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An yi amfani da Red ginseng a cikin maganin gargajiya na Asiya don daruruwan shekaru.A cikin wannan binciken, mun kimanta ikon nau'ikan ginseng iri hudu (ginseng ja na kasar Sin, ginseng ja na Koriya A, ginseng ja na Koriya B, da ginseng ja na Koriya C) da ake girma a yankuna daban-daban don hana samuwar da haɓakar huhu da ke haifar da carcinogen. ciwace-ciwace.An gudanar da gwajin benzo (a) pyrene (B(a)P) akan berayen A/J, kuma an gano jajayen ginseng na Koriya ta Arewa shine mafi inganci wajen rage nauyin kumburi a cikin nau’in ginseng guda hudu.Bugu da ƙari, mun bincika abubuwan da ke cikin ginsenosides daban-daban (Rg1, Re, Rc, Rb2, Rb3, Rb1, Rh1, Rd, Rg3, Rh2, F1, Rk1 da Rg5) a cikin ruwan ginseng guda hudu kuma mun gano cewa ginseng na Koriya ta Koriya yana da mafi girman matakan ginsenoside Rg3 (G-Rg3), yana nuna cewa G-Rg3 na iya taka muhimmiyar rawa a cikin tasirin warkewa.Wannan aikin yana nuna cewa G-Rg3 yana da ƙarancin ƙarancin bioavailability.Duk da haka, lokacin da aka haɗa G-Rg3 tare da P-gp inhibitor verapamil, zubar da jini na G-Rg3 a cikin sel Caco-2 ya ragu, yawan ƙwayar hanji na G-Rg3 ya karu a cikin samfurin bera, kuma G-Rg3. aka ƙara.A cikin sel Caco-2, fitowar Rg3 yana raguwa, kuma matakin ƙaddamarwar Rg3 yana raguwa.G-Rg3 yana ƙaruwa a cikin hanji da plasma, kuma ikonsa na hana ciwace-ciwacen daji yana haɓaka a cikin ƙirar bera na B(a) Turigenesis mai haifar da P.Mun kuma gano cewa G-Rg3 ya rage B (a) P-induced cytotoxicity da DNA adduct samuwar a cikin huhu huhu Kwayoyin, da kuma mayar da magana da kuma aiki na lokaci II enzymes ta hanyar Nrf2 hanya, wanda zai iya zama alaka da m tsarin aiki. na G hanawa -Rg3..Game da faruwar ciwon huhu.Nazarin mu yana nuna muhimmiyar muhimmiyar rawa ga G-Rg3 a cikin niyya da ciwace-ciwacen huhu a cikin ƙirar linzamin kwamfuta.Ana haɓaka bioavailability na baka na wannan ginsenoside ta hanyar niyya P-glycoprotein, ƙyale kwayoyin halitta suyi tasirin anticancer.
Mafi yawan nau'in ciwon daji na huhu shine ciwon huhu mara ƙananan ƙwayoyin cuta (NSCLC), wanda shine daya daga cikin manyan abubuwan da ke haifar da mutuwar ciwon daji a China da Arewacin Amirka1,2.Babban abin da ke ƙara haɗarin kamuwa da cutar kansar huhu mara ƙanƙanta shine shan taba.Shan taba sigari ya ƙunshi fiye da 60 carcinogens, ciki har da benzo (a) pyrene (B(a)P), nitrosamines, da kuma radioactive isotopes daga rubewar radon.3 Polycyclic aromatic hydrocarbons B(a) P ne babban dalilin guba a cikin sigari. hayaki.Bayan bayyanar da B (a) P, cytochrome P450 ya canza shi zuwa B (a) P-7,8-dihydrodiol-9,10-epoxide (BPDE), wanda ke amsawa tare da DNA don samar da BPDE-DNA adduct 4. Bugu da ƙari, waɗannan adducts haifar da ciwon huhu na huhu a cikin beraye tare da matakin ƙari da kuma histopathology kama da ciwon huhu na ɗan adam5.Wannan fasalin ya sa samfurin ciwon huhu na huhu na B (a) P ya zama tsarin da ya dace don kimanta mahadi tare da yiwuwar maganin ciwon daji.
Ɗaya daga cikin dabarun da za a iya hana ci gaban ciwon huhu na huhu a cikin ƙungiyoyi masu haɗari, musamman masu shan taba, shine amfani da magungunan chemopreventive don hana ci gaban ciwon neoplastic intraepithelial kuma ta haka ne ya hana ci gaban su zuwa malignancy.Nazarin dabbobi ya nuna cewa daban-daban na chemopreventive agents suna da tasiri6.Rahoton mu na baya7 ya nuna kyakkyawan tasirin rigakafin jan ginseng akan ciwon huhu.An yi amfani da wannan ganye tsawon ƙarni a cikin maganin gargajiya na Asiya don tsawaita rayuwa da lafiya, kuma an rubuta cewa yana da tasirin antitumor8.
Abubuwan da ke aiki na ginseng shine ginsenoside, wanda aka yi amfani da shi azaman alamar alama don kimanta ingancin kayan ginseng.Ƙididdigar ƙididdiga na ginseng tsantsa yawanci ya ƙunshi amfani da ginsenosides da yawa, ciki har da RK1, Rg1, F1, Re, Rb1, Rb2, Rb3, Rd, Rh1, Rh2, Rg3, Rg5, da Rc9,10.Ginsenosides ba su da ɗan amfani na asibiti saboda ƙarancin ƙwayar ƙwayar cuta ta baki11.Kodayake tsarin don wannan rashin lafiyar rashin lafiya ba a bayyana ba, zubar da ginsenosides da P-glycoprotein (P-gp) 12 ya haifar na iya zama dalilin.P-gp yana ɗaya daga cikin mafi mahimmancin masu jigilar kaya a cikin mai ɗaukar kaset mai ɗaukar nauyi na ATP superfamily, wanda ke amfani da makamashi na ATP hydrolysis don sakin abubuwa na cikin salula a cikin yanayin waje.Ana rarraba masu jigilar P-gp a cikin hanji, koda, hanta da shingen kwakwalwar jini13.P-gp yana taka muhimmiyar rawa wajen sha na hanji, kuma hana P-gp yana ƙara yawan sha na baki da samun wasu magungunan ciwon daji12,14.Misalan masu hanawa da aka yi amfani da su a baya a cikin wallafe-wallafe sune verapamil da cyclosporine A15.Wannan aikin ya haɗa da kafa tsarin linzamin kwamfuta don nazarin B (a) P-induced ciwon huhu na huhu don kimanta iyawar jan ginseng daban-daban daga Sin da Koriya don tasiri ga malignancies.An yi nazarin abubuwan da aka samo asali daban-daban don gano takamaiman ginsenosides waɗanda zasu iya shafar carcinogenesis.Bayan haka an yi amfani da Verapamil don ƙaddamar da P-gp da haɓaka haɓakar ƙwayoyin cuta na baka da tasirin warkewa na ginsenosides masu cutar kansa.
