PhloretinPhloretin is a plant-derived dihydrochalcone polyphenol primarily found in various species of apple (J. Nutr. 2005;135:172-8) reportedly capable of demonstrating antioxidant activity,.This flavonoid exhibits potent antioxidant activity in peroxynitrite scavenging and in the suppression of lipid peroxidation (Biochem. Biophys. Res. Commun. 2002;295:9-13). Along with its glucoside phloridzin, phloretin is believed to be an important contributor to the health benefits of apples (J. Agric. Food Chem. 2003;51:6347-53).

Phloretin also has been identified in tomatoes, and is considered an important source of dietary flavonoids (J. Agric. Food Chem. 2008;56:2436-41). In addition, it was once used as a substitute for quinine.

Research on the potential cutaneous benefits of phloretin began more than 20 years ago, when two botanically derived flavonoids - phloretin and the structurally related compound nordihydroguaiaretic acid - were found to strongly inhibit keratinocyte growth. The investigators suggested that the compounds be considered antipsoriatic agents (Int. J. Dermatol. 1987;26:660-6).

Heightened PermeationNine years ago, phloretin was evaluated for its potential to enhance the transdermal penetration of lidocaine hydrochloride. Investigators treated excised human skin samples with a methanolic solution of phloretin 12 hours before lidocaine application, at pH 4.0 and 7.0. At a pH of 4.0, a 3.2-fold increase in total permeation was seen, compared with control samples after 24 hours.

In a subsequent test, unilamellar phosphatidylcholine liposomes were used as a vehicle for phloretin, and a 5.4-fold greater permeation of lidocaine was observed in pretreated skin, compared with control skin after 24 hours. The investigators concluded that phloretin indeed demonstrated potential as a transdermal penetration enhancer for lidocaine (J. Pharm. Sci. 2001;90:485-92).

In 2003, Auner et al. showed that permeation of porcine skin with phloretin and 6-ketocholestanol prior to treatment with 5-aminolevulinic acid increased acid diffusion (the permeation of which was enhanced by cetylpyridinium chloride and benzalkonium chloride) at pH 7.0 approximately 1.7-fold (Int. J. Pharm. 2003;255:109-16).

In an experiment also published in 2003, the same team studied the same compounds - phloretin and 6-ketocholestanol included in unilamellar liposomes - for their viability in enhancing the transport of sodium fluorescein across rat, porcine, and human skin. Phloretin was found to have a significant positive effect on sodium fluorescein diffusion in rat and porcine skin after 30 hours but no influence on human skin as compared to control, whereas 6-ketocholestanol exhibited a positive effect on all skin types (J. Control. Release 2003;89:321-8).

By using various methods to evaluate membrane interactions, some of the same investigators subsequently determined that phloretin and 6-ketocholestanol interact with the lipid layer and alter the structure, rendering a greater fluidity in the membrane (Eur. J. Pharm. Biopharm. 2004;57:329-36).

In the same issue of the European Journal of Pharmaceutics and Biopharmaceutics in which these findings were published, Auner and Valenta published a study on the effects of phloretin on the topical permeation of lidocaine using one hydrophilic and three lipophilic delivery systems. The researchers conducted standard diffusion experiments with Franz diffusion cells through porcine skin, and found that phloretin enhanced lidocaine permeation 1.39-fold in the hydrophilic formulation and 1.25- to 1.76-fold in the lipophilic formulations (Eur. J. Pharm. Biopharm. 2004;57:307-12).

More recently, Auner et al. shed light on the mechanisms of action of phloretin and 6-ketocholestanol. An increase in intercellular lipid bilayer fluidity in the stratum corneum is thought to confer the observed penetration-enhancing effects associated with these compounds. Evaluation of the effects of these compounds on phase transition and enthalpy revealed that both compounds decrease the diffusional resistance of the stratum corneum to drugs with a hydrophilic-lipophilic equilibrium (Int. J. Pharm. 2005;294:149-55).

Antioxidant ActionsResearchers evaluated the contribution of the major phenolic phytochemicals in apples to the total antioxidant capacity of the fruit using a 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging assay. They found a linear relationship between phenolic concentration and total antioxidant activity, and estimated that the greatest phenolic contribution to the total antioxidant capacity of apples was derived from quercetin, followed in order by epicatechin, procyanidin B(2), phloretin, and chlorogenic acid, with the contribution from vitamin C falling just ahead of that of phloretin (J. Agric. Food Chem. 2003;51:6516-20).

Phloretin has also recently been studied in a combination solution. In a paper now under review for publication, Oresago et al. evaluated the effects of a topical antioxidant formulation containing phloretin, vitamin C, and ferulic acid in mitigating ultraviolet (UV)-induced harm. Biomarkers of cutaneous damage, including the formation of sunburn cells and thymine dimers, and the expression of matrix metalloproteinase-9 and p53, were assessed in 10 normal healthy volunteers. Pretreatment with the antioxidant mixture effectively inhibited the deleterious effects of UV irradiation and also prevented UV exposure from inducing immunosuppressive effects.

