Spermidine Alleviates Intrauterine Hypoxia-Induced Offspring Newborn Myocardial Mitochondrial Damage nyob rau hauv nas Los ntawm Inhibiting Oxidative Stress Thiab Regulating Mitochondrial Quality Control Part 2

4.4. Cov teebmeem ntawm Spermidine ntawm Myocardial Antioxidative Activity thiab Apoptosis hauv cov menyuam yug tshiab raug rau Intrauterine Hypoxia

Glycoside ntawm cistanche tuaj yeem ua rau muaj kev ua haujlwm ntawm SOD hauv plawv thiab daim siab cov ntaub so ntswg, thiab txo cov ntsiab lus ntawm lipofuscin thiab MDA hauv txhua cov ntaub so ntswg, tshem tawm ntau yam reactive oxygen radicals (OH-, H₂O₂, thiab lwm yam) thiab tiv thaiv DNA puas. los ntawm OH-radicals. Cistanche phenylethanoid glycosides muaj peev xwm tshem tawm cov dawb radicals, muaj peev xwm txo tau ntau dua li cov vitamin C, txhim kho cov haujlwm ntawm SOD hauv cov phev ncua, txo cov ntsiab lus ntawm MDA, thiab muaj qee yam kev tiv thaiv ntawm cov phev membrane muaj nuj nqi. Cistanche polysaccharides tuaj yeem txhim kho kev ua haujlwm ntawm SOD thiab GSH-Px hauv erythrocytes thiab ntsws cov ntaub so ntswg ntawm cov nas senescent sim los ntawm D-galactose, nrog rau txo cov ntsiab lus ntawm MDA thiab collagen hauv lub ntsws thiab ntshav, thiab nce cov ntsiab lus ntawm elastin, muaj Cov nyhuv scavenging zoo ntawm DPPH, ncua lub sijhawm ntawm hypoxia hauv cov nas senescent, txhim kho cov haujlwm ntawm SOD hauv cov ntshav, thiab ncua lub physiological degeneration ntawm lub ntsws hauv kev sim cov nas nrog cellular morphological degeneration, kev sim tau pom tias Cistanche muaj peev xwm antioxidant zoo. thiab muaj peev xwm los ua ib qho tshuaj tiv thaiv thiab kho cov kab mob ntawm daim tawv nqaij laus. Nyob rau tib lub sijhawm, echinacoside hauv Cistanche muaj lub peev xwm tseem ceeb los tshem tawm DPPH dawb radicals thiab tuaj yeem tshem tawm cov pa oxygen reactive, tiv thaiv dawb radical-induced collagen degradation, thiab kuj muaj kev kho zoo ntawm thymine dawb radical anion puas.

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Peb ntsuas cov dej num ntawm antioxidant enzymes SOD thiab CAT hauv myocardium los ntawm colorimetry (Figures 4A thiab B). Nws tau pom tias cov dej num ntawm SOD thiab CAT hauv pawg IUH tau qis dua cov hauv pawg tswj hwm (P < 0.05); Piv nrog rau pawg IUH, cov haujlwm ntawm SOD thiab CAT hauv pawg SPD tau nce ntau heev (P < 0.05), thiabDFMO tshem tawm cov txiaj ntsig ntawm SPD (P < 0 . 05). Tom qab ntawd, peb soj ntsuam cell apoptosis los ntawm kev kuaj TUNEL-positive nuclei (Daim duab 4CandD) thiab kev qhia ntawm pro-apoptosis protein BAX thiab anti-apoptosis BCl-2 (Figures 4E thiab F). Peb pom tias tus naj npawb ntawm TUNELpositive cardiomyocytes thiab BAX / BCL2 protein qhia piv tau ntau dua hauv IUH pawg dua li cov hauv pawg tswj hwm (P <0.05). Hauv qhov sib piv, qhov piv ntawm TUNEL-zoo hlwb thiab BAX / BCL2 protein qhia piv tau qis dua hauv myocardium ntawm SPD-kho nas dua li hauv IUH pawg (P <0.05). DFMO tshem tawm cov nyhuv ntawm SPD (P <0.05). Txhawm rau ua kom tiav, SPD muab rau hauv utero tuaj yeem thim rov qab qhov txo qis ntawm cov tshuaj tiv thaiv kab mob antioxidant thiab qhov nce ntawm cell apoptosis hauv cov menyuam lub siab raug ntxias los ntawm IUH.

