Abstract
Background and purpose:
Chlorogenic acid (CA) is a natural chemical that promises antiaging activity against photoaging skin damage. This research examined CA activities in mitigating skin photoaging.
Experimental approach:
UV-exposed human skin fibroblast cells were subjected to CA at 6.25, 12.5, and 25 μg/mL. The protein levels of cell secretion, such as cyclooxygenase (COX)-2, nitric oxide (NO), and interleukin (IL)-6 were measured using ELISA and colorimetry methods. Meanwhile, the mRNA expressions of glutathione peroxidase (GPX)-1, tissue inhibitor metalloproteinase (TIMP)-1, matrix metalloproteinase (MMP)-1, caspase (CASP)-3, CASP-8, and fibroblast growth factor (FGF)-2 were quantified using the qRT-PCR method.
Findings/Results:
CA treatment reduced inflammatory and aging biomarkers. CA at 6.25 μg/mL lowered NO, COX-2, and IL-6 levels to 89.44 μmol/L, 8.10 ng/mL, and 62.75 pg/mL, respectively. CA at 25 μg/mL resulted in the most significant down-regulation of MMP-1, CASP-3, and CASP-8 genes’ expression (3.27, 1.25, and 3.59, respectively). Furthermore, treatment with CA at 25 µg/mL demonstrated the most notable activity in up-regulating antioxidant markers, specifically GPX-1, and extracellular matrix (ECM) integrity markers, including TIMP-1 and FGF-2 genes’ expression.
Conclusion and implications:
CA imposes its anti-aging activity by decreasing inflammatory and aging biomarkers, and increasing cellular antioxidant and ECM integrity.
Keywords: Antiaging, Chlorogenic acid, Fibroblast, qRT-PCR, Ultraviolet
INTRODUCTION
Ultraviolet (UV) rays are the major factor in promoting dermal aging by releasing cellular reactive oxygen species (ROS), which generate lipid oxidation, DNA impairment, and protein deformation (1,2) subsequently leading to apoptosis (3). ROS molecule, including nitric oxide (NO), promotes the release of cytokines such as interleukins (IL-6, IL-12, and IL-1β), cyclooxygenase II (COX-2), and tumor necrosis factor-α (TNF-α); activates the nuclear factor-kappa B (NF-kB) cascade; and provokes T cells infiltration to cause inflammation (4). These proteins remarkably contribute to the pathogenesis of skin photoaging. In the study by Surowiak et al., COX-2 expression was much higher in keratinocytes and fibroblasts from photoaged skin than in skin samples from younger people or people who were naturally getting older (5).
Besides, IL-6 has recently been identified as a potential target in inflammatory diseases contributing to aging, earning it the moniker “gerontologist’s cytokine” (6,7). Furthermore, NO interacts with the superoxide anion (O2-) to generate the strong oxidant peroxynitrite (ONOO-), which then interacts with DNA, lipids, and proteins by means of direct oxidation reactions or through indirect mechanisms facilitated by radicals. ONOO- is associated with various organelle pathologies, such as oxidation, cytotoxicity induction, and apoptosis (8). The ROS-stimulated apoptosis is indicated by the increases in caspase 3 (CASP-3), CASP-8, CASP-6, CASP-9, and CASP-7 (3).
ROS obliterates the antioxidant enzymes, including glutathione peroxidase (GPX); stimulates mitogen-activated protein kinase (MAPK)/activator protein-1 (AP-1) cascade activity, which then activates matrix metalloproteinases (MMPs), and damages tissue integrity (9). An increase in MMPs results in the activation of AP-1. The AP-1 stimulates MMP gene expression while restraining transforming growth factor β (TGF-β) signaling. A continuous MMP activity leads to collagen degradation; hence, it causes lower collagen I levels in photoaging skin (10). As individuals age, MMPs like stromelysin-1 (MMP-3), collagenase-1 (MMP-1), and gelatinase (MMP-2) reduce collagen and elastin fibers within the dermis. Tissue inhibitors of metalloproteinase-1 (TIMP-1) naturally counteract MMP to slow the aging of fibroblasts (11).
