Nutr Res Pract.  2023 Aug;17(4):641-659. 10.4162/nrp.2023.17.4.641.

Protective effects of red orange (Citrus sinensis [L.] Osbeck [Rutaceae]) extract against UVA-B radiation-induced photoaging in Skh:HR-2 mice

• Kim YH
• Lim CY
• Jung JI
• Kim TY
• Kim EJ

• KMID: 2545182
• DOI: http://doi.org/10.4162/nrp.2023.17.4.641

Abstract

BACKGROUND/OBJECTIVES
The skin is the outermost organ of the human body and plays a protective role against external environmental damages, such as sunlight and pollution, which affect anti-oxidant defenses and skin inflammation, resulting in erythema or skin reddening, immunosuppression, and epidermal DNA damage.
MATERIALS/METHODS
The present study aimed to investigate the potential protective effects of red orange complex H extract (ROC) against ultraviolet (UV)-induced skin photoaging in Skh:HR-2 mice. ROC was orally administered at doses of 20, 40, and 80 mg/ kg/day for 13 weeks, along with UV irradiation of the mice for 10 weeks.
RESULTS
ROC improved UV-induced skin barrier parameters, including erythema, melanin production, transepidermal water loss, elasticity, and wrinkle formation. Notably, ROC inhibited the mRNA expression of pro-inflammatory cytokines (interleukin 6 and tumor necrosis factor α) and melanogenesis. In addition, ROC recovered the UV-induced decrease in the hyaluronic acid and collagen levels by enhancing genes expression. Furthermore, ROC significantly downregulated the protein and mRNA expression of matrix metalloproteinases responsible for collagen degradation. These protective effects of ROC against photoaging are associated with the suppression of UV-induced phosphorylation of c-Jun NH2-terminal kinase and activator protein 1 activation.
CONCLUSIONS
Altogether, our findings suggest that the oral administration of ROC exerts potential protective activities against photoaging in UV-irradiated hairless mice.

Keyword

Skin aging; collagen; erythema; matrix metalloproteinases; hyaluronic acid

Figure

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  Fig. 1 Effect of ROC administration on the MED of the dorsal skin in Skh:HR-2 mice. ROC was administered via oral gavage for 13 weeks. The backs of mice were divided into 6 sections and irradiated with various UVA-B doses (30, 50, 70, 90, 120, and 150 mJ/cm2). After 24-h UVA-B irradiation, the MED was established. Each bar represents the mean ± SEM (n = 5).ROC, red orange complex H extract; MED, minimum erythema dose; UV, ultraviolet; CON, control group; R20, 20 mg/kg body weight/day red orange complex H extract-administered group; R40, 40 mg/kg body weight/day red orange complex H extract-administered group; R80, 80 mg/kg body weight/day red orange complex H extract-administered group.Means without the same letter differ significantly (P < 0.05).

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  Fig. 2 Effect of ROC administration on skin index in UVA-B-irradiated Skh:HR-2 mice. ROC was administered via oral gavage for 13 weeks. After 3-week ROC administration, mice were exposed to UVA-B irradiation 3 times per week for 10 weeks. Various skin indices were estimated using an individual skin analyzer. (A) Erythema index; (B) Melanin index; (C) TEWL; (D) Elasticity index (E2, gross elasticity; E5, net elasticity); and (E) Wrinkle index (R1, total roughness; R2, average roughness; R3, maximum roughness; R4, smoothness depth; R5, arithmetic average roughness). Each bar represents the mean ± SEM (n = 10).ROC, red orange complex H extract; UV, ultraviolet; NOR, normal control group; UV + C, ultraviolet-irradiated control group; UV + R20, ultraviolet-irradiated and 20 mg/kg body weight/day red orange complex H extract administration group; UV + R40, ultraviolet-irradiated and 40 mg/kg body weight/day red orange complex H extract administration group; UV + R80, ultraviolet-irradiated and 80 mg/kg body weight/day red orange complex H extract administration group; TEWL, transepidermal water loss; AU, arbitrary unit.**P < 0.01 and ***P < 0.001 indicate statistically significant differences from the NOR group.Different letters indicate significant differences among the UV + C, UV + R20, UV + R40, and UV + R80 groups (P < 0.05).

