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. 2022 Mar 28;31(5):617–625. doi: 10.1007/s10068-022-01055-6

Shinorine and porphyra-334 isolated from laver (Porphyra dentata) inhibit adipogenesis in 3T3-L1 cells

Su-Young Choi 1,#, Su Yeon Lee 2,#, Hyung Gyun Kim 3, Jae Cheon Jeong 3, Don Carlo Batara 1, Sung-Hak Kim 1,✉, Jeong-Yong Cho 2,✉
PMCID: PMC9033900  PMID: 35529689

Abstract

Mycosporine-like amino acids (MAAs) such as shinorine and porphyra-334 from Porphyra spp. are bioactive compounds with strong photoprotective and antioxidant properties. In this study, the anti-adipogenic effect of shinorine and porphyra-334 was examined in vitro utilizing 3T3-L1 preadipocytes. Shinorine and porphyra-334 were extracted from laver (Porphyra dentata) 50% methanolic (MeOH) extract of and their structures were elucidated by MS and NMR spectroscopy. Both compounds had no cytotoxic effect in 3T3-L1 cells (< 200 μg/mL) and inhibited the accumulation of lipid droplets in 3T3-L1 mature adipocytes in a dose-dependent manner (0.1 and 1.0 μM). Interestingly, both compounds had also significantly reduced the expression of adipogenic-related genes such as peroxisome proliferator-activated receptor γ2 (PPARγ2), CCAAT/enhancer-binding protein α (C/EBPα), adiponectin, and leptin in 3T3-L1 cells. The findings suggest that shinorine and porphyra-334 have the potential to inhibit adipogenesis in 3T3-L1 preadipocytes.

Keywords: Porphyra dentata, Laver, Shinorine, Porphyra-334, Adipocyte differentiation, Adipogenesis

Introduction

Obesity has become a global health issue due to its link to metabolic disorders such as dyslipidemia, cardiovascular disease (CVD), hypertension, cancers, and type 2 Diabetes Mellitus (T2D) (Fruh, 2017). Several anti-obesity drugs have been registered for clinical usage in recent years, however, the vast majority have been pulled from the market due to severe side effects (Kang and Park, 2012). Natural compounds such as epigallocatechin gallate (EGCG) (Li et al., 2018), resveratrol (Carpéné et al., 2019), lycopene (Mounien et al., 2019), and flavonoids (Kawser Hossain et al., 2016) have been found to have anti-obesity properties. Thus, harnessing these compounds might be a potential strategy for obesity prevention and treatment in a more natural way.

Laver (Porphyra spp.) is a popular edible red seaweed in China, Japan, and Korea. Laver has high in mineral content (iron, copper, selenium, manganese, and zinc), vitamins (A, B, and C), and proteins, and has fewer simple carbohydrates than other edible seaweeds (Sanjeewa et al., 2018). It has also several bioactive compounds such as phycobiliproteins, polysaccharides, phenolic compounds, peptides, and mycosporine-like amino acids (MAAs) (Bito et al., 2017). Studies show that these bioactive compounds have anti-inflammatory (Suh et al., 2014), anti-oxidant (Nishida et al., 2020), anti-tumor (Do Thi and Hwang, 2014), photoprotective (Rui et al. 2019), and anti-obesity (Yang et al., 2019) properties. Recently, it was found that laver extract can inhibit adipogenesis in the early phases of differentiation by inhibiting PPARγ2 and C/EBPα mRNA expressions in 3T3 L1 cells (Choi et al., 2020).

One of the bioactive compounds present in Porphyra spp. are MAAs. So far, there are more than 20 MAAs that have been identified, and this includes shinorine and porphyra-334 (Lomartire et al., 2021). Accordingly, studies show that shinorine and porphyra-334 have great photoprotective properties against UV radiation (Bhatia et al., 2011), antioxidant (Gacesa et al., 2018), anti-aging and anti-inflammatory (Kageyama and Waditee-Sirisattha, 2019) properties. Although shinorine and porphyra-334 have shown several bioactivities, their anti-adipogenic property has not been reported. Therefore, the present study aims to evaluate the anti-adipogenic potential of shinorine and porphyra-334 from laver (P. dentata) in vitro using 3T3-L1 preadipocytes.