The investigators concluded that the dual role of phloretin, as a strong antioxidant and penetration enhancer, helps to augment the availability of the other antioxidants to the skin (Oresago C, et al. Photoprotective effects of a topical antioxidant mixture containing vitamin C, ferulic acid, and phloretin against UV-induced oxidative stress in human skin. Submitted for publication, 2010).

Skin Care PotentialIn 2007, Lin et al. isolated and identified 13 compounds from the Formosan apple (Malus doumeri var. formosana), a native Taiwanese botanical. The compounds, which included 3-hydroxyphloretin, demonstrated potent antioxidant and cellular tyrosinase-reducing activities in human epidermal melanocytes.

In addition, 3-hydroxyphloretin was found to be one of the two most active constituents, along with catechol, also exhibiting activity as a competitive inhibitor in a kinetic analysis of mushroom tyrosinase. The investigators concluded that both compounds have potential as cosmetic agents (Phytochemistry 2007;68:1189-99). The tyrosinase-reducing activities of phloretin also suggest intriguing potential as a skin-lightening agent.

Several of the same investigators previously reported on seven phenolic compounds isolated from the Formosan apple that were assessed for their potential application in skin care. The researchers found that the compounds 3-hydroxyphloridzin, 3-hydroxyphloretin, and quercetin showed the most potent free radical-scavenging properties against 1,1-diphenyl-2-picrylhydrazyl (DPPH) and superoxide radicals. The phloretin compounds (phloridzin is the glucosidic form) also exhibited inhibitory activity against xanthine oxidase and elastase.

In addition, these compounds inhibited matrix metalloproteinase-1 synthesis in human fibroblast cells. The results are significant because these enzymes break down key dermal constituents, contributing to cutaneous aging. The team concluded that the phloretin extracts as well as quercetin show potential for use in antiaging or other cosmetic formulations (Biol. Pharm. Bull. 2006;29:740-5).

More recently, investigators examined the phytochemicals in apples and apple juices to ascertain the compounds' relative contributions to potential chemopreventive properties. The researchers fractionated a polyphenol-enriched apple juice extract and measured antioxidant effects, modulation of carcinogen metabolism, anti-inflammatory and antihormonal activities, and antiproliferative potential. Phloretin and epicatechin were identified as the strongest inhibitors of cyclooxygenase-1, which could contribute to an anti-inflammatory effect (Mol. Nutr. Food Res. 2008;52(S1):S28-S44). The researchers concluded that the combination of various constituents exhibiting complementary properties may lead to increased total chemopreventive benefits.

Notably, phloretin has also been found to inhibit the growth of several cancer cells and to induce apoptosis of B16 melanoma, HL60 human leukemia cells, and HT-29 human colon cancer cells. In an investigation of the effects of the flavonoid on human colon cancer cells, Park et al. speculated that the inhibitory effects may be mediated via mitochondrial membrane permeability alterations and activation of caspase pathways (J. Med. Food 2007;10:581-6).

ConclusionsThe quantity of research thus far conducted on phloretin, a phenolic compound found most abundantly in various species of apples and pears, is relatively modest. Nevertheless, evidence suggests that phloretin exhibits antioxidant activity and exerts a potentially significant influence on the skin, particularly in enhancing the permeation of other ingredients.

Although much more research is necessary, particularly randomized controlled trials, this botanical ingredient is an intriguing addition to the ever-expanding roster of naturally derived ingredients with the potential to impart significant health benefits to the skin. It is found in Phloretin CF (SkinCeuticals Inc.).

Dr. Baumann writes the "Cosmeceutical Critique" column, which appears regularly in Skin & Allergy News, an Elsevier publication. Dr. Baumann is in private practice in Miami Beach. To respond to this column, or to suggest topics for future columns, write to her at sknews@elsevier.com._____________________PHLORETIN CFDerived from apples and the root bark of fruit trees including apple, pear, and grapefruit, phloretin is a broad- spectrum molecule newly identified for its antioxidant properties and recently studied for use as a pigment- regulating and penetration-enhancing agent in the medical community. Classified as a special family of flavonoids called dihydrochalcones, phloretins unique carbonyl structure is responsible for particularly potent antioxidant activity in peroxynitrite scavenging and in the inhibition of lipid peroxidation. Additionally, it displays a wide range of bioactivities such as anticancer, antifungal, antibacterial, antiviral, and anti-inflammatory.Phloretin CF represents a new class of preventive and corrective topical antioxidant treatment. This patent- pending breakthrough technology combines the broad-range power of phloretin with vitamin C and ferulic acid in a synergistic biodiverse formulation to divide and conquer sources of damage at every level of the skin. Phloretin CF is a broad-spectrum treatment that protects against not only free radicals, but the range of other reactive molecules known to cause damage and DNA mutations among the integral cell types.In addition to preventing photodamage, it corrects existing damage by stimulating the synthesis of essential proteins and fibers and accelerating cell turnover. The result a strengthened support structure on the inside and a more youthful, firm, radiant appearance on the outside.Benefits:Synergistic Antioxidant Combination / Broad-Spectrum Formulationprevents premature signs of aging and corrects existing photodamage, especially age spots and laxitydivides and conquers the range of reactive oxygen species (ROS) throughout the skinfacilitates cellular repair and maintains cell diversityreconstructs the skins support structureboosts skins natural immunity against DNA impairment to preserve cellular integrity and help prevent serious skin conditions like skin cancerprovides significantly better results than any one antioxidant aloneproperly formulated with optimal concentrations at the precise pH to ensure maximum bioavailiability2% Phloretin neutralizes free radicals and suppresses radiation-induced oxidative reactions accelerates cell turnover inhibits UV-induced melanogenesis10% L-Ascorbic Acid neutralizes free radicals and suppresses radiation-induced oxidative reactions prevents UV immunosuppression promotes collagen synthesis0.5% Ferulic Acid neutralizes free radicals and suppresses radiation-induced oxidative reactions inhibits UV-induced melanogenesis

