Reno-protective Effects Of Neutral CB1 Receptor Antagonists AM6545 Thiab AM4113 Ntawm Metabolic Syndrome

Hu rau: Audrey Hu Whatsapp / hp: 0086 13880143964 Email:audrey.hu@wecistanche.com

PART Ⅱ: Kev cuam tshuam nrog TGF 1-Mediated Inflammation and Fibrosis Underlies Reno-Protective Effects of CB1 Receptor Neutral Antagonists AM6545 thiab AM4113 nyob rau hauv tus nas Model ntawm Metabolic Syndrome

Basma G.Eid, Thikryat Neamatallah, Abeer Hanafy, Hany M.El-Bassossy & et al.

Abstract

Lub luag haujlwm ntawm cannabinoid receptors hauv nephropathy tau txais kev saib xyuas ntau. Txoj kev tshawb no tshawb xyuas qhov cuam tshuam ntawm ob qhov nruab nrab CB1 receptor antagonists,ib 6545thiabTIAB SA 4113, ntawm nephropathy txuam nrogmetabolicsyndrome(MetS). MetS(Metabolicsyndrome) raug ntxias hauv cov nas los ntawm kev noj zaub mov uas muaj fructose siab ntsev rau 12 lub lis piam.ib 6545, lub peripheral uas ntsiag to antagonist, thiabTIAB SA 4113, qhov nruab nrab nruab nrab antagonist tau tswj hwm hauv 4 lub lis piam dhau los. Thaum kawg ntawm txoj kev tshawb no, cov ntshav thiab cov zis tau sau rau kev tshuaj ntsuam biochemical thaum lub raum tau excised rau kev tshawb nrhiav histopathological thiab hloov pauv qhov kev loj hlob-beta 1 (TGF 1) ntsuas. MetS(Metabolic Syndrome) tau cuam tshuam nrog rau lub raum ua haujlwm tsis zoo raws li qhia los ntawm kev nce proteinuria thiab albumin excretion rate. Ob lub tebchaw sib npaug inhibited qhov nce proteinuria thiab albumin excretion tus nqi thaum tsis muaj kev cuam tshuam rau creatinine clearance thiab ntshav siab. Ntxiv rau,ib 6545thiabTIAB SA 4113alleviated qhov pom o thiab inflammatory hlwb infiltration nyob rau hauv ntau lub raum qauv. Ntxiv mus,ib 6545thiabTIAB SA 4113alleviated cov soj ntsuam histopathological alterations nyob rau hauv lub raum qauv ntawm Met nas. MetS(Metabolicsyndrome) tau cuam tshuam nrog kev nce qib ntawm cov zis uric acid thaum ob lub tebchaw thaiv qhov kev nce ntxiv no. Tsis tas li ntawd,ib 6545thiabTIAB SA 4113tiv thaiv tag nrho cov collagen deposition thiab kev qhia siab ntawm TGF1 pom hauv MetS (Metabolicsyndrome) tsiaj. Hauv kev xaus,ib 6545thiabTIAB SA 4113, muaj cov kev tiv thaiv reno-tiv thaiv los ntawm kev cuam tshuam nrog TGF 1- nruab nrab lub raum mob thiab fibrosis, ntawm peripheral ua.

