Reno-tiv thaiv nyhuv ntawm AM6545 thiab AM4113 Kev Kho Mob ntawm Metabolic Syndrome
Mar 21, 2022
Hu rau: Audrey Hu Whatsapp / hp: 0086 13880143964 Email:audrey.hu@wecistanche.com
PART Ⅰ: Kev cuam tshuam nrog TGF 1-Kev Kho Mob Kho Mob thiab Fibrosis Underlies Reno-Protective Effects ntawm CB1 Receptor Neutral Antagonists AM6545 thiab AM4113 nyob rau hauv tus nas qauv ntawm Metabolic Syndrome
Basma G.Eid, Thikryat Neamatallah, Abeer Hanafy, Hany M.El-Bassossy & et al.
1. Taw qhia
Metabolicsyndrome(MetS), yog kev sib xyaw ua ke ntawmmetabolicQhov txawv txav uas feem ntau tshwm sim xws li insulin tsis kam (IR), plab rog rog, dyslipidemia, thiab ntshav siab [1]. Cov neeg mob MetS (Metabolicsyndrome) muaj kev pheej hmoo siab ntawm kev tsim ntshav qab zib, kab mob atherosclerotic cardiovascular (CVD), thiab lub raum tsis zoo [2]. Tag nrho cov kab mob no sawv cev rau cov mob hnyav thiab feem ntau tuag taus uas muaj nyob hauv ntau lub tebchaws. Qhov tshwm sim ntawm MetS (Metabolicsyndrome) tab tom nce thoob ntiaj teb nrog ntau dua ib lab tus tib neeg tam sim no cuam tshuam [3]. Qhov kev nce no yog txuam nrog lub cev tsis ua haujlwm, kev noj zaub mov muaj calorie ntau thiab dej qab zib ntxiv nrog cov suab thaj [4,5]. Kev sib raug zoo ntawm MetS(Metabolicsyndrome) thiab mob raum mob (CKD) yog qhov tsis txaus ntseeg. Txawm li cas los xij, ntau qhov kev tshawb fawb tau tshaj tawm tias kev noj zaub mov nplua nuj fructose induces MetS (Metabolicsyndrome) uas tom qab ntawd nce mus rau ntau yam kev tshwm sim ntawm nephropathy xws li txo glomerular pom, albuminuria, uricosuria, proteinuria thiab kev hloov hauv lub raum morphology [6-8]. Cov txheej txheem ua tau ntawm lub raum tsis zoo tuaj yeem suav nrog kev tso tawm ntawm cov tshuaj tiv thaiv cytokine, dawb radicals thiab oxidative kev nyuaj siab hauv MetS (Metabolicsyndrome[9,10] ib. Qhov tseeb, qhov tshwm sim ntawm CKD hauv cov neeg mob MetS (Metabolicsyndrome) yog 2.6-fold siab dua hauv cov tib neeg uas tsis muaj MetS(Metabolicsyndrome) cov khoom [11].
Cov txiaj ntsig ntawm cistanche extract: anti-bacterial
Kev pab kho mob rau MetS (Metabolicsyndrome) suav nrog kev hloov pauv ntawm kev ua haujlwm dhau ntawm endocannabinoid (EC) system los ntawm inhibition ntawm cannabinoid CB1 receptor subtype|12]. Inhibition ntawm CB1 receptor tau pom tias tswj kev qab los noj mov, noj zaub mov, thiab lipogenesis hauv cov nas rog rog [13-15]. CB1 yog ib chav kawm A Rhodopsin-zoo li G-protein coupled receptor (GPCR) uas ua haujlwm feem ntau G i/o proteins [16]. Cov CB1 receptors nyob rau txhua qhov chaw muaj ntau heev nyob rau hauv lub hauv nruab nrab lub paj hlwb (CNS), uas yuav ua rau kom qhov tshwm sim ntawm neuropsychiatric mob [17]. Nws tau raug tsim kom muaj tag nrho cov kab ke endocannabinoids muaj nyob rau hauv lub raum thiab muaj lub luag haujlwm tseem ceeb hauv lub raum homeostasis nrog rau kev txhim kho ntshav qab zib nephropathy thiab tej yam kev mob xws li CKD[18].CB1 thiab CB2 receptors tau tshaj tawm tias muaj nyob hauv. ntau qhov chaw ntawm nephron nrog rau lwm lub raum hlwb hauv tib neeg thiab nas [19]. Tsis tas li ntawd, endocannabinoid system hauv lub raum plays lub luag haujlwm tseem ceeb hauv lub raum hemodynamics [20].
