Part 1|Suav Herbal Formula, Tonic Lub raum, txhim kho cov leeg nqaij Atrophy ntawm kev tswj cov txheej txheem Mitochondrial Zoo hauv 5/6 Nephrectomised nas

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

Dongtao Wang1,3, Jianping Chen2, Xinhui Liu1, Ping Zheng1, Gaofeng Song1, Tiegang Yi1,2 & Shunmin Li1

Cov leeg nqaij atrophy yog ib qho teeb meem loj ntawm cov kab mob raum ntev (CKD). Dysregulation ntawm mitochondrial zoo tswj (MQC) txheej txheem, nrog rau txo qis mitochondrial biogenesis, impair mitochondrial dynamics thiab induce activation ntawm mitophagy, plays lub luag hauj lwm tseem ceeb nyob rau hauv kev kho cov nqaij ntshiv. Txoj kev tshawb no tsom xyuas cov teebmeem ntawm Jian-Pi-Yi-Shen (JPYS) decoction ntawm cov leeg nqaij atrophy hauv CKD nas thiab tshawb xyuas nws cov txheej txheem ua tau ntawm kev tswj hwm ntawm MQC cov txheej txheem. 5/6 nephrectomized nas tau muab faib ua 2 pawg: CKD pawg thiab JPYS pawg. Tsis tas li ntawd, sham-operated nas yog ib pab pawg neeg sham. Txhua tus nas raug kho rau 6 lub lis piam. Cov txiaj ntsig tau pom tias kev tswj hwm ntawm JPYS decoction tiv thaiv lub cev qhov hnyav, cov leeg tsis muaj zog, cov leeg nqaij fiber ntau txo, cov leeg nqaij protein degradation, thiab nce nqaij protein synthesis. Tsis tas li ntawd, JPYS decoction nce cov ntsiab lus mitochondrial thiab biogenesis proteins thiab down-regulated autophagy thiab mitophagy proteins. Tsis tas li ntawd, JPYS decoction nce mitochondrial fusion proteins, thaum txo qis mitochondrial fission proteins. Hauv kev xaus, JPYS decoction nce mitochondrial cov ntsiab lus thiab biogenesis, rov qab qhov sib npaug ntawm fission thiab fusion, thiab inhibited txoj kev autophagy-lysosome (mitophagy). Ua ke, peb cov ntaub ntawv tau pom tias JPYS decoction muaj txiaj ntsig zoo rau cov leeg nqaij atrophy hauv CKD, uas yuav cuam tshuam nrog kev hloov kho ntawm MQC txheej txheem.

Cistanche tubulosa tiv thaiv kab mob raum, nyem qhov no kom tau txais cov qauv

Mob raum mob(CKD) yog tus cwj pwm los ntawm kev poob qis hauv lub raum ua haujlwm nyob rau lub hlis lossis xyoo. Cov kev tshawb fawb loj tau pom tias nws cov txheej txheem kev ua haujlwm cuam tshuam nrog kev sib txuam ntau dhau ntawm cov cellular matrix thiab podocyte poob thiab o, nrog rau kev ua haujlwm tsis zoo ntawm lipid metabolism thiab amino metabolism 1-6. Ob peb tsab ntawv ceeb toom qhia tias CKD yog txuam nrog cov leeg nqaij atrophy, uas ncaj qha cuam tshuam nrog kev tuag thiab kev mob morbidity7. Muaj peev xwm stimuli ntawm cov leeg nqaij atrophy hauv CKD suav nrog acidosis, angiotensin II ntau lawm, o, nce-txoj cai ntawm ubiquitin-proteasome, thiab autophagy-lysosome systems (UPS thiab ALS), thiab dysregulation ntawm mitochondrial zoo tswj (MQC) txheej txheem8, 9. Hmoov tsis zoo. , kev tiv thaiv thiab kho cov kev cuam tshuam uas thaiv cov leeg nqaij atrophy tseem nyob rau theem pib ntawm kev loj hlob. Ntau thiab ntau tus neeg mob tau txais kev kho ntxiv lossis lwm txoj kev kho mob xws li tshuaj suav tshuaj (TCM)10–14. Peb tshuaj xyuas seb atshuaj suav tshuaj, Jian-Pi-Yi-Shen (JPYS) decoction, yuav tiv thaiv cov leeg nqaij atrophy los ntawm kev hloov kho cov txheej txheem MQC.

