PART 2 Yuav ua li cas echinacoside induce venous so?

NYEEM NO PART 1

Yog xav paub ntxiv thov hu rau:Joanna.jia@wecistanche.com

Cistanche deserticola muaj ntau yam teebmeem, nyem qhov no kom paub ntau ntxiv

Kev sib tham

Rau qhov zoo tshaj plaws ntawm peb txoj kev paub, qhov no yog thawj qhov kev tshawb fawb soj ntsuam cov txiaj ntsig ntawmECHnyob rau hauv vascular tone ntawm nas pulmonary artery. Peb pom qhov ntawdECHinduced vasorelaxation ntawm nas pulmonary artery precontracted nrog NE nyob rau hauv ib tug concentration-dependent yam, thiab cov teebmeem no tuaj yeem pom nyob rau hauv ob qho tib si endothelium thiab endothelium-denuded rings. Nyob rau hauv cov hlab ntsha pulmonary, ECH attenuated ob extracellular calcium influx thiab intracellular calcium tso, thiab NO-cGMP txoj kev thiab qhib K^ntxivchannel (loj conductance Ca^{2 plus}- qhib K^ntxivchannel thiab sab hauv rectifier K^ntxivchannels) tau tshwm sim los ua lub luag haujlwm hauvECH-induced nas pulmonary artery vasorelaxation. Hauv nas PASMCs,ECHtuaj yeem txo cov calcium hauv cov cell ncaj qha. Cov kev tshawb fawb yav dhau los kuj tau qhia tiasECHtuaj yeem kho qhov endothelium-dependent vasodilator nkaus hauv nas thoracic aortic rings los ntawm txoj kev NO-cGMP^[7].

echinacoside cov tshuajhauv cistanche tauanti-inflammatory

ECH-induced vasorelaxation tuaj yeem pom nyob rau hauv ob qho tib si endothelium thiab endothelium-denuded rings. Txawm li cas los xij, kev tshem tawm ntawm endothelium ua rau txo qis hauv cov lus teb siab tshaj plaws thiab nce hauv EC₅₀txheeb ze rau cov rings endothelium tsis zoo. Nws tau raug pom tias tsis muaj-cGMP thiab PGI₂-cAMP txoj hauv kev ua lub luag haujlwm tseem ceeb hauv kev tswj hwm endothelium-dependent vascular so^[9]. Txhawm rau tshawb xyuas qhov teeb meem no, peb ntxiv 100 μmol / L ntawmL-NIM, ib qho inhibitor ntawm TSIS synthesis rau hauv endothelial hlwb. Cov txiaj ntsig tau pom tiasL-NAME tseem ceeb attenuated vasodilation ntawmECH, tawm tswv yim tias TSIS yog yuav ua lub luag haujlwm hauv vasorelaxation ntawmECH. Peb kuj pom tias IMT, ib qho inhibitor ntawm cyclo-oxygenase (ib qho tseem ceeb PGI₂synthetase), tsis muaj cov nyhuv zoo li no, qhia tias PGI₂Nws tsis zoo li yuav koom nrog hauv vasorelaxation ntawm ECH. Yog li, ECH tuaj yeem txhim kho TSIS MUAJ ntau lawm los ntawmL-arginine nyob rau hauv vascular endothelium thiab qhib guanylate cyclase, yog li catalyzing hloov dua siab tshiab ntawm GTP rau cGMP. Tom qab kev sim raws tu qauv, cov rings tau pom cov toj roob hauv pes uas muaj kev cog lus siab feem pua ​​​​ntawm NE (1 μmol / L), uas qhia tau hais tias cov rings tau pretreated nrogECH(30 mus rau 300 μmol / L) pom kev ua haujlwm zoo (Daim duab 2A thiab 2B).

Vascular tone yog tswj los ntawm intracellular Ca^{2 ntxiv [12]}. Peb pom tias ECH (100 thiab 300 μmol / L) txo qis phasic contraction induced los ntawm NE hauv endothelium-denuded pulmonary arterial rings hauv Ca.^{2 plus}-dawb KH cov tshuaj, thiab cov nyhuv no tau tshaj tawm nrog qhov siab dua ntawm ECH (300 μmol / L), qhia tau hais tias cov nyhuv inhibitory ntawm ECH ntawm NE-induced contraction ntawm pulmonary arterial rings tau kho los ntawm kev cuam tshuam hauv lub peev xwm ntawm IP3. txhawb kev tso tawm ntawm intracellular Ca^{2 plus}. NE ua rau ntawm -receptor los kho vascular contraction, yog li nce intracellular