Ntsiab lus:metabolicsyndrome; cannabinoids;ib 6545; TIAB SA 4113; raum; nas

cistanche cov txiaj ntsig: kho mob raum

NYEM QHOV NO RAU PART Ⅰ

3. Kev sib tham

Kev loj hlob ntawm nephropathy yog ib qho teeb meem loj ntawm MetS (Metabolicsyndrome) uas tam sim no nce thoob ntiaj teb.ib 6545thiabTIAB SA 4113yog ob qho tib si nruab nrab antagonists rau CB1 receptor, uas tau pom tias yog hyper-activated hauv MetS (MetabolicsyndromeIb.) [27]. Hauv txoj kev tshawb no, peb tau tshuaj xyuas cov txiaj ntsig ntawm cov tshuaj no ntawm MetS (Metabolicsyndrome)-ua rau nephropathy. Kev pheej hmoo ntawm kev tsim kab mob raum hauv MetS (Metabolicsyndrome) tau sau tseg zoo [6-8]. Tsis ntev los no peb tau pom tias yim lub lis piam ntawm high-fructose thiab siab ntsev loading nyob rau hauv Wistar nas yog txaus los ntxias ib lub xeev ntawm MetS (Metabolicsyndrome) tshwm sim los ntawm kev rog, hyperinsulinemia, hyperuricemia thiab dyslipidemia [28]. Tsis tas li ntawd, peb tau ua pov thawj tias kev kho mob ua ntej ntawm cov tsiaj no nrog ob qho tib siib 6545los yogTIAB SA 4113ua rau muaj kev txo qis ntawm kev tsim khometabolicsyndrome. Qhov no tau tshwm sim los ntawm inhibition ntawm insulin tsis kam, txo lub cev hnyav, tiv thaiv dyslipidemic, anti-hyperuricemic raws li kev tiv thaiv kev ua haujlwm. Peb tau ua pov thawj tias thaj chaw nyob hauv qab ntawm qhov nkhaus ntawm qhov ncauj qhov ncauj qhov siab qhov ntsuas tom qab qhov kev sib tw ntawm qhov ncauj yog siab dua nyob rau hauvmetabolicsyndromepab pawg txheeb ze rau cov tswj. Cov teebmeem ntawm cov ntshav qabzib tau ua kom zoo dua tom qab ob qho tib siib 6545los yogTIAB SA 4113kev tswj hwm [28]. Ntxiv mus, kev tshawb fawb los ntawm cov tswv cuab ntawm peb pab pawg tau pom tias ob qho tib siib 6545thiabTIAB SA 4113txo cov zaub mov noj hauv nas thiab yog li tuaj yeem pab tau rau kev kho mob rog [22,29].

Tus qauv high-fructose high- ntsev ntawm MetS (Metabolicsyndrome) tau pom tias ua rau muaj kev hloov pauv morphological hauv ob lub raum thiab cim qhov siab ntawm lub raum raug mob [10]. Hauv kev tshawb fawb tam sim no, peb tau pom tias MetS (Metabolicsyndrome) nas muaj zog endocannabinoid tone raws li qhia los ntawm elevated anandamide thiab 2-AG cov nyiaj hauv lub raum. Yog li ntawd, peb xav tias siv CB1 antagonistsib 6545thiabTIAB SA 4113tuaj yeem txo cov suab nrov thiab ua kom lub raum ua haujlwm tsis zoo. Txawm tiasmetabolicsyndromecov nas muaj ntshav siab ntau dua piv nrog cov nas tswj, kev tswj hwm ntawm ob qho tib siib 6545tsis yogTIAB SA 4113tsis muaj kev cuam tshuam ntxiv rau ntshav siab hauv cov qauv tam sim no. Qhov no zoo ib yam nrog kev tshawb fawb tsis ntev los no los ntawm cov tswv cuab ntawm peb pab pawg, uas tau tshaj tawm tiasib 6545tsis ua rau muaj kev hloov ntshav siab thaum siv rau streptozotocin-induced ntshav qab zib nas [30]. Qee qhov kev tshawb fawb tau tshaj tawm tias thaiv CB1 receptors ua haujlwm txhim kho cov ntshav siab hauv cov ntshav siab, insulin resistant thiab rog rog [31,32]. Txawm li cas los xij, cov teebmeem ntawmib 6545thiabTIAB SA 4113ntawm cov ntshav siab thiab cov hlab plawv system yog ib qho chaw yuav tsum tau soj ntsuam ntxiv. Qhov kev tshawb pom ntawm peb txoj kev tshawb fawb thiab ntawm Barutta li al. (2018) hais tiasib 6545thiabTIAB SA 4113tej zaum yuav tsim lawv cov teebmeem ntawm lub raum ntawm nws tus kheej ntawm ntshav siab [18].

