Synergistic Anti-inflammatory los ntawm Laminaria Japonica Fucoidan Thiab Cistanche Tubulosa Extract
Mar 03, 2022
Hu rau: Audrey Hu Whatsapp / hp: 0086 13880143964 Email:audrey.hu@wecistanche.com
Abstract
Covanti-inflammatorycov teebmeem ntawm fucodan thiabCistanche tubulosa (CT) extract tau tshawb xyuas hauv Vitro macrophage kab lis kev cai thiab hauv vivo carrageenan-induced cua hnab o qauv.Cistanche TubulosaExtract inhibited nitric oxide ntau lawm los ntawm activated RAW 264.7 macrophage hlwb, thaum fucoidan tsis ua haujlwm. Hauv vivo cua hnab ntim cov qauv, carrageenan-vim vascular exudation, thiab nce nitric oxide thiab prostaglandin E2 concentrations nyob rau hauv cov exudates tau synergistically suppressed los ntawm co-administration ntawm fucoidan los yogCistanche Ttubulosarho tawm. Tsis tas li ntawd, cov ntaub so ntswg o tau txo qis los ntawm kev sib xyaw ua ke. Txawm li cas los xij, tsis muaj kev sib koom ua ke tawm tsam covmobcell infiltration, txawm tias fucoidan thiab CT(Cistanche tubulosa)rho tawm txhua markedly txo cov xov tooj ntawm tes. Yog li, nws tau pom tias fucoidan blocks infiltration ntawmmobcell, thaum CT (Cistanche tubulosa) extract inhibits kev ua kom lub hlwb, thiab hais tias lawv cov kev kho mob sib xyaw ua ke yuav yog ib tus neeg sib tw zoo rau kev pab ntawm ntau hom mob.
Cov lus tseem ceeb: Carrageenan, mob, fucoidan, Cistanche tubulosa extract.
Raws li kev tiv thaiv kab mob tiv thaiv txawv teb chaws antigens, macrophages tso tawm cov cytokines pro-inflammatory xws li qog-necrosis factor- (TNF- ), interleukin -1 (IL-1 ), IL-6, thiab lwm yam. [1,2]. Xws li cytokines induce ib tug chemotactic influx ntawm granulocytes, monocytes, lymphocytes, thiab mast hlwb rau puas cov ntaub so ntswg uas txhawb nqa antigen tshem tawm thiab cov ntaub so ntswg rov qab [3,4]. Txawm li cas los xij, ntau dhau infiltration thiab ua kom cov hlwb ua rau cov ntaub so ntswg ua rau raug mob, ua rau edema (vascular exudation) thiab mob uas yog qhov paub zoo ntawm qhov mob.
TNF- yog ib qho tseem ceeb rau inducing nitric oxide synthase (iNOS) noob qhia nyob rau hauv ntau lub cell kab.iNOS ua kom ua rau nitric oxide (NO) ntau lawm[5-7] uas tsis tsuas yog modulates ntau lub cev muaj zog xws li bactericidal thiab vasodilatation. tab sis kuj ua rau mob [8,9]. Tom qab cov ntaub so ntswg raug mob, degradation los ntawm phospholipases ntawm cell membrane phospholipids generates arachidonic acid. Arachidonic acid yog ntxiv decomposed los ntawm cyclooxygenase (COX) rau prostaglandins (PGs) [10]. Ib qho nyiaj ntau ntawm PGE2 tsim los ntawm COX-II induces ob peb cytokines rau o. Txij li ob qho tib si TSIS thiab PGE2 ua raws li qhov tseem ceeb rau o thiab mob induction, TNF- -thiab COX-II-PGE2 txoj hauv kev yog cov kwj ntawm cov txheej txheem inflammatory, uas yog inhibited los ntawm corticosteroids thiab non-steroidal.anti-inflammatorytshuaj (NSAIDs), feem [10,11].
Txawm hais tias muaj ntau yam steroids thiab NSAIDs rau kev kho mob ntawm cov kab mob inflammatory, cov tshuaj no tuaj yeem ua rau muaj kev cuam tshuam tsis zoo rau lub cev tsis muaj zog, plab hnyuv, raum, siab, nruab nrab paj hlwb, ntshav siab, thiab kab mob plawv [12-14 ]. Yog li ntawd, nws yog ib qho tsim nyog yuav tsum txo qis qhov tsis zoo ntawm cov tshuaj kho mob los ntawm kev hloov lawv los yog siv lawv ua ke nrog cov khoom ntuj tsim.
