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• W2042590400 abstract "human dermal fibroblast reduced folate carrier-1 TO THE EDITOR Skin is subject to age-associated structural and functional changes over time. Clinically, aging skin is characterized by the appearance of wrinkles, reduced skin elasticity, and an increased roughness (Kligman, 1989Kligman L.H. Photoaging, manifestations, prevention and treatment.Clin Geriatr Med. 1989; 5: 235-251PubMed Google Scholar). Approximately 80% of overall aging-associated skin changes can be attributed to extrinsic factors such as UV light harming skin cells in both epidermis and dermis. Among those inflicted damages are effects on cellular DNA that are a major factor in the process of skin aging (Krutmann, 2001Krutmann J. New developments in photoprotection of human skin.Skin Pharmacol Appl Skin Physiol. 2001; 14: 401-407Crossref PubMed Scopus (39) Google Scholar; Berneburg et al., 2005Berneburg M. Gremmel T. Kurten V. Schroeder P. Hertel I. von Mikecz A. et al.Creatine supplementation normalizes mutagenesis of mitochondrial DNA as well as functional consequences.J Invest Dermatol. 2005; 125: 213-220Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). A vitamin that plays a central role in DNA synthesis and repair is folic acid. It exists in a number of different forms, which occur naturally in different food sources such as dark green leafy vegetables, dried beans, and asparagus (Rampersaud et al., 2003Rampersaud G.C. Kauwell G.P.A. Bailey L.B. Folate: a key to optimizing health and reducing disease risk in the elderly.J Am College Nutr. 2003; 22: 1-8Crossref PubMed Scopus (74) Google Scholar) or as folic acid, which is the synthetic form of the vitamin used in supplements. A large body of evidence indicates that an adequate folate intake is crucial for a variety of physiological processes (Rampersaud et al., 2003Rampersaud G.C. Kauwell G.P.A. Bailey L.B. Folate: a key to optimizing health and reducing disease risk in the elderly.J Am College Nutr. 2003; 22: 1-8Crossref PubMed Scopus (74) Google Scholar), for instance throughout gestation to guarantee normal development and growth (Bailey et al., 2003Bailey L.B. Rampersaud G.C. Kauwell G.P.A. Folic acid supplements and fortification affect the risk for neural tube defects, vascular disease and cancer: evolving science.J Nutr. 2003; 133: 1961S-1968SPubMed Google Scholar). Folate was utilized in the treatment of oral ulcers from methotrexate and also to inhibit gingival hyperplasia from phenytoin use and pregnancy (Thomas and Pack, 1982Thomas M.E. Pack A.R. Effects of extended systemic and topical folate supplementation on gingivitis of pregnancy.J Clin Periodontol. 1982; 9: 275-280Crossref PubMed Scopus (38) Google Scholar; Barrett, 1986Barrett A.P. Topical folinic acid therapy in methotrexate-induced oral ulceration.J Periodontol. 1986; 57: 318-320Crossref PubMed Scopus (10) Google Scholar; Drew et al., 1987Drew H.J. Vogel R.I. Molofsky W. Baker H. Frank O. Effect of folate on phenytoin hyperplasia.J Clin Periodontol. 1987; 14: 350-356Crossref PubMed Scopus (31) Google Scholar). On the other hand, folate deficiency is associated with chromosomal damage and gene mutations in lymphocytes and the hemopoietic system (Blount, 1997Blount B.C. Folate deficiency causes uracil misincorporation into human DNA and chromosomal breakage: implications for cancer and neuronal damage.Proc Natl Acad Sci USA. 1997; 94: 3290-3295Crossref PubMed Scopus (1142) Google Scholar; Fenech et al., 1997Fenech M.F. Dreosti I.E. Rinaldi J.R. Folate, vitamin B12, homocysteine status and chromosomal damage rate in lymphocytes of older men.Carcinogenesis. 1997; 18: 1329-1336Crossref PubMed Scopus (132) Google Scholar). With respect to normal skin, however, there is only very little knowledge regarding the role of folates although there are several studies on folate status and skin disease. We, therefore, hypothesized that skin cells might benefit from an exogenous folic acid supplementation. To tackle this question experimentally, we first focused on human dermal fibroblasts (HDFs), which play an important role in connective tissue metabolism. HDFs were cultured by outgrowth from skin biopsies obtained from different donors as described previously (Stäb et al., 2000Stäb F. Wolber R. Blatt T. Keyhani R. Sauermann G. Topically applied antioxidants in skin protection.Methods Enzymol. 