Hanyar da ginseng saponins ke yin tasirin warkewa akan carcinogenesis ya kasance ba a sani ba.Bincike ya nuna cewa nau'in ginsenosides daban-daban na iya rage lalacewar DNA da ke haifar da carcinogens ta hanyar rage danniya na oxidative da kunna lokaci na II detoxification enzymes, don haka hana lalacewar cell.Glutathione S-transferase (GST) wani nau'in enzyme ne na yau da kullun na II wanda ake buƙata don rage lalacewar DNA da ke haifar da carcinogens17.Nuclear erythroid 2-related factor 2 (Nrf2) wani muhimmin abu ne na rubutun rubutu wanda ke tsara redox homeostasis kuma yana kunna maganganun lokaci na enzymes na II da kuma martanin antioxidant cytoprotective18.Har ila yau, bincikenmu yayi nazarin sakamakon da aka gano ginsenosides akan rage B (a) P-induced cytotoxicity da BPDE-DNA adduct samuwar, da kuma haifar da lokaci II enzymes ta hanyar daidaita hanyar Nrf2 a cikin kwayoyin huhu na al'ada.
Ƙirƙirar ƙirar linzamin kwamfuta na B(a) ciwon daji da ke haifar da P ya dace da aikin da ya gabata5.Hoto 1A yana nuna ƙirar gwaji na 20-mako na maganin ciwon daji na linzamin kwamfuta wanda B(a) P ya haifar, ruwa (control), Sinanci ja ginseng cire (CRG), Korean ja ginseng cire A (KRGA), da kuma Korean ja. ginseng.Cire B (KRGB) da Red Ginseng Extract C (KRGC).Bayan makonni 20 na maganin ginseng na ja, an yi hadaya da mice ta CO2 asphyxiation.Hoto na 1B yana nuna ciwace-ciwacen huhu na macroscopic a cikin dabbobin da aka bi da su tare da nau'ikan ginseng na ja, kuma Hoto 1C yana nuna micrograph mai wakiltar haske na samfurin ƙari.Nauyin ƙwayar cuta na dabbobin da aka yi wa KRGB (1.5 ± 0.35) ya kasance ƙasa da na dabbobi masu sarrafawa (0.82 ± 0.2, P <0.05), kamar yadda aka nuna a cikin Hoto 1D.Matsakaicin matakin hana ƙwayar ƙwayar cuta shine 45%.Sauran abubuwan jan ginseng da aka gwada ba su nuna irin waɗannan canje-canje masu mahimmanci a cikin nauyin ƙari ba (P> 0.05).Babu wani tasiri mai tasiri a cikin samfurin linzamin kwamfuta a lokacin 20 makonni na jiyya na ginseng ja, ciki har da wani canji a cikin nauyin jiki (bayanan da ba a nuna ba) kuma babu hanta ko ciwon koda (Figure 1E, F).
Jan ginseng tsantsa yana magance ci gaban ƙwayar cutar huhu a cikin mice A / J.(A) Zane na gwaji.(B) Manyan ciwace-ciwacen huhu a cikin ƙirar linzamin kwamfuta.Ana nuna ciwace-ciwace ta kibiyoyi.a: rukunin ginseng ja na kasar Sin.b: rukunin A na ginseng ja na Koriya.c: Korean ja ginseng rukuni B. d: Korean ja ginseng rukuni C. d: Ƙungiyar sarrafawa.(C) Hasken micrograph yana nuna ciwon huhu.Girma: 100. b: 400. (D) Tumor load a cikin jan ginseng tsantsa kungiyar.(E) Matakan Plasma na hanta enzyme ALT.(F) Matakan Plasma na renal enzyme Cr.Ana bayyana bayanai azaman ma'anar ± daidaitaccen karkacewa.*P <0.05.
Abubuwan da aka samo asali na ginseng na ja da aka gano a cikin wannan binciken an bincika su ta hanyar ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS / MS) don ƙididdige ginsenosides masu zuwa: Rg1, Re, Rc, Rb2, Rb3, Rb1, Rh1, Rd, Rg3, Rh2, F1, Rk1 da Rg5.An kwatanta yanayin UPLC da MS da aka yi amfani da su don auna masu nazari a cikin rahoton da ya gabata19.UPLC-MS/MS chromatograms na jajayen ginseng guda huɗu an nuna su a cikin Hoto 2A.Akwai bambance-bambance masu mahimmanci a cikin jimlar ginsenoside, tare da mafi girman adadin ginsenoside a cikin CRG (590.27 ± 41.28 μmol / L) (Hoto 2B).Lokacin kimanta ginsenosides guda ɗaya (Hoto 2C), KRGB ya nuna matakin G-Rg3 mafi girma idan aka kwatanta da sauran ginsenosides (58.33 ± 3.81 μmol / L don G-Rg3s da 41.56 ± 2.88 μmol / L don G -Rg3r).L).nau'in ginseng ja (P <0.001).G-Rg3 yana faruwa a matsayin nau'i na stereoisomers G-Rg3r da G-Rg3s, wanda ya bambanta a matsayin ƙungiyar hydroxyl a carbon 20 (Fig. 2D).Sakamakon ya nuna cewa G-Rg3r ko G-Rg3 na iya samun mahimmancin maganin ciwon daji a cikin samfurin linzamin kwamfuta na B (a) P.