Material and methods

General experimental procedures

The purified compounds were dissolved in deuterated water (D2O; Merck Co., Billerica, MA, USA) to generate their nuclear magnetic resonance (NMR) spectra. The 1H- and 13C-NMR spectra were verified on a unityINOVA 500 spectrometer (Varian, Walnut Creek, CA, USA; KBSI, Gwangju Center) with 500 MHz (1H) and 125 MHz (13C) operating frequencies. MS analyses were carried out on a hybrid ion-trap/time-of-flight mass spectrometer (SYNAPT G2; Waters, Cambridge, UK) outfitted with an electrospray ionization (ESI) source. A column chromatography was performed with silica gel (SNAP ZIP KP-Sil 340g; Biotage, Seongnam, Korea) and octadecylsilane (ODS; SNAP Ultra C18 240g; Biotage, Seongnam, Korea). A medium performance liquid chromatography (MPLC; Biotage, Seongnam, Korea) with a photodiode detector array (PDA) was used to isolate and purify the compounds from laver solvent extracts. At a flow rate of 25 mL/min, the compounds were measured at 330 nm. All the other solvents and chemicals used were of analytical standards.

Materials and chemicals

Dried laver (P. dentata) samples were provided by the Mokpo Marine Food-industry Research Center (Mokpo, Jeonnam, Korea). DMEM-high glucose (DMEM-HG) was obtained from Hyclone™ (Logan, UT, USA). Gibco-BRL (Gaithersburg, MD, USA) provided the fetal bovine serum (FBS). Dexamethasone (DEX), 3-isobutyl-1-methylxanthine (IBMX), pioglitazone, insulin, and Oil Red O powder were from Sigma-Aldrich Chemical Co. (St. Louis, MO, USA). Formaldehyde was from Fujifilm Wako Pure Chemical Corporation (Osaka, Japan). 2-Propanol-GR was purchased from Merck (Kenilworth, NJ, USA). The American Type Culture Collection (ATCC®, CL-173™; Rockville, CT, USA) provided the 3T3-L1 cells.

Purification and isolation of compounds from dried laver

The procedure in the preparation of laver 50% aqueous MeOH extracts had been previously reported by Choi et al. (2020). Briefly, 50% aqueous MeOH extract was obtained from dried laver (5 g) was dissolved in methanol (15 g), and absorbed into silica gel (50 g; silica gel 60 F254, 0.25-mm thickness, Merck). The solvent was evaporated and dried under a vacuum at 40 °C and then subjected to silica gel (430 g)-MPLC. Elution was performed using a stepwise system CHCl3/MeOH/H2O with steps of 12:8:1 and 8:12:1 (v/v, each step 4000 mL) to enable two fractions (A and B). Fraction B (CHCl3/MeOH/H2O = 8:12:1, v/v, 617 mg) was purified using an ODS-MPLC and eluted with an isocratic system of 100% H2O. Compounds 1 (tR 11.5 min, 64.8 mg) and 2 (tR 16.0 min, 56.3 mg) were obtained.

HPLC analysis

The two purified compounds were analyzed using an HPLC connected with an ODS column (Capcellpak C18 AQ column, 4.6 × 150 mm, 5.0 μm; Shiseido, Tokyo, Japan) and PDA. The mobile phase was made of H2O and acetonitrile (A) and eluted with a gradient system: 0% A for 5 min, 0% A to 20% A for 5 to 20 min, and 20% A for 20 to 25 min. The flow rate was set at 1.0 mL/min, and the compounds were measured at 330 nm (SPD-M20A, Shimadzu).

Cell culture and adipocyte differentiation

The preadipocyte 3T3-L1 cells (1.0 × 105 cells/well) were cultured at 37 °C in 5% CO2 in DMEM-HG with 10% FBS, and 1% penicillin/streptomycin (Welgene; Gyeongsan, Korea) in a 6-well plate and maintained to confluence for 48 h. Adipogenesis was stimulated after confluence by adding differentiation media (DMEM-HG supplemented with 10% FBS, 1.0 μM DEX, 0.5 mM IBMX, 1.0 μM pioglitazone (PIO), and 10 μg/mL insulin). The media was replaced every 2 days with DMEM-HG containing 10% FBS and 10 μg/mL insulin. The process of adipogenesis lasted until day 8. The preadipocytes control was maintained with DMEM-HG with 10% FBS only and media change was done every 2 days. To study the effects of the isolated compounds on adipogenesis, 3T3-L1 cells were treated with a medium containing shinorine and porphyra-334 (0.1 and 1 μM/mL) every 2 days. For the RT-PCR experiment, 3T3-L1 cells were collected after 5 days of compound treatment. Meanwhile, for the Oil Red O staining experiment, the 3T3-L1 adipocytes were fixed in 4% formalin after 8 days of compound treatment.