Some plant metabolites have anti-aging activity by protecting the skin from oxidation, inflammation, and tissue deformation (10,12). The anti-aging activity is manifested by reducing wrinkles, pigmentation, and skin lines. This repair is caused by promoting dermal growth factor activity, such as fibroblast growth factor 2 (FGF-2). FGF family proteins can increase fibroblast proliferation and activation in skin aging control by promoting the production of type I collagen. FGFs promote angiogenesis and are crucial in cell repair (13). Photoaging therapy may involve inhibiting the expression or activity of an antioxidant enzyme that contributes to the aging process (5). Chlorogenic acid (CA) is considered one of the most promising classes of natural compounds with the ability to control such enzymes and thus have potential as antioxidants and antiaging agents (14).
A phenolic substance, CA 5-O-caffeoylquinic acid), is present in some vegetables and fruits (12,15). Several studies on CA’s antioxidant, antitumor, antiviral, anticancer, and anti-inflammatory effects have been so far carried out (16). A prior study reported that CA has antiaging properties by decreasing ROS levels and increasing COL-3 gene expression in a human fibroblast photoaging model (14). However, there is no comprehensive report about the CA effect in mitigating skin aging through assessment of the biomarkers related to oxidative stress, which is concomitant with inflammation, extracellular matrix, and apoptosis. Therefore, this research aimed to find out more about the impact of CA on the antioxidant marker, GPX-1; inflammatory proteins, NO, COX-2, and IL-6; extracellular matrix (ECM) integrity-related genes, MMP-1, TIMP-1, and FGF-2; and cell death markers, CASP-3 and CASP-8.
MATERIALS AND METHODS
Cell culture
Human skin fibroblast cells (BJ, ATCC® CRL-2522TM) were maintained in Aretha Medika Utama, Bandung, Indonesia. It was grown in a medium containing 1% antibiotic/antimycotic (ABAM, L0010-100; Biowest, France), 10% fetal bovine serum (FBS, S1810-500; Biowest, France), 1% amphotericin B (L0009-050; Biowest, France), 0.1% gentamicin (15750060; Gibco, United States), L-glutamine solution (G8540; Sigma-Aldrich, United States), and minimum essential medium (MEM, L0416-500; Biowest, France). The culture was maintained in an incubator set to 37 °C with 5% CO2. The 80% confluent cells were harvested with 0.25% trypsin-EDTA (25200072; Gibco, United States) for the treatment (14,17).
UV irradiation and treatment
The harvested cells were cultured in six-well plates (n = 106 cells) and then incubated for 24 h at 37 ℃ with 5% CO2 until reaching 80% confluency. The cells were exposed to UVB for 75 mins (300 J/cm2) once the fresh medium was added. The CA (BP0345; Chengdu Biopurify Phytochemical, China) was added in UV-exposed BJ cells at final concentrations of 6.25, 12.5, and 25 μg/mL The cells were grown for 4 days at 37 ℃ with 5% CO2, then harvested (13).
Total protein measurement
The bovine serum albumin (BSA) stock was defined as a standard solution. Briefly, 2 mg of BSA (Sigma, A9576, Lot SLB2412, United States) was dissolved in 1000 L ddH2O to make the stock. A 96-well plate was used for the preparation. A volume of 200 µL Quick Start Dye Reagen 1X (Biorad, 5000205, United States) was introduced to 20 µL of standard solutions and samples in each well. Subsequently, the plate underwent an incubation period of 5 min, followed by the absorbance measurement (595 nm) using a microplate reader (14).
Inflammation protein marker measurement using ELISA and colorimetric assays
Inflammation-related proteins are secreted by the cells into the medium, or “conditioned medium.” Therefore, the conditioned medium was measured for the levels of COX-2, IL-6, and NO according to the human IL-6 ELISA kit (E-EL-H 6156, Elabscience, China), human COX-2 ELISA kit (E-EL-H1846, Elabscience, China), and NO colorimetric assay (E-BC-K035-M, Elabscience, China) at 450 nm, 450 nm, and 550 nm, respectively. The absorbance readings were obtained by employing a microplate reader (Multiskan Go, Thermo Scientific) (14,18).
