MinKyun Na {2012), l^ghiSn ciJm v^ d^c dilm thirc vjt ciia cay 1^ tan phy thu hdi tjii Sa Pa", T<fp chi Dugc li?u, 17(2X 63-68.6.
Gewali, MB (2008), Aspects of Traditional Medicine in Nepal, Institute of Natural Medicine, University of Toyama, Japan, 81- 82. 7. Ph^m Qu6c Tuin, NguySn Dure Hijng, Nguyin (Juoc Tuin, Nguyin Minh Khoi, MinKyun Na, Phirong Thi?n Thuong (2013),'•TTiinhphanflavonoidtirphSntrfeim}! dit ciia cay lac tan phy", Tgp chi Dupc lieu. 18(2), 97-102. 8. Sun H-X et al.
(2003). Cytotoxic pcntacyclic triterpenoids from the rhizome of Astilbe chinensis, Helvetica Chimica Ada, 86, 2414-2423. 9.
Jong SY et al. (2006), "Steroids from aerial paits of Atermisia princeps Pampanini", Korean Journal of Medicinal Crop Science, 14(5), 273-277. 10. Angelika L et al (2005), "Phenolic and terpenoid compounds from Chione venosa (SW.) URBAN var.
venosa (Bois Bande'), Phytochemistry, 66, 2381-2387. 11. Antonio G, Francesco P (1984), "A butenonide atypical of the Ranunculaceae' Aquilegjolide from Aquilegia atrata fvar. atroviolacea)". Phytochemistry, 23 (10), 2394-2396. 12. Nighat N et al. (2011), "Evaluation of antioxidant and antimicrobial activities of Bergenin and hs derivatives obtained by chemoenzymatic synthesis", European Journal of Medicinal ChemistryA6,2415-2420.
Tgp chiDiffrc lieu, tap 19, s6 4/2014 (Trang 201 -206)
NGHIEN c i r u SANG LQC CAO CHIET CON Xtf CAC LOAI TAG BIEN VI$T NAM CO HO/^T TINH KICH HO^T THV THE PPARs
VA GIAM HAM LI/ONG LIPID 6 TE BAG GAN HepG2 Hoang Minh Hien'', Ngd Thi Hoii Tliu', Luu Thj Tim', Le Thi Tham', Nguyin Cim Hi', Bang Diim Hon^, Sung-Joon Le^
' Vien Cong nghe sinh hoc Vien Han Idm Khoa hoc va Cong nghe Viet Nam ' Tritang Dgi hoc Korea, Hdn Quoc
* E m a i l : [email protected] (Nhjn bSi ngiy 25 IhSng 6 nam 2014)
T6m tSt
Receptor d w c host hoi bjng chat ISng sinh peroxisom (PPARs) d6ng vai trt quan trong trong ph6ng ngto cSc benh lien quan din xo vfla dOng msch, mO miu v4 gan nhiem mO. Trong nghien cim njy, chung toi da liin hinh sing Igc chil liich how Ihv Ihi PPARa, PPAR8/p va PPARy ICr cao chiit c6n ciia 4 loai tao biin Codium fragile, Sargassum duplicatum.
Caulerpa racemosa vi Gracilaria asiatlca b k g phin tich gen chi Ihi lociferase va qPCR Kit qua nghiin ciiu Ihu dugc da cho thiy cao chiit c6n tir tao Ivc C. fragile l<ich host thu thi PPARa vS PPAR8/p cao gip 2-4 lin so vcSi d6i chiing Cao C.
fragUeii khong gay doc t i bao va c6 ISc dung giam nong do cholesterol (• 28%) v4 Iriglyccril (- 49%) nong li bao gan HepG2 Dim trin cSc kit qua nghien ciru thu duoc, ehiing loi riu ra kit lu}n cao chiit cin tir C fragile kich hoat thu the PPARo vi PPARS/p dan din giam ham lirong lipid 6 t i bao gan HepG2.
Tit kh6«: Codium fragile. Gan nhiim md. HepC2. PPARa. PPARS/f. Rai loan chuyin hoa lipid Summary
Screening of the PPARs Activator Reducing Hepatic Lipid from EtOH Extract of Vietnamese Seaweeds Using HepG2 Hepatocytes
Peroxisome proliferalor-aclivated leceptois (PPARs) play cntical rales in die treatment "f atherosclerosis, hypemiglycendemia and hcpalic steatosis. In diis smdy, we screened PPARs aclivaton itom 4 seaweed cthanol extracts Codium fragile. Sargamim duplkalum. Caulerpa racem«a. and Cradlaria osiatica by reporter gene assay-based luciferase and qPCR.