cistanche tubolosa extract: txhim kho lub raum ua haujlwm

Hauv kev tshawb fawb tam sim no, kev ntsuam xyuas ntawm lub raum morphology qhia tias tsis kho MetS (MetabolicsyndromeCov nas pom pom glomerular, tubular, thiab stromal raug mob hauv lub raum cortex. Raws li, Alderson et al. (2004) tau hais txog qhov loj ntawm glomeruli uas tau pom nyob rau hauv peb txoj kev tshawb fawb rau kev hloov pauv ntawm cov qauv thiab kev ua haujlwm. Qhov no nws thiaj li ua rau hyperfiltration hauv nephrons thiab feem ntau tshaj tawm hauv focal segmental glomerulosclerosis [33]. Tsis tas li ntawd, muaj ob peb lub glomeruli uas nthuav tawm atrophy thiab nthuav qhov chaw capsular. Qhov no yog raws li lwm cov kev tshawb fawb, uas tau faib cov glomerulus li shrunken thiab sclerotic [34].

Txoj kev tshawb no kuj tau saib cov txiaj ntsig ntawm PCT, tshwj xeeb tshaj yog cov tubular hlwb. Qhov no yog qhov uas cov fructose transporters (GLUT-2 thiab GLUT-5) tau pom nrog rau qhov chaw uas cov enzyme keto kinase tau qhia. Ketokinase tau tshaj tawm tias yog ib qho enzyme tseem ceeb hauv fructose metabolism [35]. Kev nthuav dav ntawm cov tubules thiab cytoplasmic vacuolation tau zoo ib yam nrog cov kev tshawb pom yav dhau los, uas pom tau tias mob tubulointerstitial nephropathy ua rau tsim cov hlwv thiab dilatation ntawm cortex tubules [34]. Tej zaum qhov infiltration ntawm hlwb qhia nyob rau hauv txoj kev tshawb no sawv cev rau ib tug mechanism uas lub raum tiv thaiv nws tus kheej thiab sai tshem tawm cov ntaub so ntswg necrotic. Tsis tas li ntawd, muaj kev cuam tshuam ntawm kev ncig vim congestion, uas thaum kawg ua rau cov ntshav capillaries 'permeability ua rau cov ntshav liab extravasation. Tsis tas li ntawd, fructose paub tias ua rau mob hauv cov nas lub raum cov ntaub so ntswg nrog rau kev ua kom o hauv endothelium[36].

Hauv kev tshawb fawb tam sim no, muaj ntau dhau ntawm collagen fibers hauv MetS (Metabolicsyndrome) cov. Qhov no tau pom zoo nrog lwm qhov kev tshawb pom uas qhia tias collagen fiber ntau muaj nyob rau hauv cov neeg mob uas muaj protein ntau urea. Lawv kuj tau tshaj tawm tias qhov no tau pom zoo hauv cov neeg mob glomerulosclerosis thiab tuaj yeem ua rau glomerular degeneration. Tsis tas li ntawd, nws tau tshaj tawm tias tsawg heev glomerular capillaries tau pom nyob rau hauv cov kab mob sclerotic, nrog collagen deposition thiab tsub zuj zuj ntawm mesangial matrix [37]. CB1 receptor activation yav dhau los tau pom tias cuam tshuam rau lub raum fibrogenesis [38]. Raws li qhov kev xav no, MetS(Metabolicsyndrome) nas nyob rau hauv txoj kev tshawb fawb tam sim no tau nthuav tawm cov nqaij mos fibrosis hauv lub raum stroma txheeb ze los tswj cov nas (Daim duab 4). Qhov no tau piav qhia ntxiv los ntawm qhov nce siab hauv TGF 1 theem (Daim duab 5). TGF 1 yog ib qho inflammatory thiab profibrogenic cytokine, uas yog koom nrog hauv cov txheej txheem pathological ntawm lub raum fibrosis [39,40]. Tseem ceeb, kev kho mob MetS(Metabolicsyndrome) nas nrogib 6545thiabTIAB SA 4113txo qis lub raum TGF 1 ntau ntau, qhia tias CB1 tuaj yeem yog tus neeg nruab nrab ntawm TGF 1 qhov taw qhia. Ua ke, qhov txo qis hauv TGF 1 yog khi nrog cov lus teb txo qis rov qab cov lus teb fibrotic thiab morphological raum hloov tau tham saum toj no, Kev sib raug zoo tau pom ntawm AER thiab qib ntawm TGF 1 hauv lub raum hauv cov tsiaj tsis kho thiab cov tsiaj kho nrog.ib 6545tab sis tsis yogTIAB SA 4113. Qhov no qhia tiasTIAB SA 4113tuaj yeem ua yeeb yam txawv me ntsisib 6545.