Rimonabant (SR141716), piv txwv li, yog CB1 receptor inverse agonist uas tau pom zoo los ntawm kev kho mob hauv lub Plaub Hlis 2006 los kho.metabolicCov teeb meem thiab rog rog hauv Tebchaws Europe [21]. Txawm li cas los xij, kev tshem tawm ntawm CNS nkag mus rau cov tshuaj rimonabant tau ua raws los ntawm European Medicines Agency txij li nws tau cuam tshuam nrog kev ntxhov siab, kev nyuaj siab thiab kev nyiam ua kom tua tus kheej [17].
Txhawm rau hla cov kev mob tshwm sim neuropsychiatric ntawm rimonabant, uas yog tshwm sim los ntawm cov teeb meem hauv nruab nrab cuam tshuam nrog nws qhov kev hloov pauv agonist profile, peb tau nrhiav ob lub tswv yim rau kev txhim kho cov txiaj ntsig zoo analogs uas tsis muaj cov kev mob tshwm sim tsis zoo. Thawj qhov ntawm cov no yog qhov nrhiav pom ntawm CB1 nruab nrab antagonists. Cov tebchaw no, tsis zoo li lawv cov agonist inverse counterparts uas ua los ntawm kev txhawb lub xeev tsis muaj zog ntawm cov receptor, tiv thaiv cov endocannabinoids tshwm sim los ntawm kev cuam tshuam nrog CB1. AM4113 sawv cev rau kev ua tiav CB1 nruab nrab antagonist uas qhia txog qhov xav tau ntawm rimonabant tab sis tsis muaj nws cov kev mob tshwm sim tsis zoo. Peb lub tswv yim thib ob yog los tsim CB1 receptor antagonists uas tsis tuaj yeem hla cov ntshav-hlwb thaiv.ib 6545sawv cev rau qhov ua tau zoo peripheral ligand, thaum tib lub sijhawm tswj hwm CB1 nruab nrab antagonist profile. Ob qho tshuaj tau tshaj tawm kom khaws cov kev kho mob hauv cov qauv tsiaj sib txawv uas muaj kev cuam tshuam tsawg dua li rimonabant [22-26].
Hauv txoj kev tshawb fawb tam sim no, peb tsom los txiav txim seb puas kho nrog CB1 receptor antagonistsib 6545thiabTIAB SA 4113yuav txhim kho lub raum ua haujlwm nyob rau hauv high-fructose high- ntsev qauv ntawmmetabolicsyndromethiab tshawb nrhiav lub hauv paus mechanism rau kev txhim kho kev ua haujlwm. Qhov kev tshawb fawb no yuav tso cai rau peb txheeb xyuas seb puas muaj qhov cuam tshuam ntawm cov tebchaw no muaj feem cuam tshuam nrog kev ua haujlwm hauv nruab nrab ntawm CB1 inactivation.
