Extensive research during the last two decades has revealed the mechanism by which continued oxidative stress leads to chronic inflammation, which in turn, mediates most chronic diseases including neurodegeneration, cancer, and skin damage [27,28,29]. government site. Although there are no studies evaluating the effects of ASX on the NER pathway, ASX is reported to improve the DNA repair capacity of cells exposed to UV radiation. ASX sourced from the microalgae H. pluvialis has been approved as a color additive in salmon feeds and as a dietary supplement for human consumption in Europe, Japan, and the USA. In particular, we will discuss the effects of ASX on cellular and molecular mechanisms, such as the regulation of antioxidant and anti-inflammatory activities, modulation of the immune response, prevention of skin damage, and regulation of DNA repair. Recently, it was suggested that modulation of the AKT signal pathway by ASX may potentially contribute to the maintenance of genomic stability and counteract DNA damage [60]. Santocono M., Zurria M., Berrettini M., Fedeli D., Falcioni G. Influence of astaxanthin, zeaxanthin and lutein on DNA damage and repair in UVA-irradiated cells. For example, ASX inhibits the UV-induced DNA damage and increases the expression of oxidative stress-responsive enzymes [21]. Poljak B., Dahmane R.G., Godi A. Intrinsic skin aging: The role of oxidative stress. Some clinical studies have shown a relationship between the intake of ASX and positive effects on cutaneous physiology; however, a lot of unknown topics need to be further investigated. Although still debated, a range of potential mechanisms through which astaxanthin might exert its benefits on skin homeostasis have been proposed, including photoprotective, antioxidant, and anti-inflammatory effects. The DNA photoproducts generated by UV-induced DNA damage are altered DNA structures that activate a cascade of responses, beginning with the initiation of cell-cycle arrest and activation of DNA repair mechanisms [53]. Astaxanthin as feed supplement in aquatic animals. Davinelli S., Scapagnini G., Denaro F., Calabrese V., Benedetti F., Krishnan S., Curreli S., Bryant J., Zella D. Altered expression pattern of Nrf2/HO-1 axis during accelerated-senescence in HIV-1 transgenic rat. Astaxanthin decreased oxidative stress and inflammation and enhanced immune response in humans. Akt: A double-edged sword in cell proliferation and genome stability. It is worth mentioning that currently, 95% of ASX available in the market is produced synthetically using petrochemicals due to cost-efficiency for mass production. This scientific opinion was reiterated later by an EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), where it was concluded that the safety of 4 mg of ASX per day (0.06 mg/kg bw) had yet to be fully established [78]. Safety of an astaxanthin-rich Haematococcus pluvialis algal extract: A randomized clinical trial. Comparative studies examining the photoprotective effects of carotenoids have demonstrated that ASX is a superior antioxidant, having greater antioxidant capacity than canthaxanthin and -carotene in human dermal fibroblasts. Interestingly, IL-1 levels in the stratum corneum were maintained only in the high-dose group. Several authors demonstrated that ASX activates the Nrf2/HO-1 antioxidant pathway by generating small amounts of ROS [23,24]. Seki T., Sueki H., Kohno H., Suganuma K., Yamashita E. Effects of astaxanthin from Haematococcus pluvialis on human skin. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (, astaxanthin, skin, aging, ultraviolet, antioxidant, anti-inflammatory, immune-enhancing, DNA repair, clinical trials, Kuhn R., Soerensen N.A. Furthermore, the clinical study demonstrated that skin moisture content and deep wrinkles were not significantly changed in the ASX-supplemented groups, whereas these parameters significantly worsened in the placebo group during the study period. Jyonouchi H., Zhang L., Gross M., Tomita Y. Immunomodulating actions of carotenoids: Enhancement of in vivo and in vitro antibody production to T-dependent antigens. Supplementating with dietary astaxanthin combined with collagen hydrolysate improves facial elasticity and decreases matrix metalloproteinase-1 and -12 expression: A comparative study with placebo. Davinelli S., Bertoglio J.C., Polimeni A., Scapagnini