Fucoidan, sulfate polysaccharide complex los ntawm seaweeds xws li Laminaria japonica thiab Cladosiphonokamuranus dav faib nyob rau hauv ntau lub teb chaws, tau siv raws li kev kho mob nyob rau hauv Oriental tshuaj rau lub sij hawm ntev. Hauv kev tshawb fawb yav dhau los, nws tau pom tias fucoidan muaj cov tshuaj tiv thaiv oxidative, tiv thaiv coagulative, tiv thaiv qog noj ntshav, thiabanti-inflammatorykev ua si [15,16]. Yog li, cov txiaj ntsig zoo ntawm fucoidan ntawm cov kab mob inflammatory, ischemia, lub cev tsis muaj zog, thiab qog nqaij hlav tau ntxim nyiam cov neeg tshawb xyuas cov xim [17,18]. Ntawm qhov tod tes,Cistanche tubulosa(CT) kuj tau siv dav rau cov tshuaj ib txwm siv hauv Suav teb. Nws tau tshaj tawm tias CT extract txo qis kev tsim khoom ntawm TNF-á thiab IL-4 uas yog yam tseem ceeb rau TSIS MUAJ ntau lawm hauv txoj kev inflammatory [19].
Cov kev tshawb pom yav dhau los no ua rau peb tshawb xyuas qhov ua tau zoo ntawm fucoidan thiab CT(Cistanche tubulosa)rho tawm ntawm 2 txoj kev loj ntawm kev mob. Txhawm rau elucidate lub mechanism ntawm kev txiav txim, peb soj ntsuam TSIS MUAJ thiab PGE2 nyob rau hauv cov exudates los ntawm carrageenan-induced cua hnab o [20].
Cov ntaub ntawv thiab cov txheej txheem
Khoom siv
Semi-purified fucodan thiab dej extract ntawm CT(Cistanche tubulosa)tau txais los ntawm Misuba RTech Co., Ltd. (Asan, Kauslim). Fucoidan thiab CT extract tau khaws cia ntawm 4oC, sib tov (1: 3) thiab yaj hauv dej huv ua ntej siv, thiab muab tshuaj rau hauv qhov ntim ntawm 5 mL / kg.
Cell kab lis kev cai thiab NO quantification
Lub murine macrophage RAW 264.7 cell kab tau yuav los ntawm American Type Culture Collection (Manassas, USA), thiab kab lis kev cai hauv Dulbecco's modified eagle's nruab nrab (Sigma, St. Louis, USA) muaj 10 feem pua fetal bovine serum thiab tshuaj tua kab mob [100 U/mLpenicillin ( Sigma) thiab 100 µg/mL streptomycin (Sigma)]. Cov hlwb raug incubated nyob rau hauv ib tug humidified 5 feem pua CO2 atmosphere ntawm 37oC.
Txhawm rau ntsuas qhov cuam tshuam ntawm fucoidan thiab CT(Cistanche tubulosa)rho tawm ntawm NO, RAW 264.7 hlwb (1 × 106 hlwb/mL) tau incubated nrog fucoidan los yog CT extract (1-320 µg/mL) rau 5 min, ua raws li interferon- (IFN- , 10 U / mL) thiab lipopolysaccharide (LPS, 10 µg / mL) rau 24 teev. Hauv peb cov kev tshawb fawb ua ntej, nws tau lees paub tias kev kho mob nrog IFN-ntxiv rau LPS rau kev ua haujlwm ntawm RAW 264.7 hlwb tsis cuam tshuam rau kev ua haujlwm ntawm cov hlwb mus txog 24 teev thiab tias fucoidan thiab CT extract tsis yog cytotoxic txog 1 mg / mL. Qhov concentration ntawm nitrite (NO2-), cov khoom oxidized ntawm NO, tau ntsuas raws li qhov ntsuas ntawm NO. Cov kab lis kev cai nruab nrab yog tov nrog qhov sib npaug ntawm Griess reagent (1 feem pua sulfanilamide, 0.1 feem pua naphthylethylenediamide hauv 2.5 feem pua phosphoric acid) [21], thiab incubated ntawm chav tsev kub rau 10 min. Nitrite concentration tau soj ntsuam ntawm 540 nm, qhov twg NaNO2 tau siv los tsim cov qauv nkhaus.
