JOURNAL OF COSMETIC SCIENCE 104 (Figure 1). Under normal conditions, heme is intact within hemoproteins, but can be released under oxidative stress and became free heme. The free heme produced in this manner is highly cytotoxic, most probably due to the iron atom contained within its porphyrin ring, which can undergo Fenton chemistry to catalyze production of free radi- cals in an uncontrolled manner (2). This property of free heme can also sensitize a variety of cell types to undergo programmed cell death in response to proinfl ammatory stimuli. This deleterious effect is thought to play an important role in the pathogenesis of certain infl ammatory diseases (3). When the infl ammation occurs around the eyes, it can, in turn, exacerbate further blood leakage. This downward spiral will cause negative effects in the eye area including the formation of dark circles. Therefore, it is critical to scavenge and dispose of free heme as quickly as possible. Heme is degraded by an essential enzyme called heme oxygenase (HO) to carbon monox- ide, iron and biliverdin, which is subsequently converted to bilirubin by biliverdin re- ductase (Figure 2). Research has shown that carbon monoxide at low concentrations can act as an endogenous mediator of cellular signaling, and has antioxidation, anti-infl ammation and antiapoptotic activities (4). The iron produced by the degradation of heme is seques- tered in ferritin. Bilirubin, and biliverdin are also very good antioxidants (5,6). Thus HO turns free heme, a very toxic molecule, into several cytoprotective products. Figure 1. Heme. Figure 2. Heme catabolites and their properties.

FUCUS EXTRACT: COSMETIC TREATMENT FOR UNDER-EYE DARK CIRCLES 105 HO occurs as three isozymes: an inducible heme oxygenase-1 (HO-1) and constitutively expressed heme oxygenase-2 (HO-2) and heme oxygenase-3 (HO-3) (7). HO-1 can be induced by variety of stimuli, which indicate that HO-1 plays a vital role in maintaining cellular homeostasis in addition to heme degradation (8). THE PROTECTIVE ROLES OF HO-1 HO-1 mediated protection of cells and tissues is supported by several animal models of oxidative injury and acute infl ammation (9,10). In these models, HO-1 elevation confers potent resistance to stress, cell injury, and lipopolysaccharide-induced death. Blocking of HO activity abrogated cytoprotection, resulting in severe tissue damage. In addition, increased HO-1 expression levels have been clinically demonstrated to resolve of a wide variety of infl ammatory conditions (11). HO-1 activity forms a feedback loop by attenu- ating leukocyte adhesion and migration and by promoting the resolution of infl ammatory responses. Overexpression of HO-1 in endothelial cells and fi broblasts protected these cells from TNF-α-mediated apoptosis (12). HO-1 also plays a role in the regulation of angiogenesis, and overexpression of HO-1 has accelerated cutaneous wound healing in mice (13). THE PROTECTIVE EFFECT OF HO-1 IS ALSO THROUGH ITS PRODUCTS: (i) CO inhibits proliferation of vascular smooth muscle cells, platelet aggregation, and protects against apoptosis. In addition, CO inhibits proinfl ammatory genes while aug- menting anti-infl ammatory cytokine production (14,15). (ii) HO-1 induction is accompanied by increased ferritin synthesis. A recent study dem- onstrated that ferritin plays a central role in cellular antioxidant defense and cytoprotec- tion (16). The elevated level of ferritin would result in increased resistance to iron-mediated oxidative stress (17). (iii) It was shown in vitro that at micromolar concentrations, both biliverdin and bilirubin are effi cient free-radical scavengers (5). In liposomes, bilirubin suppressed oxidation even more effectively than α-tocopherol or vitamin E, which is regarded as an excellent anti- oxidant. These results indicate that bilirubin is a very good antioxidant and provides potent protection against oxidative injury and infl ammation (18). HO-1 and its products: CO, ferritin, and bilirubin all working together, play an essential role in antioxidation, anti-infl ammation, and cytoprotection. COLLAGEN AND WRINKLES Collagen, a group of naturally occurring fi brous proteins, is a major component of the extracellular matrix (ECM) that supports tissues. It is also the main component of fascia and skin (19), providing them with strength and elasticity. With aging, the amount of collagen production in the skin decreases, which results in the formation of fi ne lines and wrinkles (20). This is especially evident around the eye area.