G. Cytoprotective Polyphenols Against Chronological Skin Aging and Cutaneous Photodamage. In vitro, ASX effectively suppresses cell damage caused by free radicals and induction of MMP-1 in skin after UV irradiation [47]. Lin K.H., Lin K.C., Lu W.J., Thomas P.A., Jayakumar T., Sheu J.R. Astaxanthin, a Carotenoid, Stimulates Immune Responses by Enhancing IFN- and IL-2 Secretion in Primary Cultured Lymphocytes in Vitro and ex Vivo. After six weeks of treatment, significant improvements were observed in skin moisture and elasticity [69]. Antitumor activity of astaxanthin and its mode of action. Moreover, unlike other carotenoids, ASX is not converted into vitamin A. Therefore, ASX exerts significant antioxidant activities not only via direct radical scavenging, but also by activating the cellular antioxidant defense system through modulation of the Nrf2 pathway. Summary of human intervention studies on skin and astaxanthin. A recent report showed that ASX inhibited the gene expression of several proinflammatory biomarkers such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor- (TNF-) in an AD animal model [31]. 8600 Rockville Pike Astaxanthin intervention ameliorates cyclophosphamide-induced oxidative stress, DNA damage and early hepatocarcinogenesis in rat: Role of Nrf2, p53, p38 and phase-II enzymes. ASX caused a significant decrease in the levels of inducible nitric oxide (iNOS) and cyclooxygenase (COX)-2, and decreased the release of prostaglandin E2 from keratinocytes after UV irradiation [30]. Several reports indicated that ASX decreased CP-induced oxidative stress and subsequent oxidative DNA damage [57,58]. The Moreover, ASX may prevent UV-induced immunosuppression. Kammeyer A., Luiten R.M. Considering the small number of subjects included in these bioavailability studies, future research should try to replicate these findings in doses equivalent to those advised by the different authorities such as the EFSA and FDA. and transmitted securely. Immune suppression and skin cancer development: Regulation by NKT cells. Kishimoto Y., Tani M., Uto-Kondo H., Iizuka M., Saita E., Sone H., Kurata H., Kondo K. Astaxanthin suppresses scavenger receptor expression and matrix metalloproteinase activity in macrophages. [64] conducted the first comprehensive study to investigate the action of dietary ASX in modulating immune response, oxidative status, and inflammation in young healthy adult female human subjects. The https:// ensures that you are connecting to the The authors also measured the levels of malondialdehyde (MDA), a recognized biomarker of systemic oxidative stress. Although the bioavailability and the configurational isomer distribution of the ASX in human plasma has been investigated in this clinical trial, a comprehensive study regarding the pharmacokinetics and tissue distribution of ASX in human skin has not been performed. Protective effects of astaxanthin on skin deterioration. EFSA, FEEDAP Panel Scientific opinion on the safety and efficacy of synthetic astaxanthin as feed additive for salmon and trout, other fish, ornamental fish, crustaceans and ornamental birds. The latest trend in antiaging strategies is to use a combination of dietary and oral supplements to produce extra physiologic benefits [71,72,73,74]. Bethesda, MD 20894, Web Policies In addition, we recommend additional research focused on stimulation of the endogenous antioxidant defense systems of the skin, particularly the expression of antioxidant responsive elements associated with the activity of detoxifying enzymes. Absorption, metabolism, and transport of carotenoids. Studies of immunomodulating actions of carotenoids II. FOIA Oxidant events of skin aging involve damage to DNA, the inflammatory response, reduced production of antioxidants, and the generation of matrix metalloproteinases (MMPs) that degrade collagen and elastin in the dermal skin layer [16,17,18]. Astaxanthin: A review of its chemistry and applications. Spiller G.A., Dewell A. Tominaga K., Hongo N., Karato M., Yamashita E. Cosmetic effects of astaxanthin for all layers of skin. Park J.S., Mathison B.D., Hayek M.G., Massimino S., Reinhart G.A., Chew B.P. A recent study also demonstrated that ASX protected against early burn-wound progression by attenuating ROS-induced oxidative stress in a rat deep-burn model. Niu T., Xuan R., Jiang L., Wu W., Zhen Z., Song Y., Hong