4.5. Kev cuam tshuam ntawm Spermidine ntawm Kev Tsim Cov Tshuaj Reactive Oxygen, Mitochondrial Membrane Potential, thiab Mitophagy hauv Cardiomyocytes raug Hypoxia

Mitochondrial dysfunction feem ntau tshwm sim raws li kev nce hauv ROS ntau lawm, txo qis hauv ATP synthesis, thiab tsub zuj zuj ntawm mitochondria dysfunctional. Mitochondrial membrane muaj peev xwm (∆Ψm) yog proton electrochemical gradient (H ntxiv rau concentration gradient thiab transmembrane muaj peev xwm sib txawv) hla cov mitochondrial puab daim nyias nyias, uas yog tsim thaum lub sij hawm hloov hluav taws xob ntawm lub mitochondrial oxidative respiratory saw, nyob rau hauv uas muaj tsawg tus ROSs yog. ua. Raws li, ROS theem thiab ∆Ψm hloov pauv yog cov cim tseem ceeb ntawm kev ua haujlwm mitochondrial. Ntau ROS ntau lawm ua rau tsub zuj zuj ntawm mitochondria dysfunctional; mitochondrial puas yog tsuas yog tshem tawm los ntawm mitophagy. Txhawm rau tshawb xyuas seb qhov exogenous SPD tuaj yeem cuam tshuam qhov kev ncaj ncees ntawm mitochondrial kev ua haujlwm hauv cardiomyocytes nyob rau hauv cov mob hypoxia, peb thawj zaug tshuaj xyuas cov qib ROS siv DHE fluorescence sojntsuam (Daim duab 5A). Peb pom tias ROS ntau lawm tom qab cardiomyocytes raug hypoxia rau 24 h (P < 0.05) thiab SPD inhibited cov hypoxia-induced ROS ntau lawm (P < 0 05); Txawm li cas los xij, DFMO tshem tawm qhov txo qis ntawm ROS ntau lawm kho los ntawm SPD thaum DFMO tau muab rau cardiomyocytes kho los ntawm SPD (P < 0.05) (Daim duab 5C). Tsis tas li ntawd, ∆Ψm tau kuaj pom siv TMRE fluorescent sojntsuam (Daim duab 5B). Qhov muaj zog ntawm cov fluorescence liab, qhov muaj peev xwm mitochondrial siab dua (P < 0.05). Peb pom tias qhov kev siv ntawm cov fluorescence liab tau qis dua hauv IUH pawg dua li hauv pawg tswj hwm (P < 0.05). Piv nrog rau pawg IUH, cov xim liab fluorescence siv ntau dua hauv kev kho SPD (P < 0.05), thiab DFMO tshem tawm cov teebmeem ntawm SPD ib zaug ntxiv (P < 0.05) (Daim duab 5D). Tom qab ntawd peb kwv yees lub colocalization ntawm mitochondria (labeled nrog MitoTracker ntsuab) nrog lysosomes (labeled los ntawm Lyso-Tracker liab), uas tso cai rau peb ntsuas qhov autophagic degradation ntawm mitochondria (Daim duab 5E). Raws li qhia hauv daim duab 5F, piv rau kev tswj hwm, hypoxia txo cov colocalization ntawm Mito-Tracker Green thiab Lyso-Tracker Liab hauv cardiomyocytes (P <0.05). Txawm li cas los xij, piv rau pawg hypoxia, qhov feem pua ​​​​ntawm cov colocalized mitochondria thiab lysosomes tau siab dua nyob rau hauv pab pawg kho mob SPD (P <0.05), thiab DFMO tshem tawm cov nyhuv ntawm SPD (P <0.05). Cov txiaj ntsig no qhia tias hypoxia nce ROS ntau lawm thiab txo ∆Ψm thiab mitophagy; SPD tuaj yeem txo qhov kev puas tsuaj ntawm mitochondrial hypoxia los ntawm stimulating mitophagy thiab inhibiting oxidative kev nyuaj siab.