cistanche phelypaes: tiv thaiv kab mob

Lwm qhov kev tshawb pom tseem ceeb yog kev kho mob MetS (Metabolicsyndrome) nas nrogib 6545thiabTIAB SA 4113Txhim kho lub raum ua haujlwm tau zoo los ntawm kev txo qis hauv lub raum fibrosis. Qhov no suav nrog kev txo qis hauv uric acid excretion, albumin excretion rate thiab tso zis protein ntau. Cov kev tshawb pom no yog ua raws li cov kev tshawb fawb yav dhau los, qhia tias CB1 blockade nrog rimonabant tau txhim kho lub raum ua haujlwm tsis zoo hauv cov rog rog fa/fa Zucker nas [14]. Luv luv, Janiak et al. (2007) tau pom tias kev tswj hwm rimonabant mus sij hawm ntev tau txhim kho creatinine tshem tawm, ua rau muaj proteinuria qeeb thiab txo qis glomerular thiab tubular qhov mob hnyav. Hauv kev tshawb fawb tam sim no, peb tshaj tawm tiasib 6545thiabTIAB SA 4113inhibited qhov nce proteinuria thiab albumin excretion tus nqi thaum tsis muaj kev cuam tshuam rau creatinine tshem tawm.

Xwb, kho cov teebmeem ntawmib 6545thiabTIAB SA 4113antagonists hauv lub raum ua haujlwm kuj tseem tuaj yeem tshwm sim los ntawm kev kho cov kab hauv qab MetS (Metabolicsyndrome) kev nyuaj siab. Ntau cov ntawv tshaj tawm tau pom tias dyslipidemia, suav nrog cov triglycerides siab thiab cov roj cholesterol siab, tuaj yeem ua rau mob raum [41,42]. Hauv peb txoj kev tshawb fawb yav dhau los, CB1 blockade nrog ob tus antagonists ua rau muaj qhov txo qis hauv cov roj cholesterol thiab triglycerides, ntshav qab zib insulin, lub cev hnyav, ntshav uric acid thiab daim siab TNF ua ke nrog nce qib adiponectin hauv tib MetS (Metabolicsyndrome) tus qauv [28]. Yog li ntawd, cov txiaj ntsig zoo no tuaj yeem cuam tshuam ncaj qha rau kev khaws lub raum ua haujlwm. Nyob rau hauv lub neej yav tom ntej, nws yuav nthuav los tshuaj xyuas seb cov CB1 antagonists no puas tuaj yeem pab kho mob raum kab mob tsis cuam tshuam rau MetS (Metabolicsyndrome).

suab puam cistanche cov txiaj ntsig: txhim kho lub raum ua haujlwm

4. Cov lus xaus

Hauv cov ntsiab lus, CB1 receptor nruab nrab antagonists,ib 6545thiabTIAB SA 4113, inhibited qhov nce proteinuria thiab albumin excretion tus nqi tsis cuam tshuam rau creatinine tshem tawm lossis ntshav siab. Peb tau pom tias qhov blockade ntawm CB1 receptor nrog ob cov tshuaj thim rov qab cov kev hloov pauv histopathological tshwm sim los ntawm high-fructose high- ntsev noj hauv lub raum cov ntaub so ntswg. Tsis tas li ntawd, ob qho tshuaj ua rau txo qis hauv lub raum pro-inflammatory cytokine TGF 1. Ua ke, cov txiaj ntsig no qhia tau tiasib 6545thiabTIAB SA 4113muaj kev tiv thaiv rau lub raum hauv MetS (Metabolicsyndrome) tsiaj qauv, tsa kev cia siab rau lawv yav tom ntej muaj peev xwm kho kev cuam tshuam hauv ntau hom kab mob raum.

cistanche hmoov

Cov ntaub ntawv

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