L., Zheng K., Zhang J., Xu Q., et al. Meephansan J., Rungjang A., Yingmema W., Deenonpoe R., Ponnikorn S. Effect of astaxanthin on cutaneous wound healing. Yuan J.P., Peng J., Yin K., Wang J.H. Okai Y., Higashi-Okai K. Possible immunomodulating activities of carotenoids in in vitro cell culture experiments. Res P.T., Cermak N.M., Stinkens R., Tollakson T.J., Haenen G.R., Bast A., Van Loon L.J. Recently, ASX has attracted considerable interest because of its potential pharmacological effects, including anticancer, antidiabetic, anti-inflammatory, and antioxidant activities as well as neuro-, cardiovascular, ocular, and skin-protective effects [8]. Chew B.P., Mathison B.D., Hayek M.G., Massimino S., Reinhart G.A., Park J.S. Several investigators examined the inhibition of nuclear factor-kappa B (NF-B) by ASX. Acta Dermatovenerol. Careers. Safety issues have arisen regarding the use of synthetic ASX for human consumption, while the ASX derived from H. pluvialis is the main source for several human applications, including dietary supplements, cosmetics, and food. Tiberio, University of Molise, Via de Sanctis s.n.c, 86100 Campobasso, Italy; ti.lominu@iningapacs.innavoig, 2FB Dermatology, Borupvang 5C, 2750 Ballerup, Denmark; moc.acserelk@nem. Molecular and morphological changes in aged skin not only compromise its protective role, but also contribute to the appearance of skin symptoms, including excessive dryness and pruritus, as well as increased predisposition to the formation or deepening of wrinkles, dyspigmentation, fragility and difficulty in healing injuries, alteration in skin permeability to drugs, impaired ability to sense and respond to mechanical stimuli, skin irritation, and tumor incidence [13,14]. In a recent study, it was demonstrated that continuous consumption of ASX for four weeks alleviated aging-related changes of residual skin surface components (RSSC). There are many dietary or exogenous sources that act as antioxidants, including polyphenols and carotenoids [19,20]. Intestinal absorption and tissue distribution of carotenoids. The absorption of ASX is affected by diet and by smoking, and in particular, concomitant food intake appears to increase the absorption and smoking appears to reduce the half-life of ASX [86]. Recently, an enriched ASX extract from H. pluvialis increased collagen content through inhibition of MMP-1 and MMP-3 expression in human dermal fibroblasts [50]. Tripathi D.N., Jena G.B. Wolf A.M., Asoh S., Hiranuma H., Ohsawa I., Iio K., Satou A., Ishikura M., Ohta S. Astaxanthin protects mitochondrial redox state and functional integrity against oxidative stress. Several studies demonstrated that the combined administration of ASX with other compounds, particularly collagen hydrolysate, may show additive or synergistic effects for preventing or reversing the skin aging process [75,76]. Astaxanthin stimulates cell-mediated and humoral immune responses in cats. Tripathi D.N., Jena G.B. This review summarizes the available data on the functional role of astaxanthin in skin physiology, outlines potential mechanisms involved in the response to astaxanthin, and highlights the potential clinical implications associated with its consumption. Learn more The authors declare no conflict of interest. ASX did not influence the concentration of plasma C-reactive proteins, but levels of 8-hydroxy-2-deoxyguanosine (8-OHdG) (a DNA damage biomarker) were dramatically lower in the group fed higher doses of ASX. Although ASX can be also synthesized by plants, bacteria, and microalgae, the chlorophyte alga Haematococcus pluvialis is considered to have the highest capacity to accumulate ASX [2]. Hart P.H., Norval M. Ultraviolet radiation-induced immunosuppression and its relevance for skin carcinogenesis. The main source of ASX intake in humans is from seafood, with wild sockeye salmon, for example, providing 2638 mg/kg of flesh [61]. In particular, ASX has been reported to have a potent capacity to block the nuclear translocation of the NF-B p65 subunit and IB degradation through its inhibitory effect on NB kinase (IKK) activity [32]. Although ASX displayed molecular and protective mechanisms of action to promote and/or improve human skin health, it may not be easy to translate these results to humans. It appears that a higher proportion of ASX is absorbed when is delivered in an oil-based