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. 2013 Sep 16;8(9):e73877.
doi: 10.1371/journal.pone.0073877. eCollection 2013.

Anti-wrinkle and anti-inflammatory effects of active garlic components and the inhibition of MMPs via NF-κB signaling

So Ra Kim  1 , Yu Ri Jung, Hye Jin An, Dae Hyun Kim, Eun Ji Jang, Yeon Ja Choi, Kyoung Mi Moon, Min Hi Park, Chan Hum Park, Ki Wung Chung, Ha Ram Bae, Yung Whan Choi, Nam Deuk Kim, Hae Young Chung
Affiliations

Anti-wrinkle and anti-inflammatory effects of active garlic components and the inhibition of MMPs via NF-κB signaling

So Ra Kim et al. PLoS One. .

Abstract

Skin aging is a multisystem degenerative process caused by several factors, such as, UV irradiation, stress, and smoke. Furthermore, wrinkle formation is a striking feature of photoaging and is associated with oxidative stress and inflammatory response. In the present study, we investigated whether caffeic acid, S-allyl cysteine, and uracil, which were isolated from garlic, modulate UVB-induced wrinkle formation and effect the expression of matrix-metalloproteinase (MMP) and NF-κB signaling. The results obtained showed that all three compounds significantly inhibited the degradation of type І procollagen and the expressions of MMPs in vivo and attenuated the histological collagen fiber disorder and oxidative stress in vivo. Furthermore, caffeic acid and S-allyl cysteine were found to decrease oxidative stress and inflammation by modulating the activities of NF-κB and AP-1, and uracil exhibited an indirect anti-oxidant effect by suppressing cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expressions levels and downregulating transcriptional factors. These results suggest that the anti-wrinkle effects of caffeic acid, S-allyl cysteine, and uracil are due to anti-oxidant and/or anti-inflammatory effects. Summarizing, caffeic acid, S-allyl cysteine, and uracil inhibited UVB-induced wrinkle formation by modulating MMP via NF-κB signaling.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Structures of active the three garlic compounds.
(A) caffeic acid, (B) S-allyl cysteine, (C) uracil.
Figure 2
Figure 2. Active compounds from garlic decreased wrinkle depth in hairless mice.
(A) Representative images of skin replicas showing that the histological formation of wrinkles was reduced by the three garlic compounds as compared with UVB-treated animals, (B) wrinkle area (%), (C) wrinkle length, and (D) wrinkle depth.
Figure 3
Figure 3. Histopathological analyses of collagen in hairless mouse skin tissues.
Skin samples were processed and stained with Masson’s Trichrome as described in Materials and Methods. Collagen staining appears blue (original magnification × 200). (A) control, (B) UVB 150 mJ/cm2, (C) pretreated with CA 5µM 2hr before UVB exposure, (D) pretreated with CA 20µM 2hr before UVB exposure, (E) pretreated with SAC 5µM 2hr before UVB exposure, (F) pretreated with SAC 20µM 2hr before UVB exposure, (G) pretreated with uracil 5µM 2hr before UVB exposure, (H) pretreated with uracil 20µM 2hr before UVB exposure; CA, caffeic acid; SAC, S-allyl cysteine; UVB, ultraviolet B.
Figure 4
Figure 4. Effects of the three garlic compounds on type І procollagen level by UVB in hairless mice.
(A) Western blotting was performed to detect cytoplasmic extracts of UVB-irradiated hairless mouse skin. (B) Blots were quantified by densitometry as percentages of control. One-factor ANOVA were used to determine significance: *p<0.05 vs. control. CA, caffeic acid; SAC, S-allyl cysteine, UVB, ultraviolet B.
Figure 5
Figure 5. Modulation of MMP expression in mice by the three garlic compounds.