Usage Recommendations

hyperpigmentation erythema uneven skin tone loss of elasticity mottled appearance photodamaged skin

Application Tips:Once daily using fingertips, apply 4-5 drops of Phloretin CFTM to face, neck, and chest.

List of Ingredients:PHLORETINL-ASCORBIC ACID (VITAMIN C)FERULIC ACID

________________________________Phloretin is a dihydrochalcone, a type of natural phenols. It can be found in apple tree leaves.Phloretin inhibits the active transport of glucose into cells by SGLT1 and SGLT2, though the inhibition is weaker than by its glycoside phlorizin.[2] Orally consumed phlorizin is nearly entirely converted into phloretin by hydrolytic enzymes in the small intestine.[3]HYPERLINK \l "cite_note-Crespy2001-4"[4] An important effect of this is the inhibition of glucose absorption by the small intestine[4] and the inhibition of renal glucose reabsorption.[3] Phloretin also inhibits a variety of urea transporters.[5]HYPERLINK \l "cite_note-6"[6] It induces urea loss and diuresis when coupled with high protein diets.Phloretin has been found to inhibit GLUT2.MetabolismPhloretin hydrolase uses phloretin and water to produce phloretate and phloroglucinolGlycosidesPhlorizin is the 2'-glucoside of phloretin.

Naringin dihydrochalcone is a diglycoside of phloretin

ReferencesJump up ^ Picinelli A.; Dapena E.; Mangas J. J. (1995). "Polyphenolic pattern in apple tree leaves in relation to scab resistance. A preliminary study". Journal of Agricultural and Food Chemistry 43 (8): 22732278. doi:10.1021/jf00056a057.Jump up ^ Chan, Stephen S.; William D. Lotspeich (1962-12-01). "Comparative effects of phlorizin and phloretin on glucose transport in the cat kidney". American Journal of Physiology -- Legacy Content 203 (6): 975979. ISSN 0002-9513. Retrieved 2012-10-21. /wiki/Help:CS1_errors^ Jump up to: a b Idris, I.; Donnelly, R. (2009). "Sodium-glucose co-transporter-2 inhibitors: An emerging new class of oral antidiabetic drug". Diabetes, Obesity and Metabolism 11 (2): 79. doi:10.1111/j.1463-1326.2008.00982.x. edit^ Jump up to: a b Crespy, V.; Aprikian, O.; Morand, C.; Besson, C.; Manach, C.; Demign, C.; Rmsy, C. (2001). "Bioavailability of phloretin and phloridzin in rats". The Journal of nutrition 131 (12): 32273230. PMID 11739871. editJump up ^ Fenton, Robert A.; Chung-Lin Chou, Gavin S. Stewart, Craig P. Smith, Mark A. Knepper (2004-05-11). "Urinary concentrating defect in mice with selective deletion of phloretin-sensitive urea transporters in the renal collecting duct". Proceedings of the National Academy of Sciences of the United States of America 101 (19): 74697474. doi:10.1073/pnas.0401704101. ISSN 0027-8424. Retrieved 2012-10-21. /wiki/Help:CS1_errorsJump up ^ Shayakul, Chairat; Hiroyasu Tsukaguchi, Urs V. Berger, Matthias A. Hediger (2001-03-01). "Molecular characterization of a novel urea transporter from kidney inner medullary collecting ducts". American Journal of Physiology - Renal Physiology 280 (3): 487F494. ISSN 1931-857X. Retrieved 2012-10-21. /wiki/Help:CS1_errors

Glycosylceramidase From Wikipedia, the free encyclopedia (Redirected from Phloretin-glucosidase) In enzymology, a glycosylceramidase (EC 3.2.1.62) is an enzyme that catalyzes the chemical reactionglycosyl-N-acylsphingosine + H2O N-acylsphingosine + a sugar