Tsiaj txhu thiab kev kho mob
Txiv neej ICR nas (7 lub lis piam) tau yuav los ntawm Daehan Biolink (Eumseong, Kauslim), thiab nyob hauv ib chav nrog ib puag ncig ib puag ncig (22 ± 2ºC;40-70 feem pua ntawm cov av noo; 12-teev lub teeb - tsaus ntuj nti; 150-300 lux brightness). Pellet pub thiab dej huv muaj nyob rau hauv libitum. Txhua qhov kev sim tsiaj tau pom zoo los ntawm Pawg Saib Xyuas Tsiaj Tsiaj thiab siv (IAACUC) ntawm Chungbuk National University (CBNU), Kaus Lim Kauslim, thiab ua raws li Cov Txheej Txheem Kev Ua Haujlwm (SOP) ntawm LaboratoryAnimal Research Center, CBNU.
Cov nas (n{0}}/pab) tau kho qhov ncauj nrog fucoidan (18 lossis 54 mg / kg), CT(Cistanche tubulosa)rho tawm (54 lossis 162 mg / kg), lossis lawv qhov sib xyaw (18 ntxiv 54, 54 ntxiv 162 lossis 90 ntxiv 270 mg / kg) ib hnub ib hnub rau 7 hnub. Cov koob tshuaj tsawg ntawm fucoidan (18 mg / kg) thiab CT extract (54 mg / kg) yog los ntawm kev kwv yees tib neeg koob tshuaj ntawm 100 mg / lub cev (70 kg) thiab 300 mg / lub cev tom qab qhov chaw txhais ntawm lub cev hnyav (Km{{14). }} rau human/Km=3 rau nas), feem. Cov koob tshuaj ntau ntawm fucoidan thiab CT extract tau teem rau ntawm 3 folds, ib leeg lossis hauv qhov sib xyaw, thiab qhov sib xyaw ua ke siab tshaj plaws tau kho ntawm 5folds los ntsuas qhov siab tshaj plaws kev sib koom ua ke.
Hnub 1 ntawm fucoidan thiab CT(Cistanche tubulosa)tshem tawm kev kho mob, nas tau txhaj tshuaj subcutaneously nrog 10 mL ntawm sterile cua rau hauv lub nraub qaum los tsim ib lub hnab [22,23]. Tom qab 2 thiab 5 hnub, lub hnab tau rov txhaj tshuaj nrog 5 mL ntawm huab cua. Ib teev tom qab kev kho mob zaum kawg, 1 mL ntawm carrageenan (1 feem pua hauv saline; Sigma) lossis nws lub tsheb (saline) tau txhaj rau hauv lub hnab.
Analysis ntawm exudates
Lub hnab huab cua tau ntxuav nrog 1 mL ntawm cov kua qaub txias 6 teev tom qab txhaj tshuaj carrageenan, thiab cov kua ntim ntim ntawm lavage tau sau tseg. Tag nrho cov naj npawb ntawm cov hlwb inflammatory, neutrophils, monocytes, thiab lymphocytes, tau txiav txim siab siv lub txee colter. Qhov ntau ntawm NO thiab PGE2 tau txiav txim siab los ntawm Griess reagent (Sigma) thiab enzyme immunoassay (EIA) siv cov khoom siv sib txuas-EIA (Assay Designs, Ann Arbor, AnnArboUSA), feem.
Kev kuaj mob histopathological
Cov ntaub so ntswg hauv ob sab phlu raug tshem tawm thiab kho hauv nruab nrab formalin daws. Paraffin-embedded cov ntaub so ntswg tau stained nrog hematoxylin-eosin thiab tshuaj xyuas nyob rau hauv lub teeb lub teeb tsom rau cov kab mob inflammatory.