Ca2 ntxiv theem ([Ca2 ntxiv]i) los ntawm G-protein txuas nrog phosphatidylinositol teeb liab txoj kev hloov [13]. Thaum ua haujlwm, qhov no ua rau tsim tus xa xov thib ob IP3 thiab diacylglycerol induced los ntawm phospholipase C[14]. IP3 tuaj yeem txav ceev ceev thiab tso tawm Ca2 ntxiv los ntawm sarcoplasmic reticulum ua rau muaj kev nce ntxiv hauv [Ca2 ntxiv] I, uas tuaj yeem cuam tshuam nrog NE-induced phasic contraction hauv pulmonary arterial rings hauv Ca2 plus -dawb nruab nrab. Txhawm rau tshawb xyuas cov txiaj ntsig ntawm ECH ntawm cov kab mob calcium ntxiv, CaCl2 (2.5 mmol / L) tau ntxiv nyob rau hauv Ca2 ntxiv rau cov xwm txheej tsis pub dawb. Qhov sib ntxiv ntawm ECH (30, 100, thiab 300 μmol / L) txo qis qhov kev cog lus siab tshaj plaws, nrog rau cov txiaj ntsig tseem ceeb tshaj plaws nrog 300 μmol / L ECH. Qhov no qhia tias ECH inhibits intracellular calcium tso tawm thiab extracellular calcium influx hauv PASMCs. Txawm li cas los xij, kev tshawb fawb ntxiv yog xav tau los qhia txog kev sib raug zoo ntawm ECH thiab inhibitors ntawm L-type calcium channels. Txhawm rau tshawb xyuas lub luag haujlwm ntawm calcium, Fluo 4-AM tau siv los txiav txim siab cov calcium hauv cov cell hauv cov nas PASMCs. Vim tias qhov sib ntxiv ntawm NE (1 μmol / L) ua rau muaj kev hloov pauv sai ntawm cov hlab ntsha rings (Daim duab 2), nas PASMCs tau thawj zaug nrog Fluo 4-AM, thiab tom qab ntawd NE thiab ECH tau ntxiv. Cov txiaj ntsig tau pom tias 1 μmol / L NE tuaj yeem ua rau cov calcium ntau ntxiv hauv cov cell, uas tau pom zoo nrog cov kev tshawb fawb yav dhau los, thiab qhov nruab nrab fluorescence siv qis dua hauv NE ntxiv rau ECH100 pawg dua li hauv pawg NE. Yog li, nws tau txiav txim siab tias ECH tuaj yeem txo qis cov calcium hauv cov cell hauv cov nas PASMCs pretreated nrog NE. Vim tias nws yog qhov zoo dua los kuaj xyuas cov calcium hauv lub cev hauv lub sijhawm tiag tiag, kev tshawb fawb ntxiv tau ua los saib xyuas lub sijhawm hloov pauv ntawm cov calcium hauv cov cell hauv lub sijhawm siv confocal microscopy.

cov channels kuj tau raug npaj los ua cov hom phiaj kho mob rau cov kab mob plawv vim tias lawv muaj peev xwm tswj hwm vascular tone [22, 23]. Peb pom tias TEA, tus inhibitor ntawm BKCa raws, ua rau cov concentration-teb lus nkhaus hloov mus thiab qhov tseem ceeb hauv EC50. Peb kuj pom tau tias ECH-vim so kom txaus yog qhov tsis muaj zog ntawm qhov siab tshaj plaws ntawm ECH hauv cov nplhaib tom qab kho nrog TEA (1 mmol / L) piv nrog kev tswj hwm. Tsis muaj kev cuam tshuam vasodilation yog vim yog ib feem ntawm cGMP-nyob, protein kinase G-mediated activation ntawm BKCa channels [24]. Yog li ntawd, peb xav tias ECH induced nas pulmonary artery vasorelaxation ntawm NO-cGMP-PKG-BKCa raws, uas ua rau txo qis hauv intracellular Ca2 ntxiv rau qib thiab so ntawm PASMCs. Ib qho kev pom zoo yog tias qhov sib txawv ntawm ECH txo qhov siab tshaj plaws contraction vim los ntawm extracellular calcium influx thiab ua kom luv luv, uas yuav cuam tshuam rau kev qhib BKCa channels.

