanoparticles Ramalingam et al.
Various nanocomposites administered by intranasal or intravenous routes also provided improved bioavailability to the brain in comparison with that for free drug administration Gao, For example, quercetin-loaded solid lipid nanoparticles provided enhanced quercetin delivery to the brain along with improved antioxidant effect to brain cells compared to those of pure quercetin, as well as improved memory retention in a rat model of Alzheimer's disease Dhawan et al.
Increased bioavailability in brain cells was also observed for nanoparticles loaded with piperine an active ingredient of black pepper Yusuf et al.
In an animal model of Alzheimer's disease, the piperine-loaded nanoparticles exhibited therapeutic effects on disease progression, supposedly by reducing oxidative stress and cholinergic degradation.
The enhanced bioavailability and improved treatment efficiency of nanoparticles loaded with curcumin, such as curcumin-loaded solid lipid nanoparticles Kakkar and Kaur, and poly lactic-co-glycolic acid nanoparticles Cheng et al.
Resveratrol and grape extract-loaded solid lipid nanoparticles were also reported to have therapeutic potential for the treatment of this disease Loureiro et al.
The promising therapeutic potential in preventing and treating Alzheimer's disease has been found for quercetin-loaded nanoparticles as well Han et al. The authors assumed that this potential was likely driven by the activity of these nanoparticles to inhibit amyloid β aggregation and scavenge free radicals.
In a rat model of Alzheimer's disease, evidence was obtained that aluminum chloride-induced adverse neurobehavioral impairments may be attenuated by EGCG-loaded nanoparticles via reducing the formation of neurofibrillary tangles and neuritic plaques Singh et al. Nanobiotechnology-based approaches were shown to have a therapeutic potential in treating Parkinson's disease as well.
For example, resveratrol-loaded polysorbate coated poly lactide nanoparticles showed protective neuroprotective effects against neurochemical and behavioral impairments caused by neurotoxin 1-methylphenyl-1,2,3,6-tetrahydropyridine known to damage dopaminergic neurons and induce Parkinson-like symptoms in a mouse model of Parkinson's disease da Rocha Lindner et al.
Oxidative stress caused by imbalance between ROS production and scavenging is undoubtedly one of key contributing factors in most aging-associated pathological conditions. Therefore, the development of therapeutic modalities to combat adverse consequences of oxidative stress, including damage to vital biomolecules, accelerated telomere attrition and systemic inflammation, is one of the most important tasks in current geroscience research.
For several decades, dietary supplementation with chemically synthesized antioxidants has been considered as the most appropriate way to prevent and treat ROS-linked disorders. However, more recent studies provided rather controversial and often discouraging results, including increased mortality in those persons who regularly consume synthetic antioxidants such as β-carotene, vitamin A, and vitamin E Bjelakovic et al.
Such discouraging results can most likely be explained by the fact that, while assumption on pro-health potential of antioxidants is mostly based on in vitro assays, these assays may not reflect the physiological mechanisms operating in vivo Shen et al.
Moreover, the ambiguity of results obtained from epidemiological studies could be likely explained by dichotomous roles of antioxidants in ROS production Halliwell, ; Milisav et al.
In addition, as oxidative stress and chronic inflammation coexist in aging-associated pathological conditions, the failing of clinical trials with synthetic antioxidants may be explained by inability to simultaneously target both oxidative stress and inflammatory responses Biswas, On the basis of these considerations, dietary supplementation with natural antioxidants mostly polyphenols seems to be a reasonable alternative to synthetic antioxidant intake since natural phyto-antioxidants are known to be able to effectively counteract both oxidative stress and inflammation Petersen and Smith, ; Ganesan et al.
The only problem is that in vivo activities of natural antioxidants may be limited owing to their low bioavailability Shen et al.
Therefore, effects obtained in in vitro experiments could likely be caused by much higher doses than those normally contained in human diet Scalbert et al.
Therefore, development of nanotechnology-based applications for targeted delivery of bioactive phenolic compounds with antioxidant properties to treat age-related chronic diseases is an urgent task of biotechnological research.
The use of nanocarrier-based systems was shown to enhance the solubility and stability of delivered bioactive phytochemicals, increase their gastrointestinal absorption, and protection from premature enzymatic degradation Conte et al. Conclusive evidence suggests that bioavailability of nanoparticle-encapsulated phytochemicals can be 5—10 times higher than that of native formulations Ganesan et al.
Moreover, such mode of oral delivery may also result in prolonging the circulation time of these compounds, thereby reducing their potential toxicity and side effects. The implementation of nanotherapeutic approaches would likely provide an opportunity to overcome many shortcomings of conventional therapeutic strategies.
Using phytochemical-loaded nanoformulations is regarded by many authors as a clinical equivalent to standard treatments with synthetic antioxidants, but with minimizing side effects Anand et al.
In addition, the beneficial feature of nanodelivery approach is that it can provide an opportunity to deliver phytochemicals to certain organs, such as the brain, following the oral administration. In conclusion, despite delivery of phyto-antioxidants by nanodelivery systems has apparent healthspan-promoting potential, several important challenges still remain to be addressed.
Nanocarriers used to encapsulate phytotherapeuticals have to be comprehensively examined to determine if these nanomaterials themselves could demonstrate adverse health effects, especially if used long-term by patients.
Indeed, since the composing chemical s may or may not be soluble in biological matrices, the toxicology of applied nanocomposites may differ greatly from that for loaded bioactive substances; it may substantially influence outcomes for different internal organs De Jong and Borm, For several nanoantioxidant formulations, a burst drug release may result in concerns related to cellular toxicity, while a slower drug release, on the contrary, may lead to insufficient therapeutic efficacy.
Therefore, the development of nanoformulations with release profiles optimized according to the physicochemical properties of carried therapeutic agents presents an essential research challenge that bears further investigation Lin et al. Given these considerations, outstanding questions also include: 1 whether applied nanomaterials might bioaccumulate in the human body?
Given these remaining challenges, it may be concluded that, even though essential steps have been made to bringing nanotherapeutic approaches closer to clinical applications, additional investigation is needed to improve the effectiveness and long-term safety of bioactive compound-loaded nanodelivery systems in therapy of aging-associated disorders.
AV, AK, AZ, and OL conceptualized and designed the manuscript. AV performed literature search and wrote the first draft of the manuscript. AK, AZ, and OL edited the manuscript and constructed the figures.
The manuscript was written through contributions of all authors. All authors approved the final version of the manuscript.
The work was partially supported by the Ministry of Education and Science of Ukraine U and Science and Technology Center in Ukraine to OL. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Antioxidanh are substances like vitamin Lice treatment for long hair, vitamin E, Antioxieant Q10, beta-carotene, acetyl-cysteine, and so on. Atioxidant neutralize free Antioxidxnt. Free radicals Replenish natural nourishment mainly Antioxidant and anti-aging effects by-product of our metabolism. Free radicals are highly reactive particles that damage our DNA, proteins and cell membranes. It has been thought for many decades that this accumulation of cellular damage by free radicals contributes to aging. And that antioxidants, which mop up these free radicals, extend lifespan.
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