SKIN-AGING AND INFLAMMAGING TREATMENT 329 AP-1 inhibition (2,72). Retinoids also increase epidermal thickening, thereby alleviating skin aging (2,72). A p rotein called cysteine-rich angiogenic inducer 61 (CCN1/Cyr61) plays a vital role in regulating infl ammation and fi brogenesis (73) thus, interventions that affect CNN1 ac- tivity play an important role in senescence (73). An in vivo study using vitamin A (retinol) as a topical treatment observed a decline in CNN1 expression in both natural and photo- aged skin (72). This study inferred that retinoids improve skin aging through downregu- lation of CNN1 and collagen production (72). Kafi et al. (74) investigated the effectiveness of retinol as an intervention for skin aging in a randomized, double-blind study over 24 weeks, showing that retinol improves wrin- kles due to induction of glycosaminoglycan and increased collagen production (74). NOV EL FORMULATIONS FOR SKIN AGING Top ical and transdermal drug delivery systems (TDDSs) eliminate risks associated with intravenous routes and drawbacks associated with oral therapy, such as altered gastric pH and hepatic metabolism (75). Moreover, the TDDS is a noninvasive method to deliver drugs, avoiding trauma and infection risks (76). How ever, SC consists of dead keratinocyte layers surrounded by a lipid matrix, making the passage of drug molecules through the skin a troublesome issue (75). Few drugs can be delivered through the TDDS (exceptionally, small and highly lipophilic drugs could be delivered via passive diffusion at therapeutic levels). In addition, most drugs are transported through the skin very slowly, with lag times exceeding several hours to reach steady-state fl ux (76). Finally, the TDDS and dermal transport suffer poor skin penetration of drugs (77). The re are multiple approaches to enhance drug penetration through skin layers, such as penetration enhancers and carrier-based formulations. There are chemical, physical, and biomaterial penetration enhancers. CHE MICAL PENETRATION ENHANCER Che mical penetration enhancers are a promising way to overcome SC barrier and permit drug permeation across the skin in adequate rates (78). A good penetration enhancer must be nonirritant, nontoxic, and inert with adequate cosmetic acceptability (79). Poly- unsaturated fatty acids, polymers, nonionic surfactants, pyrrolidones, and terpenes are commonly incorporated in topical formulations for chemical enhancers. Cur cumin applications as antioxidants are limited because of poor absorption and exces- sive hepatic metabolism after oral administration (78). Patel et al. (78) developed a topi- cal gel to deliver curcumin, using menthol as a chemical penetration enhancer, showing that menthol markedly increased percutaneous fl ux as well as the enhancement ratio of curcumin across excised rat epidermis (Supplementary Table 1) (78). PEN ETRATION ENHANCER Dif ferent approaches have been used to facilitate drug penetration through the skin based on physical principle (80).

JOURNAL OF COSMETIC SCIENCE 330 Bio materials as penetration enhancers. Dif ferent biomaterials have recently emerged as safer skin penetration enhancers. For example, cell-penetrating protein, such as arginine, magainin, and lysine, facilitates the delivery of various cosmeceuticals through the skin (81). Arginine-rich peptide improves transdermal delivery of proteins into skin tissue (Supplementary Table 1) (82). Moreover, Li et al. (83) used trypsin as a biochemical en- hancer to enhance insulin transdermal delivery (83). Nas rollahi et al. (84) studied the ability of cell-penetrating peptides to transport elastin into fi broblast as skin-aging treatment. The study confi rmed the transport of the elastin–peptide complex across fi broblast cell culture via a fl uorescent microscope, which occurred by phys- ical interactions between the peptide and the membrane (Supplementary Table 1) (84). Car rier-based formulations. Ves icular systems of nanometer size are commonly used to en- hance skin penetration of drugs and other cosmeceuticals. Nanocarriers have received researchers’ attention because of their various advantages, such as improving drug phar- macokinetics, prolonging its half-life, and reducing its metabolism. In addition, nanocar- riers protect the drug in vitro and in vivo (85). Lip osome. Fir st introduced in 1961, liposomes are spherical vesicles with phospholipid bilayers that carry portions of the surrounding solvent within (86). This allows for the incorporation of hydrophilic, hydrophobic, and amphiphilic drugs. Natural and synthetic phospholipids are used in liposome formation along with cholesterol and surfactants (87). It was hypothesized that liposomes enhance cosmeceutical delivery by increasing skin barrier permeability and changing the intracellular lipids (88). Because of liposomes’ rapid partition, the cosmeceutical agent is carried to the SC, and as the vesicle remains in this layer, the drug passes to deeper layers (89). However, liposomes are greatly limited by their instability, aggregation, and molecule leakage. Also, their diffusion into the skin is heterogenous and inhibited by the skin barrier (90). Tsa i et al. (91) developed and investigated NGN-loaded elastic liposomal formulations via an ex vivo study (91). The NGN accumulation in different skin layers in case of elastic liposomes was signifi cantly higher relative to Tween 80 and saturated aqueous solutions. Furthermore, elastic liposome formulations caused less skin irritation when applied to rat skin than a standard irritant, indicating that elastic liposomes can be considered a good carrier for topical formulations of NGN (91). Cad deo et al. (92) created liposomal formulation to deliver two different phenols: resve- ratrol (lipophilic) and gallic acid (hydrophilic), both of which have protective skin effects against oxidation and infl ammation (92). The formulation’s ability to protect fi broblasts from oxidative damage of H2O2 was evaluated in vitro. In addition, therapeutic effi cacy was evaluated in mice based on capability to inhibit chemically induced edema and my- eloperoxidase activity (Supplementary Table 1) (92). Nio somes. Nio somes are vesicles consisting of nonionic surfactants such as Span 60, Span 80, Tween 60, and Tween 80, which are safe and cheap for pharmaceutical applications. They are good carriers of hydrophilic and hydrophobic cosmeceutical agents (93). Niosomes have advantages over liposomes, as they are more stable, cheaper, and easier in production (85). However, they showed reduced molecule fl uxes compared with liposomes (94). Gal lic acid derived from Terminalia chebula showed antiaging effects because of its anti- oxidant properties. However, its extract suffers chemical instability and inactivity on exposure to environmental conditions (95). Manosroi et al. (95) developed elastic and