4.6. Cov teebmeem ntawm SPD ntawm myocardial MQC system hauv cov menyuam yug tshiab tawm-caij nplooj ntoos hlav raug rau IUH

Mitochondrial zoo tswj (MQC), suav nrog cov txheej txheem ntawm mitochondrial autophagy, mitochondrial biosynthesis, thiab mitochondrial fusion thiab fission, yog qhov tseem ceeb rau kev tswj hwm qhov qub morphology, kom muaj nuj nqis, thiab kev ua haujlwm ntawm mitochondria thiab ua kom muaj kev ua haujlwm zoo thiab cov metabolism hauv hlwb. Mitophagy tswj MQC thiab kho kom haum autophagic degradation ntawm mitochondria nyob rau hauv teb rau txoj kev-thiab physiological hloov. Peb thawj zaug ntsuas mitophagy los ntawm kev soj ntsuam qhov tsim ntawm mitophagosome nrog TEM (Daim duab 6A - C). Raws li cov txiaj ntsig tau, qee cov qauv txawv txav lossis kev sib cais ntawm mitochondria tau kaw nyob rau hauv ob chav membrane autophagic membrane, uas yog mitophagosomes, thiab qhia tau hais tias mitophagy tau ua haujlwm hauv pawg tswj hwm. Txawm li cas los xij, tus naj npawb ntawm mitophagosomes poob qis hauv myocardium ntawm IUH pawg. Interestingly, lub myocardium ntawm SDP pab pawg tau pom yuav luag zoo tib yam mitophagy phenotypes rau ntawm pawg tswj hwm, thaum DFMO tshem tawm cov teebmeem tshwm sim los ntawm SPD. Mitochondria yog cov organelles uas muaj zog heev, ua rau muaj kev cuam tshuam tas li thiab cov xwm txheej fusion cuam tshuam nrog lawv txoj haujlwm. Tom ntej no peb soj ntsuam mitochondrial fragmentation siv TEM (Daim duab 6A). Peb pom tias cov naj npawb ntawm cov me me thiab tawg mitochondria tau nce los ntawm IUH, piv rau kev tswj hwm (P < 0.05), qhia tias mitochondrial fission tau nthuav dav. Qhov kev hloov pauv no tau txwv los ntawm kev kho SPD, thiab DFMO kuj tau tshem tawm lub luag haujlwm ntawm SPD ib zaug ntxiv (Daim duab 6D). Tsis tas li ntawd, DRP1 thiab MFN2 (kev tswj cov proteins ntawm mitochondrial dynamics) tau kuaj pom (Daim duab 6E - G). MFN2 poob qis, qhov DRP1 nce thiab tau pom hauv IUH pawg piv rau pawg tswj hwm (P < 0.05). Txawm li cas los xij, DRP1 tsis raug tswj hwm thiab MFN2 tau kho nrog kev kho mob ntawm exogenous SPD (P < 0 05), DFMO tshem tawm cov teebmeem tshwm sim los ntawm SPD. Mitochondrial biosynthesis ua haujlwm nrog mitophagy kom tshem tawm cov mitochondria puas lossis ntau dhau, tsim cov mitochondria tshiab, thiab tswj cov homeostasis ntawm MQC nyob rau hauv kev ntxhov siab. Thaum kawg, peb tau soj ntsuam cov kev qhia ntawm mitochondrial biosynthesis ntsig txog cov proteins, suav nrog SIRT-1, PGC-1 , NRF-2, thiab TFAM, los ntawm kev tshuaj ntsuam immunoblot (Daim duab 6H - L). Piv nrog rau pawg tswj hwm, cov lus qhia ntawm SIRT-1, PGC-1 , NRF-2, thiab TFAM poob qis hauv myocardium ntawm IHU pawg (P <0.05). Piv rau pawg IUH, cov lus qhia cov protein ntawm SIRT-1, PGC-1 , NRF-2, thiab TFAM hauv pawg SPD tau nce ntau (P <0.05). DFMO tshem tawm cov txiaj ntsig ntawm SPD (P <0.05). Txhawm rau suav nrog, cov txiaj ntsig no qhia tau tias IUH ua rau MQC ua haujlwm tsis zoo hauv myocardial ntawm ib hnub-laus cov xeeb ntxwv thiab tias kev kho SPD cuam tshuam qhov tsis txaus ntawm MQC system hauv cov xeeb leej xeeb ntxwv uas raug rau IUH.