Gene expression analysis
Total cellular RNA extraction was performed under the manufacturer’s protocol. AurumTM Total RNA Minikit (732-6820, Bio-Rad) and iScript Reverse Transcription Supermix for quantitative reverse transcriptase polymerase chain reaction (qRT-PCR; 170-8841, Bio-Rad) were used for cDNA synthesis and analyzed using qRT-PCR (G8830A, AriaMx Real-time PCR System). β-actin gene was used to normalize the MMP-1, TIMP-1, CASP-3, CASP-8, FGF-2, and GPX-1 gene expression, and analyzed using AriaMx RT-PCR system with SsoFast Evagreen Supermix (172-5200, Bio-Rad). The reaction mix was based on the previous studies (14,18) with modification on annealing temperature based on optimization of the primer. The primers and RNA properties are shown in Tables S1 and S2.
Table S1.
Primer sequences
| Genes | Primer sequence (5’ to 3’) | Size (bp) | Annealing (°C) | Cycle | NCBI references sequence |
|---|---|---|---|---|---|
| β-actin | Forward: 5'-TCTGGCACCACACCTTCTACAATG-3' Reverse: 5'-AGCACAGCCTGGATAGCAACG-3' |
230 | 60 | 40 | NM_001101.5 |
| MMP1 | Forward: 5'-AGTCCAAGAGAATGGCCGAG-3' Reverse: 5'-CTGAAGGTGATGAAGCAG-3' |
230 | 60 | 40 | NM_001191642.1 |
| TIMP1 | Forward: 5'-TTTCAGAGCCTTGGAGGAGCTGGTC-3' Reverse: 5'-AGTCAACCAGACCACCTTATACCA-3' |
230 | 60 | 40 | NM_003254.3 |
| Casp3 | Forward: 5'-CAGTGTTCTCCATGGATACCTTTATT-3' Reverse: 5'-CTGGTTTTCGGTGGGTGT-3' |
230 | 60 | 40 | NM_001354783.2 |
| Casp8 | Forward: 5'-GGTCACTTGAACCTTGGGAA-3' Reverse: 5'-AGGCCAGATCTTCACTGTCC-3' |
230 | 60 | 40 | NM_001400660.1 |
| FGF-2 | Forward: 5'-GGCTTCTTCCTGCGCATCCA-3' Reverse: 5'-GCTCTTAGCAGACATTGGAAGA-3' |
230 | 58 | 40 | NM_002006.6 |
| GPX-1 | Forward: 5'-CCAAGCTCATCACCTGGTCT-3' Reverse: 5'-TCGATGTCAATGGTCTGGAA-3' |
230 | 58 | 40 | NM_001329455.2 |
MMP, matrix metalloproteinase; TIMP, tissue inhibitor of matrix; FGF, fibroblast growth factor; Casp, caspase; GPX, glutathione peroxidase.
Table S2.
RNA properties used for cDNA synthesis
| Treatment | RNA concentration (ng/mL) | RNA purity (λ260/λ280 nm) |
|---|---|---|
| Negative control | 627.25 | 2.1690 |
| Positive control | 80.85 | 2.2518 |
| DMSO control | 102.1 | 2.1701 |
| Chlorogenic acid (6.25 μg/mL) | 252.20 | 2.2660 |
| Chlorogenic acid (12.5 μg/mL) | 179.55 | 2.3541 |
| Chlorogenic acid (25 μg/mL) | 163.25 | 2.2754 |
Statistical analysis
The entire set of data was displayed as mean ± SD. Normally distributed data were processed employing SPSS software (version 20.0). The statistical analysis involved the utilization of ANOVA alongside Tukey’s HSD post hoc tests. P-values ≤ 0.05 were regarded as statistically significant.
RESULTS
CA effect on protein level
Based on Fig. 1, UV induction led to a decrease in total protein, compared to the negative control. CA treatment at all concentrations could elevate total protein, with CA at 12.5 μg/mL as the most effective. Additionally, all CA treatments exhibited comparable results to the negative control. The total protein levels were used as a benchmark to compare NO, COX-2, and IL-6 levels against the total protein content in the photoaging cells model, providing a reference point for evaluating the effects of CA on protein regulation.
Fig. 1.