KIR channels yog cov channel yooj yim tshaj plaws, tsuas yog ob lub transmembrane domains. Lawv koom nrog hauv kev tswj hwm lub zog tsav rau calcium nkag rau hauv cov hlab ntsws vascular endothelial hlwb; yog li ntawd, lawv tau cuam tshuam rau kev tswj hwm vascular permeability[25] thiab cov lus teb rau kev ntxhov siab shear[26]. Hauv txoj kev tshawb no, peb tau pom tias KIR inhibitor ua rau qhov kev xav tau ntawm cov lus teb nkhaus hloov mus thiab qhov nce ntxiv hauv EC50 thiab tias ECH (300 μmol / L) ua rau muaj kev so tsis muaj zog dua piv nrog kev tswj hwm. Tag nrho cov txiaj ntsig no tau qhia tias ECH muaj cov txiaj ntsig vasorelaxant ntawm cov hlab ntsha pulmonary ntawm KIR raws. Txawm li cas los xij, muab lub luag haujlwm nyuaj ntawm K ntxiv rau hauv kev tswj hwm lub suab nrov, cov kev tshawb fawb ntxiv yuav tsum tau ua kom paub meej qhov teeb meem no. K ntxiv cov channel tsis ntev los no tau hais kom koom nrog hauv kev kho mob vascular los ntawm kev tswj cov cell proliferation thiab apoptosis[18]. Ntiaj teb no hypoxia, raws li nws tshwm sim nyob rau hauv high altitudes, ua rau pulmonary vasoconstriction los yog vascular remodeling thiab nce pulmonary vascular resistance [27]. Impaired K ntxiv raws (KATP, KCa, VK, thiab KIR) nyob rau hauv vascular du leeg hlwb kuj muaj feem xyuam rau txoj kev loj hlob ntawm Hypoxic inhibition ntawm K ntxiv channels tshwm sim nyob rau hauv daim nyias nyias depolarization, lub activation ntawm voltage-dependent Ca2 ntxiv (Cav) raws, extracellular Ca2 plus influx, thiab intracellular Ca2 ntxiv tso tawm, yog li ua rau nce hauv [Ca2 ntxiv] I, ua raws li pulmonary vasoconstriction thiab proliferation ntawm PASMCs [29]. Qhib K ntxiv cov channel pab txhawb rau kev tswj hwm ntawm hypoxic pulmonary vasoconstriction thiab vascular remodeling. Yog li, ECH tuaj yeem qhib K ntxiv cov channel, yog li txo qis hypoxic pulmonary vasoconstriction nrog rau txo qis vascular remodeling. ntshav siab[22, 28].

Kev xaus ECH induces vasorelaxation nyob rau hauv nas pulmonary hlab ntsha precontracted nrog NE, thiab xws li ib tug tshwm sim tuaj yeem pom nyob rau hauv ob qho tib si endothelium thiab endothelium-denuded rings. Qhov no feem ntau yuav muaj feem cuam tshuam nrog kev qhib NO-cGMP-PKG-BKCa channels thiab txo qis ntawm intracellular Ca2 ntxiv rau qib, yog li txo qis PASMCs (Daim duab 8).

Kev lees paub

Peb ua tsaug Liang YANG thiab nws qhov chaw kuaj mob (Center for Mitochondrial Biology thiab Tshuaj, Lub Chaw Haujlwm Tseem Ceeb ntawm Biomedical Information Engineering ntawm Ministry of Education, Lub Tsev Kawm Ntawv ntawm Lub Neej Science thiab Technology thiab Frontier Institute of Science thiab Technology, Xi'an Jiaotong University, Xi'an , Tuam Tshoj) rau lawv cov kev pab nyob rau hauv kev soj ntsuam cov intracellular calcium concentration ntawm nas PASMCs. Txoj haujlwm no tau txais kev txhawb nqa los ntawm National Program ntawm Cov Kev Tshawb Fawb Tseem Ceeb ntawm Tuam Tshoj (Tsis yog 2012CB518200), Txoj Haujlwm Kev Tshawb Fawb Txog Kev Tshawb Fawb thiab Kev Tshawb Fawb Txog Kev Tshawb Fawb ntawm Tuam Tshoj (Tsis yog 2011DFA32720), National Natural Science Foundation ntawm Tuam Tshoj (Tsis yog 31160219), Lub Chaw Haujlwm Tseem Ceeb Txoj Haujlwm Kev Txhim Kho ntawm Qinghai Xeev (Tsis muaj 2013-Z-Y05, Tsis muaj 2014-ZY-30, thiab Tsis yog 2014-ZY-07), Qinghai-Utah Kev Tshawb Fawb Kev Sib Koom Lab rau High Altitude Medicine, National Natural Science Foundation of China (No 81160012), Ministry of Education New Century Outstanding Talents Support Program of China (No NCET-12-1022) thiab Natural Science Foundation of Qinghai (Tsis yog {{ 17}}Z-915Q).