TUe oblained results showed that C fragile extiact activated PPARn and PPAR5([3 activity by 2 to 4 tunes higher dian by the controls. Cfraglle extmcl exhibited no cytotoxic activity on HcpG2 cultured hepatocytes. Cultured hepatocytes stimulated with C fragile extmcl signillcanlly reduced cellular cholesterol and triglyceride concennalions by - 28% and - 49%, lespcctively In conclusion, C fragile extract is hypolipidemic and hepatic steatosis agem by Bclivalion of PPARa and PPAR8/p.
Keywords: Codium fragile, HepG2. PPARa. PPARS/f. Hyperlriglyeeridemla. Hepatic neatcis
i TfpM Duac lilu, tip 19, si 412014 201
1. Dat van de
Roi loan chuy6n hoa lipid, tang md mau, la mot tinh trzing lam sang dac tnmg bcri nong do triglycerid (TG) va cac acid beo d6ng thai voi ham lirgfng lipoprotein - cholesterol ^ trong thap (LDL) trong huyet tucrng cao (2). Tang md mau la nguyen nhan gay xo vfta dong mach, cac benh lien quan d6n tim m^ch, gan nhiem md, d6 khang insulin, va cac roi loan chuyin hoa khac. CJ Viet Nam s6 nguoi mac b?nh r6i logn chuyen hoa lipid dang c6 chieu huong gia tang nhanh chong trong thai gian gan day. Theo kit qua nghien cuu nam 2011 cua Vien Dinh duSng, rdi loan chuyin hoa lipid co ty 1? 26% 6 nhung nguai tuoi tir 25 den 74. Rieng tEii cac thanh pho lan nhu Ha Noi, TP.HCM, ty le neu tren co thi len din hon 40%.
Do v^y, dilu tri cac bfnh lien quan din rli loan chuyin hoa lipid la mpt thach thurc khong nho so v6i tinh trang gia tang manh nhu hien nay.
Receptor dugc boat hoa bang chat tang sinh peroxisom (Peroxisome proliferator - activated receptors; PPAR) la thy thi thuoc ho cac receptor hormon ngi bao, dugc Issemann va Green (4) phat hi$n lan dau tien a te bao gan chugt vao nam 1990. PPAR khong chi tham gia vao qua trinh chuyin hoa lipid, glucose, bi?t hoa te bao md ma chung con lien quan den vi^c lam giam ung thu va khang viem (5, 8). Cho den nay co 3 lo£ii dong phan PPARs da dugc xae djnh - PPARa, PPARy va PPARS/p. Trong do, PPARa dugc nghien cihi nhilu nhat tiep din la PPARy va PPAR5/p.
PPARa CO vai tro quan trgng trong kiem soat P oxy hoa acid beo a peroxisom va trong cac qua trinh chuyin hoa acid beo khac nhu: hSp thu acid beo, van chuyin lipoprotein, oxy hoa acid beo va chuyen hoa cholesterol. Chat kich boat PPARa bao gom cac din xukt cua fibrat, chiing co kha nang lam giam TG va tang lipoprotein cholesterol ty trgng cao (HDL; cholesterol t6t) trong mau qua do gop phan dilu tn, phong ngira xa viia dgng m^ch va cac bien chung tim mach (5). PPARy dong vai tro trung tam trong viec hinh thanh mo ma va trong qua trinh dieu hoa glucose. PPARy co chkt kich hoat la cac din xuat cua thiazolidinedione (troglitazon, pioglitazon va rosiglitazone). Khi cac chat kich ho^t nay gin vai PPARy, chung lam tang tfnh nhay cam cCia cac mo vai insulin, do vay tSng cuang su dyng
glucose va lam giam lugng glucose trong mau (5) PPARS/p dugc cho la tham gia vao qud trinh trao d6i lipid va dilu boa nSng lugng. Khi PPAR6/p dugc kich ho^t se ket n6i ca va te bao mo din den cam ling sinh nhi^t, do do lam giam tich tiiy ma trong cac mo ma va dieu khiSn giam md trong ca the (1). Vi vay, viec xae dinh cac chat co kha nang kich ho^t PPARs va do do giup cho viec ngan ehan va dilu trj roi loan chuyen hoa lipid va cac b^nh co lien quan v6i hi^u qua cao va an toan la rdt cin thiet.