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  Fig. 3 Effect of ROC administration on IL-6 and TNF-α levels in the dorsal skin in UVA-B-irradiated Skh:HR-2 mice. ROC was administered via oral gavage for 13 weeks. After 3-week ROC administration, mice were exposed to UVA-B irradiation 3 times per week for ten weeks. Dorsal skin tissues were excised and homogenized. The levels of IL-6 (A) and TNF-α (B) in the skin homogenate were measured using enzyme-linked immunosorbent assay kits. Each bar represents the mean ± SEM (n = 10).ROC, red orange complex H extract; UV, ultraviolet; NOR, normal control group; UV + C, ultraviolet-irradiated control group; UV + R20, ultraviolet-irradiated and 20 mg/kg body weight/day red orange complex H extract administration group; UV + R40, ultraviolet-irradiated and 40 mg/kg body weight/day red orange complex H extract administration group; UV + R80, ultraviolet-irradiated and 80 mg/kg body weight/day red orange complex H extract administration group; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α.***P < 0.001 significantly different from the NOR group.Different letters indicate significant differences among UV + C, UV + R20, UV + R40, and UV + R80 groups (P < 0.05).

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  Fig. 4 Effect of ROC administration on melanin content in the dorsal skin in UVA-B-irradiated Skh:HR-2 mice. ROC was administered via oral gavage for 13 weeks. After 3-week ROC administration, mice were exposed to UVA-B irradiation 3 times per week for ten weeks. (A) Dorsal skin sections were stained with Fontana-Masson’s silver stain. Representative images of staining are presented. Scale bar, 50 μm. (B) Melanin content in the dorsal skin. Each bar represents the mean ± SEM (n = 10).ROC, red orange complex H extract; UV, ultraviolet; NOR, normal control group; UV + C, ultraviolet-irradiated control group; UV + R20, ultraviolet-irradiated and 20 mg/kg body weight/day red orange complex H extract administration group; UV + R40, ultraviolet-irradiated and 40 mg/kg body weight/day red orange complex H extract administration group; UV + R80, ultraviolet-irradiated and 80 mg/kg body weight/day red orange complex H extract administration group.***P < 0.001 indicates statistically significant differences from the NOR group.Different letters indicate significant differences among UV + C, UV + R20, UV + R40, and UV + R80 groups (P < 0.05).

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  Fig. 5 Effect of ROC administration on HA synthesis in the dorsal skin in UVA-B-irradiated Skh:HR-2 mice. ROC was administered via oral gavage for 13 weeks. After 3-week ROC administration, mice were exposed to UVA-B irradiation 3 times per week for 10 weeks. (A) Dorsal skin tissues were excised and homogenized. HA levels in the skin homogenate were measured using enzyme-linked immunosorbent assay kits. (B-D) Total RNA in the dorsal skin tissues was extracted and reverse-transcribed, and real-time polymerase chain reaction was conducted. The expression of each mRNA was normalized to that of Gapdh and is represented relative to that of the NOR group. Each bar represents the mean ± SEM (n = 10).ROC, red orange complex H extract; HA, hyaluronic acid; UV, ultraviolet; NOR, normal control group; UV + C, UV-irradiated control group; UV + R20, UV-irradiated and 20 mg/kg body weight/day red orange complex H extract administration group; UV + R40, UV-irradiated and 40 mg/kg body weight/day red orange complex H extract administration group; UV + R80, UV-irradiated and 80 mg/kg body weight/day red orange complex H extract administration group; Has, hyaluronic acid synthase; Hyal, hyaluronidase; Aqp3, aquaporin 3; Gapdh, glyceraldehyde 3-phosphate dehydrogenase.*P < 0.05, **P < 0.01, and ***P < 0.001 indicate statistically significant differences from the NOR group.Different letters indicate significant differences among UV + C, UV + R20, UV + R40, and UV + R80 groups (P < 0.05).

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  Fig. 6 Effect of ROC administration on collagen synthesis in the dorsal skin in UVA-B-irradiated Skh:HR-2 mice. ROC was administered via oral gavage for 13 weeks. After 3-week ROC administration, mice were exposed to UVA-B irradiation 3 times per week for ten weeks. (A) Dorsal skin sections were stained with collagen 1 antibody. Representative immunofluorescence staining images are displayed. Scale bar, 50 μm. (B) Dorsal skin tissues were excised and homogenized. The levels of collagen in skin homogenates were measured using hyaluronic acid enzyme-linked immunosorbent assay kits. (C) Total RNA in the dorsal skin tissues was extracted, reverse-transcribed, and subjected to real-time polymerase chain reaction. The expression of each mRNA was normalized to that of Gapdh and is represented relative to that of the NOR group. Each bar represents the mean ± SEM (n = 10).ROC, red orange complex H extract; UV, ultraviolet; NOR, normal control group; UV + C, ultraviolet-irradiated control group; UV + R20, ultraviolet-irradiated and 20 mg/kg body weight/day red orange complex H extract administration group; UV + R40, ultraviolet-irradiated and 40 mg/kg body weight/day red orange complex H extract administration group; UV + R80, ultraviolet-irradiated and 80 mg/kg body weight/day red orange complex H extract administration group; Col1a1, collagen type 1 alpha 1 chain; Col3a1, collagen type 3 alpha 1 chain; Col4a1, collagen type 4 alpha 1 chain; Col7a1, collagen type 7 alpha 1 chain; Gapdh, glyceraldehyde 3-phosphate dehydrogenase.*P < 0.05, significantly different from the NOR group.Different letters indicate significant differences among UV + C, UV + R20, UV + R40, and UV + R80 groups (P < 0.05).