echinacoside cov tshuajhauvcistanchetuaj yeem kho mob raum

Sau ntawv pab

Ri-li GE thiab Xiang-Yun GAI tsim txoj kev kawm; Xiang-Yun GAI, Yu-hai WEI, Ta-na WUREN, Ya-ping WANG, Zhan-Qiang LI, thiab Yi ZHOU ua qhov kev tshawb fawb; Wei ZHANG thiab Yu-hai WEI pab txhawb cov reagents tshiab thiab cov cuab yeej tshuaj ntsuam xyuas; Xiang-yun GAI thiab Shou LIU txheeb xyuas cov ntaub ntawv; Xiang-Yun GAI sau ntawv, thiab Lan MA thiab Dian-Xiang LU hloov daim ntawv.

Cistancheechinacoside cov tshuajtuaj yeem tiv tausapoptosis

Cov ntaub ntawv

1 Hultgren HN, editor. High Altitude Tshuaj. Stanford: Hultgren Publications; Xyoo 1997.

2 Humbert M, Sitbon O, Simonneau G. Kev kho mob pulmonary arterial hypertension. N Engl J Med 2004; 351: 3 : kuv.

3 ib RL. Lub neej ntawm Qinghai-Tibetan Plateaus. Beijing: Peking

University Medical Xovxwm; 2007. Suav.

4 Xin Y, Hu F, Dong Q, Peng M. Kev txiav txim siab ntawm echinacoside thiab acteoside hauv Tibetan tshuaj ntsuab Lagotis brevituba Maxim. Chin J Pharm Anal 2012; 32: 1183–5.

5 Zhao Q, Gao J, Li W, Cai D. Neurotrophic thiab neurorescue teebmeem ntawm Echinacoside hauv subacute MPTP nas qauv ntawm tus kab mob Parkinson. Brain Res 2010; 1346: 224–36.

6 Yang XL, LF, Yang YN, Shen JY, Zou R, Zhu PP, et al. Kev ua tau zoo thiab kev nyab xeeb ntawm echinacoside hauv cov qauv nas osteopenia. Evid Based Complement Alternat Med 2013; 2013: 1–10.

7 He WJ, Fang TH, Ma X, Zhang K, Ma ZZ, Tu PF. Echinacoside elicits endothelium-dependent so nyob rau hauv nas aortic rings ntawm txoj kev NO-cGMP. Planta Med 2009; 75:1400–4.

8 Warshaw DM, Mulvany MJ, Halpern W. Mechanical and morphological properties of arterial resistance vessels in the young and old spontaneously hypertensive nass. Circ Res 1979; 45:250–9.

9 Shen M, Zhao L, Wu RX, Yue SQ, Pei JM. Cov nyhuv vasorelaxant ntawm resveratrol ntawm lub plab aorta ntawm nas thiab nws cov txheej txheem hauv qab. Vascul Pharmacol 2012; 58:64–70.

10 Gai XY, Tang F, MA J, Zeng KW, Wang SL, Wang YP, et al. Anti-proliferative nyhuv ntawm echinacoside ntawm nas pulmonary artery smooth nqaij hlwb nyob rau hauv hypoxia. J Pharmacol Sci 2014; 126:155–63.

11 Mandal SK, Pendurthi UR, Rao LVM. Cov ntaub so ntswg kev lag luam hauv fibroblasts: kev koom tes ntawm protease-activated receptor-mediated cell signaling. Ntshav 2007; 110: 161–70.

12 Toque HA, Teixeira CE, Priviero FB, Morganti RP, Antunes E, De Nucci G. Vardenafil, tab sis tsis yog sildenafil lossis tadalafil, muaj calcium-channel thaiv kev ua haujlwm hauv luav cais pulmonary artery thiab tib neeg ntxuav platelets. Br J Pharmacol 2008; 154: 4: XIV.

13 Fonseca-Magalhães PA, Sousa DF, de Siqueira RJ, Jorge RJ, Meneses GC, Alves RS, et al. Inhibitory cuam tshuam ntawm sertraline nyob rau hauv nas cais perfused ob lub raum thiab nyob rau hauv cais nplhaib npaj ntawm cov hlab ntsha. J Pharm Pharmacol 2011; 63: 1186–94.

