ª Ÿ (Korean J. Medicinal Crop Sci.) 19(2) : 117 125 (2011) ³ z ù x Melatonin Serotonin w e w Jin Ling*Á½ **Á **Á *Á *Á *Á ***Á x *, ** * w œw, ** w Á w, *** l The Effect of Extracts of Berberis koreana Bark by Lactobacillus Fermentation on the Concentration of Serotonin and Melatonin in the Serum of Treated ICR Mice Jin Ling*, Ji Seon Kim**, Yong Chang Seo**, Woon Yong Choi*, Ju Hee Ahn*, Choong Je Ma*, Chang Soon Yoon*** and Hyeon Yong Lee*, ** *College of Bioscience and Biotechnology, Kangwon National University, Chuncheon 200-701, Korea. **Medical & Bio-Material Research Center and College of Bioscience and Biotechnology, Kangwon National University, Chuncheon 200-701, Korea. ***Shebah Biotech Co., Hallym Business Incubator/Industry-University, Coop Center #301, Chuncheon 200-702, Korea. ABSTRACT : This study was to investigate the effect of fermentation extracts on the concentration of serotonin and melatonin in the serum of the ICR mice. The ICR mice were divided into water control group, lactobacillus fermentation solution including (Lactobacillus paracasei and Bifidobacterium longum B6) control group, positive control group (milk and doxylamine succinate), negative control group (caffein) and the groups treated with the extracts of Berberis koreana bark (WE: water extracts, FE-L.P: fermentation extracts of Lactobacillus paracasei, FE-B.L: fermentation extracts of Bifidobacterium longum B6). After ten-day feeding treatment, the mean concentration of serotonin for water control, WE, FE-L.P and FE- B.L group was 134.72, 183.01, 232.09 and 223.78 ng/, respectively. The mean concentration for FE-L.P and FE-B.L group were approximately 66% larger than that for water control group. The mean concentration of melatonin for water control, WE, FE-L.P and FE-B.L group was 76.92, 106.66, 157.56 and 141.81 pg/, respectively. The mean concentration of melatonin for FE-L.P and FE-B.L group were also larger than that for water control group. Our results indicated that the fermentation extracts of Berberis koreana bark have relatively greater potential to induce secretion of serotonin and melatonin. Therefore, the fermentation extracts have antidepressant effect. Key Words : Berberis koreana bark, Fermentation, Serotonin, Melatonin, Antidepressant ƒ w wù ƒ w ù h ö wš rwš w (Park et al., 2004). 6~17% š û 2 ùkùš (Song and Li, 2002), p z, s» p» ƒ w š š (Kim et al., 2000; Chung, 1996). w wì,,, ƒ,. šm 2 y k k y w ƒ š w (Hong et al., 1998). w yw ³ w wš w,, z w. p norepinephrine, serotonin monoamine v»w ƒ w (Kim and Lee, 2004). x, e w w monoamine w y w tricyclic antidepressants (TCA) monoamine w w monoamine yz monoamine Corresponding author: (Phone) +82-33-250-6455 (E-mail) hyeonl@kangwon.ac.kr Received 2010 November 5 / 1st Revised 2011 April 19 / 2nd Revised 2011 April 21 / Accepted 2011 April 22 117