Abun ciki na ginsenosides a cikin nau'ikan ginseng ja daban-daban.(A) UPLC-MS/MS chromatograms na ginseng ja guda huɗu.(B) Ƙididdiga na jimlar ginsenoside a cikin abubuwan da aka nuna.(C) Gano kowane ginsenosides a cikin abubuwan da aka lakafta.(D) Tsarin ginsenoside stereoisomers G-Rg3r da G-Rg3s.An bayyana bayanai azaman maƙasudin ± daidaitaccen karkacewar ƙayyadaddun ƙayyadaddun ƙayyadaddun abubuwa uku.***P <0.001.
Nazarin UPLC-MS / MS yana buƙatar ƙididdige ginsenosides a cikin hanji da samfuran jini bayan makonni 20 na jiyya.Jiyya tare da KRGB ya nuna kasancewar 0.0063 ± 0.0005 μg/ml Rg5 kawai a cikin jini.Babu sauran ginsenosides da aka gano, yana nuna rashin lafiyar baka da rashin lafiya don haka rage bayyanar da waɗannan ginsenosides.
Layin cell na adenocarcinoma na hanji Caco-2 yana da ilimin halittar jiki kuma yana kama da kwayoyin epithelial na hanji na mutum, yana nuna amfanin sa wajen tantance jigilar enterocyte a kan shingen epithelial na hanji.Wannan bincike ya dogara ne akan binciken farko na 20.Figures 3A,B,C,D,E,F suna nuna hotunan wakilci na jigilar transcellular na G-Rg3r da G-Rg3 ta amfani da samfurin Caco-2 monolayer.Transcellular sufuri na G-Rg3r ko G-Rg3 a fadin Caco-2 monolayers daga basolateral zuwa apical gefen (Pb-a) ya kasance mafi girma fiye da daga apical zuwa basolateral gefen (Pa-b).Don G-Rg3r, ƙimar Pa-b shine 0.38 ± 0.06, wanda ya karu zuwa 0.73 ± 0.06 bayan jiyya tare da 50 μmol / L verapamil kuma zuwa 1.14 ± 0.09 bayan jiyya tare da 100 μmol / L verapamil (p <0.01) bi da bi;3 A).Abubuwan lura don G-Rg3 sun bi irin wannan tsari (Fig. 3B), kuma sakamakon ya nuna cewa maganin verapamil ya inganta jigilar G-Rg3r da G-Rg3.Maganin Verapamil kuma ya haifar da raguwa mai mahimmanci a cikin ma'anar Pb-a da G-Rg3r da G-Rg3s efflux ratios (Figure 3C, D, E, F), yana nuna cewa maganin verapamil yana rage abun ciki na ginsenoside a cikin Caco-2 efflux sel..
Jirgin transcellular na G-Rg3 a cikin Caco-2 monolayers da sha na hanji a cikin gwajin perfusion na bera.(A) Ƙimar Pa-b na ƙungiyar G-Rg3r a cikin Caco-2 monolayer.(B) Ƙimar Pa-b na ƙungiyoyin G-Rg3s a cikin Caco-2 monolayer.(C) Ƙimar Pb na ƙungiyar G-Rg3r a cikin Caco-2 monolayer.(D) Ƙimar Pb na ƙungiyoyin G-Rg3s a cikin Caco-2 monolayer.(E) Rabon rabon ƙungiyoyin G-Rg3r a cikin caco-2 monolayer.(F) Rabon rabon ƙungiyoyin G-Rg3 a cikin caco-2 monolayer.(G) Kashi na sha na hanji na G-Rg3r a cikin gwajin turare a cikin berayen.(H) Kashi na sha na hanji na G-Rg3 a cikin gwajin turare a cikin berayen.Permeability da sha an kwatanta ba tare da ƙari na verapamil ba.An bayyana bayanai azaman ma'anar ± daidaitaccen karkacewar gwaje-gwaje masu zaman kansu guda biyar.P <0.05, **P <0.01, *** P <0.001.
Daidai da aikin farko na 20, an yi perfusion na intestine na berayen don sanin ko sha G-Rg3 a cikin hanji yana ƙaruwa bayan maganin verapamil.Figures 3G,H suna nuna kididdigar perfusion na wakilai don kimanta adadin yawan sha na hanji na G-Rg3r da G-Rg3 a cikin berayen ƙirar ciwon daji a lokacin lokutan sama.Kashi na farko na raunin G-Rg3r kusan 10% ya karu zuwa fiye da 20% bayan jiyya tare da 50 μM verapamil kuma zuwa fiye da 25% bayan jiyya tare da 100 μM verapamil.Hakanan, G-Rg3, wanda ke da haɓakar farko na 10%, ya kuma nuna kololuwar sama da 20% bayan jiyya tare da 50 μM verapamil da kusan 30% bayan jiyya tare da 100 μM verapamil, yana ba da shawarar hana P-gp ta hanyar verapamil. G-absorption na hanji Rg3 a cikin samfurin linzamin kwamfuta na ciwon huhu.
Bisa ga hanyar da ke sama, B(a) P-induced model cancer model an raba su da kayyade zuwa kungiyoyi shida, kamar yadda aka nuna a cikin Hoto 4A.Ba a sami asarar nauyi mai mahimmanci ko alamun asibiti na guba ba a cikin rukunin jiyya na G-Rg3 idan aka kwatanta da ƙungiyar kulawa (bayanan da ba a nuna ba).Bayan makonni 20 na jiyya, an tattara huhun kowane linzamin kwamfuta.Hoto na 4B yana nuna ciwace-ciwacen huhu na macroscopic a cikin mice a cikin ƙungiyoyin jiyya na sama, kuma Hoto na 4C yana nuna alamar micrograph mai wakilci na ƙari mai wakilci.Game da nauyin ƙwayar ƙwayar cuta a cikin kowane rukuni (Fig. 4D), ƙimar berayen da aka bi da su tare da G-Rg3r da G-Rg3s sun kasance 0.75 ± 0.29 mm3 da 0.81 ± 0.30 mm3, bi da bi, yayin da ƙimar G Mice ke bi da su. tare da -Rg3s sun kasance 1.63 bi da bi ± 0.40 mm3.sarrafa mice (p <0.001), yana nuna cewa G-Rg3 magani ya rage nauyin ƙwayar ƙwayar cuta a cikin mice.Gudanar da verapamil ya ƙara haɓaka wannan raguwa: ƙimar a cikin berayen verapamil + G-Rg3r sun ragu daga 0.75 ± 0.29 mm3 zuwa 0.33 ± 0.25 mm3 (p <0.01), da ƙimar verapamil + daga 0.81 ± 0.30 ± .2. mm3 a cikin G. -Rg3s-maganin mice (p <0.05), yana nuna cewa verapamil na iya haɓaka tasirin hanawa na G-Rg3 akan tumorigenesis.Nauyin Tumor bai nuna bambance-bambance ba tsakanin ƙungiyar kulawa da ƙungiyar verapamil, ƙungiyar G-Rg3r da ƙungiyar G-Rg3s, da ƙungiyar verapamil + G-Rg3r da ƙungiyar verapamil + G-Rg3s.Bugu da ƙari, babu wani muhimmin hanta ko ƙwayar koda da ke hade da jiyya da aka kimanta (Hoto 4E, F).
