The Effects of Panduratin A Isolated from Kaempferia pandurata on the Expression of Matrix Metalloproteinase-1 and Type-1 Procollagen in Human Skin Fibroblasts

• Abstract
• Abbreviations
• Introduction
• Materials and Methods
• Plant material
• Extraction and isolation
• Instrumentation
• Cell culture and cell viability
• UV irradiation
• Western blot analysis
• Reverse-transcriptase PCR
• Detection of reactive oxygen species production
• Statistics
• Results
• Discussion
• Acknowledgements
• References

Abstract

Exposure of ultraviolet (UV) light on the skin induces photoaging associated with up-regulated matrix metalloproteinase (MMP) activities and decreased collagen synthesis. We investigated the effects of panduratin A isolated from Kaempferia pandurata Roxb. on the expression of matrix metalloproteinase-1 (MMP-1) and type-1 procollagen in UV-irradiated human skin fibroblasts. Cultured human fibroblasts were irradiated with UV (20 mJ/cm²) and panduratin A was added into the medium of the fibroblast culture. The expressions of MMP-1 and type-1 procollagen levels were measured using Western blot analysis and RT-RCR. Panduratin A in the range of 0.001 - 0.1 μM significantly reduced the expression of MMP-1 and induced the expression of type-1 procollagen at the protein and mRNA gene levels. Panduratin A showed stronger activity than epigallocatechin 3-O-gallate (EGCG) known as a natural anti-aging agent. The results suggest that panduratin A can be a potential candidate for the prevention and treatment of skin aging brought about by UV.

Abbreviations

UV:ultraviolet

MMP:matrix metalloproteinase

ROS:reactive oxygen species

DCFH-DA:2′,7′-dichlorofluorescein-diacetate

EGCG:epigallocatechin 3-O-gallate

RT-PCR:reverse transcriptase-polymerasechain reaction

Introduction

The skin aging process can be divided into intrinsic aging and photoaging. Damage to human skin due to repeated exposure to ultraviolet (UV) radiation (photoaging) and damage occurring as a result of the passage of time (intrinsic aging) are considered to be distinct entities rather than similar skin aging processes [1]. UV irradiation leads to direct or indirect DNA damage, formation of reactive oxygen species (ROS), and the associated inflammatory response and damage to the extracellular matrix integrity [2]. UV irradiation induces the synthesis of MMPs in fibroblasts, and up-regulation of some MMPs is responsible for the enhanced degradation of dermal collagen during UV-induced skin aging [3].

The matrix metalloproteinases (MMPs) are synthesized by a variety of cell types and most of them are secreted from cells as latent forms (proMMPs). Activation of proMMPs is primarily brought about by the action of proteolytic cascades, mainly catalysed by neutral proteinases [4]. MMPs are a family of structurally related matrix-degrading enzymes that play important roles in various destructive processes, including inflammation, tumor invasion and skin aging [5]. Moreover, the expression of various UV-induced MMPs in dermal fibroblasts leads to the breakdown of collagen and other extracellular matrix proteins and is thus related to photoaging in human skin [6]. The most abundant structural protein in skin connective tissue is type-1 collagen, which is responsible for conferring strength and resiliency. Aging of the skin is primarily related to reductions in the levels of type-1 collagen, which is the principal component of skin dermis. Type-1 collagen is the main structural component of the extracellular matrix (ECM), which is known to perform a pivotal function in the maintenance of the structure of the skin dermis [7].