UPS tau lees paub tias yog tus pab txhawb rau cov leeg nqaij proteolysis, lub luag haujlwm rau 50 feem pua ​​lossis ntau dua ntawm tag nrho cov protein degradation hauv cov leeg pob txha. UPS yog txoj hauv kev loj ntawm cov protein degradation, uas 1Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, 518033, Suav. 2Shenzhen Key Laboratory ntawm Tsev Kho Mob Suav Tshuaj Npaj, Shenzhen Traditional Suav Tshuaj Tsev Kho Mob, Guangzhou University of suav tshuaj, Shenzhen, 518033, Suav teb. 3 Department of Nephrology, Ruikang Affiliated Tsev Kho Mob, Guangxi University of suav tshuaj, Nanning, 530011, Suav. Dongtan Wang thiab Jianping Chen tau pab tib yam rau txoj haujlwm no. Kev xa ntawv thiab kev thov rau cov ntaub ntawv yuav tsum tau hais rau DW tuaj yeem degrade myofibril proteins rau hauv lawv cov khoom (actin, myosin, troponin, thiab tropomyosin) 15. Cov proteins no yog tsom thiab degraded los ntawm ob leeg nqaij tshwj xeeb E3 ubiquitin(Ub) ligases, nqaij atrophy F-Box (MAFbx/ Atrogin-1) thiab nqaij leeg-specific RING ntiv tes protein (MuRF1)16, 17. Parallel mus rau saum toj no txoj kev, ALS ntseeg hais tias lub hom phiaj thiab cleaves ntev-nyob proteins, tej cytoplasm, thiab organelles los ntawm lub lysosomal machinery18. Te activation ntawm UPS thiab ALS cov noob caj noob ces feem ntau raug thaiv los ntawm Akt los ntawm kev tswj tsis zoo ntawm Forkhead box O (FoxO) cov ntaub ntawv hloov pauv, suav nrog FoxO1, FoxO3a, thiab FoxO4. Te translocation thiab transcriptional activation ntawm FoxO cov tswv cuab yog txaus los nce atrogin -1 thiab MuRF1 qhia, thiab ua rau nqaij atrophy.

Cov txheej txheem MQC yog nruj tswj hwm los ntawm ntau cov txheej txheem, xws li biogenesis, fusion, fission, thiab mitophagy. Nws tau tshaj tawm tiaskab mob ntevqhib lub mitochondrial teb uas ameliorates lub "zoo" ntawm skeletal leeg mitochondria hlwb ntawm txawv molecular theem: (i) biogenesis los ntawm qhov kev txiav txim ntawm tus tseem ceeb regulators 'peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC{{2). }}), nuclear respiratory factor 1/2 (NRF-1/2), adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK), thiab ATP synthesis; (ii) dynamics los ntawm mitochondrial remodeling GTPase cov proteins xws li mitofusin-2 (Mfn-2) thiab optic atrophy 1 (OPA-1) rau fusion thiab dynamin-related protein 1 (DRP{{ 16}}) thiab fission 1 (Fis{18}}) rau fission; (iii) kev hloov pauv ntawm kev puas tsuaj mitochondria los ntawm mitophagy los ntawm PTEN induced putative kinase 1 (PINK1), Parkin thiab Bnip3 / Nix (BNIP3L); thiab (iv) kev tswj kom zoo los ntawm degradation ntawm misfolded proteins los yog dua ib feem ntawm puas mitochondria los ntawm lub proteolytic system nrog chaperones thiab proteases20. Nws tau raug tshaj tawm tias mitochondrial biogenesis tau txo qis koom nrog cov leeg nqaij atrophy, uas tau txhawb nqa los ntawm PGC-1 thiab AMPK 21, 22. Txawm li cas los xij, cov txheej txheem ntawm MQC suav nrog mitochondrial fusion, fission, biogenesis, thiab mitophagy hauv CKD nqaij atrophy. tseem tsis paub meej.