Cell viability assay

The 3T3-L1 preadipocytes (7.5 × 102 cells/well) were seeded in a 96-well plate with 200μL of DMEM-HG medium containing 10% FBS. After seeding, different concentrations (6.25, 12.5, 25, 50, 200 μM) of the compounds were added then incubated at 37 °C with 5% CO2. After 24 h incubation, AlamarBlue™ Cell Viability Reagent (Thermo-Fisher Scientific; Waltham, MA, USA) was added. A SYNERGY multi-mode reader (BioTek, Seoul, Korea) was used to measure the fluorescence values at 530–560 nm and 590 nm. The cell viability was determined using the AlamarBlue assay based on the manufacturer’s procedure.

Oil Red O staining

Oil Red O staining was performed to measure the accumulation of cell lipid droplets in 3T3 -L1 adipocytes. Before being fixed in formalin (4%) at room temperature, 3T3-L1 adipocytes were washed twice with PBS. After 10 min, the formalin solution was removed, and a new formalin solution (4%) was added then incubated at room temperature. After 1 h incubation, the formalin solution was removed and cells were rinsed with tertiary distilled water. Then 60% isopropanol was added to the cells and was removed after 5 min. Cells were allowed to dry at room temperature and 1 mL of Oil Red O solution was added to each well. After 20 min incubation at room temperature, Oil Red O solution was removed and cells were rinsed thrice with tertiary distilled water. Cells were imaged with a Leica Microscopy, DE/Polyvar SC (Leica, Wetzlar, Germany).

Real-time qPCR analysis

The total RNA was extracted using Hybrid-R™ (GeneAll Biotechnology; Seoul, Korea). RNA purity and concentration were confirmed using Nanodrop 2000 spectrophotometer (ThermoFisher Scientific; Waltham, MA, USA). A RevertAid First Strand cDNA Synthesis kit (ThermoFisher Scientific; Waltham, MA, USA) was used to synthesize the cDNA from the total RNA (1ug). Finally, RT-qPCR of the target genes were detected using TB Green® Premix EX Taq™ (Tli Rnase H plus; Takara Bio, Kusatsu, Japan) in CFX96™ Real-Time PCR Detection System (Bio-rad; Hercules, CA, USA). All samples were tested in triplicate and quantified using the relative standard curve method (2−ΔΔCt) with L32 serving as endogenous control. The following are the forward and reverse primer sets was used in this study: L32-F: 5′-TCTGGTGAAGCCCAAGATCG-3′; L32-R: 5’-CTCTGGGTTTCCGCCAGT-3′; PPAR-γ2-F: 5′-GTGCTCCAGAAGATGACAGAC-3′; PPAR-γ2-R: 5′-GGTGGGACTTTCCTGCTAA-3′; C/EBPα,-F: 5′-TGGACAAGAACAGCAACGAG-3′; C/EBPα-R: 5′-TCACTGGTCAACTCCAGCAC-3′; ADIPOQ-F: 5′- CCGTTCTCTTCACCTACGAC-3′; ADIPOQ-R: 5′-TCCCCATCCCCATACAC-3′; Leptin-F: 5′-TCAACTCCCTGTTTCCAAAT-3′; Leptin-R: 5′-TCTTCACGAATGTCCCACGA-3′.

Statistical analysis

GraphPad Prism 0.8 Software (San Diego, CA, USA) was used to perform all statistical analyses. All the data were analyzed using a one-way analysis of variance (ANOVA) with multiple comparisons. The two-tailed Student’s t-test was used to compare group differences, and the p value (< 0.05) was considered statistically significant. All tests were performed in triplicate, and the results were expressed as mean ± standard error of the mean (SEM).

Results and discussion

Isolation and identification of compounds from the laver

Two MAAs (1 and 2) compounds were purified and isolated from laver (5.0 g) 50% MeOH extract on column chromatography of silica gel and ODS. The purity of the compounds was determined using an HPLC–PDA system. As shown in Fig. 1, the purity of both MAA 1 and 2 were high (> 95%) based on their HPLC chromatograms and UV spectra, which were confirmed by LC–MS and 1H-NMR experiment. The chemical structures of the isolated compounds were elucidated using MS and NMR experiments.