Jin LingÁ½ Á Á Á Á Á Á x oxidase inhibitor (MAOI) š,, m, x ƒ š š š (Lee et al., 2003). w ƒ w š. ù (Berberis koreana) ù ù ù z ƒ w p wù,» w û s (Jin et al., 2008; Cho and Kim, 1974). jƒ 2m y q ƒ ƒ ù w x š 2 ƒ š 1 ƒ ƒ ƒ ù. w wš ù, m, w, x, w³, w y, w, z ƒ š (Jin et al., 2009; Qadir et al., 2009). w ù ethanol y e ethanol n ƒ š ƒ w š š š (Cho and Kim, 1974), ù y Majarine (5,6- Dihydro-9,10 dimethoxybenzo [g]-1,3-benzodioxolo [5,6-a] quinolizinium) n x w w e š š š (Kim, 1986). wr, z ƒ» t, t, y t w y š wì w t z x ¾ ƒ š». z t y» t š (Park et al., 2006), p v p (probiotics) ³» x w š. ³ z t p t w w ü y,, ³, g l w, w w wš e w š (Kim et al., 2002). w w ü w p p» w š, ³ z w z w ƒ š š (Yoon et al., 2009). w, ¾ ù z» w ù w z w w. ù w z y wš x mw yw d w serotonin melatonin y d w. w z» w» w z ù w z z y š wz ù» z t w» w w w» w x ww. 1. x x ù w p w, k z w. 100 g ù v y þƒ»ƒ v j 10 w 100æ 12 2z w. z óù z, ù ³ Lactobacillus paracasei (L.P) y Bifidobacterium longum B6 (B.L) 10 CFU/ w 5 0.05% L-cysteine HCl ƒ MRS broth w 37æ x» Gaspak anaerobic system (BBL, Cockeysville, MD, USA) 96 w. ƒƒ w z» (rotary vaccum evaporator N-N series, Evela, Tokyo, Japan) w w w x w. 2. s s x s s s HEK293 (human embryonic kidney cell, ATCC, Manassas, VA, USA) w š Roswell Park Memorial Institute Medium (RPMI 1640) 10% Fetal bovine serum (FBS) ƒw incubator (37æ, 5% CO 2 ) w. 3. s d ù s w» w s HEK293 w sulforhodamine B (SRB) assay (Kim et al., 2007) w s d w. SRB assay s w s ù d w x s HEK293 (in 10% FBS media) 4~5 10 4 cell/ 96 well plate ƒ well 100 ƒw 24 (37æ, 5% CO 2 )w z ƒƒ 0.2, 0.4, 0.6, 0.8, 1.0 / 100 ƒw 48 w. z wš ƒ 10% (w/v) trichloroacetic acid (TCA) 100 ƒw 4æ 1 ew z 4~5z w TCA wš plate w ƒ well 1% (v/v) acetic acid 0.4% (w/ v) SRB 100 ƒwš 30 g. w w 1% acetic acid 4~5z, k z 10 mm tris buffer 118
melatonin serotonin w ù z e w 100 ƒw ü z 540 microplate reader (THERMO max, Molecular Devices, Sunnyvale, CA, USA) w Ÿ d w. 4. x,, 1) x x p (Orient Bio Inc. Seongnam, Korean) f ICR (4, 22~24 g) w w 9 ù w 20 w. 2) 24 ± 1æ 55 ± 10% g, y»z 10~15 z/hr, 12» w. šx w, ³w w. x 10 k z x w. 3) n milk 1, (doxylamine succinate) 10 1 w š caffein 0.6 1 w. ù [water extract (WE), fermentation extract by Lactobacillus paracasei (FE-L.P), fermentation extract by Bifidobacterium longum B6 (FE-B.L)] ƒƒ 75 1 w. ³ w š w» w 8log CFU/ z ³ z (L.P B.L) ƒƒ 1 w. w n w. 4) x serotonin melatonin d w Serotonin ELISA kit Melatonin ELISA kit GENWAY (San Diego, USA) l w š doxylamine succinate Boram Pharm (Ansan, Korea) l w w, caffein Samchun pure Chem. (Pyeongtaek, Korea) l w w. 5. x x 2 w n 2 z x w. ƒ 4 kw x tube w (retro-orbital sinus bleeding) x w z, 3000 rpm 15 w x EDTAƒ tube w w. 6. ELISA w serotonin d 1) Sample vr 20 x polystyrene tube z 100 assay buffer š vortexw. 