Kaempferia pandurata Roxb. is a perennial herb of the Zingiberaceae family mainly cultivated in tropical countries, including Indonesia and Thailand. The fresh rhizome has been used as a food material and also as a folk medicine for the treatment of colic disorder, aphrodisiac, dry cough, rheumatism and muscular pains [8]. Several studies showed various biological activities of K. pandurata, including anti-inflammatory, antitumor, antidiarrhea, antidysentery, antiflatulence and antiepidermophytid effects [9], [10]. It has been reported that the rhizomes of K. pandurata contain essential oil, pinostrobin, cardamonin, boesenbergin, 5, 7-dimethoxyflavone, 1,8-cineole, panduratin A, and others [11]. Panduratin A ([Fig. 1]) isolated from K. pandurata showed anticancer, antioxidative, antimutagenic and antibacterial activities [12], [13], [14], [15], [16], [17], [18]. However, its anti-aging effect has not yet been examined. In this study, we investigated the effect of panduratin A on the expression of MMP-1 and type-1 procollagen in UV-irradiated human skin fibroblasts.

Materials and Methods

Plant material

Dried rhizomes of Kaempferia pandurata Roxb. were collected in Jakarta, Indonesia, and identified by Dr. Baek N. I., Department of Oriental Medicinal Materials and Processing, Kyunghee University (Yongin, Korea). A voucher specimen (H082) is deposited in the Department of Biotechnology, Yonsei University (Seoul, Korea).

Extraction and isolation

The ground Kaempferia pandurata Roxb. (100 g) was extracted with 95 % ethanol (400 mL), and the extract (11.95 g) was further fractionated with ethyl acetate (2 × 200 mL). The ethyl acetate fraction was applied to a silica gel column (5 × 45 cm, 650 g of silica gel; 70 - 230 mesh; Merck & Co.) and eluted with n-hexane-chloroform-ethyl acetate 15 : 5 : 1.5 (2 L, v/v/v) to give seven fractions (fraction 1 to fraction 7). Fraction 3 (0.9 L - 1 L, 1.51 g) was further separated with n-hexane-ethyl acetate-methanol 18 : 2:1 (1.5 L, v/v/v), yielding fraction 3-B (1.1 g). Fraction 3-B was eluted with 100 % methanol (0.8 - 0.9 mL) using recycling preparative HPLC [(JAIGEL W-252 column, 20.0 mm i. d. × 500 mm L; Japan Analytical Industry Co., Ltd.); detection by UV absorption at 365 nm; mobile phase used was 100 % MeOH; flow rate 3 mL/min] and compound 3-B (300 × 400 mL, 0.9 g) was finally obtained as a single compound. Careful comparison of several spectral data of compound 3-B including ¹³C-NMR, ¹H-NMR, ¹³C-DEPT, ¹H-¹H COSY, ¹H-¹³C HSQC, ¹H-¹³C HMBC and FAB-MS with those in the literature [13], [19] suggested the chemical structure to be panduratin A (98 %, [Fig. 1]) or (4-methoxy-2,6-dihydroxyphenyl)-[3′-methyl-2′-(3″-methybut-2″-enyl)-6′-phenylcyclohex-3′-enyl]methanone. Optical rotation was measured with a Perkin-Elmer 241 polarimeter as [α]: + 0.0066 (c 0.1, CHCl₃).

Instrumentation

NMR spectra were recorded on a Bruker Avance-600 spectrometer at 600 MHz for ¹H and ¹³C in CDCl₃ with TMS as an internal standard. Complete proton and carbon assignments were based on 1 D (¹H, ¹³C, ¹³C-DEPT) and 2 D (¹H-¹H COSY, ¹H-¹³C HSQC, ¹H-¹³C HMBC) NMR experiments. Mass spectra (FAB-MS) were measured using a JMS-700 (JEOL Ltd.). All instrumental data are available upon request.

Cell culture and cell viability

Human skin fibroblast cells (CCD-986sk) were purchased from the American Type Culture Collection (ATCC). Cells were cultured in Dulbeccos’s modified Eagle’s medium (DMEM; Gibco) supplemented with antibiotics (100 U/mL of penicillin A and 100 U/mL of streptomycin) and 10 % heat-inactivated fetal bovine serum (Gibco). Cells were maintained at 37 °C in a humidified incubator containing 5 % CO₂. The tetrazolium dye colorimetric test (MTT test) was used to determine the viability of fibroblast cells [20]. The MTT assay is based on the ability of functional mitochondria to catalyse the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide to insoluble formazan, the concentration of which can be measured spectrophotometrically.