14 Berridge MJ. Inositol trisphosphate thiab calcium signaling mechanisms. Biochim Biophys Acta 2009; 1793: 933–40.

15 Hu F, Koon CM, Chan JY, Lau KM, Kwan YW, Fung KP. Kev koom tes ntawm calcium channel thiab potassium channel hauv Danshen thiab Gegen decoction induced vasodilation hauv porcine coronary LAD hlab ntsha. Phytomedicine 2012; 19:1051–8.

16 Matsumoto T, Kobayashi T, Ishida K, Hirasawa Y, Morita H, Honda T, et al. Vasodilator nyhuv ntawm Cassiarin A, ib tug tshiab antiplasmodial alkaloid los ntawm Cassia siamea, nyob rau hauv nas cais mesenteric hlab ntsha. Biol Pharm Bull 2010; 33:844–8.

17 Dubuis E, Potier M, Wang R, Vandier C. Nruam nqus pa ntawm carbon monoxide attenuates hypoxic pulmonary hypertension txoj kev loj hlob txawm tias los ntawm kev ua kom BKCa raws. Cardiovasc Res 2005; 65: 751–61.

18 Moudgil R, Michelakis ED, Archer SL. Lub luag haujlwm ntawm K ntxiv rau hauv kev txiav txim siab pulmonary vascular tone, oxygen sensing, cell proliferation, thiab apoptosis: cuam tshuam rau hypoxic pulmonary vasoconstriction thiab pulmonary arterial hypertension. Microcirculation 2006; 13:615–32.

19 Eichhorn B, Dobrev D. Vascular loj-conductance calcium-activated poov tshuaj raws: lub luag hauj lwm thiab kev kho mob muaj peev xwm. Naunyn Schmiedebergs Arch Pharmacol 2007; 376: 145–55.

20 Ko EA, Han J, Jung ID, Park WS. Lub luag haujlwm ntawm lub cev ntawm K ntxiv rau hauv cov leeg nqaij leeg. J Smooth Muscle Res 2008; 44:65–81.

21 Ledoux J, Werner ME, Brayden JE, Nelson MT. Calcium-activated potassium channels thiab kev tswj ntawm vascular tone. Physiology 2006; 21:69–78.

22 Bonnet S, Archer SL. Potassium channel ntau haiv neeg nyob rau hauv cov hlab ntsha pulmonary thiab pulmonary veins: cuam tshuam rau kev tswj ntawm pulmonary vasculature hauv kev noj qab haus huv thiab thaum lub sij hawm pulmonary hypertension. Pharmacol Ther 2007; 115:56–69.

23 Feletou M. Calcium-activated potassium channels thiab endothelial dysfunction: cov kev xaiv kho mob? Br J Pharmacol 2009; 156: 545–62.

24 Archer SL, Huang J, Hampl V, Nelson DP, Shultz PJ, Weir EK. Nitric oxide thiab cGMP ua rau vasorelaxation los ntawm kev ua kom lub chary- biotoxin-sensitive K channel los ntawm cGMP-dependent protein kinase. Proc Natl Acad Sci USA 1994; 91: 7583–7.

25 Shimoda LA, Welsh LE, Pearse DB. Inhibition ntawm inwardly rectifying K ntxiv raws los ntawm cGMP hauv pulmonary vascular endothelial hlwb. Am J Physiol Mob ntsws Cell Mol Physiol 2002; 283: L297–304 : kuv.

26 Chatterjee S, Al-Mehdi AB, Levitan I, Stevens T, Fisher AB. Shear596 kev ntxhov siab nce kev qhia ntawm KATP channel hauv nas thiab bovine pulmonary vascular endothelial hlwb. Am J Physiol Mob ntsws Cell Mol Physiol 2003; 285: C959–67 : kuv.

27 Bartsch P, Maggiorini M, Ritter M, Noti C, Vock P, Oelz O. Kev tiv thaiv ntawm high-altitude pulmonary edema los ntawm nifedipine. N Engl J Med 1991; 325: 1284–9.

28 Park WS, Han J, Earn YE. Lub luag haujlwm physiological ntawm sab hauv rectifier K ntxiv rau hauv cov leeg nqaij leeg. Pflugers Arch 2008; 457: 137–47.

29 Wang YX, Zheng YM. ROS-dependent signaling mechanisms rau hypoxic Ca2 ntxiv rau cov lus teb hauv pulmonary artery myocytes. Antioxid Redox Signal 2010; 12:611–23.