Kev txheeb cais
Cov txiaj ntsig tau nthuav tawm raws li txhais tau tias ± SE. Kev sim sib piv pab pawg tau ua los ntawm ib txoj kev tsom xam ntawm qhov sib txawv ua raws li Tukey qhov kev sim kho. P-tus nqi<0.05 was="" considered="" statistically="">
Cov txiaj ntsig
Hauv vitro RAW 264.7 kab lis kev cai ntawm tes, IFN- , thiab LPStreatment ua rau tsis muaj ntau lawm (Daim duab 1). Pretreatment nrog fucoidan (1–320 µg / mL) tsis cuam tshuam rau NO tso tawm ntawm macrophage cell kab (Daim duab 1A). Hauv kev sib piv, CT(Cistanche tubulosa)extract (32–320 µg/mL) tseem ceeb suppressed tsis muaj ntau lawm, qhia ntawmanti-inflammatorykev ua si (Daim duab 1B).
Kev txhaj tshuaj ntawm carrageenan rau hauv nas lub hnab huab cua tau nce ntxiv ntawm cov khoom ntim hauv lub hnab (Daim duab 2). Xws li exudation ntau ntxiv tau txo qis los ntawm kev kho mob nrog fucoidan (18 mg / kg) thiab CT(Cistanche tubulosa)extract (54 thiab 162 mg / kg). Qhov tseem ceeb, kev sib xyaw ua ke ntawm fucodan thiab CT(Cistanche tubulosa)extract ntxiv txo cov exudates ntim, piv rau cov teebmeem ntawm tus kheej, txawm hais tias ntau dua kev sib xyaw ua ke (54 ntxiv rau 162 mg / kg thiab 90 ntxiv rau 270 mg / kg) tsis tau nthuav tawm cov txiaj ntsig ntxiv rau qhov qis tshaj qhov sib xyaw ua ke (18 ntxiv 54 mg / kg) (Daim duab 2A). Tsis muaj cov ntsiab lus nyob rau hauv lub hnab kuj nce zuj zus tom qab txhaj tshuaj carrageenan (Daim duab 2B). Hauv kev sib piv nrog cov nyhuv me me ntawm fucoidan, CT(Cistanche tubulosa)extract markedly txo qhov NO concentration. Kev kho mob sib xyaw ua ke ntawm fucoidan thiab CT extract ntxiv txo qis tsis muaj qib nyob rau hauv koob tshuaj. Ib yam li ntawd, cov ntsiab lus nce PGE2 tau sib koom ua ke los ntawm kev sib xyaw ua ke ntawm fucoidan thiab CT.(Cistanche tubulosa)extract (Daim duab 2C).In parallel nrog cov inflammatory mediators nyob rau hauv lub hnab, cov xov tooj ntawm inflammatory hlwb rhiab heev los ntawm carrageenan txhaj: 37.8, 4.8, thiab 24.1folds tswj theem rau neutrophils, monocytes, thiab lymphocytes, raws li (Table 1) . Txawm li cas los xij, fucodan thiab CT(Cistanche tubulosa)extract tau txo cov kab mob ntawm tes infiltration, uas fucoidan yog me ntsis superior rau CT extract. Kev npaj txhij txog, tsis muaj kev sib koom ua ke hauv cov kab mob ntawm tes infiltration tau txais los ntawm kev tswj hwm ntawm fucoidan thiab CT.(Cistanche tubulosa)rho tawm.
Raws li inferred los ntawm inflammatory cell infiltration nyob rau hauv lub exudates, cov ntaub so ntswg subcutaneous nyob ib ncig ntawm cov pa hnab nthuav tawm qhov mob hnyav (Daim duab 3). Ntau lub hlwb hauv cov ntaub so ntswg thickened subcutaneous raug pom los ntawm carrageenan (Daim duab 3B), piv nrog cov yam ntxwv ze li qub hauv cov tsiaj tswj (Daim duab 3A). Cov kab mob inflammatory no tau zoo kawg nkaus los ntawm kev kho mob nrog fucoidan (Figures 3C thiab 3D) los yog CT.(Cistanche tubulosa)extract (Daim duab 3E thiab 3F). Qhov tseem ceeb, cov tshuaj tiv thaiv kab mob siab dua tau txais los ntawm kev sib xyaw ua ke nrog fucoidan thiab CT(Cistanche tubulosa)extract(Figures 3G-3I)
Kev sib tham
Siv ib qho hauv vivo carrageenan-induced huab cua hnab ntim cov qauv, kev txhaj tshuaj ntawm huab cua mus rau sab nraub qaum ntawm cov nas induces proliferation ntawm cov hlwb uas stratify rau saum npoo ntawm kab noj hniav los tsim ib tug qauv zoo li lub synovium. Hauv cov qauv no, kev txhaj tshuaj ntawm carrageenan-induced inflammatory cell infiltration nce exudate, uas yog qhia txog vascular to. Lub hnab huab cua ua haujlwm ua lub chaw cia khoom ntawm cov kab mob inflammatory thiab cov neeg kho kom haum xeeb uas tuaj yeem ntsuas tau yooj yim hauv cov kua dej uas ntim hauv zos.