2. Cov txiaj ntsig
2.1.Effect ntawm AM6545 thiab AM4113 Kev Kho Mob ntawm Lub Raum Endocannabinoid Tone
Kev ntsuas ntawm anandamide (AEA) thiab 2-arachidonoyl glycerol (2-AG) nyob rau hauv lub raum homogenates tau ua nyob rau hauv thiaj li yuav soj ntsuam cov endocannabinoid tone nyob rau hauv lub raum. Raws li qhia hauv Table 1, thaum tswj nas (C) raug kho nrog ob qho tib siib 6545(C plus A65) los yogTIAB SA 4113(C ntxiv rau A41) tsis muaj qhov cuam tshuam loj rau cov ntsiab lus ntawm AEA thiab 2-A Gin lub raum. Tsiaj nrogmetabolicsyndrome(MetS) tau nthuav tawm qib siab ntawm ob qho tib si AEA thiab 2-AG piv rau kev tswj hwm (C). Tom qab kho covmetabolicsyndromenas nrog rauib 6545(M plus A65) los yogTIAB SA 4113(M ntxiv rau A41), cov tsiaj tseem pom ntau dua ntawm ob qho tib si AEA thiab 2-AG hauv ob lub raum txheeb ze rau kev tswj hwm.
Table 1. Lub raum cov ntsiab lus ntawm anandamide thiab 2-arachidonoyl glycerol.
2.2.Effect of AM6545 and AM4113 Treatments on Renal Function in MetS (Metabolic Syndrome) nas
MetS(Metabolicsyndrome) vim tias kev noj zaub mov muaj fructose siab-ntsev yog txuam nrog kev ua haujlwm ntawm lub raum tsis zoo raws li qhia los ntawm kev nce albumin excretion rate (AER) thiab proteinuria piv rau kev tswj hwm (p<0.05, figure="" 1a,="" b).="" both="">ib 6545thiabTIAB SA 4113tseem ceeb inhibited (p<0.05)the elevated="" proteinuria="" and="" albumin="" excretion="" rate="" to="" similar="" levels="" suggesting="" protection="" of="" renal="" function="" in="">Metabolicsyndrome). Tsis yogib 6545tsis yogTIAB SA 4113cuam tshuam rau AER lossis proteinuria thaum tswj hwm tsiaj (Daim duab 1A, B). Creatinine clearance tau xam thiab tau qis dua nyob rau hauvmetabolicsyndromepawg(M) piv rau cov tswj (Daim duab]C). Kev tswj hwm ib leegib 6545(M ntxiv rau A65) lossis AM4113 (M ntxiv rau A41) rau qhovmetabolicnas tsis muaj kev cuam tshuam rau kev tshem tawm creatinine (Daim duab 1C).
Daim duab 1. Cov CB1 receptor antagonistsib 6545thiabTIAB SA 4113txhim kho lub raum kev ua haujlwm tsis zoo nyob rau hauv high-fructose high-ntsev ntsevmetabolicsyndromenas.
(A) qhia cov albumin excretion rate (AER), (B) qhia cov proteinuria, thiab (C) qhia cov creatinine clearance ntsuas los tswj.
(C) thiabmetabolicsyndrome(M) nas thiab tom qab 4 lub lis piam ntawm kev txhaj tshuaj intraperitonealib 6545hauv kev tswj hwm (C ntxiv rau A65) thiabmetabolicnas (M ntxiv rau A65) lossis AM4113 hauv kev tswj hwm (C ntxiv rau A41) lossismetabolicnas (M ntxiv rau A41) ntawm ib koob ntawm 10mg / kg / hnub.
Cov txiaj ntsig tau pom raws li cov phiaj xwm lub thawv thiab qhov txhais tau hais tias yog (ntxiv rau )(n=8).*p<0.05 relative="" to="" the="" control="" group=""><0.05 relative="" to="" the="">metabolicsyndromepab pawg los ntawm ib txoj kev ANOVA ua raws li Tukey's post hoc test.
2.3.Effect of AM6545 thiab AM4113 Kev Kho Mob Ntshav Siab
Kev ntsuas ntshav siab uas siv cov txheej txheem uas tsis yog-tus Tsov tus tw-cuff qhia tias MetS (Metabolicsyndrome) tsiaj (M, M ntxiv rau A65, M ntxiv rau A41) tau pom cov ntshav siab ntau dua systolic thiab diastolic hauv kev sib piv los tswj cov tsiaj. Kev kho mob ntawm cov tsiaj nrog ib qhoib 6545los yogTIAB SA 4113tsis ua rau muaj kev hloov pauv tseem ceeb hauv systolic thiab diastolic ntshav siab (Table 2).