2000; 319: 465-478Crossref PubMed Google Scholar). All donors provided written, informed consent. HDFs were seeded in culture dishes in a density of 1.6 × 104 cells/cm2 using folic acid-free medium (Biochrom AG, Berlin, Germany). This modified DMEM did not contain any serum to avoid addition of undefined amounts of folic acid. HDFs were cultivated in folic acid-free medium or medium that contained 9.1 μm (1 ×) or 36.4 μm (4 ×) folic acid, respectively. A concentration of 9.1 μm folic acid corresponds to the folic acid concentration used in standard culture media for HDF (Stäb et al., 2000Stäb F. Wolber R. Blatt T. Keyhani R. Sauermann G. Topically applied antioxidants in skin protection.Methods Enzymol. 2000; 319: 465-478Crossref PubMed Google Scholar). After preincubation of 52 hours at 37°C in an atmosphere of 7% CO2, cells were washed with folic acid-free medium and the medium was changed. After a postincubation of 2 hours, cell extracts were prepared from each group. Protein quantification was performed using the Experion Pro260 analysis kit and experion automated electrophoresis system (BioRad, München, Germany) to allow for standardization of folic acid concentration relative to protein content. Quantitative determination of folic acid was carried out by means of HPLC–tandem mass spectrometry. For HPLC: Agilent 1100 series (Agilent Technologies GmbH, Waldbronn, Germany), separation column: LiChrospher RP select B, 60 × 2 mm, 5 μm (Merck, Darmstadt, Germany). Mobile phase: gradient: A: 0.25% aqueous acetic acid, B: acetonitrile: 0 minute: 95% A, 5% B, 2–5 minutes: 60% A, 40% B, 6–10 minutes: 100% B, 11–17 minutes: 95% A, 5% B. Flow rate: 300 μl/minutes, injection volume: 5 μl. For mass spectrometry: Quattro micro (Micromass-Waters, Eschborn, Germany), operating in positive ion mode. The detection was carried out by “multireaction monitoring” of the transition m/z 442.0 [M+H]+ → m/z 295.0 (quantifier) and m/z 442.0 [M+H]+ → m/z 312.0 (qualifier). Quantification was carried out by external standard calibration. To determine if dermal cells have the ability to take up folic acid, HDFs were cultured in folic acid-free medium or medium that contained 9.1 μm (1 ×) or 36.4 μm (4 ×) folic acid, respectively. Individual results are depicted in Figure 1a and statistical significance was confirmed by Wilcoxon's signed rank test (P≤0.05, n=6). This type of data presentation clearly shows that six out of six volunteers display a dose-dependent folic acid uptake, however, with varying amplitudes. As demonstrated in Figure 1a, extracts of cultured cells without folic acid supplementation showed vitamin concentrations below the detection limit. Interestingly, folic acid is dose-dependently taken up by these cells. For these studies, we used synthetic folic acid because it is more easily absorbed than naturally occurring food folates. Specifically, it does not require intestinal enzymatic cleavage before absorption (Rampersaud et al., 2003Rampersaud G.C. Kauwell G.P.A. Bailey L.B. Folate: a key to optimizing health and reducing disease risk in the elderly.J Am College Nutr. 2003; 22: 1-8Crossref PubMed Scopus (74) Google Scholar) and displays in addition an enhanced chemical stability. As folic acid plays a central role in cellular metabolism, particularly in DNA repair, we investigated whether UV irradiation affects folic acid uptake. HDFs were again cultured in the absence or presence of increasing amounts of folic acid and either exposed to UV irradiation or sham-irradiated. The effects of UV exposure were determined by subjecting cells to 135 mJ/cm2 solar-simulated irradiation and preparing cell extracts after 24 hours. The UV source (UV solar simulator; Oriel Corporation, Stratford, CT) was equipped with UV-B and UV-C safety filters. UV density was determined using an IL-1700 radiometer (International Light, Newburyport, MA). Under all conditions, investigated cell viability was verified by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assay. Figure 1b shows folic acid concentration in HDF with the indicated folic acid supplementation 24 hours after exposure (+UV) or nonexposure (−UV) to 135 mJ/cm2 solar-simulated irradiation (n=7). Individual results are depicted and statistical significance was confirmed by Wilcoxon's signed rank test (P≤0.05, seven out of nine