Nauyin ƙwayar cuta bayan jiyya na G-Rg3 da plasma ko na hanji G-Rg3r da matakan G-Rg3 a cikin ƙungiyoyin da aka nuna.(A) Zane na gwaji.(B) Ciwon daji na macroscopic a cikin ƙirar linzamin kwamfuta.Ana nuna ciwace-ciwace ta kibiyoyi.ku: g-r3r.b: g-r3s.c: G-Rg3r a hade tare da verapamil.d: G-Rg3 a hade tare da verapamil.d: Verapamil.e: iko.(C) Micrograph na gani na ƙari a haɓakawa.Amsa: 100x.b: 400x.(D) Tasirin G-Rg3 + magani na verapamil akan nauyin ƙari a cikin mice A / J.(E) Matakan Plasma na hanta enzyme ALT.(F) Matakan Plasma na renal enzyme Cr.(G) Matakan Plasma na G-Rg3r ko G-Rg3 na ƙungiyoyin da aka nuna.(H) Matakan G-Rg3r ko G-Rg3s a cikin hanjin ƙungiyoyin da aka nuna.An bayyana bayanai azaman maƙasudin ± daidaitaccen karkacewar ƙayyadaddun ƙayyadaddun ƙayyadaddun abubuwa uku.P <0.05, **P <0.01, *** P <0.001.
Matakan G-Rg3 a cikin B (a) P-induced ciwon daji samfurin mice an kiyasta ta UPLC-MS / MS bayan lokacin jiyya na mako-mako na 20 bisa ga hanyar da aka bayyana a cikin Sashen Hanyoyi.Figures 4G da H suna nuna matakan plasma da na hanji G-Rg3, bi da bi.Matakan Plasma G-Rg3r sun kasance 0.44 ± 0.32 μmol / L kuma sun karu zuwa 1.17 ± 0.47 μmol / L tare da gudanarwa na lokaci-lokaci na verapamil (p <0.001), yayin da matakan G-Rg3r na hanji sun kasance 0.53 ± 0.08 .µl.Lokacin da aka haɗa tare da verapamil, g ya karu zuwa 1.35 ± 0.13 μg/g (p <0.001).Don G-Rg3, sakamakon ya bi irin wannan tsari, yana nuna cewa maganin verapamil ya karu da kwayoyin halitta na G-Rg3 a cikin A / J mice.
An yi amfani da ƙididdigar iyawar ƙwayar cuta don kimanta cytotoxicity na B(a) P da G-Rg3 akan ƙwayoyin hel.An nuna cytotoxicity da B (a) P ya haifar a cikin ƙwayoyin hEL a cikin Hoto 5A, yayin da abubuwan da ba su da guba na G-Rg3r da G-Rg3 suna nunawa a cikin Figures 5A da 5B.5B, C. Don kimanta tasirin cytoprotective na G-Rg3, B (a) P an haɗa shi tare da nau'i-nau'i daban-daban na G-Rg3r ko G-Rg3 a cikin sel hEL.Kamar yadda aka nuna a cikin Hoto 5D, G-Rg3r a ƙididdiga na 5 μM, 10 μM, da 20 μM sun dawo da damar tantanin halitta zuwa 58.3%, 79.3%, da 77.3%, bi da bi.Hakanan ana iya ganin sakamako iri ɗaya a cikin rukunin G-Rg3s.Lokacin da adadin G-Rg3s ya kasance 5 µM, 10 µM da 20 µM, an dawo da iyawar tantanin halitta zuwa 58.3%, 72.7% da 76.7%, bi da bi (Hoto 5E).).An auna kasancewar BPDE-DNA adducts ta amfani da kit ɗin ELISA.Sakamakonmu ya nuna cewa BPDE-DNA matakan ƙaddamarwa sun karu a cikin ƙungiyar B (a) P da aka kwatanta da ƙungiyar kulawa, amma idan aka kwatanta da G-Rg3 haɗin gwiwa, BPDE-DNA matakan ƙaddamarwa a cikin ƙungiyar B (a) P. B a cikin rukunin da aka kula da su, an rage yawan matakan DNA.Sakamakon jiyya tare da B (a) P kadai ana nunawa a cikin Hoto 5F (1.87 ± 0.33 vs. 3.77 ± 0.42 don G-Rg3r, 1.93 ± 0.48 vs. 3.77 ± 0.42 don G -Rg3s, p <0.001).
Halin kwayar halitta da BPDE-DNA adduct samuwar a cikin ƙwayoyin hEL da aka bi da su tare da G-Rg3 da B (a) P.(A) Dogarowar sel hel da aka bi da su tare da B(a) P.(B) Ƙwaƙwalwar ƙwayoyin hel da aka yi da G-Rg3r.(C) Dogarowar ƙwayoyin hel da aka yi da G-Rg3.(D) Ƙwararrun ƙwayoyin hel da aka bi da su tare da B(a) P da G-Rg3r.(E) Dogarowar ƙwayoyin hel da aka yi da B(a) P da G-Rg3.(F) Matakan BPDE-DNA a cikin ƙwayoyin hel da aka bi da su tare da B (a) P da G-Rg3.An bayyana bayanai azaman maƙasudin ± daidaitaccen karkacewar ƙayyadaddun ƙayyadaddun ƙayyadaddun abubuwa uku.P <0.05, **P <0.01, *** P <0.001.