5. Kev sib tham

Kab mob plawv yog ib qho nyuaj rau kev noj qab haus huv thoob ntiaj teb. Nws tau raug pom tias qhov mob ntawm tus menyuam hauv plab hypoxia tuaj yeem ua rau lub hauv paus pib ntawm lub plawv tsis ua haujlwm thiab ua rau muaj kev pheej hmoo ntawm kev mob plawv hauv cov menyuam yaus. Lub plawv muaj cov kab mob metabolic siab, thiab nws qhov kev cia siab ntawm mitochondrial muaj nuj nqi rau kev tsim hluav taws xob yog qhov tseem ceeb rau kev ua haujlwm ntawm lub plawv. Txawm li cas los xij, cov txiaj ntsig ntawm IUH ntawm lub plawv mitochondrial muaj nuj nqi thiab nws cov txheej txheem cuam tshuam thiab kev tsom ntawm cardio-tiv thaiv kev tiv thaiv lub tswv yim ntawm mitochondria hauv cov menyuam yug tshiab tseem tsis tau paub. Hauv txoj kev tshawb fawb tam sim no, peb pom tias ib hnub cov nas tsuag tawm ntawm lub caij nplooj ntoo hlav raug rau IUH pom qhov txawv txav hauv kev loj hlob thiab kev loj hlob, cardiomyocytes maturation, tshwj xeeb tshaj yog nyob rau hauv myocardial mitochondrial qauv thiab kev ua haujlwm, thiab exogenous SPD supplementary hauv utero tuaj yeem txo qhov IUH-induced. hloov los ntawm inhibiting myocardial oxidative kev nyuaj siab thiab txo apoptosis. Qhov tseem ceeb, peb pom tias kev kho SPD ua ntej yug me nyuam tuaj yeem thim rov qab qhov txawv txav ntawm mitophagy thiab biogenesis, thiab mitochondrial fragmentation hauv myocardium ntawm cov menyuam yug tshiab nas raug ntxias los ntawm IUH. Rau qhov zoo tshaj plaws ntawm peb txoj kev paub, qhov kev tshawb fawb no yog thawj daim ntawv tshaj tawm txog kev tiv thaiv ntawm SPD ntawm IUH-vim cov menyuam yug tshiab lub plawv puas los ntawm kev tswj hwm MQC mechanism thiab tom qab ntawd txhim kho mitochondrial muaj nuj nqi.