responders). Our data demonstrate that HDFs increase their intracellular folate levels when exposed to UV irradiation provided that sufficient amounts of folic acid are supplied externally. Based on these observations we hypothesized that higher intracellular folate concentrations as a result of UV irradiation are paralleled by enhanced expression of folate carriers. For folates, several carrier systems have been identified with the reduced folate carrier-1 (RFC-1) representing the major transport system in mammalian cells and tissues (Matherly, 2001Matherly L.H. Molecular and cellular biology of the human reduced folate carrier.Prog Nucleic Acid Res Mol Biol. 2001; 67: 131-162Crossref PubMed Google Scholar). This carrier serves to maintain sufficient levels of intracellular folates which play a central part in one-carbon transfer reactions (Bailey and Gregory, 1999Bailey L.B. Gregory III, J.F. Folate metabolism and requirements.J Nutr. 1999; 129: 779-782Crossref PubMed Scopus (354) Google Scholar). It is speculated that a decreased RFC-1 expression in human tissues contributes to disease states associated with an inadequate folate status (Whetstine et al., 2002Whetstine J.R. Flatley R.M. Matherley L.H. The human reduced folate carrier gene is ubiquitously and differentially expressed in normal human tissues: identification of seven non-coding exons and characterization of a novel promoter.Biochem J. 2002; 367: 629-640Crossref PubMed Scopus (108) Google Scholar). Consequently, we isolated full-thickness human skin biopsies after acute UV irradiation and investigated RFC-1 gene expression. Before UV exposure, the respective individual minimal erythemal dose, solar-simulated irradiation for each volunteer, was determined according to the European Cosmetic, Toiletry and Perfumery Industry Guidelines using the SU 5,000 solar sun simulator (m.u.t. GmbH, Wedel, Germany). After that, buttock skin was irradiated with an individual dose of two minimal erythemal dose solar-simulated irradiation (n=8, age 26–62 years). Twenty-four hours after UV exposure, full-thickness punch biopsies from UV-exposed as well as UV-protected control areas were obtained, dermis and epidermis were separated using dispase digestion and RFC-1 mRNA was determined by quantitative reverse transcription–PCR. Total RNA was isolated as published (Südel et al., 2003Südel K.M. Venzke K. Knußmann-Hartig E. Moll I. Stäb F. Wenck H. et al.Tight control of matrix metalloproteinase-1 activity in human skin.Photochem Photobiol. 2003; 78: 840-845Crossref Scopus (34) Google Scholar). Reverse transcription of RNA was performed using the high capacity cDNA archive kit (Applied Biosystems, Foster City, CA) according to the manufacturer's recommendation. The analysis of mRNA expression was carried out with the ABI PRISM sequence detection system 7700 (Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA) using TaqMan® assay reagents (Applied Biosystems) containing gene-specific PCR primers (RFC ordering no. HS 00953342_m1; batch no. 39347; Lot-Nr. 393472 925 A04) as well as FAM™-labelled probe. For quantification, RFC-1 gene expression was normalized to the housekeeping gene 18S rRNA. The amplification protocol was as follows: 2 minutes at 50°C, 10 minutes at 95°C, 15 seconds at 95°C, and 1 minute at 59°C (40 cycles). Interestingly, compared with control areas RFC-1 gene expression was significantly increased in irradiated skin (24 hours: 425±116%; 72 hours: 212±50% with the control being set as 100%, clinical study approval number by the Ethics Committee of the Medical Association of Hamburg (OB/IV/02), all donors provided written, informed consent). Specifically, following irradiation, carrier expression was significantly enhanced in both human epidermis and dermis with the dermal compartment (clinical study approved by the Ethics Committee of the Medical Association of Hamburg (OB/VI/03), all donors provided written, informed consent) displaying higher baseline levels (Figure 1c). These studies suggest that in both epidermal and dermal cells folic acid uptake is significantly increased after UV irradiation. To answer the question to which extent folic acid is able to penetrate human skin in vivo, volunteers treated one of their forearms in a home-in-use study with a cream that contained 0.03% folic acid. The cream largely resembled commercially available cosmetic