Fig. 1.

Fig. 1

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HPLC chromatograms and UV spectra of shinorine (A) and porphyra-334 (B) isolated from laver

MAA 1 has a molecular weight of 332 g/mol according to the protonated molecular ion peak [M + H]+ at m/z 333.2, observed in the ESIMS spectrum. The 1H-NMR spectrum showed the presence of cyclohexanone ring moiety corresponding to 2 methylene protons at δ 2.75–2.97 (H-4 and H-6), an oxygenated methylene proton at δ 3.60 (H-7), and a methoxy proton at δ 3.70 (H-8). Additionally, there were proton signals of glycine related to methylene at δ 4.10 (H-8) and serine related to oxygenated methylene at δ 4.04–495 (H-13a and H-13b) and a nitrogenated methylene at δ 4.39 (H-12). The MS and 1H-NMR data were also consistent with the 13C-NMR data that exhibited the presence of 13 carbon signals, including two carbonyl carbons at δ 174.2 (C-10) and 174.4 (C-11) and three quaternary carbons at δ 160.3 (C-3), 158.9 (C-1), and 125.5 (C-2). The MS and 1D NMR data proposed to be that of shinorine composed of serine and glycine in cyclohexenone ring moiety. The 1H- and 13C-NMR data of MAAs 1 were consistent with those of shinorine isolated from Palmaria palmata (Hartmann et al., 2015). Consequently, MAA 1 was identified as shinorine (Fig. 2).

Fig. 2.

Fig. 2

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The structures of shinorine (1) and porphyra-334 (2) isolated from the 50% MeOH extract of the laver. Arabic number means the carbon position of MAAS

MAA 2 has a molecular weight of 346 g/mol according to the protonated molecular ion peak [M + H]+ at m/z 347.1, found in the ESIMS spectrum. MAA 2's 1H- and 13C-NMR results were remarkably comparable to MAAs 1 (Table 1). The 1H- and 13C-NMR data of MAA 2 exhibited the presence of threonine moiety assignable to proton and carbon signals of one methyl [δ 1.13 (H-14) and 19.3 (C-14)] and oxygenated methine [δ 4.29–4.33 (H-13) and 68.0 (C-13)] instead of an oxygenated methylene proton and carbon signals observed in the spectra of MAA 1. The MS and 1D NMR data proposed to be that of porphyra-334 composed of threonine and glycine in cyclohexenone ring moiety. MAA 2 1H- and 13C-NMR results were comparable with threonine extracted from Bangia atropurpurea (Chuang et al., 2014). Consequently, MAA 2 was identified as porphyra-334 (Fig. 2).

Table 1.

1H- (500 MHz) and 13C- (125 MHz) NMR data of shinorine and porphyra-334 in D2O

Position Shinorine Porphyra-334
δH (int., mult., J in Hz) δC δH (int., mult., J in Hz) δC
1 – 158.9 – 158.9
2 – 125.5 – 125.5
3 – 160.3 – 160.4
4 2.75–2.87 (2H, m)a 32.7 2.93–2.73 (2H, m)b 32.7
5 – 70.9 – 70.9
6 2.80–2.97 (2H, m)a 33.2 2.89 (2H, m)b 33.1
7 3.60 (2H, s) 62.3 3.44 (2H, s) 67.3
8 3.70 (3H, s) 59.1 3.56 (3H, s) 59.2
9 4.10 (2H, br. d, 2.0) 46.2 4.06 (2H, br. d, 2.5) 46.5
10 – 174.2 – 174.6
11 – 174.4 – 64.2
12 4.39 (1H, dd, 6.5, 3.8) 60.2 4.09 (1H, d, 4.5) 175.1
13a 4.02 (1H, dd, 12.0, 3.8) 67.3 4.29–4.33 (1H, m) 68.0
13b 4.95 (1H, dd, 12.0, 6.5)
14 1.13 (3H, d, 6.5) 19.3
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a,bThe signals of H-4 and H-6 in compounds overlapped