An gano bayanin GST enzyme bayan haɗin gwiwa tare da 10 μM B(a) P da 10 μM G-Rg3r ko G-Rg3s.Sakamakonmu ya nuna cewa B (a) P ya kashe GST magana (59.7 ± 8.2% a cikin rukunin G-Rg3r da 39 ± 4.5% a cikin rukunin G-Rg3s), kuma B (a) P yana da alaƙa da ko dai tare da G-Rg3r. , ko tare da G-Rg3r, ko tare da G-Rg3r.Haɗin gwiwa tare da G-Rg3s an dawo da bayanin GST.Maganar GST (103.7 ± 15.5% a cikin rukunin G-Rg3r da 110 ± 11.1% a cikin rukunin G-Rg3s, p <0.05 da p <0.001, bi da bi, Fig. 6A, B, da C).An tantance ayyukan GST ta amfani da kayan aikin tantancewa.Sakamakonmu ya nuna cewa ƙungiyar haɗin gwiwar tana da aikin GST mafi girma idan aka kwatanta da ƙungiyar B (a) P kawai (96.3 ± 6.6% vs. 35.7 ± 7.8% a cikin ƙungiyar G-Rg3r vs. 92.3 ± 6.5 a cikin ƙungiyar G-Rg3r. ).% vs 35.7 ± 7.8% a cikin rukunin G-Rg3s, p <0.001, Hoto 6D).
Bayanin GST da Nrf2 a cikin ƙwayoyin hel da aka bi da su tare da B (a) P da G-Rg3.(A) Gano furcin GST ta hanyar gogewar Yamma.(B) Ƙididdigar ƙididdigar GST a cikin ƙwayoyin hel da aka yi da B(a) P da G-Rg3r.(C) Ƙididdigar GST a cikin ƙwayoyin hel da aka yi da B(a) P da G-Rg3s.(D) Ayyukan GST a cikin ƙwayoyin hel da aka yi da B(a) P da G-Rg3.(E) Gano Nrf2 magana ta Yamma.(F) Ƙididdigar ƙididdiga na Nrf2 a cikin ƙwayoyin hel da aka bi da su tare da B (a) P da G-Rg3r.(G) Ƙididdigar ƙididdiga na Nrf2 a cikin ƙwayoyin hel da aka bi da su tare da B (a) P da G-Rg3s.An bayyana bayanai azaman maƙasudin ± daidaitaccen karkacewar ƙayyadaddun ƙayyadaddun ƙayyadaddun abubuwa uku.P <0.05, **P <0.01, *** P <0.001.
Don bayyana hanyoyin da ke tattare da G-Rg3-matsakaici na kashewar B (a) P-induced tumorigenesis, an tantance Nrf2 magana ta Yammacin Turai.Kamar yadda aka nuna a cikin Figures 6E, F, G, idan aka kwatanta da ƙungiyar kulawa, kawai matakin Nrf2 a cikin ƙungiyar kula da B (a) P ya rage;duk da haka, idan aka kwatanta da ƙungiyar kulawar B (a) P, B (a) matakan Nrf2 a cikin ƙungiyar PG-Rg3 sun karu (106 ± 9.5% don G-Rg3r vs. 51.3 ± 6.8%, 117 ± 6. 2% don G-Rg3r vs. 41 ± 9.8% na G-Rg3s, p <0.01).
Mun tabbatar da aikin rigakafin Nrf2 ta hanyar murkushe Nrf2 magana ta amfani da takamaiman ƙananan RNA (siRNA).An tabbatar da ƙwanƙwasa Nrf2 ta hanyar lalatawar Yamma (Fig. 7A,B).Kamar yadda aka nuna a cikin Figures 7C, D, haɗin gwiwa na ƙwayoyin hel tare da B (a) P da G-Rg3 sun haifar da raguwa a cikin adadin BPDE-DNA adducts (1.47 ± 0.21) idan aka kwatanta da jiyya tare da B (a) P. kadai a cikin ƙungiyar siRNA mai sarrafawa.) G-Rg3r shine 4.13 ± 0.49, G-Rg3s shine 1.8 ± 0.32 da 4.1 ± 0.57, p <0.01).Duk da haka, tasirin hanawa na G-Rg3 akan tsarin BPDE-DNA an soke shi ta hanyar Nrf2 knockdown.A cikin ƙungiyar siNrf2, babu wani bambanci mai mahimmanci a cikin BPDE-DNA adduct samuwar tsakanin B (a) P da G-Rg3 haɗin gwiwar magani da B (a) P kawai (3.0 ± 0.21 don G-Rg3r vs. 3.56 ± 0.32). ).don G-Rg3r da 3.6 don G-Rg3s da ± 0.45 da 4.0± 0.37, p> 0.05).
Tasirin Nrf2 knockdown akan BPDE-DNA adduct samuwar a cikin ƙwayoyin hel.(A) An tabbatar da bugun Nrf2 ta hanyar lalatawar Yamma.(B) Ƙididdigar ƙarfin Nrf2 band.(C) Tasirin Nrf2 knockdown a kan matakan BPDE-DNA a cikin ƙwayoyin hel da aka bi da su tare da B (a) P da G-Rg3r.(D) Tasirin Nrf2 knockdown akan matakan BPDE-DNA a cikin ƙwayoyin hel da aka bi da su tare da B (a) P da G-Rg3.An bayyana bayanai azaman maƙasudin ± daidaitaccen karkacewar ƙayyadaddun ƙayyadaddun ƙayyadaddun abubuwa uku.P <0.05, **P <0.01, *** P <0.001.