formulations but was optimized in terms of folic acid stability. This cream was applied twice daily for 4 weeks according to written instructions. The recommendations of the current version of the Declaration of Helsinki Principles and the guideline of the International Conference on Harmonization Good Clinical Practice were observed as applicable to a nondrug study. All subjects provided written, informed consent. Folic acid content was determined in suction blister fluid isolated from untreated control areas or areas treated with the folic acid-containing formulation. To analyze folic acid concentration, 50 μl 0.25% aqueous ammonia solution was added to 100 μl of suction blister fluid. After homogenization, soluble proteins were precipitated with 100 μl acetonitrile and separated by centrifugation. Folic acid concentration was analyzed in the supernatant by means of HPLC–tandem mass spectrometry as described above. Results in Figure 2 are depicted as mean±SD (n=17 females, age 35–56 years). Significant differences are marked with an asterisk (*P≤0.05). As normal distribution could not be assumed (Shapiro–Wilk test) Blom-transformed ranks of original data were analyzed by means of analysis of variance (generalized Tukey test) with subjects as repeated measures and folic acid concentration as qualitative factor. As shown in Figure 2, folic acid concentration in suction blister fluids was substantially increased after treatment compared with the untreated control area. These data demonstrate that folic acid exhibits physicochemical properties (e.g., log P=-2.63±0.85, molecular weight=441.4 g) that allow for penetration through the skin barrier making this vitamin bioavailable in human skin. Folic acid is sensitive to UV irradiation, giving rise to the hypothesis that skin pigmentation, among other biological functions, serves to protect folic acid in skin (Jablonski and Chaplin, 2000Jablonski N.G. Chaplin G. The evolution of human skin coloration.J Hum Evol. 2000; 39: 57-106Crossref PubMed Scopus (782) Google Scholar). Photolysis of this vitamin generates molecules such as pterine-6-carboxylic acid that can exert toxic effects on cells. For that reason, we extensively tested specifically formulated folic acid-containing creams for skin compatibility and (photo-)toxicology. Overall, in our in vitro and in vivo studies involving more than 600 volunteers (i.e., different test areas with test periods for up to 6 months), not a single skin incompatibility was detected. These data clearly show the safety of topically applied folic acid in the specific formulation used. In summary, skin cells increase both their folic acid uptake and their RFC-1 gene expression in response to UV exposure. As folic acid levels are increased in suction blister fluids after topical application, this approach appears to be a targeted means to enhance the cutaneous supply of this vitamin in human skin. It can be speculated that the UV exposure-mediated increase of RFC-1 serves to ensure sufficient cellular folate supply. This hypothesis is based on previous findings that demonstrate both the induction of RFC-1 expression (Sprecher et al., 1998Sprecher E. Bergman R. Sprecher H. Maor G. Reiter I. Krivoy N. et al.Reduced folate carrier (RFC-1) gene expression in normal and psoriatic skin.Arch Dermatol Res. 1998; 290: 656-660Crossref PubMed Scopus (11) Google Scholar) and the loss of folates in psoriasis, probably owing to increased utilization of folate by epidermal skin cells (Fry et al., 1971Fry L. MacDonald A. Almeyda J. Griffin C.J. Hoffbrand A.V. The mechanism of folate deficiency in psoriasis.Br J Dermatol. 1971; 84: 539-544Crossref PubMed Scopus (28) Google Scholar; Touraine et al., 1973Touraine R. Revuz J. Zittoun J. Jarret J. Tulliez M. Study of folate in psoriasis: blood levels, intestinal absorption and cutaneous loss.Br J Dermatol. 1973; 89: 335-341Crossref PubMed Scopus (22) Google Scholar). However, future studies will have to address this issue to further elucidate the physiological relevance of our findings. The authors state no conflict of interest. We thank Mrs Leneveu-Duchemin for conducting expert statistical analysis." @default.
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• W2042590400 title "Folic Acid: Cellular Uptake and Penetration into Human Skin" @default.
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