(A) Western blot analysis was performed to detect MMP3, MMP9, MMP12, and TIMP4 protein levels in cytosolic extract of the skins of from hairless mice. (B) Blots were quantified by densitometry as percentages of the control. One-factor ANOVA was used to determine significance: # p<0.05 vs. control, *p<0.05 vs. the UVB-irradiated group; CA, caffeic acid; MMP, matrix metalloproteinase; SAC, S-allyl cysteine; TIMP4, tissue inhibitor of metalloprotease4; UVB, ultraviolet B.
Figure 6
Figure 6. Changes in the activities of nuclear NF-κB and AP-1 caused by three compounds in UVB-irradiated hairless mice.
(A) Western blotting was performed to determine nuclear p50, p-p65, Ac-p65, p65, cFOS, and p-cJun protein levels in nuclear extracts of the skins of UVB-irradiated hairless mice. The protein levels of NF-κB family members and of AP-1 component increased after UVB irradiation, but these increases were reduced by all three compounds. (B) Blots were quantified by densitometry as percentages of the control. One-factor ANOVA was used to determine significance: # # # p < 0.001 vs. control, *p<0.05, **p < 0.01 and ***p < 0.001 vs. UVB-irradiated group respectively. AP-1, activator protein 1; UVB, ultraviolet B.
Figure 7
Figure 7. Inhibition of the expressions of NF-κB-dependant genes by the three garlic compounds.
(A) To determine the effect of UVB on the expressions of NF-κB dependent genes, we examined the expressions of COX-2 and iNOS in vivo. (B) Blots were quantified by densitometry as percentages of the control. One-factor ANOVA was used to determine significance: # # # p < 0.001 vs. control, *p<0.05, **p < 0.01 and ***p < 0.001 vs. UVB-irradiated group.
Figure 8
Figure 8. Modulation of the NF-κB signaling pathway the three compounds.
Western blotting was performed on cytoplasmic extracts from UVB-irradiated hairless mice. (A) (B) Phosphorylations of NIK, Akt and IKK were quantified as p-NIK, p-Akt, and p-IKKα/β, respectively, and MAPK phosphorylation was detected using antibodies for p-ERK, p-p38 and p-JNK. ERK (extracellular regulated signal kinase) in UVB-irradiated hairless mouse skin, (C) Western blotting was performed to quantify p-ERK, p-p38, and p-JNK protein levels in UVB-irradiated hairless mice skin; JNK, c-Jun N-terminal kinases; NF-κB, nuclear factor-kappa B; NIK, NF-κB-inducing kinase; IKK, IκB kinase; COX-2, cyclooxygenase-2; UVB, ultraviolet B.
Figure 9
Figure 9. Effects of the three compounds on intracellular ROS/ONOO¯ in UVB-irradiated hairless mice.
(A) (B) ROS and ONOO¯ generations by UVB in hairless mouse skins were decreased concentration-dependently by pretreating animals with each of the three compounds. Results are expressed as means±SEs of three determinations. Significance was determined using one-factor ANOVA: # # # p < 0.001, # # p < 0.01 vs. control; *p < 0.05, **p < 0.01 and ***p < 0.001 vs. UVB-irradiated group; CA, caffeic acid; COX-2, cyclooxygenase-2; iNOS, inducible nitric oxide synthase; MMP1, matrix metalloproteinase1; MMP3, metalloproteinase3; MMP9, metalloproteinase9; MMP13, matrix metalloproteinase13; ONOO¯, peroxynitrite; ROS, reactive oxygen species ; UVB, ultraviolet B.
Figure 10
Figure 10. Possible mechanism of active three garlic compounds about effects on anti-wrinkle.
COX-2, cyclooxygenase-2; iNOS, inducible nitric oxide synthase; MMP1, matrix metalloproteinase1; MMP3, metalloproteinase3; MMP9, metalloproteinase9; MMP13, matrix metalloproteinase13; UVB, ultra violet B.
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Grants and funding

This work was carried out with the support of the “Cooperative Research Program for Agriculture Science & Technology Development (Project No. PJ00652213)” Rural Development Administration, Republic of Korea. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.