Effect of CA on protein level in photoaging cells model. Group I: normal cells (negative control); group II: UV-exposed cells (positive control); group III: UV-exposed cells treated with DMSO 1% (vehicle control); and groups IV-VI: UV-exposed cells treated with CA at 6.25; 12.5, and 25 μg/mL, respectively. The data represent mean ± SD. There is no statistically significant difference among the groups with similar alphabetic letters
CA effect on inflammation protein markers
As depicted in Fig. 2A, C, E, UV induction led to alterations of inflammatory markers. UV induction significantly elevated NO, COX-2, and IL-6 levels compared to the negative control, marked an inflammation rise. However, CA was able to regulate corresponding inflammatory markers, notably reducing them. Among three concentrations of CA, 6.25 µg/mL exhibited as the most active in decreasing all target inflammatory markers. Moreover, out of the total protein that could be secreted by the medium, CA has the ability to reduce the levels of all inflammatory markers (Fig. 2B, D, F). The result revealed that CA at 6.25 µg/mL exhibited the most significant reduction in NO, COX-2, and IL-6 levels (728.12 pg/mg protein; 0.07 ng/mg protein; and 510.81 pg/mg protein, respectively).
Fig. 2.
Effect of chlorogenic acid on NO, COX-2, and IL-6 levels in photoaging cells model. Group I: normal cells (negative control); group II: UV-exposed cells (positive control); group III: UV-exposed cells treated with DMSO 1% (vehicle control); and groups IV-VI: UV-exposed cells treated with CA at 6.25; 12.5, and 25 μg/mL, respectively. The data represent mean ± SD. No significant statistical difference was found among the groups with similar alphabetic letters. NO, Nitric oxide; COX, cyclooxygenase; IL, Interleukin.
Antioxidant and aging-related mRNA expressions
The mRNA relative expressions of GPX-1, MMP-1, TIMP-1, FGF-2, CASP-3, and CASP-8 were quantified using the qRT-PCR method. UV exposure significantly up-regulated MMP-1, CASP-3, and CASP-8 and down-regulated GPX-1, TIMP-1, and FGF-2 mRNA expressions compared to the negative control (Fig. 3A-F). In contrast, CA treatment significantly down-regulated MMP-1, CASP-3, and CASP-8, as well as upregulated GPX-1, TIMP-1, and FGF-2 mRNA expressions compared to the positive control. CA at 25 μg/mL was the most effective to down-regulate relative gene expression of MMP-1, CASP-3, and CASP-8 (3.27, 1.25, and 3.59, respectively), and was the most active concentration to upregulate the relative gene expression of GPX-1, TIMP-1, and FGF-2 (0.46, 0.93, and 0.12, respectively).
Fig. 3.
The effect of chlorogenic acid on relative mRNA expression of GPX-1, MMP-1, TIMP-1, FGF-2, CASP-3, and CASP-8 in photoaging cells model. Group I: normal cells (negative control); group II: UV-exposed cells (positive control); group III: UV-exposed cells treated with DMSO 1% (vehicle control); and groups IV-VI: UV-exposed cells treated with CA at 6.25; 12.5, and 25 μg/mL, respectively. The data represent mean ± SD. No significant statistical difference was found among the groups with similar alphabetic letters. GPX, Glutathione peroxidase; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of matrix; FGF, fibroblast growth factor; CASP, caspase.
DISCUSSION
UV light is one of the causative aspects of facial skin aging (1). Exposure to UV light generates excessive ROS production, activates NF-kB, and activates other aging cascades, such as MMPs and inflammation (19). The current study reported that the levels of NO, COX-2, and IL-6 in the UV-exposed skin fibroblast cells increased indicating oxidative stress and inflammation.