TCM tau tshaj tawm tias muaj txiaj ntsig zoo rau kev kho mob ntawm cov leeg nqaij atrophy23-26. Txawm li cas los xij, tsis muaj cov ntaub ntawv me me muaj nyob hauv cov ntaub ntawv hais txog seb cov tshuaj suav tshuaj ntsuab nrog cov tshuaj tiv thaiv cov leeg nqaij tuaj yeem cuam tshuam cov txheej txheem MQC hauv CKD. JPYS decoction tau siv dav hauv kev kho mob malnutrition nrog tus po thiab lub raum qi deficiency syndrome hauv CKD tau ntau xyoo. Txawm li cas los xij, kev kawm ntxiv ntawm nws cov ncauj lus kom ntxaws los tiv thaiv kev noj zaub mov tsis zoo thiab rov qab cov leeg nqaij atrophy tseem xav tau. Ntawm no, peb tsom mus tshuaj xyuas seb qhov kev tswj hwm ntawm MQC cov txheej txheem ua rau cov nqaij ntshiv thiab seb JPYS decoction inhibits nqaij atrophy los ntawm kev hloov kho MQC txheej txheem zoo.

cistanche tubulosa extract: kho mob raum kab mob

Cov txiaj ntsig

Kev hloov hauv lub raum ua haujlwm.

Thaum kawg ntawm txoj kev tshawb no, CKD pab pawg tau pom ntau dua cov ntshav creatinine (Scr) thiab ntshav urea nitrogen (BUN) qib piv nrog cov sham pawg. Interestingly, JPYS decoction tau pom los txo cov theem ntawm Scr thiab BUN. Txawm li cas los xij, qib ntawm serum albumin (ALB) tsis txawv ntawm txhua pawg (Table 1).

JPYS decoction txhim kho cov leeg nqaij atrophy.

Lub cev hnyav ntawm pawg CKD tau qis dua li ntawm pawg neeg txaj muag thaum pib kho; Txawm li cas los xij, tsis muaj qhov sib txawv ntawm lub cev hnyav ntawm CKD thiab JPYS pawg. Interestingly, pawg JPYS tau pom pom kev txhim kho ntawm lub cev hnyav ntawm kev kho mob ntawm 5 thiab 6 lub lis piam thaum piv nrog CKD pawg (Fig. 1a). Qhov nce hauv lub cev hnyav los ntawm kev ntxiv JPYS suav nrog qhov nce ntawm qhov hnyav ntawm gastrocnemius (Gastroc) thiab tibialis anterior (TA) cov leeg hauv CKD pawg (Fig. 1b,c). Te txhim kho cov leeg nqaij hauv pawg JPYS tau lees paub los ntawm qhov nce ntawm qhov nruab nrab ntu ntu ntawm myofibers hauv TA cov leeg hauv CKD pawg (Fig. 1d, e).

JPYS decoction nce protein synthesis thiab suppresses protein degradation.

Cov protein synthesis tus nqi qis dua hauv pawg CKD ntau dua li ntawm pawg sham, thiab JPYS decoction tau pom tias yuav ua rau kom cov protein synthesis (Fig. 2a). Ntawm qhov tod tes, cov protein degradation tus nqi siab dua nyob rau hauv pawg CKD ntau dua li hauv pawg sham, uas tau inhibited tag nrho los ntawm JPYS decoction (Fig. 2b).

JPYS decoction inhibits ubiquitin-proteasome system thiab FoxO3a ua kom.

Protein markers nyob rau hauv cov leeg ubiquitin-proteasome system thiab FoxO3a tau nthuav tawm hauv daim duab 3a. CKD pawg tau nthuav tawm qhov kev nthuav qhia ntawm Atrogin-1 thiab MuRF-1, thiab cov kev hloov no tau raug tshem tawm los ntawm JPYS decoction (Fig. 3b,c). Tsis tas li ntawd, txhawm rau paub meej txog qhov cuam tshuam ntawm cov kev hloov pauv hauv cov leeg nqaij proteolysis pom hauv CKD nas, peb ntsuas cov dej num ntawm 20 S proteasome. Ob leeg chymotrypsin- thiab trypsin-zoo li kev ua ub no tau siab dua hauv pawg CKD ntau dua li ntawm pawg sham, thaum tsis muaj zog nrog JPYS decoction (Daim duab 3g, h). Tsis tas li ntawd, phosphorylated (p)-FoxO3a thiab p-FoxO3a/FoxO3a piv tau txo qis hauv pawg CKD, thaum JPYS decoction ua rau muaj kev nce ntxiv raws li piv rau CKD pawg (Fig. 3d,f). Raws li pom nyob rau hauv daim duab 3e, cov ntsiab lus basal protein ntawm FoxO3a tau nce-tswj hauv CKD pawg, thiab qhov no kuj tau tiv thaiv los ntawm JPYS decoction.

JPYS decoction txhim kho cov leeg nqaij mitochondrial cov ntsiab lus thiab aberrant nqaij morphological nta.