Cov pov thawj txaus qhia tias kev txwv txoj kev loj hlob ntawm lub tsev menyuam cuam tshuam nrog txoj kev loj hlob ntawm lub cev hauv plab, uas tuaj yeem ua rau lub plawv ua haujlwm tom qab lub neej (5, 7, 37). Hauv peb txoj kev tshawb fawb, IUH ua rau muaj kev loj hlob qeeb thiab lub plawv puas tsuaj hauv cov menyuam yug tshiab nas, vim tias ib hnub cov nas yug tshiab raug rau IUH pom qhov txo qis hauv BW, thiab HW thiab nce hauv HW / BW piv. Tsis tas li ntawd, cov txheej txheem ntawm myocardial fibers raug teeb meem, myofilaments tau tawg, inflammatory cell infiltration tau pom ntawm myofilaments, thiab myocardial collagen deposition tau nce. Cov kev tshawb pom no zoo ib yam nrog kev tshawb pom los ntawm Ducsay li al. (2) thiab Thompson et al. (7). Hauv ntau tus qauv tsiaj, lub siab lub ntsws ntawm tus menyuam hauv plab uas raug mob hypoxia pom tau txo qis cardiomyocyte maturation thiab proliferation thiab txo qis cardiomyocyte endowment (38, 39). Ib yam li ntawd, peb cov kev tshawb fawb kuj tau pom tias qhov kev faib ua feem ntawm binucleate cardiomyocytes tau nce thiab kev qhia ntawm Ki67 txo qis hauv IUH pawg. Lub sij hawm uas cardiomyocytes dhau los ua bi/multi-nucleated coincides nrog lub sij hawm thaum cov tsiaj nyeg poob lawv cov peev xwm regenerative (40). Lub plawv fetal maturation yog ib qho tseem ceeb rau cov me nyuam lub plawv noj qab haus huv. Raws li, IUH ua rau cardiomyocytes tshem tawm ntawm lub voj voog ntawm tes ua ntej, thiab cardiomyocyte maturation disorder ua rau lub cev tsis zoo ntawm lub plawv tom qab yug me nyuam.

Needless yuav tsum nco ntsoov tias mitochondria yog lub ntsiab cellular organelles koom nyob rau hauv zus tau tej cov ROS; mitochondria dysfunctional tsis yog tsuas yog tsim nyob rau hauv cov lus teb rau txo ATP ntau lawm tab sis kuj mus rau oxidative kev nyuaj siab thiab apoptosis (41). Hauv txoj kev tshawb no, IUH txo qis kev ua haujlwm ntawm cov tshuaj tiv thaiv oxidative SOD thiab CAT, txo qis mitochondrial ua pa ua haujlwm thiab ATP qib, nce kev qhia ntawm BAX / BCL2, thiab ua rau cov qauv mitochondrial hauv myocardium ntawm ib hnub yug menyuam nas. Cov kev tshawb pom no tau txais kev txhawb nqa los ntawm lwm cov kws tshawb fawb (11), uas tau sau tseg tias niam txiv mob hypoxia raug mob thaum cev xeeb tub tuaj yeem txo qis mitochondrial complex IV kev ua thiab ua rau apoptosis hauv lub siab ntawm cov nas nyob ze. Peb tau sib cav tias mitochondrial kev cuam tshuam yuav ua rau muaj kev ntxhov siab oxidative thiab lub zog tsis ua haujlwm thaum lub sij hawm fetal kev loj hlob culminating nyob rau hauv perinatal mob plawv. Qhov no tuaj yeem yog qhov laj thawj tseem ceeb rau kev pheej hmoo ntawm cov hlab plawv hauv cov xeeb leej xeeb ntxwv uas muaj teeb meem los ntawm kev mob fetal hypoxia. Raws li, nws muaj peev xwm siv mitochondrial los ua lub hom phiaj ntawm kev kho mob los tiv thaiv lub plawv ua haujlwm hauv cov xeeb ntxwv. Aljunaidy et al. qhia tias kev kho niam nrog mitochondrial antioxidant MitoQ tiv thaiv placental oxidative kev nyuaj siab, cawm fetal kev loj hlob, thiab txhim kho lub plawv muaj nuj nqi nyob rau hauv cov me nyuam raug IUH (42).