25 acylation reagent (3% acetic acid anhydride in acetone) z vortex k z, tube 37æ 15 g. š 2 assay buffer z vortex k z 1,500 g 10 w e jš û w. 2) Serotonin vr 50 standard acylated control acylated sample ELISA well plate ƒƒ š, 50 serotonin-biotin 50 serotonin arntiseum (wx ) š plate z, plate y 2~8æ 16~20 g. plate y wš 250 wash buffer (phosphate buffer) 3z w z wash buffer w. vr 150 enzyme conjugate ƒw z y incubator (18~25æ, 500 rpm) 60 w. y wš w z 250 wash buffer 3z w. ƒƒ well 200 para-nitrophenylphosphate (PNPP) substrate solution š incubator (18~25æ, 500 rpm) 30 w z, ƒƒ well 50 PNPP stop solution k 405 Ÿ d w (Hong et al., 1999). 7. ELISA w melatonin d 1) Column Melatonin w column methanol (undiluted) 1 1 200 g 2z w š,» 2 column 1 200 g 2z w. 2) Sample Column tube š 0.5 standard, control sample ƒƒ column š 200 g 1 wš, 10% 1 methanol 500 g 1 2z w column w. polystyrene tube column wš column 1 methanol (undiluted) 1 200 g w. Column wš tube sw methanol k z 0.15 w. 119
Jin LingÁ½ Á Á Á Á Á Á x 3) Melatonin vr 50 ELISA well plate standard, control sample š 50 melatonin-biotin 50 melatonin-antiserum (wx ) ƒwš, y w 2~8æ 14~20 g. wš 250 assay buffer 3z w z w. vr secondary antibody enzyme 150 w jš y 120 k z 3z w. ƒƒ well 200 PNPP» z, (18~24æ) orbital shaker 30 g. 3 M PNPP stop solution 50 k 405 Ÿ d w (Hong et al., 1999). 8. HPLC w ù phenolic acids w œ ù phenolic acids w š š j m v (HPLC; High-peroformance Liquid Chromatography) w w. HPLC»» UV absorbance detector (280, 0.05 AUFS)ƒ š j m v (HPLC, Waters M600E, Milfold, MA) w, phenolic acids w» w Waters Spherisord ODS2 Column [250 4.6 (inside diameter), 5 ] w. œ ù w HPLC water 0.2 syringe filter wš Injection volume 20 d w. A [1 mm trifluoroacetic acid (TFA)ƒ w 10% (V/V) acetonitrile], B [1 mm TFAƒ w 40% methanol 40% acetonitrile] w š (0 min 90% A 10% B; 0~10 min 90% A 10% B; 10~15 min 60% A 40% B; 15~24 min 60% A 40% B; 24~ 40 min 0% A 100% B; 40~45 min 90% A 10% B; 45~50 min 90% A 10% B) w 1.0 / min. Phenolic acids t vanillin, vanillic acid, p-hydroxybenzoic acid, p-hydroxybenzaldehyde, trans-p-coumaric acid, trans-cinnamic acid, trans-ferulic acid 10, 50, 100 / w w (He et al., 2010). 9. Scanning electron microscope (SEM) y z ùkü ù p š ù z œ x (Low Vacuum-Scanning Electron, 1 K) xk w. 3% glutaraldehyde 3 š w z, 0.1 M sodium phosphate buffer (ph 6.87.2) 15 3z w. 2% aqueous osimium tetroxide w 4æ 26 zš (postfixation) 0.1 M sodium phosphate buffer 15 3z. 30% acetone 10% graded acetone series k eš, k isoamyl acetate 34z z 4æ þ. z Hitachi HCP-2 critical point dryer w liquid CO 2 w (critical point drying, CPD) Hitachi E-1030 sputter e 10 Ì v (Au gold coating) z œ x w image data file z ƒƒ x k wš w (Kim and Lee, 2005). 10. m e mean ± SD ùkþ. x m v SPSS 16.0 w, (ANOVA: analysis of variance) w z α =0.05 Duncan (DMRT: Duncan's multiple range test) w. š 1. s d x ù ƒƒ 0.2, 0.4, 0.6, 0.8, 1.0 / w s HEK293 w s d w. Fig. 1 s w, p WEƒ 0.6 /» s ƒw ùkü. FE-L.Pƒ û s ùkü WE 0.6 / l Fig. 1. Cytotoxicity of Berberis koreana bark on human normal cell line, HEK293. (WE: water extract at 100, control. FE-LP: fermentation extract by Lactobacillus paracasei. FE- B.L: fermentation extract by Bifidobacterium longum B6.). Each value represents the mean±sd. 120