Tao biln la mgt nhom thirc v^t song d biln.
Chung chura nhieu chdt dinh duong va cac chat co ho^t tfnh dugc hgc co Igi cho siic khoe cua con nguai nhu la chat chong oxy hoa, chong viem va ung thu. Ben canh do, tao bien con chua rit nhieu khoang chit da va vi lugng, vitamin va cac acidacid beo khong bao hoa (7). Trong nghien ciiu nay, chung toi sang Igc cao chiet con co kha nang kich boat thy the PPARs tir 4 loai tao bien Viet Nam bling phan tich gen chi thj luciferase va qPCR. Ben c^nh do, chiing toi ciing nghien cuu hoJit tinh doc t l bao va tac dung dugc ly len sir thay doi ham lugng lipid cua cao chiet con co kha nang kich boat thy the PPARs a te bao gan HepG2.
2. f>6i tuvng va phirong phap nghiSn cuu Quy trinh tdch chiet dich co hogi tinh kich hogt PPARs
4 loai tao bien Codium fragile, Sargassum duplicatum, Caulerpa racemosa va Gracilaria asiatica do phong Cong nghe tao, Vi$n Cong ngh? sinh hgc cung d p . Cac mau rong biln dugc nia sach bang nuac biln va nuac ngpt, phcri kho a nhiet dg phong din dg Im 20- 30 % va nghiln thanh bgt. Bgt rong dugc bao quan a -20''C.
Trong cac loai dung moi dugc sir dyng cho viec chiet chit co ho^t tinh sinh hgc tir thyc vat, con la dung moi dugc nhieu nha ngbiSn ciu l\ra chgn dau tien bdi: con co kha nang hoa tan va khuylch tan nhanh cac chat tan vao dung moi;
tang sy djch chuyen ciia cac phan tu chat tan qua vach te bao; va quan trgng nhlt la djch chiet tir con CO tinh an toan cao cho nguai sii dyng so voi cac lo^i dung moi khac (3). Vai myc dfeh tach chiit va nghien cuu ho^t tinh sinh hgc ciia chiing tren mo hinh te bao, bgt rong biln dugc ngdm chiet nhilu lln vcri con 80%. Cat quay duoi dung
202 Tgp chi Duac lieu, tdp 19, s64l20U
mdi, thu va xdc djnh trgng lugng cao chiit con.
Sau qua trinh chiet, cao chiit con ciia 4 loai nghien cuu c6 dg Im 10-20 % vcri hieu suit tach d^t dugc tir 2-4 %.
Nudi cay te bao va cdc thi nghiem oSi vdi dfch chiet dir^c tien hdnh tren te bdo
HepG2 la dong te bao on djnh dugc tach tii t l bdo gan ciia be trai nguai My 15 tu6i bi mic b^nh ung thu bieu mo gan biet hoa. Bai vi te bao HepG2 CO sy on djnh cao vl hinh thai t l bao va chuc ndng biet boa trong nuoi cay in vitro, nen dong te bao nay dugc su dyng cho cac nghien ciru ve trao ddi chat trong gan nhu trao doi cholesterol, lipit va cac nghien ciiu lien quan din thuoc (6). Te bao HepG2 dugc nuoi ciy tren moi trudng Dulbecco's modified Eagle's medium (DMEM) cd chira 10% fetal bovine serum (FBS), 100 U/mL penicillin, and 0,1 mg/mL streptomycin trong tii nuoi cdy vd triing d 37°C, 5% CO2.
Doi vdi cdc thi nghiem cd su dyng cao chiet tdo, ban ddu cac te bao HepG2 dugc nuoi ciy 24 h trong mdi trudng DMEM trong dTa nudi ciy loai 6 gieng vdi mat dg 1 x 10^ te bao/ giing. Sau 24 h nudi ciy tl bao HepG2 dugc u vdri nhilu dai n^ng dg ciia djch chiet (tir 4 den 10 |ig/mL) va 10
^M chat kich ho^t cua PPARa (fenofibrat), hoac PPARy (troglitazon), hoac PPAR5/p (GW0472) trong 24 h tiep theo. 0,1% DMSO dugc su dung nhu la ddi chiing. Sau 24 h, thu t l bao va sir dyng cho cdc thf nghi?m ve phan tfch ham lugng lipid ho^c phdn tich bieu hi^n gen.