Cytotoxicity of shinorine and porphyra-334 in 3T3-L1 preadipocytes

Recently, it was found that laver (P. dentata) 50% MeOH extract (25 μg/mL) had significantly inhibited lipid droplet accumulation during 3T3-L1 cells adipogenesis without causing cytotoxic effect (Choi et al., 2020). Likewise, other researchers also found that MeOH extract (5 mg/mL) from P. yezoensis has high MAAs (120 mg/g dried extract) can inhibit adipogenesis and proapoptotic properties in 3T3-L1 cells (Kim et al., 2015). To determine the cytotoxic effects of shinorine (1) and porphyra-334 (2), an AlamarBlue assay was performed on 3T3-L1 cells exposed to various compound concentrations for 24 h. Results show that both shinorine and porphyra-334 (< 200 μM) had no cytotoxic effects on 3T3-L1 cells (Fig. 3). Furthermore, microscopic observation on 3T3-L1 cells treated with both compounds did not cause any morphological changes similar to the control group (data not shown).

Fig. 3.

Fig. 3

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Cell cytotoxicity of shinorine and porphyra-334 on 3T3-L1 preadipocytes. 3T3-L1 preadipocytes were treated with various concentrations (6.25, 12.5, 25, 50, and 200 μM) of shinorine and porphyra-334 and determined by alamarBlue assay

Oil-Red O staining and intracellular lipid accumulation

Porphyra spp. contains biologically active substances, including carotenoids, polysaccharides, phenolic compounds, and MAAs. Several reports have shown that carotenoids, fucoidan, and phenolic compounds such as EGCG, are present in laver and have been demonstrated to inhibit the accumulation of lipid droplets in 3T3-L1 cells (Montero et al., 2018; Mounien et al., 2019; Park et al., 2011). During the 3T3-L1 differentiation, cells increase triglyceride biosynthesis and acquire adipose-like features. Triglycerides build up as lipid droplets and are embedded in the cytoplasm (Rizzatti et al., 2013). Pre-adipocyte differentiation into adipocytes was stimulated with 1-methyl-3-isobutyl-xanthine, dexamethasone, and insulin (MDI). The 3T3-L1 adipogenesis can be measured with Oil Red O staining (Kim et al., 2015). Oil-Red O can specifically stain triglycerides and cholesteryl oleate and can be used to assess the degree of intracellular lipid accumulation (Ramírez-Zacarías et al., 1992).

The 3T3-L1 preadipocytes were cultured in a 6-well plate with a differentiation medium containing MDI and PIO for 8 days to evaluate the adipogenesis inhibitory effects of shinorine and porphyra-334 (Yang et al., 2018). Cells were stained with Oil-Red O after differentiation and measured the level of intracellular lipid accumulation (Fig. 4a). Results revealed that both shinorine and porphyra-334 had significantly suppressed adipocyte differentiation at 1 μM concentration, evident with lesser red staining compared with the control treatment (Fig. 4b). This suggests both compounds can decrease lipid accumulation and inhibit adipogenesis.

Fig. 4.

Fig. 4

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Decreased accumulation of lipid droplets in differentiated 3T3-L1 cells treatment with shinorine and porphyra-334. (A) Time-schedule of the culture with extracts during the differentiation of 3T3-L1 preadipocytes. Two days after 3T3-L1 cells to confluence, cells added MDI + pioglitazone medium with different concentrations of shinorine and porphyra-334. Two days after differentiation medium treatment, mediums were changed with a new medium containing each extract and 10 μg/ml insulin. This process was every 48 h executed until 8 days, after that followed by staining with Oil Red O staining. The control 3T3-L1 cells changed every 48 h to a fresh medium containing 10% FBS. (B) Effect of shinorine and porphyra-334 on lipid droplets accumulation using Oil Red O staining. Eight days after differentiation, lipid droplets accumulation was confirmed by Oil Red O staining. Upper panels, scale bar: 100 μm. Lower panels, scale bar: 50 μm. MDI, methyl-isobutyl-xanthine, dexamethasone, insulin; PIO, pioglitazone; FBS, fetal bovine serum

Effects of shinorine and porphyra-334 on the mRNA expression of genes involved in adipogenesis

