y, the intercellular a single, the drug travels by way of the lipid matrix that occupies the intercellular spaces involving the corneocytes, therefore creating it the preferred permeation route for lipophilic molecules. However, in the transcellular way, also called the intracellular pathway, the drug diffuses through the many skin layers and dead cells, permitting for the transport of hydrophilic or polar molecules. Finally, in the polar pathway, the drugs permeate by means of the skin via polar pores accessible at its surface. This observed flux of drugs across the a variety of layers in the skin is called transdermal drug delivery [15,18,38,39].Figure 3. Schematic representation of distinctive entry pathways for molecules in to the skin.Right after passing by means of the SC and diffusing by way of the viable epidermis and dermis, the drug becomes obtainable for its uptake in to the systemic circulation [5]. Systemic absorptionAntioxidants 2021, 10,six ofdepends on the application internet site, its area, and also the nature from the delivery program. An additional option towards the oral administration of drugs is topical delivery, in which the drug is intended to become absorbed at distinct Aurora A web places of your skin instead of becoming targeted for systemic delivery. Examples of drugs topically delivered towards the skin include things like corticosteroids, antifungals, antivirals, antibiotics, antiseptics, and regional anesthetics [40]. 5. Flavonoids: Relevant Biochemical and Biological Properties In addition to their well-reported sturdy antioxidant activity, flavonoids also exhibit the capability to modulate important cellular signaling pathways and enzymatic reactions involved inside a wide array of pathophysiological events such as cell proliferation, inflammation, immune response, platelet aggregation, and cytotoxicity [415]. Research indicate that the biological properties of flavonoids are helpful in solving or controlling skin problems. The following subsections briefly describe the antioxidant, anti-inflammatory, anticancer, and antibacterial activities of flavonoids, elucidating the molecular targets and mechanism of actions with an effect on skin problems (Table 2).Table 2. Synopsis from the principal molecular targets and mechanisms of action of flavonoids.Flavonoid Catechin, Epigallocatechin Molecular Targets ERK, NF-kB, Rac1, AP-1, p38 Biological Part Mechanisms of Action Inhibition of iNOS expression Reduction of NF-kB and AP-1 activity Inhibition of intercellular adhesion molecule-1 (ICAM-1), VCAM-1, and E-selectin expression Inhibition of prostaglandin synthesis and IL-6 production Inhibition from the upregulation of monocytes adhesion and VCAM-1 expression and NF-kB activity Inhibition of NO production and iNOS protein expression Inhibition of cyclooxygenase and lipoxygenase activities Blood lipid-lowering and cholesterol-lowering agents Ref.Anticarcinogenic[469]HDAC10 site ApigeninAkt, ERK, caspase-12, caspase-3, MAPK, ROS, COX-2, IL-6, TNF-, IL-1, iNOS, PGEAnti-inflammatory, Anticarcinogenic[9,46,47,50,51]LuteolinAkt, ERK, caspase-12, caspase-3, MAPK, ROS, COX-2, IL-6, TNF-, IL-1, iNOS, PGE2 PKC, AP-1, H2 O2 , iNOS, MDA, citrate synthase, MMP-9, MMP-2, COX-2, ERKAnti-inflammatory, anticarcinogenic[9,46,47,50,51]QuercetinAntioxidant, anti-inflammatory[46,47,52]HesperetinGSH reductase, iNOS, 3-nitropropionic acid, COX2, NF-kB, IL-1, TNF-Antioxidant[46,47,52]5.1. Antioxidant Properties Among the best-described properties of flavonoids is their capacity to act as effective antioxidants. In reality, flavonoids have the ability to act a