Ntawm cov sib txawv inflammatory mediators uas tuaj yeem ua rau cov hlab ntsha permeability, nws paub zoo tias NO thiab PGE2 yog qhov tseem ceeb cuam tshuam rau hauv cov kab mob ntawm ntau cov kab mob inflammatory [24,25]. Lawv kuj tseem hu ua tus neeg nruab nrab ntawm qhov mob induction thiab kev nkag siab [10,11]. iNOS, uas tau nthuav tawm thiab qhib rau hauv ntau hom ntawm tes los ntawm kev txhawb nqa nrog TNF- thiab / lossis LPS thaum lub sijhawm mob, ua rau muaj siab, tsis tu ncua ntawm NO [3,5-7]. TSIS yog ib qho tseem ceeb tswj molecule nyob rau hauv ntau yam physiological functions, xws li vasodilatation ua rau vascular to [8,9].PGE2, uas yog generated los ntawm arachidonic acid ntawm cox, contributes rau txoj kev loj hlob ntawm ntau inflammatory kab mob [26,27], thiab overproduction ntawm PGE2 nyob rau hauv teb rau ntau yam inflammatory stimulations yog txuam nrog up-regulation ntawm COX-II theem thiab kev loj hlob ntawm o [28]. Yog li, TNF- -NO thiab COX-II-PGE2 txoj hauv kev tau raug suav tias yog ob txoj hauv kev tseem ceeb ntawm cov txheej txheem inflammatory, uas yog thaiv los ntawm inhibitors ntawm iNOS (corticosteroids) thiab COX (NSAIDs), feem [22,29].
Hauv kev tshawb fawb tam sim no, kev sib koom ua ke ntawm fucoidan thiab CT(Cistanche tubulosa)extract txo cov exudate ntim hauv lub hnab, qhia tias lawv muaj kev tawm tsam tawm tsam vascular to (Daim duab 2A). Hauv kev sib piv nrog tus kheej cov teebmeem ntawm txhua tus fucoidan thiab CT(Cistanche tubulosa)extract, kev kho kev sib xyaw ua ke ntxiv ntxiv, implying tias ob lub tebchaw 'ua haujlwm synergistically. Xws li kev sib koom ua ke ntawm fucoidan thiab CT extract tau txais kev txhawb nqa los ntawm lawv cov dej num ntawm NO thiab PGE2 qib hauv cov exudates (Figures 3B thiab 2C).
Interestingly, txawm li cas los xij, nws tau lees paub tias fucoidan tsis ncaj qha cuam tshuam rau kev ua haujlwm ntawm macrophages invitro assay (Daim duab 1A). Ib yam li ntawd, lub peev xwm inhibitory ntawm fucoidan ntawm NO thiab PGE2 tsub zuj zuj hauv bioassay kuj qis dua li ntawm CT.(Cistanche tubulosa)extract (Daim duab 2B thiab 2C). Xws li kev ua haujlwm ntawm fucoidan yog qhov sib txawv ntawm kev ua haujlwm ncaj qha ntawm cov hlwb los ntawm CT extract (Daim duab 1B). Los ntawm kev sib piv, fucoidan tau ua kom muaj txiaj ntsig zoo ntawm kev cuam tshuam ntawm cov cell infiltration hauv lub hnab (Table 1). Fucoidan yog qhov zoo tshaj rau CT extract hauv thaiv kev tsiv teb tsaws ntawm neutrophils, monocytes, thiab lymphocytes mus rau carrageenan-induced cov ntaub so ntswg raug mob. Interestingly, tsis muaj kev sib koom ua ke los tiv thaiv kev tsiv teb tsaws, qhia txog kev sib txawv ntawm kev ua haujlwm ntawm fucoidan thiab CT extract: piv txwv li, fucoidan blocks infiltration ntawm inflammatory cells, thaum CT.(Cistanche tubulosa)Extract inhibits kev ua kom lub hlwb.