Table 2. Cov nyhuv ntawm AM6545 thiab AM4113 ntawm systolic thiab diastolic ntshav siab (BP) ntawm metabolic syndrome (MetS)-vim nas.
2.4.Ib feem ntawm AM6545 thiab AM4113 Kev Kho Mob ntawm Lub Raum Histopathology hauv MetS (Metabolic Syndrome) Cov nas
Kev tshuaj xyuas H&E-stained seem los ntawm MetS(Metabolicsyndrome) nas pom tau tias muaj kev hloov pauv ntawm cov kab mob hauv lub raum, tshwj xeeb tshaj yog nyob rau hauv lub raum cortex qhov kev hloov pauv txawv txav tau pom nyob rau hauv cov glomeruli thiab cov tubules sib thooj thiab lub raum stroma txheeb ze rau pawg tswj hwm. Lub raum ntawm cov nas tswj tau pom cov qauv ntawm lub raum cortex (Daim duab 2A, B), uas muaj feem ntau ntawm lub raum corpuscles uas muaj glomerular capillaries uas tau muab kaw los ntawm Bowman's capsule. Tsis tas li ntawd, muaj qhov chaw capsular nruab nrab ntawm qhov sib thooj (PCT) thiab distal convoluted tubules (DCT). Qhov siab cuboidal hlwb uas muaj eosinophilic cytoplasm nrog lub hauv paus puag ncig nuclei lined cov tubules sib thooj. Qhov siab microvilli tau ntim cov lumen ntawm cov tubules, uas pom cov txhuam luminal ciam teb. Lub distal convoluted tubules tsis tshua muaj txheeb ze rau PCT. Hauv MetS(Metabolicsyndrome) nas, lub raum pom qhov sib txawv ntawm cov kev hloov pauv (Figure2C-E) qhov twg qee qhov glomeruli tau hypertrophied nrog dilated glomerular capillaries thaum lwm cov glomeruli tshwm atrophic. Tsis tas li ntawd, feem ntau PCTs tau dilated nrog poob ntawm txhuam ciam teb; Lawv lub hlwb muaj vacuolated cytoplasm thiab tsaus pyknotic nuclei. Ntxiv mus, DCT tau nthuav tawm qee qhov kev hloov pauv nrog cov phab ntsa thiab vacuolated cytoplasm. Tsis tas li ntawd, qhov chaw interstitial, peritubular hemorrhage, thiab mononuclear inflammatory cellular infiltration tau pom nyob rau hauv ntau qhov chaw ntawm lub raum cortex. Interestingly, MetS(Metabolicsyndrome) nas kho nrogib 6545(Daim duab 3A, B) thiab AM4113 (Daim duab 3C, D) tau pom tias muaj kev txhim kho nyob rau hauv lub raum histological profile uas tshwm sim los ntawm ze li ib txwm glomeruli thiab PCT yam tsis muaj cov tsos mob ntawm degeneration thiab / lossis inflammatory cells infiltration.
Daim duab 2. Cov neeg sawv cev photomicrographs ntawm cov qauv histological ntawm lub raum cortex hauv kev tswj thiabmetabolicsyndromenas.
Cov pab pawg tswj (A, B) qhia pom lub raum glomeruli (G) thiab tubules (PCT, DCT), thaum nyob hauvmetabolicsyndromepawg (CE) qee qhov glomeruli tshwm atrophied (G1) thaum lwm tus tshwm sim hypertrophied (G2) nrog dilated capillaries ().
Feem ntau ntawm PCT tshwm sim degenerated nrog widened lumen, poob ntawm txhuam ciam teb, thiab pyknotic nuclei (hauv ib lub voj voog).
Nco ntsoov lub xub ntiag ntawm interstitial wide spaces (*), ntshav extravasation (*), thiab infiltration nrog inflammatory cells (ICI). (H&E—A, C × 200—B, D, E × 400).