UV irradiation

The fibroblast cells were grown in 6-cm culture dishes (SPL) and subsequently the medium was replaced by 2 mL of phosphate-buffered saline. Then, the cells were exposed to UV (20 mJ/cm²) light. After irradiation, the cells were washed with phosphate-buffered saline and cultured for 48 h in the serum-free media with or without samples. The same conditions without UV irradiation were used for the control group. A green tea polyphenol, epigallocatechin 3-O-gallate (EGCG; >95 %, Sigma-Aldrich Co.), was also included in this study as a positive control.

Western blot analysis

Fibroblast-conditioned medium was collected and protein concentrations were then determined with protein assay reagents (Bio-Rad Laboratories Inc.). For the Western blotting, equal amount of proteins were boiled for 3 min and chilled on ice, subjected to 10 % sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and electrophoretically transferred to a nitrocellulose membrane (Amersham International). The membranes were blocked with 5 % powdered skim milk in a saline buffer. MMP-1 and type-1 procollagen were detected with the monoclonal anti-MMP-1 antibody (Calbiochem) and polyclonal anti-procollagen type-1 antibody (Santa Cruz Biotechnology Inc.) diluted 1 : 1000 and 1 : 500 in the blocking buffer, respectively, then incubated with the secondary antibody horseradish peroxidase-conjugated anti-mouse IgG antibody at a 1 : 1000 dilution and anti-goat IgG antibody at a 1 : 500 dilution, respectively. Blotted antibody was visualized by a chemiluminescence (ECL) detection system (Amersham International). The densities of bands were measured by RFLPscan version 2.1 software program (Scanalytics Inc.).

Reverse-transcriptase PCR

Total RNA was isolated with Trizol reagent (Invitrogen) from human skin fibroblast cells. The oligonucleotide primers of MMP-1, type-1 procollagen and GAPDH target genes were designed using a PCR primer selection program at the website of the Virtual Genomic Center from the GenBank database. The reaction solution (25 μL final volume) contained 0.5 μL of AMV reverse transcriptase (5 Units), 12.5 μL of AccessQuick™ RT-PCR System Master Mix (2X) (Promega) and 100 pM of each primer. The total RNA was reverse-transcribed and amplified according to the manufacturer’s instructions with a thermal cycler (Perkin-Elmer PCR Thermal Cycler, Perkin-Elmer). PCR consisted of 25 amplification cycles (94 °C, 30 sec; 50 °C, 1 min; 72 °C, 1 min) for MMP-1 and 28 amplification cycles (94 °C, 30 sec; 60 °C, 1 min; 72 °C, 1 min) for type-1 procollagen using the oligonucleotide primer sets detailed in [Table 1]. In parallel, the GAPDH house-keeping gene was amplified in each RNA sample. Reaction products were electrophoresed in 1 % agarose gels and visualized with ethidium bromide.

Detection of reactive oxygen species production

Fibroblast cells were pretreated with the indicated concentrations of panduratin A for 24 h, washed with PBS, and stained with 50 μM of 2′,7′-dichlorofluorescein diacetate (DCFH-DA; Sigma-Aldrich Co.) for 30 min. The cells were then irradiated with UV (20 mJ/cm²) and analysed using FACScan flow cytometer (FACStar; Becton-Dickinson). EGCG was used as a positive control.

Statistics

Each experiment was performed at least in triplicate. All data are presented as the mean ± standard deviation (SD). The data analysis was performed using one-way analysis of variance (ANOVA). The difference between treated and control groups were also analysed by the Duncan test (SPSS 12.0). *p-values < 0.05 were considered statistically significant.