Mitochondrial cov ntsiab lus tau soj ntsuam siv SDH staining ntawm Gastroc cov leeg (Fig. 4a). Qhov kev ua ntawm SDH, uas sawv cev rau tus nqi mitochondrial, tau txo qis hauv pawg CKD thiab JPYS decoction antagonized cov lus teb no (Fig. 4b). Ntawm qhov tod tes, SDH staining tau qhia tias hom I (slow oxidative) thiab kuv (ceev oxidative glycolytic) cov nqaij fibers, uas yog mitochondria-nplua nuj fibers, tau txo qis, thiab hom IIb (ceev glycolytic) fibers tau nce hauv pawg CKD. . Txaus siab heev, JPYS decoction tau nthuav tawm qhov hloov pauv ntawm cov leeg nqaij fiber ntau hauv CKD pawg, uas yog qhov txo qis hauv hom IIb fibers thiab nce qhov tseem ceeb hauv hom I thiab IIa nqaij fibers (Fig. 4c). Raws li qhov txo qis hauv SDH kev ua haujlwm, TEM morphologic kuj tau nthuav tawm cov kev hloov pauv loj ntawm qib sarcomeric, nrog cov kev txawv txav tsis zoo nrog tsawg thiab me me mitochondria (dub xub xub; Fig. 4e,f) thiab nrog cov kab Z-kab thinner (dawb xub; Fig. . 4d) hauv CKD pawg. Ib yam li ntawd, I-band, feem ntau yog tsim los ntawm nyias actin filaments, tshwm sim thinner los yog tsis muaj nyob rau hauv pawg CKD (cov hlua khi; Fig. 4d). Qhov tseem ceeb, cov kev hloov no tau tiv thaiv los ntawm JPYS decoction kho.

tiv thaiv kab mob raum: cistanche tubulosarho tawm

JPYS decoction nce mitochondrial biogenesis.

Protein markers nyob rau hauv nqaij mitochondrial biogenesis yog nthuav tawm nyob rau hauv daim duab 5a. Te Cox IV cov protein tuaj yeem siv tau zoo raws li kev tswj hwm kev thauj khoom mitochondrial thiab sawv cev rau cov ntsiab lus mitochondrial, uas tau ua raws li cov txiaj ntsig ntawm SDH kev ua (Fig. 5b). Tsis tas li ntawd, mitochondrial biogenesis proteins NRF-1 thiab PGC-1 kuj tau txo qis hauv pawg CKD thiab cov kev hloov no tau thim rov qab nrog JPYS decoction (Fig. 5c–e). Txawm li cas los xij, cov qib protein ntau rau ATP5B thiab p-AMPK / AMPK ration tsis hloov ntawm txhua pawg (Fig. 5d-f).

JPYS decoction inhibits autophagy thiab mitophagy txoj kev.

Te autophagy thiab mitophagy-related proteins tau kuaj pom los ntawm Western blotting (Fig. 6a). Te qib ntawm Beclin-1 protein thiab LC3II/LC3I ration tau nce-tswj nyob rau hauv pawg CKD thiab qhov no tau retarded los ntawm JPYS decoction (Fig. 6b,c). Kev koom tes ntawm autophagy adapter p62 tau pom tias yuav tsum tau siv rau mitophagy, uas tau nce hauv pawg CKD thiab attenuated los ntawm JPYS decoction (Fig. 6d). Interestingly, cov qib PINK1 thiab Parkin proteins tau nce ntau hauv pawg CKD, thiab cov kev hloov no tau tiv thaiv los ntawm JPYS decoction (Fig. 6f,g). Txawm li cas los xij, tsis muaj qhov sib txawv hauv BNIP3L kev qhia ntawm txhua pawg (Fig. 6e).

JPYS decoction txo qis mitochondrial fission thiab nce mitochondrial fusion.

Te mitochondrial fusion thiab fission-related proteins tau kuaj pom los ntawm Western blotting (Fig. 7a). Te tseem ceeb fission proteins Fis-1 thiab Drop-1 qib tau siab dua hauv pawg CKD, thaum cov kev hloov pauv no cuam tshuam los ntawm kev kho JPYS (Fig. 7b,c). Txawm li cas los xij, qhov tseem ceeb fusion proteins OPA-1 thiab Mfn-2 qib tau txo qis hauv pawg CKD, thiab qhov txo qis no tau tiv thaiv los ntawm kev kho JPYS (Fig. 7d,e).

tiv thaiv lub raum tsis ua haujlwm cistanche tubulosa extract