Daim duab 3. Cov neeg sawv cev photomicrographs ntawm cov qauv histological ntawm lub raum cortex hauv cov nas pawg ntawmmetabolicsyndromekho nrogib 6545(A, B) thiabTIAB SA 4113(C, D) CB1 receptor antagonists.
Daim ntawv ceeb toom kev kho dua tshiab ntawm qhov zoo li qub piv rau pawg tswj hwm txog glomeruli (G) thiab tubules (PCT, DCT). (H&E—A, C × 200—B, D × 400)
2.5. Cov nyhuv ntawm AM6545 thiab AM4113 Kev Kho Mob ntawm UIric Acid Levels hauv MetS (Metabolic Syndrome) Cov nas
Muab qhov tseem ceeb ntawm uric acid nyob rau hauv lub raum o thiab kev loj hlob mus rau lub raum tsis zoo, daim duab 4 qhia tau hais tias MetS(Metabolicsyndrome) cov tsiaj muaj kaum npaug ntawm cov zis uric acid cov ntsiab lus ntawm kev tswj hwm (p<0.05). however,="" both="" cb1="" antagonists,="">ib 6545thiabTIAB SA 4113, heev (p<0.05) inhibited="" this="" increased="" uric="" acid="" content="" while="" restoring="" it="" to="" near="" normal="" values.="" meanwhile,="" neither="">ib 6545tsis yogTIAB SA 4113ho cuam tshuam cov zis cov ntsiab lus ntawm uric acid nyob rau hauv cov tsiaj tswj.
2.6. Cov nyhuv ntawmib 6545thiabTIAB SA 4113Kev kho mob ntawm TGF 1 Qib hauv MetS(Metabolicsyndrome) Cov
Txoj kev tshawb fawb ntxiv tau tshawb xyuas lub luag haujlwm ntawm TGF 1 uas yog tus neeg nruab nrab tseem ceeb ntawm kev mob plab thiab fibrosis. Raws li pom nyob rau hauv daim duab 5, cov ntaub so ntswg concentration ntawm TGF 1 nyob rau hauv ob lub raum cais los ntawm MetS (Metabolicsyndrome) nas tau markedly (p<0.05) increased="" than="" in="" normal="" animals.="" however,="" the="" four="" weeks="" of="" treatment="" with="">ib 6545thiabTIAB SA 4113ua rau muaj qhov tseem ceeb (p<0.05)reduction of="" tgfβ1="" concentrations,="" restoring="" it="" to="" normal="" values.="" while="" neither="">ib 6545tsis yogTIAB SA 4113Qhov cuam tshuam loj heev rau TGF 1 cov ntaub so ntswg concentration hauv tswj lub raum. Qhov txiaj ntsig no qhia tias CB1 receptor muaj lub luag haujlwm tseem ceeb hauv kev kho mob o thiab mob raum fibrosis.
Kev sib txheeb coefficient raug xam los ntsuas qhov sib txheeb ntawm cov albumin excretion rate thiab lub raum theem ntawm TGF 1 (Table 3). Kev sib raug zoo muaj zog tau tshwm sim ntawm AER thiab TGF 1 hauv kev tswj hwm thiabmetabolicsyndrometsiaj txhu. Kev sib raug zoo kuj muaj nyob rau hauv cov tsiaj kho nrogib 6545, tab sis tsis nrogTIAB SA 4113.
Daim duab 4. Cov CB1 receptor antagonistsib 6545thiabTIAB SA 4113blocked tenfold nce nyob rau hauv cov zis uric acid cov ntsiab lus nyob rau hauv high-fructose high- ntsev inducedmetabolicsyndromenas.
Qhov concentration ntawm uric acid tau ntsuas nyob rau hauv cov zis ntawm kev tswj (C) thiabmetabolicsyndrome(M) nas thiab tswj thiabmetabolicnas kho nrogib 6545(C ntxiv rau A65) thiab (M ntxiv rau A65) raws li los yogTIAB SA 4113(C ntxiv rau A41) thiab (M ntxiv rau A41) raws li ntawm koob tshuaj 10 mg / kg / hnub. Cov txiaj ntsig tau pom raws li lub thawv ntawv thiab qhov txhais tau tias yog (ntxiv rau )(n=8).*p<0.05relative to="" the="" control="" group="" and=""><0.05 relative="" to="" the="">metabolicsyndromepab pawg los ntawm ib txoj kev ANOVA ua raws li Tukey's post hoc test.