melatonin serotonin w ù z e w s ùkü. š 1.0 / w WE 20.52% s w FE-B.L FE-L.P ƒƒ 17.39%, 15.96% w 3.1%~4.5% z ƒ ùkü. š œ w Spirulina maxima w (Oh et al., 2010) 13.8%~18.6% s w ùkü, š œ Spirulina maxima s 1.7%~4.8% z w w ùk ü. w w ³ z z w in vivo w z z ƒ ƒ û ùkü, z w ùkü p ƒ q, x» š (Yoon et al., 2009). ³ z mw z ù x y q g jš ww y j d.» ³ z mw z w wz ù w» t t ƒ w, w zœ w, j š. 2. Serotonin Monoamine serotonin (5-hydroxytryptamine : 5HT),, m w y (Kwon et al., 2000)w, œ w (Lee et al., 1996), w ƒ š š (Choi et al., 1988). Fig. 2 10 n 2 x w x serotonin d w. ù (WE, FE-LP, FE-B.L) w (water), ³ z (L.P B.L), (milk) (doxylamine succinate) w er (caffein) w w. ú milk, doxylamine succinate, WE, FE-L.P FE-B.L n serotonin w ƒw w, p 10 ƒƒ 180.29 ng/, 237.36 ng/, 216.62 ng/, 265.35 ng/ 272.35 ng/ ƒ ùkû. û caffein n serotonin w w 8 69.12 ng/ ƒ û. 10 ³ z n w L.P B.L serotonin w water w ùkù l ³ z w e (P < 0.05). Serotonin w y n l w, milk û w ƒw ù water m w ƒ š doxylamine succinate WE ƒƒ 4, 8 l š FE- L.P FE-B.L ƒƒ 2 l water ƒw, caffein 8 ú l (P <0.05). ù z doxylamine succinate z serotonin w e y w. 10 ù»k n x serotonin s³w w water, milk, doxylamine succinate, caffein, L.P Fig. 2. Comparison of serotonin concentration in the serum of ICR mice by different oral administration treatment [water, milk, doxylamine succinate, caffein, lactobacillus fermentation solution (L.P and B.L) and the extracts of Berberis koreana bark (WE, FE- L.P and FE-B.L)]. Each value represents the mean±sd. Means followed by different letters differ significantly (P <0.05). 121
Jin LingÁ½ Á Á Á Á Á Á x B.L ƒƒ 134.72 ng/, 167.58 ng/, 194.11 ng/, 100.08 ng/, 147.63 ng/ 145.21 ng/ ùkü. w r ù n WE 183.01 ng/, FE- L.P 232.09 ng/, FE-B.L 223.78 ng/. Doxylamine succinate, WE, FE-L.P FE-B.L n serotonin w water w ƒƒ 44.08%, 35.84%, 72.28% 66.11% m w ƒw š milk n 24.39% ƒw ù ƒ caffein n 25.71% w (P < 0.05). Lee w (~ ), w ( «), ( Œ) y ( Ž) n x serotonin w d w w ƒƒ 52.75%, 47.76%, 31.37% 41.76% ƒw š š (Lee et al., 2000). w x ù z n x serotonin ƒ 66% ƒw ù z serotonin z š š. w FE-L.P FE-B.L w WE w 20% ƒw l z mw ù ƒ» w serotonin z š y w, z mw y ƒw ù y z ù» serotonin ƒ. 3. Melatonin Melatonin (N-acetyl-5-methoxytryptamine) s y,, w y, w,, w ù» w e š w (Kang and Baick, 2008; Na et al., 2008). Table 1 ICR w 10 2 x w x melatonin w d w. ú milk, doxylamines succinate, WE, FE-L.P FE-B.L n melatonin w ƒw w š 10 ƒƒ 159.46 pg/, 226.21 pg/, 124.01 pg/, 195.94 pg/, 187.33 pg/ ƒ ùkþ. û caffein n melatonin w w 10 