Spermidine yog polyamine nrog ntau yam kev ua haujlwm lom neeg. Raws li peb tau hais, SPD tuaj yeem cuam tshuam H2O2- induced ROS tsub zuj zuj thiab tiv thaiv qhov txo qis hauv mitochondrial membrane muaj peev xwm (MMP) thiab ATP qib hauv kab lis kev cai nas neonatal 'cardiomyocytes thiab H9C2 hlwb. Ntxiv mus, SPD tuaj yeem txhawb nqa mitochondrial biogenesis thiab txhim kho mitochondrial muaj nuj nqi hauv lub plawv laus (43). Polyamines spermine thiab spermidine tuaj yeem cuam tshuam rau dynamic mitochondrial proteome, yog li tiv thaiv hnub nyoog txog kev hloov pauv hauv kev ua haujlwm plawv thiab mob plawv (36). Lwm cov kev tshawb fawb kuj tau pom tias SPD ntxiv ncua kev mob plawv los ntawm kev txhim kho mitophagy thiab txhawb kev ua pa ntawm mitochondrial hauv nas (44). ODC yog ib qho tseem ceeb enzyme ntawm polyamine synthesis, thiab nws tau tshaj tawm tias nyob rau hauv vivo knockdown ntawm ODC los yog daim ntawv thov ntawm DFMO, ib tug irreversible inhibitor ntawm ODC ua rau cuam tshuam lub tswvyim ntawm kev loj hlob thiab fetal kev loj hlob retardation vim tsis txaus ntawm polyamines (45, 46). Peb txoj kev tshawb fawb tam sim no qhia tau hais tias kev kho mob nrog 5 mg / kg / d ntawm SPD hauv cov nas uas raug IUH tiv thaiv kev loj hlob retardation thiab kev hloov pauv ntawm lub plawv morphological qauv thiab kev loj hlob ntawm cov me nyuam mos thaum caij nplooj ntoos hlav. Tsis tas li ntawd, IUH-induced cardiac oxidative stress enhancement, apoptosis nce, thiab mitochondrial respiratory deficiency in neonatal offspring kuj raug tiv thaiv los ntawm SPD, thaum DFMO muab rau leej niam tshem tawm SPD-mediated tiv thaiv rau lub plawv neonatal. Nws tau zoo sau tseg tias polyamines koom nrog placental angiogenesis thiab embryogenesis nrog rau embryonic thiab fetal loj hlob thiab kev loj hlob (47). Zhu et al. tau tshaj tawm tias cov qib polyamine tau qis dua hauv cov hlab ntsha hauv plab plasma los ntawm kev txwv txoj kev loj hlob ntawm tus menyuam hauv plab (IUGR) porcine fetuses, thiab ntxiv SPD rau leej niam tuaj yeem tiv thaiv IUGR (48). Spermidine yog ib qho kev sib xyaw nrog kev nyab xeeb tsim nyog thiab qis dua toxicity (49). Cov naj npawb ntawm cov kws kho mob thiab kws kho mob tau nce ntxiv tau qhia tias kev noj zaub mov SPD muaj kev noj qab haus huv xws li kev tiv thaiv kev laus, kev tiv thaiv kab mob plawv, neuromodulation, thiab kev tiv thaiv kev ua haujlwm, xws li kev txhaj tshuaj intraperitoneal ntawm SPD (50 mg / kg) hauv nas tiv thaiv collagen-induced. mob caj dab los ntawm inhibiting polarization ntawm M1 macrophages hauv cov ntaub so ntswg synovial (50). Ntxiv nrog rau 10 mg / kg / d ntawm SPD thim rov qab hnub nyoog ntsig txog kev mob plawv hauv nas (36). Qhov tseem ceeb tshaj, leej niam yog ib qho kev cuam tshuam nrog 5 mg / kg / d ntawm SPD thaum cev xeeb tub lig los txhim kho IUHinduced kev txawj ntse thiab neural muaj nuj nqi poob qis (51) thiab lub plawv oxidative kev nyuaj siab puas tsuaj rau cov menyuam nas (32). Raws li, peb tau siv tib koob tshuaj SPD (5 mg / kg / d) rau cov nas cev xeeb tub raug rau IUH ib yam li hauv peb txoj kev tshawb fawb dhau los. Peb xav tias niam txiv SPD supplementation thaum cev xeeb tub hypoxic tuaj yeem nce qib SPD hauv cov menyuam hauv plab, uas tej zaum yuav muaj feem cuam tshuam txog kev tiv thaiv oxidative kev nyuaj siab uas ua rau cov placenta, uas yuav tiv thaiv mitochondria hauv lub plawv loj hlob los ntawm kev ua haujlwm los ntawm IUH, qhov kev txiav txim ntawm SPD tuaj yeem ua tiav los ntawm nws cov tshuaj tiv thaiv oxidative muaj zog, tiv thaiv apoptosis, thiab kev txhawb nqa kev loj hlob.