Phdn tich gen chi thj luciferase Phdn tich gen chi thi luciferase dugc thuc hi?n bdng each sir dyng t l bao HepG2. Ddu tien, te bdo HepG2 sS dugc nudi ciy trong mdi trudng DMEM d dTa nudi ciy logi 24 gieng vdi mat dg 2 X 10^ tl bdo/ gieng. Sau dd, cac tl bao dugc gdy nhilm vdi cdc vector pCMV-3xPPRELuc, 0- galactosidase - PSV va pSG5 - PPARa hoac pBABE - Zeo - PPARy hodc pAdTrack - CMV - PPARS/p (Addgene, Cambridge, MA). Sau 24h gay nhiem, te bdo gdy nhilm dugc li vdi ddi ndng dp ciia cao chiet con tir cdc loai tao bien Vi?t Nam (tir 4 fig/mL din IOO ^ig/mL) va 10 p ^ fenofibrate, GW0742 vd troglitazol trong 24h tilp theo. 0,1% DMSO dugc sii dyng lam ddi chiing.
Sau dd, cac te bao truyen nhiem dugc dung giai vd phan tich gen chi thj luciferase vdi kit phan
tich luciferase ciia Biotum (Hayward, CA, USA), phan tich ham lugng ^-galactosidase vdi kit Beta- gal Assay (Promega, CA, USA) theo hudng ddn cua nhd cung cdp. Ket qua phdn tich gen chi thi luciferase dua tren ti le chuin boa luciferase vdi hdm lugng /9-galactosidase.
Hogt ti'nh dpc te bdo
Khd nang sdng sdt ciia te bao sau khi u vdi djch chiet dugc phan tich theo phuang phap cua Malek vd cs., (6). Ban ddu cdc tl bdo HepG2 vdi mat do 5x10 te bao/mL dugc nudi cdy va li vdi cao chiet C. fragile d 24-48 gid trong mdi trudng DMEM trong dTa nudi cdy loai 6 giing; Sau 24- 48 gid, loai bd mdi trudng nudi cu va bd sung 100 fiL mdi trudng nudi mdi; Tiep tyc bd sung 10 (iL dung djch MTT gdc vao timg gieng trong dia nudi cay. Ddi chiing dm dugc bo sung 10 ^iL dung dich PBS; U dTa nudi d 37°C trong vdng 4 gid; Bd sung 100 nL dung djch SDS-HCI vao tirng gieng trong dTa nudi vd trpn diu bing pipette; Tiep tyc li dTa nudi d 37°C trong vdng 4 gid; Trdn diu mdu bdng pipette va dpc kit qua d budc sdng 570 nm.
Phan tich hdm lir^ng lipid trong te bdo Tach chiet lipid tdng sd theo cdng bd cua Malek va cs., (6). Ham lugng lipid se duac xdc djnh bdng phuang phap enzym va do tren mdy phan tich ty dpng Cobas C111 (Roche Diagnostic Systems Inc., Indianapolis, IN, USA). Protein tong sd dupc xae djnh vdi kit Bradford protein assay (Bio-Rad, Hercules, CA, USA). Ham lugng lipid trong tl bao sau dd se dugc chuan hoa vdi ndng dp cua protein tdng sd.
Phirffng phdp tdch chiet RNA, tdng hpp cDNA vdphan tich qPCR
RNA tong sd ciia te bao dugc tach chiet theo phuong phapTrizol. cDNA dugc tdng hgp theo kit MultiScribe Reverse Transcription. Miic dg bilu hien cua gen PPARa, PPAR6/p vd PPARy dugc phan tich theo phuong phap ciia Malek va cs., (6).
Thong kephdn tich so li^u
Sd li?u duac trinh bay bang MEAN ± SEM.
Ket qua dugc xCr Iy thdng ke theo phuong phap Student's t-test bang phan mem excel.
3. Ket qua va ban tuan
Sang Ipc kha ndng kich ho^t thu the PPARa, PPARS/p va PPARy tir cao chiet con ciia 4 loai tao bien Vi|t Nam
Tgp cMDugtc lieu, tap 19, so 412014 203
Kha nang kich boat thy thi PPARa, PPAR5/p va PPARy ciia cao chiet cdn tu 4 loai tdo bien C.
fragile, S. diqjlicatum, C. racemosa va G. asiatica dugc xdc djnh bdng phuong phap phan tich gen chi thj luciferase vd djnh lugng qPCR vdi cac ca^
moi dac hieu (Hmh 1).