38.58 pg/ ƒ û. water ³ z n (L.P B.L ) 10 w yƒ j. Melatonin w y n w 2, 4, 6 milk, doxylamine succinate, FE-L.P FE-B.L n w 4 ƒƒ water ùkü š 8 l L.P B.L w water ùkü (P <0.05). melatonin w n w š w. 10 ù»k n x melatonin s³w w milk doxylamine succinate water (76.92 pg/ ) w ƒƒ 0.7 1.4 ƒw wr, caffein 0.3 (P < 0.05). ù w w FE-L.P (157.56 pg/ )>FE-B.L (141.81 pg/ )>WE (106.66 pg/ ) ùkü, water w 38% w ƒ. Hong w melatonin w ƒ ùkù k (20.4%) ƒ ù ƒ melatonin {wš y w (Hong et al., 1999). FE-L.P melatonin w 157.56 Table 1. Melatonin concentration in the serum of ICR mice by different oral administration treatment [water, milk, doxylamine succinate, caffein, lactobacillus fermentation solution (L.P and B.L) and the extracts of Berberis koreana bark (WE, FE-L.P and FE-B.L)]. Samples Melatonin concentration (pg/ ) 2 day 4 day 6 day 8 day 10 day Water 575.67±8.33 de 578.44±5.59 de 574.32±4.79 de 577.04±4.85 d 579.14±3.33 e* Milk 105.50±7.95 ab 127.39±14.57 bc 125.13±7.22 bc 135.66±23.53 b 159.46±16.60 c Doxylamine succinate 122.90±15.66 a 168.29±28.39 a 205.06±18.36 a 201.29±12.08 a 226.21±21.07 a Caffein 573.66±6.15 e 547.86±4.39 e 552.83±4.24 e 541.09±3.75 f 538.58±3.61 f L.P 580.66±5.36 cde 586.62±9.80 d 594.76±15.73 cd 599.36±11.91 cd 595.35±12.56 de B.L 586.93±10.49 bcde 582.57±9.67 de 585.65±9.16 de 591.36±9.44 cd 593.66±12.98 de WE 599.07±9.82 ad 593.03±19.83 cd 101.77±15.61 cd 115.41±21.47 bc 124.01±19.66 d FE-L.P 117.50±18.09 a 162.35±19.47 ab 122.89±24.11 bc 189.14±18.26 a 195.94±21.33 ab FE-B.L 104.55±7.82 ac 110.34±11.07 cd 162.35±28.96 b 144.46±21.43 b 187.33±16.67 bc * Mean±SD with different capital superscripts in the same column are significantly different at P < 0.05. 122
melatonin serotonin w ù z e w Fig. 3. Typical HPLC chromatogram of phenolic acid standards (A: p- hydroxybenzoic acid. B: vanillic acid. C: p-hydroxybenzaldehyde. D: vanillin. E: trans-p-coumaric acid. F: trans-ferulic acid. G: trans-cinnamic acid.). Table 2. Comparison of phenolic acids in the extracts of Berberis koreana bark according to different extraction processes. ( /100 g) Sample p-hydroxybenzoic acid vanillic acid p-hydroxybenzaldehyde vanillin trans-p-coumaric acid trans-ferulic acid FE-L.P 25.60 50.65 1.28 23.22 27.18 32.00 FE-B.L 17.72 57.70 14.60 18.20 39.73 FE-LP: fermentation extract by Lactobacillus paracasei. FE-B.L: fermentation extract by Bifidobacterium longum B6. pg/ ù ƒ doxylamine succinate 184.75 pg/ ¾ w w. ù FE-L.P doxylamine succinate m ƒ ùkù l melatonin w z š (P <0.05). l ù z serotonin melatonin w e y w š p z» w ù z ƒ, w n w y w. wz ù w w w ù z y w v w. 4. HPLC w ù z phenolic acids w ù v phenolic acids w w» w p-hydroxybenzoic acid, vanillic acid, p- hydroxybenzaldehyde, vanillin, trans-p-coumaric acid, transferulic acid, trans-cinnamic acid 7ƒ t w š HPLC w d w ƒƒ 9.95, 11.34, 