Mitochondrial zoo tswj mechanisms yog qhov tseem ceeb rau kev tswj lub cev morphology, tus lej, thiab kev ua haujlwm ntawm mitochondria thiab ua kom cov hlwb ua haujlwm zoo thiab cov metabolism (16). Cov pov thawj tsis ntev los no tau qhia tias MQC cov txheej txheem ua lub luag haujlwm txiav txim siab hauv perinatal myocardial mitochondrial maturation thiab lub plawv loj hlob (14). Gong et al. thawj zaug tau tshaj tawm tias qhov tsis paub qab hau zoo li mitochondria yog ncaj qha degraded los ntawm Parkin-mediated mitophagy thaum lub sij hawm ntxov postnatal (19). Nyob rau hauv lub sijhawm no, mitochondrial biogenesis nce ntau (52), thiab mitochondrial fusion thiab fission yam yog transcriptionally upregulated nyob rau hauv lub plawv tom qab yug me nyuam (20, 21). Txawm li cas los xij, tsawg dua paub txog cov txiaj ntsig ntawm IUH ntawm MCQ hauv myocardium ntawm cov xeeb ntxwv neonatal. Hauv txoj kev tshawb no, peb xub pom tias tus naj npawb ntawm mitophagosome tau txo qis hauv myocardium ntawm pawg IUH, qhia tias IUH ua rau muaj kev cuam tshuam rau myocardial mitophagy ntawm cov menyuam yug tshiab nas. Tom ntej no, peb tau pom qhov txo qis ntawm PGC-1 (tus tswj hwm tseem ceeb ntawm mitochondrial biogenesis) thiab kev qhia ntawm nws cov dej ntws ntws thiab nqes dej taw qhia, suav nrog SIRT-1, TFAM, thiab NRF{{10} } hauv myocardium ntawm IUH pawg. Ntxiv mus, peb pom tias IUH raug ua rau me me los yog fragmented mitochondria thiab kev qhia ntawm DRP1 nce; Txawm li cas los xij, qhov kev qhia ntawm MFN2 tau txo qis hauv myocardium ntawm cov menyuam yug tshiab nas, qhia tias mitochondrial fission tau kho, thiab fusion tau txo qis. Cov kev tshawb pom no tau cuam tshuam qhov ua rau-thiab-tshuaj cuam tshuam kev sib raug zoo ntawm qhov tsis sib xws ntawm MQC mechanism thiab IUH-induced myocardium kev puas tsuaj rau cov menyuam yug tshiab. Cov txheej txheem MQC no ua haujlwm hauv kev hais kwv txhiaj nrog ib leeg txhawm rau tshem tawm cov kev ua haujlwm tsis zoo ntawm mitochondria hauv ib qho tshwj xeeb thiab lub hom phiaj thiab tswj cov biogenesis ntawm cov organelles tshiab, uas yog qhov tseem ceeb rau kev mob plawv homeostasis. Ntau cov kab mob hauv lub cev thiab cov xov tooj ntawm tes tuaj yeem tswj hwm MQC cov xwm txheej, suav nrog kev ntxhov siab oxidative, muaj peev xwm ua rau daim nyias nyias, apoptosis, thiab lwm yam. Ntawm no, qhov tsis sib xws ntawm mitochondrial MQC tuaj yeem raug ntaus nqi los txhim kho oxidative kev nyuaj siab thiab nce apoptosis hauv plawv ntawm cov menyuam nas raug rau IUH. Raws li, nws yog ib qho tseem ceeb kom tswj tau qhov tsim nyog MQC mechanism los xyuas kom meej lub mitochondrial network noj qab nyob zoo nyob rau hauv lub plawv ntawm cov me nyuam yug tshiab raug rau IUH.