Wannan binciken ya kimanta tasirin rigakafin daban-daban na ginseng na jan ƙarfe akan ƙirar linzamin kwamfuta na B(a) cutar kansar huhu ta P, kuma jiyya na KRGB ya rage nauyin ƙari sosai.Idan akai la'akari da cewa G-Rg3 yana da mafi girman abun ciki a cikin wannan ginseng tsantsa, an yi nazarin muhimmiyar rawa na wannan ginsenoside don hana ƙwayar cuta.Dukansu G-Rg3r da G-Rg3 (wasu epimers guda biyu na G-Rg3) sun rage nauyin ƙwayar cuta a cikin ƙirar linzamin kwamfuta na B(a) ciwon daji na P.G-Rg3r da G-Rg3 suna yin tasirin anticancer ta hanyar haifar da apoptosis na ƙwayoyin tumor21, hana ci gaban ƙwayar cuta22, kama da sake zagayowar tantanin halitta23 kuma yana shafar angiogenesis24.Hakanan an nuna G-Rg3 don hana metastasis na salula25, kuma ikon G-Rg3 don haɓaka tasirin chemotherapy da radiotherapy an rubuta su26,27.Poon et al ya nuna cewa G-Rg3 magani zai iya rage tasirin genotoxic na B (a) P28.Wannan binciken yana nuna yuwuwar warkewa na G-Rg3 a cikin niyya ga ƙwayoyin cuta na muhalli da hana cutar kansa.
Duk da kyakkyawar damar da suke da ita na rigakafi, rashin lafiyar baka na ginsenosides yana haifar da kalubale ga amfani da asibiti na waɗannan kwayoyin.Binciken Pharmacokinetic na gudanar da baki na ginsenosides a cikin berayen ya nuna cewa kasancewarsa har yanzu ƙasa da 5%29.Waɗannan gwaje-gwajen sun nuna cewa bayan lokacin jiyya na mako 20, matakan jini na Rg5 kawai ya ragu.Duk da cewa tsarin da ake amfani da shi na rashin lafiyar halittu ya kasance da za a bayyana shi, P-gp ana tunanin yana da hannu a cikin zubar da ginsenosides.Wannan aikin ya nuna a karon farko cewa gudanarwa na verapamil, mai hana P-gp, yana ƙara haɓakar ƙwayoyin cuta na G-Rg3r da G-Rg3s.Don haka, wannan binciken yana nuna cewa G-Rg3r da G-Rg3s suna aiki azaman sinadarai na P-gp don daidaita fitar sa.
Wannan aikin yana nuna cewa haɗin gwiwar jiyya tare da verapamil yana ƙaruwa da bioavailability na baka na G-Rg3 a cikin ƙirar linzamin kwamfuta na ciwon huhu.Wannan binciken yana goyan bayan haɓakar jigilar jigilar hanji na G-Rg3 akan toshewar P-gp, ta haka yana haɓaka sha.Binciken da aka yi a cikin ƙwayoyin Caco2 ya nuna cewa maganin verapamil ya rage zubar da jini na G-Rg3r da G-Rg3s yayin da yake inganta haɓakar membrane.Nazarin Yang et al.Nazarin ya nuna cewa jiyya tare da cyclosporine A (wani P-gp blocker) yana haɓaka bioavailability na ginsenoside Rh2 daga ƙimar tushe na 1% 20 zuwa fiye da 30%.Ginsenosides mahadi K da Rg1 kuma sun nuna irin wannan sakamako30,31.Lokacin da aka yi amfani da verapamil da cyclosporin A, zubar da jini na fili K a cikin sel Caco-2 ya ragu sosai daga 26.6 zuwa ƙasa da 3, yayin da matakan intracellular ya karu 40-fold30.A gaban verapamil, matakan Rg1 sun karu a cikin ƙwayoyin huhu na huhu, suna ba da shawara ga P-gp a cikin ginsenoside efflux, kamar yadda Meng et al.31 ya nuna.Duk da haka, verapamil ba shi da irin wannan tasiri a kan zubar da wasu ginsenosides (irin su Rg1, F1, Rh1 da Re), yana nuna cewa ba su da tasiri ta hanyar P-gp substrates, kamar yadda Liang et al.32 .Wannan kallo na iya kasancewa yana da alaƙa da shigar da wasu masu jigilar kaya da madadin tsarin ginsenoside.
Hanyar rigakafin G-Rg3 akan kansa ba a sani ba.Nazarin da suka gabata sun nuna cewa G-Rg3 yana hana lalacewar DNA da apoptosis ta hanyar rage damuwa na oxidative da kumburi16,33, wanda zai iya zama tsarin da ya dace don hana B (a) P-induced tumorigenesis.Wasu rahotanni sun nuna cewa genotoxicity da B(a) P ya jawo za a iya rage ta hanyar daidaita enzymes na lokaci II don samar da BPDE-DNA34.GST wani nau'in enzyme ne na lokaci na II wanda ke hana BPDE-DNA adduct samuwar ta hanyar inganta ɗaurin GSH zuwa BPDE, don haka rage lalacewar DNA ta hanyar B(a) P35.Sakamakonmu ya nuna cewa G-Rg3 magani yana rage B (a) P-induced cytotoxicity da BPDE-DNA adduct samuwar a cikin sel hEL kuma ya mayar da GST magana da aiki a cikin vitro.Duk da haka, waɗannan tasirin ba su kasance ba a cikin rashin Nrf2, yana nuna cewa G-Rg3 yana haifar da tasirin cytoprotective ta hanyar Nrf2.Nrf2 shine babban mahimmancin rubutu don lokaci na II detoxification enzymes wanda ke inganta ƙaddamar da xenobiotics36.Kunna hanyar Nrf2 yana haifar da cytoprotection kuma yana rage lalacewar nama37.Bugu da ƙari, rahotanni da yawa sun goyi bayan rawar Nrf2 a matsayin mai hana ƙwayar cuta a cikin carcinogenesis38.Bincikenmu ya nuna cewa ƙaddamar da hanyar Nrf2 ta hanyar G-Rg3 yana taka muhimmiyar rawa a cikin tsarin B (a) P-induced genotoxicity ta hanyar haifar da B (a) P detoxification ta hanyar kunna lokaci II enzymes, don haka ya hana tsarin tumorigenesis.
Ayyukanmu yana bayyana yuwuwar jan ginseng a cikin hana B (a) P-induced ciwon huhu na huhu a cikin mice ta hanyar mahimmancin ginsenoside G-Rg3.Rashin rashin lafiyar baka na wannan kwayar halitta yana kawo cikas ga aikace-aikacen sa na asibiti.Duk da haka, wannan binciken ya nuna a karon farko cewa G-Rg3 wani nau'i ne na P-gp, kuma gudanarwa na P-gp inhibitor yana ƙaruwa da bioavailability na G-Rg3 a cikin vitro da in vivo.G-Rg3 yana rage B (a) cytotoxicity P-induced ta hanyar daidaita hanyar Nrf2, wanda zai iya zama wata hanya mai mahimmanci don aikin rigakafinta.Nazarin mu ya tabbatar da yuwuwar ginsenoside G-Rg3 don rigakafi da maganin ciwon huhu.