Ket qud trong Hinh 1 cho thiy, trong 4 lodi dugc thii n^iem chi cd cao chiit con tii tdo lye C.
fragile Id cd khd nang kich hoat thy the PPARa va PPAR8/p. Kit qua phan tich gen chi Ihj luciferase chi ra rang te bdo HepG2 dugc u vdi cao C. fragile a cac ndng dp 4, 20 va 100 [xg/mL tang kha ndng kich hoat thy the PPARa gap 2 vd 3 lln so vdi t l bdo dupc ii 0,1% DMSO (ddi chiing), dat y nghTa thdng ke ve sinh hpc (Hinh I A). Tuong tu, C.
fragile cung tang kha nang kich ho&t thu thi
PPARS/p khi ndng do u cao chiet cdn tdng, tang 0,4 va 1,4 lln d cac ndng dp 20 va 100 jig/mL, dgt y nghia thdng ke ve sinh hgc (Hinh IB). Muc dp bilu hipn gen cua PPARa va PPARS/p cung tang trong \i bao dugc u vdi cao chiet C. fragile (Hinh ID, E). Khi so sanh vdi t l bao dugc ii vdi fenofibrat va GW0742, chiing tdi n h ^ thiy rdng cao chiit cdn tii lodi C. fragile cung cdc tac dyng kich ho?it thy thi PPARa va PPARS/p tuang ducmg hoac thdm chi cao hon vdi chdt chuan.
Tuy nhien, khong loai nao trong tong sd 4 loai cd kha nang kich boat thy the PPARy. Trong khi do chat chuan troglitazon tang khd nang kich ho^t va muc dp bieu hien gen PPARy tuang irng gip 0,5 va 0,8 lan so vdi ddi chirng, d^t y nghTa thong ke vl sinh hgc (hinh IC, F).
Hinh I. Djch chiet C fragile kich ho^t thy the PPARa va PPAR8/p trong te bko gan HepG2. Kha nSng kfch ho^t thy the PPARa (A). PPARS/p (B) va PPARy (C) ciia cao chiit Codium fragile trong 16 bio HepG2 dirpc xSc dinh bang phirong phip phan tich gen chi thj luciferase. (B) Miic d? bi&u hien gen PPARa (D), PPAR5/p (E) \k PPARy (F) trong te bJo HepG2 dupc li v6i djch chi6t Codium fragile trong vong 24h. Miic dp bilu hi^n gen dirpc d ^ h gid bai qPCR vk dirpc chuan h6a vi3i miic dp bieu hi$n gen cyclophilin. So lieu dirpc trinh bay bang mean ± SEM. *P < 0,05, so vdi nh6m doi chiing (li v6i 0,1%
DMSO). Chit chudn cho PPARa la fenofibrat, cho PPARS/p \k GW0742 vk cho PPARy \k troghtazon
204 Tgp chiDucrc lieu, tap 19, so 412014
Tir cdc kit qua thu dugc d tren, chiing tdi chpn ra lodi cd khd nang kich bo^it thu thi PPARa va PPARS/p cao vd ddng thdi cd trir lugng ldn td Codium fragile dl thyc hi?n cac nghien cuu sdu han ve boat tinh doc te bao vd tdc dyng gidm rdi lo^n chuyin hda lipid ciia chiing tren cac ddng t l bdo gan HepG2.
Ket qua thir doc te bao cua cao Codium fragile len te b^o HepG2
Cao chiit cdn td C. fragile dugc khdo sat hoiit
tinh gdy ddc te bao HepG2 thdng qua phuang phdp so mdu MTT [3-(4,5 - dimethyIthiazol-2-yl) - 2,5 -diphenyltetrazoliumbromid] (Hinh 2). Kit qud trong Hinh 2 cho thiy, khdng co su khdc bift mang y nghTa thdng ke ve ti le sdng sot ciia tl bao khdng dugc li (ddi chirng) va dupc ti vdi djch chiet C. fragile a nhieu nong do khdc nhau.