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  Fig. 7 Effect of ROC administration on MMP-2 and MMP-13 expression in the dorsal skin in UVA-B-irradiated Skh:HR-2 mice. ROC was administered via oral gavage for 13 weeks. After 3-week ROC administration, mice were exposed to UVA-B irradiation 3 times per week for ten weeks. (A) Total lysates of dorsal skin tissues were prepared and analyzed using Western blotting with the indicated antibodies. Images of Western blots representative of 3 independent experiments are displayed. (B) Quantitative analysis of Western blot results. The protein abundance was normalized to β-actin and expressed relative to that of the NOR group. (C) Total RNA in the dorsal skin tissues was extracted, reverse-transcribed, and subjected to real-time polymerase chain reaction. The expression of each mRNA was normalized to that of Gapdh and is represented relative to that of the NOR group. Each bar represents the mean ± SEM (n = 10).ROC, red orange complex H extract; UV, ultraviolet; NOR, normal control group; UV + C, ultraviolet-irradiated control group; UV + R20, ultraviolet-irradiated and 20 mg/kg body weight/day ROC administration group; UV + R40, ultraviolet-irradiated and 40 mg/kg body weight/day ROC administration group; UV + R80, ultraviolet-irradiated and 80 mg/kg body weight/day ROC administration group; MMP, matrix metallopeptidase; Gapdh, glyceraldehyde 3-phosphate dehydrogenase.*P < 0.05, **P < 0.01, ***P < 0.001 significantly different from the NOR group.Different letters indicate significant differences among UV + C, UV + R20, UV + R40, and UV + R80 groups (P < 0.05).

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  Fig. 8 Effect of ROC administration on JNK signaling pathway in the dorsal skin in UVA-B-irradiated Skh:HR-2 mice. ROC was administered via oral gavage for 13 weeks. After 3-week ROC administration, mice were exposed to UVA-B irradiation 3 times per week for ten weeks. (A) Total lysates of dorsal skin tissues were prepared and analyzed using Western blotting with the indicated antibodies. Images of Western blots representative of 3 independent experiments are displayed. (B) Quantitative analysis of Western blot results. The protein abundance was normalized to β-actin and expressed relative to that of the NOR group. (C) Nuclear protein from dorsal skin tissues was extracted, and the AP-1 content in the nuclear protein was measured. Each bar represents the mean ± SEM (n = 10).ROC, red orange complex H extract; UV, ultraviolet; NOR, normal control group; UV + C, ultraviolet-irradiated control group; UV + R20, ultraviolet-irradiated and 20 mg/kg body weight/day red orange complex H extract administration group; UV + R40, ultraviolet-irradiated and 40 mg/kg body weight/day red orange complex H extract administration group; UV + R80, ultraviolet-irradiated and 80 mg/kg body weight/day red orange complex H extract administration group; p-JNK, phospho c-Jun NH2-terminal kinase; JNK, c-Jun NH2-terminal kinase; AP-1, activator protein 1.*P < 0.05, **P < 0.01 statistically significant differences from the NOR group.Different letters indicate significant differences among UV + C, UV + R20, UV + R40, and UV + R80 groups (P < 0.05).

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  Fig. 9 Summary of the effects of the ROC on the photoaging.UV, ultraviolet; ROS, reactive oxygen species; ROC, red orange complex H extract; JNK, c-Jun NH2-terminal kinase; ERK1/2, extracellular signal-regulated kinase 1/2; AP-1, activator protein 1; MMP, matrix metalloproteinases; COL1a1, collagen type 1 alpha 1 chain; COL3a1, collagen type 3 alpha 1 chain; COL4a1, collagen type 4 alpha 1 chain; COL7a1, collagen type 7 alpha 1 chain; HYAL1, hyaluronidase 1; HAS, hyaluronic acid synthase; NF-κB, nuclear factor-κB; IL-6, interleukin 6; TNF-α, tumor necrosis factor α.

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