Polymorphonuclear hlwb, tshwj xeeb tshaj yog neutrophils, yog lub ntsiab cellular Cheebtsam recruited rau mob inflammatory sites induced los ntawm carrageenan. Tsis tas li ntawd, ua rau cov kab mob inflammatory xws li macrophages thiab lymphocytes tseem ua lub luag haujlwm tseem ceeb hauv cov txheej txheem inflammatory los ntawm secreting cytokines [22,30,31]. Thaum pretreated nrog fucodan lossis CT(Cistanche tubulosa)extract, tus naj npawb ntawm cov qe ntshav dawb uas tsiv mus rau hauv lub carrageenan txhaj cov hnab ntim cua tau pom tau zoo heev. Cov txiaj ntsig no tau ua raws li cov txiaj ntsig uas yuav tau txais los ntawm corticosteroids xws li dexamethasone, tab sis tsis yog los ntawm NSAIDs suav nrog indomethacin [23,30]. Yog li ntawd, nws yog assumed tias fucoidan thiab CT(Cistanche tubulosa)Extract muaj ib feem ntawm cov khoom ntawm steroids.
Ntxiv rau qhov thaiv kev ua haujlwm ntawm inflammatory cell chemotaxis, CT(Cistanche tubulosa)extract tau tshwm sim los suppress lub activation ntawm macrophages. Qhov no tau lees paub los ntawm nws cov inhibitory kev ua ntawm TSIS MUAJ nyob rau hauv vitro thiab hauv vivo, uas yog tus loj inflammatory mediator tsim los ntawm macrophages. Yog li, cov nyhuv ntawm CT(Cistanche tubulosa)extract ntawm macrophages tej zaum yuav yog vim muaj kev cuam tshuam ntawm mRNA kev qhia thiab / lossis kev cuam tshuam ncaj qha ntawm iNOS kev ua hauv cov hlwb.
PGE2 yog ib qho ntawm cov kab mob sib kis loj, ib yam nkaus. Nws nce ntxiv nrog rau cov ntaub so ntswg edema, uas yog suppressed los ntawm NSAIDs, inhibitors ntawm COX [21,22]. Carrageenan tuaj yeem nce PGE2 ntau lawm los ntawm inducingCOX-II mRNA thiab COX-II protein nyob rau hauv lub hnab exudate [32]. Hauv cov qauv no, carrageenan nce qhov nyiaj ntawm PGE2 thiab nws tau raug tshem tawm los ntawm CT.(Cistanche tubulosa)rho tawm. Nws yog qhov nthuav kom nco ntsoov tias qhov txiaj ntsig no tau ua raws li cov txiaj ntsig uas yuav tau txais los ntawm NSAID indomethacin [23]. Yog li, nws tau txiav txim siab los ntawm cov txiaj ntsig uas CT extract muaj cov cuab yeej ntxiv ntawm NSAIDs. Ua ke, ntseeg tau tias CT(Cistanche tubulosa)extract exerted ob qho tib si corticosteroid thiab NSAID-zoo li cov teebmeem hauv carrageenan-induced o qauv, thiab fucoidan txhim kho qhovanti-inflammatoryCov teebmeem ntawm CT extract los ntawm kev thaiv cov cell infiltration.
Txawm hais tias kev txhais cov txheej txheem ntawm kev ua haujlwm yuav tsum tau kawm ntxiv, kev sib xyaw ntawm fucoidan thiab CT(Cistanche tubulosa) tshem tawm cov cim qhia kev mob tshwm sim los ntawm kev thaiv TNF- -NO thiab COX-II-PGE2 txoj hauv kev hauv carrageenan-vim lub hnab ntim cua. Cov kev tshawb pom no muab pov thawj tias kev sib xyaw ua ke ntawm fucoidan thiab CT(Cistanche tubulosa)extract tej zaum yuav yog ib tus neeg sib tw ua tau zoo rau kev pab ntawm ntau hom kev mob uas ua rau cov tshuaj corticosteroids lossis NSAIDs.
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