Muab hais tias qib placental SPD muaj kev cuam tshuam nrog kev txwv kev loj hlob ntawm fetal (53), SPD tuaj yeem tswj MQC hauv cov qauv tsiaj sib txawv. Piv txwv li, SPD yog lub zog thiab tshwj xeeb inducer ntawm autophagy rau kev nthuav dav, uas tuaj yeem tiv thaiv kev laus ntawm ntau cov ntaub so ntswg, nrog rau lub plawv, lub hlwb, thiab cov leeg pob txha (44, 54, 55). Spermidine tuaj yeem txo cov mob plawv los ntawm kev txhim kho mitochondrial biogenesis (43). Hauv txoj kev tshawb no, peb tau siv SPD rau cov niam txiv nas thiab pom tias SPD tuaj yeem ua rau qhov tsis sib xws ntawm myocardium MQC hauv cov xeeb ntxwv uas raug IUH. Txawm li cas los xij, kev kho niam nrog ODC inhibitor DFMO tshem tawm cov teebmeem ntawm SPD, qhia tias kev cuam tshuam SPD tuaj yeem tiv thaiv qhov txawv txav MQC hauv myocardium ntawm ib hnub cov menyuam nas raug rau IUH. Raws li qhov tshwm sim, kev ua haujlwm zoo ntawm MQC hauv myocardium ntawm cov menyuam yug tshiab tuaj yeem ua kom zoo ntawm cov qauv mitochondrial, kev ua haujlwm, thiab kev loj hlob, yog li paub txog kev hloov pauv ntawm intrauterine glycolysis muaj peev xwm rau postnatal fatty acid oxidation zog thiab ua tau raws li lub plawv dhia tom qab yug me nyuam. . Tsis tas li ntawd, peb qhov kev sim ntawm cardiomyocytes qhia tias SPD tuaj yeem cuam tshuam qhov nce hauv hypoxia-induced ROS ntau lawm, qhov txo qis hauv ∆Ψm, thiab qhov tsis zoo autophagic degradation ntawm mitochondria. Peb tau txiav txim siab tias qhov txiaj ntsig zoo ntawm SPD tuaj yeem ua rau muaj qhov nce SPD theem hauv placental thiab ncig los ntawm kev siv niam txiv SPD, yog li tiv thaiv cov xeeb ntxwv myocardial mitochondrial los ntawm kev txhim kho kev tsim kho los ntawm IUH.

5.1. Xaus

Txoj kev tshawb fawb tam sim no qhia tias kev kho SPD hauv utero tuaj yeem tiv thaiv myocardium ntawm ib hnub - cov xeeb leej xeeb ntxwv lub plawv los ntawm kev cuam tshuam tsis zoo ntawm prenatal hypoxia. Cov kev hloov tom qab yug me nyuam los ntawm SPD tuaj yeem ua tiav los ntawm kev tiv thaiv oxidation thiab anti-apoptosis thiab los ntawm kev tswj MQC txoj hauv kev, yog li txo qis kev loj hlob mitochondrial programmed hauv lub plawv raug rau IUH. Muaj qee qhov kev txwv rau txoj kev tshawb no. Peb tsis tau ua cov kev sim tshuaj pharmacokinetic ntawm SPD, thiab yog li, peb tsis tuaj yeem txiav txim siab qhov tseeb SPD theem hauv plab hauv plab thaum leej niam tau tswj hwm nrog SPD. Hauv peb cov kev tshawb fawb yav tom ntej, peb yuav tshawb xyuas ntxiv txog cov ntshav concentration ntawm SPD siv cov placenta ntawm tus me nyuam hauv plab. Cov kev tshawb pom tam sim no muab lub hauv paus tshiab rau cov kev tshawb fawb yav tom ntej los txheeb xyuas lub luag haujlwm ntawm SPD hauv kev tiv thaiv myocardial mitochondria ntawm IUH cov xeeb ntxwv neonatal.

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