Protective effects of Oxya chinensis sinuosa Mishchenko against ultraviolet B-induced photodamage in hairless mice

The process of skin aging can be classified as intrinsic or extrinsic aging [1]. Intrinsic aging is a natural process induced by metabolic, hormonal, and internal genetic factors, while extrinsic aging is induced by sun exposure, smoking, and environmental factors. Extrinsic aging induced by ultraviolet B (UVB) radiation causes skin alterations, including epidermal thickness, wrinkle formation, and matrix macromolecule degradation [2]. UVB irradiation qualitatively alters extracellular matrix (ECM) proteins, leading to collagen degradation induced by the upregulation of matrix metalloproteinases (MMPs) expression, and pro-collagen synthesis inhibition [3]. MMPs, which are known to play an important role in inflammation, cancer metastasis, and skin aging are enzymes that degrade skin ECM [4].

Skin dehydration is also involved in skin aging, and the principal skin moisture molecule hyaluronic acid (HA), also called hyaluronan or hyaluronate, is able to bind to and retain water molecules [5]. While skin moisture maintenance is essentially dependent on the stratum granulosum, HA binding with water is critically important in skin hydration retention in the dermis and the vital epidermis [6]. Also, the most widely used skin barrier function determination index is transepidermal water loss (TEWL) [7]. Thus, skin hydration maintenance is important in skin aging prevention.

Skin wrinkles are induced by skin elasticity reduction due to elastic fiber tortuosity and collagen fiber degradation [8]. UVB irradiation is known to increase the production of MMPs, thereby degrading the ECM and increasing wrinkles [9]. Reactive oxygen species (ROS) induces the secretion of MMPs from skin fibroblasts and keratinocytes, leading to collagen synthesis impairment, collagen and ECM proteins degradation, wrinkle formation, and skin photoaging [10]. The increased expression of MMP-1 due to increased mitogen-activated protein kinases (MAPKs) expression destroys skin tissue collagen matrix, thereby reducing skin elasticity and causing wrinkles [11].

UVB irradiation induces an increase in skin damage and inflammation, owing to the secretion of various cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α, which are cell-produced immune regulators [12]. Also, UVB-induced cell damage activates ROS-sensitive signaling molecules and pathways such as inflammatory cytokines and the MAPKs pathway [13], and increased ROS expression induced by UVB, causes inflammatory responses that promote skin aging.

Because of the increased concerns regarding global exhaustion of food supplies, due to the growing world population, insects have markedly attracted the interest of nutritional and toxicological fields [14]. Due to the increased need to identify and develop additional food and feed resources, owing to growing world population and the decreasing availability of arable land, insects are considered to be an important potential food source [15]. Thus, edible insects can serve as an excellent source of proteins and other nutrients. However, the possibility that the consumption of these edible insects could influence the human microbiome, due to the intake of the relatively understudied fiber source chitin, should also be considered [16]. Traditionally in Korea, Oxya chinensis sinuosa Mishchenko (Oc), belonging to the phylum Arthropoda (Order, 54 Orthoptera; Family, Acrididae; Subfamily, Oxyinae), is well known as the “famine relief insect” and was recently registered as a food in the Korean Food Standards Codex of the Ministry of Food & Drug Safety (MFDS) [17], and traditionally, it has been used to treat asthma, bronchitis, cough, whooping cough, paralysis, and seizures [18]. Although there is little information on treatment for various diseases, recent studies reported antiplatelet, antimicrobial effects of Oc [17, 18]. Moreover, our previous study showed its hepatoprotective effects in animal model of nonalcoholic fatty liver disease [19]. However, its ameliorating effects on photodamage and photoaging remains unclear. Thus, in this study, the potential protective effect of its ethanol extract (Oc.Ex) against UVB-induced skin damage was investigated.

Photoaging skin exhibits distinct alterations, including coarse and deep wrinkle formation, thickened and leathery appearance, and irregular pigmentation [20], and these morphological alterations are often induced by chronic UVB irradiation [21]. Skin exposure to UVB, a minor but highly carcinogenic component of sunlight, induces several biological responses, including inflammation, systemic immunosuppression, erythema, hyperpigmentation, hyperplasia, and skin cancer [22].

Chronic exposure to UVB results in skin aging, which causes wrinkle formation, acute erythema, and loss of hydration and elasticity [23]. The index widely used to evaluate skin barrier integrity is TEWL and skin capacitance [24]. A low TEWL and a high capacitance are associated with skin barrier integrity, whereas the contrary indicates barrier disruption [25]. HA plays important roles in healthy skin by regulating epithelial cell phenotype, and it regulates general skin functions, including water retention, turgidity, elasticity, and nutrient diffusion [26]. Also, TGF-β critically regulates collagen homeostasis through pro-collagen I and III stimulation, and MMP-1 transcription inhibition [27]. This study demonstrated that a high TEWL value and low capacitance value were associated with UVB-irradiated skin, whereas Oc. Ex administration improved skin barrier function and restored the UVB irradiation-induced decrease in the expression of HA, TGF-β, and pro-collagen.

The distinctive features of photoaging are collagen degradation and abnormal elastin accumulation in the superficial dermis, and a number of MMPs are reported to be involved in these processes [28]. Exposure to UV radiation frequently aggravates wrinkle formation, skin pigmentation, and stimulates the expression and activation of MMPs, which are well known to play a leading role in the damage of skin connective tissues, due to collagen degradation and collagen synthesis inhibition [29]. Consistent with these previous studies, this study revealed that Oc. Ex treatment remarkably suppressed the expression of MMP-1 and MMP-9.

UV-induced oxidative stress upregulates ROS production by counteracting the activities of endogenous antioxidants, including SOD, CAT, and glutathione (GSH), which neutralize ROS before cell changes in oxidative production [30]. Skin oxidative stress is closely associated with UV irradiation-induced skin damage, and SOD and CAT are critical enzymes in oxidative stress [31]. Likewise, this study revealed that the antioxidant activity of skin tissue exposed to UVB irradiation can be determined by estimating SOD and CAT levels.

UV-induced ROS causes the oxidative damage of DNA, proteins, and cell membrane lipids in the exposed cells, and increases the expression of collagen, elastin, and HA degrading enzymes [32]. ROS production initiates UVB-induced photoaging, and activates a number of receptors such as IL-1, TNF-α, and keratinocyte growth factor, in epidermal keratinocytes [33]. In the present study, Oc. Ex treatment reduced the mRNA expression levels of IL-1β, IL-6, and TNF-α in the skin of UVB-irradiated hairless mice, establishing its inhibitory effect on the increased production of UVB-induced pro-inflammatory cytokines.

Finally, this study demonstrated the involvement of MAPKs in the antioxidant effect of Oc. Ex against UVB-induced oxidative stress. The MAPKs pathway, which includes molecules such as MEK, ERK, p38, and JNK, is upregulated by the response to extracellular stimuli such as UV irradiation [34]. To elucidate the pathway by which Oc. Ex mediates its photoprotective effect, its effects on the ERK, MEK, p38, and JNK MAPKs pathways were evaluated.

To conclude, this study reports the photoprotective effect of Oc. Ex against skin damage, using UVB-induced hairless mice. It revealed that Oc. Ex inhibited UVB-induced skin thickening and wrinkle formation, and increased skin hydration factors and antioxidant enzymes in hairless mice. Further, Oc. Ex treatment attenuated UVB-induced MMPs, pro-inflammatory cytokines, and MAPK phosphorylation, suggesting that it prevents UVB-induced skin damage and photoaging.