CA is a phenolic component found in coffee, tea, and various fruits and vegetables (12,15). CA is a hydrocinnamic family member and one of the water-soluble phenolic compounds acknowledged as an antioxidant to fight free radicals (20). CA is reported to lower cytokines, including pro-inflammatory ILs, and modulate NF-kB and COX-2 (21). As an indication of mitigation, this study reported that CA up-regulates the antioxidant gene, including GPX-1, and reduces the inflammatory proteins, NO, COX-2, and IL-6 in the UV-exposed skin fibroblast cells. As reported by our previous findings, CA reduced ROS levels in UV-activated human fibroblast skin cells (14) and Pb-induced skin fibroblast cells (17). Additionally, CA isomers significantly lessened DNA damage from the free radical OH*, which increased antioxidant activity (22). CA suppresses IL-6 mediated signaling, which triggers the initiation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) and NF-kB signaling pathways in the inflammatory response, consequently reducing the levels of the pivotal cytokine involved in these signaling pathways (23 of). CA protects cells from UV-induced inflammation by lowering IL-1 and TNF-α (14). The previous study reported that CA up-regulated the expression of the collagen-forming gene COL3A in UV-induced BJ cells and inhibited cell death as an indication of aging mitigation (14). This study reported the decrease of MMP-1 and the increase of TIMP-1 and FGF-2 mRNA expressions in a photoaging cell model as a CA treatment. The inhibitions of inflammation and ROS generation result in low MMP expression, allowing collagen regeneration in the skin (24). MMP inhibition stimulates TIMP activity to reduce skin photodamage caused by UVB penetration (25). The protection of FGF-2 from degradation can reveal anti-aging activity by significantly improving the elasticity, density, and texture of the skin and reducing wrinkles (13).
This study showed that CA reduced cell apoptosis by decreasing the mRNA expressions of the CASP-3 and CASP-8 genes. Several studies have found that CA suppression affects apoptosis. The research by Chen et al. showed a decrease in CASP-3 and CASP-9 in the intestines of CA-fed pigs (26). Ali et al. found that CA lowered CASP-3 and CASP-9 to stop hepatocyte apoptosis in a rat model of hepatotoxicity (27). The anti-apoptotic effect of CA treatment could be associated with increasing GPX-1, which belongs to the nuclear factor erythroid 2-related factor-2 family. As revealed by Kim et al. the increase of NRF-2 contributed to the anti-apoptotic effect of phycocyanin from Spirulina to protect skin cells (28).
According to the current study results, CA has potential as an antiaging agent. Current studies have shown that CA has antioxidant and antiapoptotic properties (12), collagenase inhibition activity (29), and collagen regeneration (14,17). The mechanism of the CA antiaging activity against aging fibroblast cells can be seen in Fig. 4.
Fig. 4.
The proposed anti-aging mechanism in CA treatment. UV exposure generates ROS-excessive production in skin fibroblast cells, leading to oxidative stress and inflammation. Subsequently, the inflammation leads to apoptosis, tissue instability, and ECM degradation. CA treatment reduces NO, COX-2, and IL-6 levels; and enhances GPX-1 production to inhibit oxidative stress and inflammation. This inhibition also keeps skin fibroblast integrity and stability by lowering CASP-3, CASP-8, and MMP-1 and improving TIMP-1 and FGF-2. CA, chlorogenic acid; ROS, reactive oxygen species; ECM, extracellular matrix; NO, nitric oxide; COX, cyclooxygenase; IL, Interleukin; GPX, glutathione peroxidase; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of matrix; FGF, fibroblast growth factor; CASP, caspase.
CONCLUSION
The research revealed that CA has potential as an anti-aging agent in UV-exposed human skin fibroblast cells. CA diminished the levels of pro-inflammatory proteins NO, COX-2, and IL-6; down-regulated dermal degeneration genes MMP-1, CASP-3, and CASP-3; additionally, CA up-regulated antioxidant genes GPX-1 and skin integrity genes TIMP-1 and FGF-2.
Conflict of interest statement
The authors stated that there were no conflict of interest in this study.
Authors’ contributions
E. Girsang, C.N. Ginting, I.N.E. Lister, and W. Widowati conceived the research design. A. Yati and H.S.W. Kusuma conducted the research. W. Widowati and R. Azis collected the data. C.N. Ginting, I.N.E. Lister, W. Widowati, and A. Yati drafted the manuscript. E. Girsang, W. Widowati, and R. Azis finalize the manuscript. The final version of the manuscript was reviewed and approved by all authors.
Acknowledgments
This study received financial support from the Indonesian Ministry of Education, Culture, Research, and Technology’s Penelitian Dasar Unggulan Perguruan Tinggi (PDUPT) 2022 (Grant No. 008/LL1/LT/K/2022). The authors appreciate Aretha Medika Utama, Indonesia, for the technical and facility support.
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