formulation. Yoon H.S., Cho H.H., Cho S., Lee S.R., Shin M.H., Chung J.H. [25] observed that ASX upregulated Nrf2 expression in irradiated cells. In another study by Tominaga et al. Astaxanthin inhibits nitric oxide production and inflammatory gene expression by suppressing I(kappa)B kinase-dependent NF-kappaB activation. Rfer C.E., Moeseneder J., Briviba K., Rechkemmer G., Bub A. Bioavailability of astaxanthin stereoisomers from wild (, http://creativecommons.org/licenses/by/4.0/, Randomized double-blind, controlled study, Monitoring of oxidative stress and skin aging, Randomized, double-blind, parallel-group, placebo-controlled, Randomized, single-blind, placebo-controlled, Two oral forms (ASX capsules; tablets collagen), Randomized, double-blind placebo-controlled, Capsules of ASX combined with topical application of ASX. Kupcinskas L., Lafolie P., Lignell A., Kiudelis G., Jonaitis L., Adamonis K., Andersen L.P., Wadstrm T. Efficacy of the natural antioxidant astaxanthin in the treatment of functional dyspepsia in patients with or without Helicobacter pylori infection: A prospective, randomized, double blind, and placebo-controlled study. Therefore, it is important to prevent normal cells from DNA damage induced by CP in clinical applications. Astaxanthin Induces the Nrf2/HO-1 Antioxidant Pathway in Human Umbilical Vein Endothelial Cells by Generating Trace Amounts of ROS. Consistent with this, a recent study with 44 healthy subjects showed that a combination of ASX (2 mg/day) and collagen hydrolysate (2 mg/day) for 12 weeks improves elasticity and barrier integrity in human skin. Tominaga et al. Jyonouchi H., Sun S., Tomita Y., Gross M.D. The authors observed an antiwrinkle effect in female human subjects (n = 3), using a topical cream containing ASX combined with other active ingredients. Okada Y., Ishikura M., Maoka T. Bioavailability of astaxanthin in Haematococcus algal extract: The effects of timing of diet and smoking habits. Furthermore, the AKT pathway plays key roles in modulating genome stability and DNA damage responses. Draelos Z.D. Abbreviations: , increase; , decrease; ASX, astaxanthin; NK, natural killer; IL-6, interleukin-6; MDA, malondialdehyde; RSSC, residual skin surface components; N/S, not specified; TEWL, transepidermal water loss; MMP, matrix metalloproteinase. Astaxanthin attenuates total body irradiation-induced hematopoietic system injury in mice via inhibition of oxidative stress and apoptosis. Astaxanthin enhances in vitro antibody production to T dependent antigens without facilitating polyclonal B-cell activation. Mantovani A., Allavena P., Sica A., Balkwill F. Cancer-related inflammation. Lorencini M., Brohem C.A., Dieamant G.C., Zanchin N.I., Maibach H.I. sharing sensitive information, make sure youre on a federal Davinelli S., Maes M., Corbi G., Zarrelli A., Willcox D.C., Scapagnini G. Dietary phytochemicals and neuro-inflammaging: From mechanistic insights to translational challenges. Carotenoids are lipid-soluble molecules, and the absorption of ASX is influenced positively by dietary lipids. Consistent with these studies, Xue et al. Chou HY., Lee C., Pan J.L., Wen Z.H., Huang S.H., Lan C.W., Liu W.T., Hour T.C., Hseu Y.C., Hwang B.H., et al. Cyclophosphamide (CP), a cytotoxic alkylating agent, is extensively used in the treatment of various cancers with high efficacy. Xu N., Lao Y., Zhang Y., Gillespie D.A. Saw C.L., Yang A.Y., Guo Y., Kong A.N. Davinelli S., Sapere N., Visentin M., Zella D., Scapagnini G. Enhancement of mitochondrial biogenesis with polyphenols: Combined effects of resveratrol and equol in human endothelial cells. These modifications lead to the loss of tensile strength and recoil capacity, wrinkle formation, dryness, and impaired wound healing [45]. Park et al. Yamahita E. Suppression of post-UVB hyperpigmentation by topical astaxanthin from krill. We thank group members of Solgar Italia Multrinutrient S.p.A. for their thorough review and helpful discussions during the preparation of this manuscript and for their help in elaborating the search strategy. Moreover, UV irradiation significantly induces pigmentation, skin wrinkling, and immunosuppression, resulting in the acceleration of photoaging. Camera E., Mastrofrancesco A., Fabbri C., Daubrawa F., Picardo M., Sies H., Stahl W. Astaxanthin, canthaxanthin and beta-carotene differently affect UVA-induced