An samo berayen A/J mace mai mako shida (20 ± 1 g) da ratsan Wistar mai mako 7 (250 ± 20 g) daga dakin gwaje-gwaje na Jackson (Bar Harbor, Amurka) da Cibiyar Nazarin Dabbobi ta Wuhan.Jami'ar (Wuhan, China).Cibiyar Tarin Al'adu ta Nau'in Sinanci (Wuhan, China) ta ba mu ƙwayoyin Caco-2 da ƙwayoyin hEL.Sigma-Aldrich (St. Louis, Amurka) shine tushen B(a) P da tricaprine.Ginsenosides masu tsabta G-Rg3r da G-Rg3s, dimethyl sulfoxide (DMSO), CellTiter-96 proliferation assay kit (MTS), verapamil, matsakaicin matsakaicin matsakaici (MEM), da ƙwayar ƙwayar ƙwayar tayi (FBS) an saya daga Chengdu Must Bio-Technology .Co., Ltd.(Chengdu, China).QIAamp DNA mini kit da BPDE-DNA adduct ELISA kit an saya daga Qiagen (Stanford, CA, Amurka) da Cell Biolabs (San Diego, CA, Amurka).Kayan aikin gwajin GST da jimillar kayan gwajin furotin (daidaita hanyar BCA) an siyi su daga Solarbio (Beijing, China).Ana adana duk abubuwan da aka samo na ginseng na ja a cikin dakin gwaje-gwaje na Mingyu 7. Jami'ar Baptist ta Hong Kong (Hong Kong, China) da Cibiyar Ciwon daji ta Koriya (Seoul, Koriya) sune tushen kasuwanci na CRG da kuma nau'o'in ginseng daban-daban na asalin Koriya (ciki har da KRGA, KRGB). da KRGC).Ana yin ginseng ja daga tushen ginseng mai shekaru 6.Ana samun tsantsar jan ginseng ta hanyar wanke ginseng tare da ruwa sau uku, sannan a mayar da hankali kan tsantsar ruwa, sannan a bushe a cikin ƙananan zafin jiki don samun foda na ginseng.Antibodies (anti-Nrf2, anti-GST, da β-actin), horseradish peroxidase-conjugated anti-zomo immunoglobulin G (IgG), transfection reagent, iko siRNA, da Nrf2 siRNA aka saya daga Santa Cruz Biotechnology (Santa Cruz, CA). .), Amurka).
An haɓaka ƙwayoyin Caco2 da hEL a cikin jita-jita na al'adun tantanin halitta 100 mm2 tare da MEM mai ɗauke da 10% FBS a 37 ° C a cikin yanayi mai ɗanɗano na 5% CO2.Don ƙayyade tasirin yanayin jiyya, ƙwayoyin hEL an haɗa su tare da nau'i daban-daban na B (a) P da G-Rg3 a cikin MEM don 48 h.Ana iya ƙara bincika ko tattara ƙwayoyin sel don shirya abubuwan da ba su da tantanin halitta.
Dukkanin gwaje-gwajen sun yarda da Kwamitin Ƙwararrun Dabbobin Gwaji na Kwalejin Kiwon Lafiya ta Tongji, Jami'ar Kimiyya da Fasaha ta Huazhong (Yin Amincewa A'a. 2019; Rajista No. 4587TH).Dukkanin gwaje-gwajen an yi su ne daidai da ka'idoji da ƙa'idodi masu dacewa, kuma an gudanar da binciken daidai da Binciken Dabbobi: Rahoto na In Vivo Experiments (ARRIVE).Berayen A/J na mako takwas an fara allurar su cikin ɓangarorin B(a) P a cikin maganin tricaprine (100 mg/kg, 0.2 ml).Bayan mako guda, an raba berayen zuwa ƙungiyoyi masu sarrafawa da ƙungiyoyin magani daban-daban, ɓeraye 15 a kowace ƙungiya, kuma ana ba da su sau ɗaya a rana.Bayan makonni 20 na jiyya, an yi hadaya da dabbobi ta CO2 asphyxia.An tattara huhu kuma an gyara shi tsawon sa'o'i 24.An ƙididdige adadin ciwace-ciwacen daji da kuma girman ƙwayar ƙwayar cuta ga kowane huhu a ƙarƙashin na'ura mai rarrabawa.An ƙididdige ƙididdige ƙimar ƙarar ƙwayar cuta (V) ta amfani da magana mai zuwa: V (mm3) = 4/3πr3, inda r shine diamita na ƙari.Jimlar jimillar adadin ƙwayar ƙwayar cuta a cikin huhu na beraye na wakiltar jimillar ƙarar ƙari, kuma matsakaicin jimlar ƙwayar ƙwayar cuta a kowace ƙungiya tana wakiltar nauyin ƙwayar cuta.An tattara dukkan samfuran jini da na hanji kuma an adana su a -80 ° C don ƙaddarar UPLC-MS / MS.An tattara ruwan magani kuma an yi amfani da na'urar nazarin sunadarai ta atomatik don nazarin alanine aminotransferase (ALT) da matakan creatinine (Cr) don tantance aikin hanta da koda.
An cire samfuran da aka tattara daga ajiyar sanyi, narke, auna, kuma an sanya su cikin bututu kamar yadda aka bayyana a sama.Don wannan an ƙara 0.5 μM phlorizin (misali na ciki) a cikin maganin methanol na 0.8 ml.An haɗa nama ɗin ta hanyar yin amfani da Tissue-Tearor kuma an canza shi zuwa wani bututu mai microcentrifuge 1.5 ml.Cakuda da aka centrifuged a 15500 rpm na 15 minutes.Bayan cire 1.0 ml na supernatant, bushe tare da nitrogen.An yi amfani da microliters dari biyu na methanol don farfadowa.Ana tattara jinin kuma ana sarrafa shi akan layi ɗaya kuma ana amfani dashi azaman nuni ga duk ma'auni.