Daim duab 5. Cov CB1 receptor antagonistsib 6545thiabTIAB SA 4113txo TGF 1 ntau lawm hauv fructose-inducedmetabolicsyndromenas.
Qhov concentration ntawm TGF 1 tau ntsuas hauv kev tswj (C) thiabmetabolicsyndrome(M) nas thiab tswj thiabmetabolicnas kho nrogib 6545(C ntxiv rau A65) thiab (M ntxiv rau A65), feem, lossis AM4113 (C ntxiv rau A41) thiab (M ntxiv rau A41), raws li, ntawm koob tshuaj 10mg / kg / hnub. Cov txiaj ntsig tau pom raws li lub thawv ntawv thiab qhov txhais tau tias yog (ntxiv rau )(n=8).*p<0.05 relative="" to="" the="" control="" group=""><0.05 relative="" to="" the="">metabolicsyndromepab pawg los ntawm ib txoj kev ANOVA ua raws li Tukey's post hoc test.
Table 3. Cov teebmeem ntawm AM6545 thiab AM113 ntawm kev sib raug zoo ntawm albumin excretion rate (AER) thiab lub raum theem ntawm transforming growth factor-beta 1(TGF1).
2.7.Effect ntawmib 6545thiabTIAB SA 4113Kev kho mob rau lub raum Fibrosis hauv MetS (Metabolicsyndrome) Cov
Daim duab 6 qhia txog lub raum seem los ntawm ntau pawg stained los ntawm Masson's Trichrome los ntsuam xyuas cov collagenous fibers, uas tshwm sim raws li ib tug xiav xim. Lub raum cortex pom tau tias muaj qhov nce ntawm collagenous fibers hauv ob lub raum los ntawm MetS (Metabolicsyndrome) nas (Daim duab 6B) piv rau cov nas tswj (Daim duab 6A). Nyob rau hauv lub interstitium thiab glomeruli, muaj ntau tshaj ntawm collagen fiber deposition. Nyob rau hauv sib piv, muaj txo deposition ntawm collagenous fibers nyob rau hauv lub raum cortex nrogib 6545(Daim duab 6C) thiab AM4113 (Daim duab 6D) kev kho mob. Quantification ntawm Masson's Trichrome staining qhia ntau feem pua ntawm covmetabolicsyndrome(M) raws li nyob rau hauvmetabolicpab pawg kho mob (M ntxiv rau A65, M ntxiv rau A41) piv rau kev tswj hwm. Txawm li cas los xij, kev kho mob MetS (Metabolicsyndrome) tsiaj nrogib 6545thiabTIAB SA 4113ua rau muaj qhov txo qis ntawm Masson tus staining txheeb ze rau cov tsis khometabolicpab pawg.
Daim duab 6. Cov neeg sawv cev photomicrographs ntawm lub raum cortex ntawm ntau pawg stained nrog Masson's Trichrome. Pom qhov cim nce ntawm collagenous fibers.
(A) hauv lub raum ntawmmetabolicsyndrome(B) nyob ib ncig ntawm lub glomeruli (G) thiab tubules (PCT, DCT) piv rau cov tswj (A). Piv txwv li,ib 6545- khometabolicsyndrome
(C) thiab AM4113- khometabolicsyndrome(D) pom qhov txo qis ntawm collagenous fibers. (Masson's Trichrome, A, B, C& D × 200).
(E) qhia qhov ntau ntawm Masson's Trichrome staining qhia raws li ib feem pua. Cov txiaj ntsig tau pom raws li cov phiaj xwm lub thawv thiab qhov txhais tau tias yog (ntxiv )(n=8).* Qhov txawv ntawm "C" ntawm p<0.05,# significantly="" different="" from"m"="" at="" p=""><>