13.52, 16.65, 20.02, 21.00, 30.63 (Fig. 3). Table 2 ù z phenolic acids w w. z ù phenolic acids vanillic acid w ƒ ùkù trans-cinnamic acid w. P- hydroxybenzoic acid, vanillin, trans-p-coumaric acid FE- L.Pƒ ƒƒ 25.60 /100 g, 23.22 /100 g, 27.18 /100 g FE-B.L w ƒƒ 44.5%, 59.0%, 49.3% w ƒw. Vanillic acid trans-ferulic acid FE-B.L w ƒƒ 57.70 /100 g, 39.73 /100 g FE-L.P w ƒƒ 13.9%, 24.2% ƒ. P-hydroxybenzaldehyde FE-L.P š FE-B.L w.» l ù ³ z phenolic acids w yƒ y w wz ù phenolic acids w ¾ ƒ v w. 5. Scanning electron microscope (SEM) ù v xk y w» w œ x w w (Fig. 4). A xk j û 123
Jin Ling 김지선 서용창 최운용 안주희 마충제 윤창순 이현용 Fig. 4. Morphology observation of Berberis koreana bark by SEM (A: water extract at 100, control. B: fermentation extract by Lactobacillus paracasei. C: fermentation extract by Bifidobacterium longum B6.). 반면 발효 추출물인 B와 C의 표면 조직이 파괴되어 작은 절 편으로 조각나 있었으며 다공성 조직이 형성되어 있음을 확인 할 수 있다. 이는 발효과정에서 생성된 유산 및 유기산으로 매자나무 조직을 느슨하게 함으로써 조직이 파괴되어 절편이 쉽게 형성되거나 혹은 발효과정에서 생성된 가스가 국부 조직 을 파괴하여 다공조직이 형성된 것으로 사료된다. SEM 사진 을 통해 유산균 발효가 매자나무 내부까지 영향을 주어 세포 벽이 깨지면서 조직 및 구조가 변형, 파괴된 것을 확인할 수 있는데, 이는 매자나무의 생리활성이 증가한 원인중의 하나로 사료된다. 또한 유산균 및 대사산물이 독성감소 및 활성증진 의 원인일 가능성도 높아 향후 유산균과 이의 대사산물에 대 한 연구가 더 필요하다고 사료된다. depression and menopausal syndroms in women at midlife. Korean Journal of Women Health Nursing. 3:230-240. Cho SH and Kim CI. (1974). Effects of Berberis koreana palibin on sleep duration and rectal temperature in mouse. Korean Journal of Pharmacology. 10:61-65. Choi BS, Jeoung HY and Han SH. (1988). Low platelet serotonin level in lnsomnia. Journal of the Korean Neuropsychiatry Association. 27:487-495. Hong SC, Han JH, Lee SP and Bang SK. (1998). The effect of tricyclic antidepressant (Dothiepin) on sleep in depressed patients. Journal of the Korean Neuropsychiatry Association. 37:728-736. Hong YY, Moon IS, Kom DI and Lee TK. (1999). A study on melatonin, serotonin secretion change and behavior in the rats treated with Yiseontang, Gammakdaejotang, Sanjointang and Sanjogammaktang. The Journal of Oriental Gynecology. 12:209-230. 감사의 글 He X, Kim SS, Park SJ, Seong DH, Yoon WB, Lee HY, Park DS and Ahn J. (2010). Combined effects of probiotic fermentation and high-pressure extraction on the antioxidant, antimicrobial, and antimutagenic activities of Deodeok (Codonopsis lanceolata). Journal of Agricultural and Food Chemistry. 58:1719-1725. 본 결과물은 2011년 교육과학기술부로부터 지원받아 수행된 연구 (지역거점연구단육성사업/의료 바이오신소재융복합연구 사업단)로 이에 감사를 드립니다. Jin L, Han JG, Ha JH, Jeong HS, Kwon MC, Ahn J, Kim JC, Choi GP, Chung EK and Lee HY. (2008). Effect of immune LITERATURE CITED activity on Berberis koreana palibin by ultra high pressure low temperature process. Korean Journal of Medicinal Crop Science. 16:439-445. Chung ES. (1996). An analysis of th relationship between 124
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