High expression of the C/EBP family (C/EBPδ and C/EBPβ) usually occurs during the onset of adipocyte differentiation. MDI can stimulate the PPARγ and C/EBPα mRNA expressions, which are the key transcription factors of adipogenesis. PPARγ and C/EBPα cooperatively stimulate adipogenesis by inducing several adipocyte-related genes, including adipocyte protein 2, lipoprotein lipase, and fatty acid synthase (Farmer, 2005; Wu et al., 1999). Also, the activation of PPARγ2 in adipocytes can result in enhanced insulin sensitivity and adiponectin upregulation (Astapova and Leff, 2012). Meanwhile, adipokines such as adiponectin and leptin are released by adipose tissue in obesity (Ghantous et al., 2015). Adiponectin abundantly occurs in the adipose tissues caused by the activation of PPARγ2 (Fang and Judd, 2018). Leptin, on the other hand, serves as a negative regulator of energy balance in the adipose tissues (Bell and Rahmouni, 2016). Through leptin resistance, adiponectin and leptin can cause the production of larger adipocytes and contribute to the build-up of excessive fat masses which are seen in obese patients (Sáinz et al., 2015). These adipokine levels were shown to be higher during the transition from preadipocytes to mature adipocytes (Tsubai et al., 2016).

The mRNA expression levels of C/EBPα, PPAR-γ2, adiponectin, and leptin in 3T3-L1 cells were assessed to assess the inhibitory effects of shinorine and porphyra-334 on adipogenesis. MDI stimulation had induced 3T3-L1 preadipocytes differentiation as evident mRNA expression levels of PPAR-γ2, C/EBPα, ADIPOQ, and leptin. Conversely, treatment with shinorine and porphyra-334 has significantly reduced PPAR-γ2, C/EBPα, adiponectin, and leptin mRNA expression in MDI-induced adipogenesis in 3T3-L1 cells in a dose-dependent manner (Fig. 5).

Fig. 5.

Fig. 5

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Expression of adipogenic related genes in 3T3-L1 cells with shinorine and porphyra-334. The expression of adipogenic related genes that PPAR-γ2, C/EBPα, ADIPOQ, and Leptin. 3T3-L1 cells cultured with a differentiation medium that contained different concentrations of shinorine and porphyra-334 (0.1 and 1 μM) were analyzed using real-time qPCR 5 days after induced adipogenesis. Shinorine and porphyra-334 treatment decreased adipogenic related genes mRNA expression on 5 days of adipogenesis. Data were presented as mean and standard errors from three experiments. ###p < 0.001 versus preadipocyte, ***p < 0.001 versus MDI + pio. All data are presented as mean ± SD, and experiments were performed three times. PPARγ2 peroxisome proliferator-activated receptor γ2; C/EBPα CCAAT/enhancer-binding protein α; ADIPOQ adiponectin; MDI methylxanthine, dexamethasone, insulin; PIO Pioglitazone

Shinorine and porphyra-334 from laver, have serine and threonine moieties in the mycosporine-2-glycine skeleton, respectively. Both shinorine and porphyra-334 (0.1 and 1.0 μM) had shown similar inhibitory effects on MDI-induced adipogenesis in 3T3-L1 cells. However, a detailed mechanism by which shinorine and porphyra-334 inhibit adipocyte differentiation and lipid accumulation still have to be elucidated.

In conclusion, shinorine and porphyra-334 isolated from laver (P. dentata) extract substantially inhibited adipocyte differentiation and lipid droplets accumulation in 3T3-L1 cells. Additionally, both compounds reduced the mRNA expression levels of adipogenic related genes including PPARγ2, C/EBPα, adiponectin, and leptin. These findings suggest that shinorine and porphyra-334 from laver have potential adipogenesis inhibitory properties. Hence, laver can be developed as a medicinal food or dietary supplement to prevent and treat obesity-related health risks and complications.

Acknowledgements

This research was supported by the Ministry of Oceans and Fisheries and Mokpo Metropolitan City through the Capacity Building Project for the Development of Mokpo Seafood Industry-Based Complex (No. B0080416003290) and the National Research Foundation (NRF) funded by the Ministry of Science and ICT (MSIT), Republic of Korea (No. 2019R1I1A3A01059211).

Declarations

Conflict of interest

None of the authors have conflicts of interest to disclose.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Su-Young Choi and Su Yeon Lee have equally contributed in this study.

Contributor Information

Su-Young Choi, Email: csy971016@naver.com.

Su Yeon Lee, Email: cogus1126@naver.com.

Hyung Gyun Kim, Email: khg8279@naver.com.

Jae Cheon Jeong, Email: noface21@naver.com.

Don Carlo Batara, Email: don_laze@yahoo.com.

Sung-Hak Kim, Email: sunghakkim@jnu.ac.kr.

Jeong-Yong Cho, Email: jyongcho17@jnu.ac.kr.

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