oxidative damage and expression of oxidative stress-responsive enzymes. [67] conducted a small pilot study with ASX from H. pluvialis to investigate the wrinkle reduction effect on the skin of 45 healthy subjects. Scapagnini G., Davinelli S., Drago F., De Lorenzo A., Oriani G. Antioxidants as antidepressants: Fact or fiction? DNA damage, apoptosis and langerhans cellsActivators of UV-induced immune tolerance. ASX-treated wounds showed significantly increased expression of wound healing biological markers such as collagen type I 1 (Col1A1) and basic fibroblast growth factor (bFGF) [52]. [70], the effect of ASX on wrinkle reduction and skin elasticity was investigated in 28 female subjects (2055 years). The biologically harmful effects associated with UV radiation exposure are largely the result of errors in DNA repair, which can lead to oncogenic mutations. It is also worth mentioning that the Food and Drug Administration (FDA) has approved ASX from H. pluvialis for direct human consumption dosages up to 12 mg per day and up to 24 mg per day for no more than 30 days [61]. Davinelli S., Di Marco R., Bracale R., Quattrone A., Zella D., Scapagnini G. Synergistic effect of L-Carnosine and EGCG in the prevention of physiological brain aging. However, ASX inhibits collagenases, MMP activity, inflammatory mediators, and ROS induction, resulting in potent antiwrinkle and antioxidant effects. The immunomodulatory action of ASX has been also reported in dogs and cats, enhancing both cell-mediated and humoral immune responses. All of the skin aging characteristics are associated with the oxidative metabolism and subsequent ROS production that define this unavoidable phenomenon. Federal government websites often end in .gov or .mil. Bar-Or D., Bar-Or R., Rael L.T., Brody E.N. Intervention of astaxanthin against cyclophosphamide-induced oxidative stress and DNA damage: A study in mice. Visioli F., Artaria C. Astaxanthin in cardiovascular health and disease: Mechanisms of action, therapeutic merits, and knowledge gaps. Park J.H., Yeo I.J., Han J.H., Suh J.W., Lee H.P., Hong J.T. Moreover, other authors have shown that ASX increased cytotoxic T lymphocyte activity in mice. Studies have shown that inhibition of AKT kinase activity impairs double-strand break (DSB) repair [59]. In addition, ASX has several essential biological functions in marine animals, including pigmentation, protection against ultraviolet (UV) light effects, communication, immune response, reproductive capacity, stress tolerance, and protection against oxidation of macromolecules [4]. It is well established that various proinflammatory markers in skin are increased as a result of UV exposure. HO-1 is regulated via various stress-sensitive transcription factors, including nuclear factor erythroid 2-related factor (Nrf2), which binds to antioxidant response elements in the promoter regions of enzymes of the detoxifying metabolism [22]. The effects of ASX on hyperpigmentation suppression, melanin synthesis and photoaging inhibition, and wrinkle formation reduction have been reported in several clinical studies [15]. Moreover, novel delivery strategies including various type of formulations such as nanoparticles, topical application cream, and defined phospholipid complexes offer significant promise and are worthy of further exploration in attempts to enhance the bioavailability of this interesting molecule. In particular, 31 middle-aged subjects received 4-mg daily doses of ASX, and the plasma levels of MDA decreased during ASX consumption (by 11.2% on day 15 and by 21.7% on day 29). Toxicological aspects have been characterized and ASX appears to be a safe and bioavailable compound. Mercke Odeberg J., Lignell A., Pettersson A., Hglund P. Oral bioavailability of the antioxidant astaxanthin in humans is enhanced by incorporation of lipid based formulations. First, these results suggest that the ASX isomer pattern in human plasma resembles that of the ingested salmon. Age-Associated Skin Conditions and Diseases: Current Perspectives and Future Options. Active ingredients against human epidermal aging. In an open-label noncontrolled study, 30 healthy female subjects received for eight weeks 6 mg per day of oral supplementation combined with 2 mL (78.9-M solution) per day of a topical application of ASX.

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