Results

To examine UV-induced MMP-1 expression and type-1 procollagen expression in cultured fibroblasts, cells were exposed with 0 - 30 mJ/cm² of UV irradiation. Because cell viability was more than 90 % up to 20 mJ/cm² (data not shown), cells were exposed to 20 mJ/cm² and further incubated for 48 h in the presence of K. pandurata extract and panduratin A. Since K. pandurata extract (0.01 - 0.5 μg/mL) significantly reduced the expression of MMP-1 and induced the expression of type-1 procollagen at the protein and mRNA levels in a dose-dependent manner (data not shown), further purification was performed to isolate panduratin A as a bioactive compound. To investigate the effect of panduratin A on the expression of MMP-1 protein levels in human skin fibroblasts, we exposed cultured fibroblast cells to 20 mJ/cm² and MMP-1 expression levels at 48 h were determined in the culture media by Western blot analysis as shown in [Fig. 2]. Treatment with panduratin A inhibited UV-induced MMP-1 expressions by 47 % at 0.001 μM, 69 % at 0.01 μM and 87 % at 0.1 μM compared to the UV-irradiated control. Epigallocatechin 3-O-gallate (EGCG), well-known as a natural anti-aging agent [21], was used as a positive control and it inhibited MMP-1 expression by 56 % at 0.1 μM. The results demonstrated that inhibitory effect of panduratin A on MMP-1 expression was higher than that of EGCG at the same concentration.

A reverse transcription-polymerase chain reaction (RT-PCR) was performed to determine how panduratin A affected MMP-1 gene expression. Panduratin A decreased the expression of MMP-1 at the mRNA gene levels in a dose-dependent manner ([Fig. 3]). Treatment with panduratin A inhibited UV-induced MMP-1 mRNA expressions by 5 % at 0.001 μM, 29 % at 0.01 μM and 35 % at 0.1 μM compared with the UV-irradiated control. Panduratin A showed higher activity than 25 % of EGCG at 0.1 μM in the mRNA gene levels.

To investigate whether panduratin A inhibits UV-induced MMP-1 expression via an antioxidant effect, total intracellular ROS levels were measured after panduratin A treatment. As shown in [Fig. 4], UV irradiation markedly increased ROS generation compared with the control, however, panduratin A treatment inhibited UV-induced intracellular ROS levels compared with the UV-irradiated control at a concentration of 0.1 μM, showing better activity than EGCG.

UV-irradiated skin fibroblast cells were treated with 0.001 - 0.1 μM of panduratin A for 48 h, and the type-1 procollagen protein expression levels were determined in the culture media by Western blot analysis. As shown in [Fig. 5], treatment with panduratin A increased the type-1 procollagen protein expression levels by 48 % at 0.001 μM, 66 % at 0.01 μM and 74 % at 0.1 μM compared with the UV-irradiated control, respectively, which was higher than 69 % for EGCG at 0.1 μM.

The level of type-1 procollagen mRNA was analysed by RT-PCR to determine the regulatory activity mechanism of type-1 procollagen production by panduratin A in UV-irradiated skin fibroblast cells. As shown in [Fig. 6], treatment with panduratin A increased the type-1 procollagen mRNA gene levels by 12 % at 0.001 μM, 41 % at 0.01 μM and 45 % at 0.1 μM compared to the UV-irradiated control, respectively, which was higher than 35 % for EGCG at 0.1 μM.

Discussion

Panduratin A isolated from Kaempferia pandurata is a cyclohexenyl-chalcone compound. Chalcones, belonging to the flavonoid family, are natural products possessing a variety of biological properties such as anti-inflammatory, analgesic, anti-cancer, hepatoprotective and anti-oxidant activities [22]. It was reported that chalcones are potential inhibitors of melanin formation in human melanocyte cells [23]. However, its anti-aging effect on the expression of MMP-1 and type-1 procollagen caused by UV irradiation has not yet been examined to date.