Tir do cho thdy djch chiit C. fragile khdng gdy dge tren te bao vdi nong dg tdi da Id 200 pg/mL trong 24h.
| - 9 0
8 20 40 C. frag//e(^gfmL)
Hinh 2. Ty le song s6t cua ta bko HepG2 dapc u vdri cao chill con C. fragile a cic nong dp khic nhau sau 24 gift.
Cao chiet con Codium fragile cd tac dung lam giam nong dp lipid trong te bao HepG2
PPARa vd PARS/p dilu hda qua trinh chuyen hda lipid npi bao thdng qua cdm ung hap thu acid beo va qua trinh y?-oxy hda acid beo trong te bao gan dan den lam gidm ndng dp TG huyet tuang. Theo Lee vd cs (5), cac chit kich ho^t hai lo^i PPAR ndy d dgng tdng hpp hay ty nhien deu co tac dyng gidm ham lupng TG bang cdch dilu hda sy bieu hipn cac gen dich ciia chiing. Song song vdi cac nghien cuu thii dpc tinh neu tren, mgt so boat tinh dugc ly nhu Id giam cholesterol vd TG giiip phdng ngira va dieu trj cdc b$nh lien quan den tim m^ch ciia djch chiet C fragile dugc xdc djnh tren cac ddng tl bdo gan HepG2.
Anh hudng ciia cao C. fragile len hdm lugng cholesterol va TG trong te bdo HepG2 dugc trinh bdy trong Hinh 3. Ket qua trong Hinh 3 cho thay tuong tu nhu ddi vdi chat chudn fenofibrat, ndng do cholesterol ngi bdo giam cd y nghTa thdng ke phy thupc vao ndng dg cao chiet cdn trong cac te bao dupc ii vdi C. fragile so vdi ddi chiing (Hinh 3A). Ben canh dd, cao C.
fragile cdn cd tdc dyng gidm ddng ke nong dp TG tir 100% trong te bao ddi chirng xudng 67%
(P<0,05) trong tl bao dugc li vdi 20 ng/mL va 51% trong te bao dugc li vdi 100 ng/mL cao chiit cdn C. fragile (P<0,01) (Hinh 3B). Tdc dyng gidm hdm lupng lipid npi bdo cd the so sanh tuong duang giira cao chiet con C. fragile vd chdt chudn fenofibrat.
Tgp chi Duffc lieu, tap 19, so 412014 205
Fenolibrate('10|ili1) - C.tragiielll]iglmL) -
t
i5 5 .
Fenolibrale(10iiM] • C. lragileiH\iglmL)
Hinh 3. Anh huong ciia cao C fragile len sy tich liiy ham l u ^ g cholesterol (A) va TG (B) trong Ie b^o HepG2. So li^u dirpc trinh b^y bSng mean ± SEM. *P < 0 05, so voi nh6m d6i chiing (li voi 0,1% DMSO).
4. Ket luan
Trong 4 loai nghien cun, chiing tdi da xdc djnh 3ugc cao chiet cdn tir loai tao luc Codium fragile :d klia ndng kich hoat thy thi PPARa va PPARS/p vk tham gia vao qua trinh dieu hda chuyen hda lipid trong te bao gan HepG2. Sd lugng benh nhan tang lipid mau vd gan nhiem ma ngay cang tang trong xa hdi phat triln; cac nghien ciiu budc dau ve tdc dyng ciia cao chiit cdn tir Codium fragile rat hiiu ich trong vi?c phdt trien thudc hoac thuc
pham chirc nang theo hudng phdng ngua vd dieu tri benh d cac giai doan tiep theo.
Loi cam ffn: Nghien cuu nay dmrc lai Ir^ bai Quy phdt trien khoa hoc va cong ngh$ quoc gia (NAFOSTED) trong di lai ma s6 W6-YS.06-2013.23.
bai Vien Cong nghe sinh hoc, Vien Hdn ldm Khoa hpc va Cong nghe Viet Nam Irong de tai ma so CSK13-01 vd CO su dung (rang ihiel bi cua PTNTDCNG, Vi^n cong nghe sinh hoc, Vien Han Idm Khoa hoc va Cdng nghe Viei Nam
Tai lifu tham khao
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Present and future prospects of seaweeds in developing functional foods Advances in Food and Nutrition Research 64: 1-15 8. Tachibana K, YamasakiD. IshimoloK. Doi T. (2008), The Role of PPARs in Cancer. PPAR Res. 2008' 102737.
206 Tgp chi Duac lieu, tap 19, so 4/2014