24-riji Transwell faranti aka iri tare da 1.0 × 105 Caco-2 Kwayoyin da rijiyar don kimanta yuwuwar haɓakar G-Rg3 kai ta hanyar ƙari na verapamil.Bayan makonni 3 na al'ada, an wanke sel tare da HBSS kuma an riga an sanya su a 37 ° C.400 μL na 10 μM G-Rg3 (G-Rg3r, G-Rg3s, ko cakuda tare da 50 ko 100 μM verapamil) an allura a kan basolateral ko apical gefen monolayer, kuma 600 μL na HBSS bayani an kara zuwa daya. gefe.Tara 100µl na matsakaicin al'ada a lokutan da aka keɓance (0, 15, 30, 45, 60, 90 da 120 minutes) kuma ƙara 100 µl na HBSS don daidaita wannan ƙarar.An adana samfurori a -4 °C har sai an gano ta UPLC-MS/MS.Ana amfani da kalmar Papp = dQ / (dT × A × C0) don ƙididdige alamun da ba a iya gani na unidirectional apical da basolateral permeability da akasin haka (Pa-b da Pb-a, bi da bi);dQ / dT shine canji a cikin maida hankali, A (0.6 cm2) shine filin sararin samaniya na monolayer, kuma C0 shine ƙaddamarwar mai bayarwa na farko.An ƙididdige ma'auni na efflux azaman Pb-a/Pa-b, wanda ke wakiltar ƙimar ƙwayar ƙwayar ƙwayar ƙwayar cuta.
An yi azumin berayen Wistar na sa'o'i 24, sun sha ruwa kawai, kuma an yi musu allura ta cikin 3.5% na maganin pentobarbital.Bututun silicone da aka shigar yana da ƙarshen duodenum a matsayin ƙofar da ƙarshen ileum a matsayin fita.Yi amfani da famfo mai ƙyalli don yin famfo mashigai tare da 10 µM G-Rg3r ko G-Rg3s a cikin HBSS na isotonic a yawan gudu na 0.1 ml/min.An kimanta tasirin verapamil ta ƙara 50 μM ko 100 μM na fili zuwa 10 μM G-Rg3r ko G-Rg3s.An yi UPLC-MS/MS akan abubuwan da aka cire na turare da aka tattara a lokacin maki 60, 90, 120, da 150 mintuna bayan farawar turare.An ƙididdige yawan yawan sha ta hanyar dabara% sha = (1 - Cout/Cin) × 100%;Matsakaicin G-Rg3 a mashigar da mashigar an bayyana ta Cout da Cin, bi da bi.
Kwayoyin hEL an shuka su a cikin faranti na rijiyoyin 96 a yawan ƙwayoyin 1 × 104 a kowace rijiyar kuma ana bi da su tare da B (a) P (0, 1, 5, 10, 20, 30, 40 μM) ko G-Rg3 a cikin DMSO. .Daga nan aka narkar da magungunan tare da matsakaicin al'ada zuwa yawa daban-daban (0, 1, 2, 5, 10, 20 μM) sama da awanni 48.Yin amfani da kit ɗin tantancewar MTS na kasuwanci, an ƙaddamar da ƙwayoyin sel zuwa ƙayyadaddun yarjejeniya sannan a auna su ta amfani da mai karanta microplate a 490 nm.Matsakaicin iyawar kwayar halitta na ƙungiyoyin da aka haɗa tare da B (a) P (10 μM) da G-Rg3 (0, 1, 5, 10, 20 μM) an kimanta su bisa ga hanyar da ke sama kuma idan aka kwatanta da ƙungiyar da ba a kula da su ba.
Kwayoyin hEL an tsara su a cikin faranti na 6-riji a yawancin ƙwayoyin 1 × 105 / da kyau kuma an bi da su tare da 10 μMB (a) P a gaban ko rashin 10 μM G-Rg3.Bayan awanni 48 na jiyya, an fitar da DNA daga ƙwayoyin hel ta amfani da QIAamp DNA Mini Kit bisa ga ka'idar masana'anta.An gano samuwar BPDE-DNA adducts ta amfani da BPDE-DNA adduct ELISA kit.Matakan dangi na BPDE-DNA adduct an auna su ta amfani da mai karanta microplate ta hanyar auna ɗauka a 450 nm.
Kwayoyin hEL an shuka su a cikin faranti na 96-riji a yawancin ƙwayoyin 1 × 104 a kowace rijiya kuma an bi da su tare da 10 μMB (a) P a cikin rashi ko gaban 10 μM G-Rg3 na 48 h.An auna ayyukan GST ta amfani da kayan aikin GST na kasuwanci bisa ga ka'idar masana'anta.An auna kunna GST na dangi ta hanyar sha a 450 nm ta amfani da mai karanta microplate.
An wanke ƙwayoyin hEL tare da PBS mai sanyi mai sanyi sannan kuma an yi amfani da su ta hanyar amfani da kayan aikin rediyoimmunoprecipitation mai ƙunshe da masu hana protease da masu hana phosphatase.Bayan ƙididdige furotin ta amfani da jimlar kit ɗin gwajin furotin, 30 μg na furotin a cikin kowane samfurin an raba shi da 12% SDS-PAGE kuma an canza shi zuwa membrane na PVDF ta hanyar electrophoresis.An toshe gabobin jiki tare da madara mai kauri 5% kuma an cushe su da ƙwayoyin rigakafi na farko cikin dare a 4°C.Bayan shiryawa tare da maganin rigakafi na biyu na horseradish peroxidase-conjugated na biyu, an ƙara ingantattun reagents na chemiluminescence don ganin alamar dauri.An ƙididdige ƙarfin kowane rukunin furotin ta amfani da software na ImageJ.
An yi amfani da software na GraphPad Prism 7.0 don nazarin duk bayanai, wanda aka bayyana azaman ma'anar ± daidaitaccen karkata.An tantance bambancin tsakanin ƙungiyoyin jiyya ta amfani da gwajin Student's t ko nazarin bambance-bambancen hanya ɗaya, tare da ƙimar P <0.05 yana nuna mahimmancin ƙididdiga.
Duk bayanan da aka samu ko aka tantance yayin wannan binciken an haɗa su cikin wannan labarin da aka buga da fayilolin ƙarin bayanai.
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Lokacin aikawa: Satumba-17-2023