MMPs play a key role in the pathophysiological mechanism of photoaging. A major mechanism by which UV irradiation causes detrimental changes to skin connective tissue is via induction of MMPs [24]. Since collagens are responsible for the strength and resiliency of skin, their disarrangement during photoaging causes the skin to appear aged [25]. Therefore, natural compounds from medicinal plants that can decrease the level of MMPs production and increase the level of procollagen synthesis have been the main focus of recent research. For examples, some flavonoid compounds, such as naringenin, apigenin, wogonin, kaempferol, quercetin were reported to regulate the MMP-1 and type-1 procollagen expression levels [26]. However, these natural compounds were usually examined at high concentrations and had little effect on MMP-1 and type-1 procollagen expression levels. EGCG treatment was also reported to effectively decrease the MMPs and increase the type-1 procollagen expression levels in the dermis due to its antioxidant effect [27]. In our study it was shown that panduratin A at concentration of 0.001 - 0.1 μM, which was not toxic to human skin fibroblast cells in vitro, significantly decreased the MMP-1 expression and increased the type-1 procollagen expression in the protein and mRNA gene levels in a dose-dependent manner, and also panduratin A was more effective than EGCG for both MMP-1 inhibition and type-1 procollagen synthesis ([Fig. 2 6]).

UV light is particularly associated with the oxidative processes involved in photoaging. Reactive oxygen species (ROS) generation is initiated following UV irradiation, which results in the up-regulation of MMP-1 and the degradation of dermal collagen [28]. ROS generation also plays a critical role in the MAPK-mediated signal transduction triggered by UV. Recent studies indicate that the MAP kinase signal transduction pathways play an important role in regulating a variety of cellular functions, including cell growth, MMP expression and type-1 procollagen synthesis [29]. In this study, it was found that panduratin A only at concentration of 0.1 μM decreased the intracellular ROS levels ([Fig. 4]). Based on these findings, the regulatory activity of panduratin A on the MMP-1 and type-1 procollagen expression levels might be related in part to inhibition of ROS generation in UV-irradiated fibroblast cells. Therefore, the MMP-1 inhibitory effect shown by panduratin A is not mediated by its antioxidant effect but may be mediated by the inhibition of the intracellular signal transduction response. The effects of panduratin A on the cell signal pathways need to be further studied.

Taken together, panduratin A isolated from Kaempferia pandurata significantly reduced the expression of MMP-1 and induced the expression of type-1 procollagen at the protein and mRNA gene levels. Thus, panduratin A can be employed as a potential candidate for the prevention and treatment of skin aging. Further studies are necessary to elucidate its anti-photoaging mechanisms, particularly those related to the signaling pathways in parallel with in vivo tests.

Acknowledgements

This work was supported partly by the Yonsei Biomolecule Research Initiative of the Brain Korea 21 Project.

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Prof. Jae-Kwan Hwang

Department of Biotechnology

Yonsei University

134 Shinchon-dong

Seodaemun-gu

Seoul 120-749

Korea

Phone: +82-2-2123-5881

Fax: +82-2-362-7265

Email: jkhwang@yonsei.ac.kr

References

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  PubMedSearch in Google Scholar
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  CrossrefPubMedSearch in Google Scholar
• 3 Moon H I, Lee J K, Zee O P, Chung J H. A glycosidic isoflavonoid from Viola hondoensis W. Becker et H. Boissieu (Violaceae), and its effect on the expression of matrix metalloproteinase-1 caused by ultraviolet irradiation in cultured human skin fibroblasts.  Biol Pharm Bull. 2005;  28 1123-5
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  CrossrefPubMedSearch in Google Scholar
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Prof. Jae-Kwan Hwang

Department of Biotechnology

Yonsei University

134 Shinchon-dong

Seodaemun-gu

Seoul 120-749

Korea

Phone: +82-2-2123-5881

Fax: +82-2-362-7265

Email: jkhwang@yonsei.ac.kr