Kev Tshawb Fawb Ntawm Ifosfamide Toxicity Induces Common Upstream Regulator in Liver and Kidney

Hu rau: emily.li@wecistanche.com

Hyoung-Yun Han, et al

Abstract:

Ifosfamide yog ib tug alkylating tus neeg sawv cev, ib tug hluavtaws analogue ntawm cyclophosphamide, siv los kho ntau yam mob qog noj ntshav. Hauv txoj kev tshawb no, qhov tshuaj lom ntawm ifosfamide tau soj ntsuam los ntawm kev siv ib leeg-thiab ntau-dose intraperitoneal kev tswj hwm hauv cov nas raws li Kev Ntsuas Zoo Zoo, thiab ib qho kev sim ntxiv microarray tau ua raws li kev txhawb nqa toxicological fifindings. Ib koob tshuaj ifosfamide (50 mg / kg) tsis ua rau muaj kev hloov pauv pathological. Lub caij no, lub raum mob hnyav tau pom nyob rau hauv 7 thiab 28 hnub sib law liag pawg tswj hwm, nrog rau cov ntshav urea nitrogen thiab creatinine nce ntxiv. Hauv kev txheeb xyuas cov tshuaj lom neeg, cov cholesterol synthesis ntsig txog cov noob feem ntau cuam tshuam rau hauv daim siab thiab lub raum tsis ua haujlwm cov noob tau cuam tshuam rau hauvraumtom qab kev tswj hwm ifosfamide. Tsis tas li ntawd, interferon regulatory factor 7 tau raug xaiv los ua tus tswj hwm cov dej ntws loj uas tau hloov pauv hauv ob qho tib sidaim siabthiabraum, thiab tau pom muaj kev cuam tshuam nrog lwm cov noob caj noob ces, xws li ubiquitin tshwj xeeb peptidase 18, radical S-adenosyl methionine domain muaj 2, thiab interferon-stimulated gene 15, uas tau lees paub ntxiv los ntawm real-time RT-PCR tsom xam. Hauv kev xaus, rov qab lees paub rau lub raum-biased ifosfamide organ toxicity thiab txheeb xyuas cov noob hloov pauv hauv ob qho tib si.daim siabthiabraum. Cov kev tshawb fawb txog toxicogenomic ntxiv yuav tsum tau nthuav tawm qhov tseeb kev sib raug zoo ntawm ifosfamide-induced noob thiab lub cev toxicity.

Ntsiab lus:ifosfamide; hepatotoxicity; nephrotoxicity; intraperitoneal toxicity

Cistanche yog qhov zoo rau lub siab thiab lub raum

1. Taw qhia

Ifosfamide yog ib tug alkylating tus neeg sawv cev, ib tug hluavtaws analogue ntawm cyclophosphamide, siv los kho ntau yam qog nqaij hlav, nrog rau sarcomas thiab lymphomas. Ifosfamide yog ib lub voj voog ntawm tes tsis muaj tshuaj tiv thaiv kab mob uas cuam tshuam nrog DNA replication thiab RNA ntau lawm [1]. Txawm hais tias ifosfamide kuj tau txais txiaj ntsig zoo piv rau lwm cov tshuaj lom alkylating, nws paub tias muaj feem xyuam nrog ntau yam kev phom sij rau lub neej uas txwv tsis pub siv tshuaj kho mob [2]. Cov kev mob tshwm sim loj ntawm ifosfamide muaj xws li mob raum mob hnyav uas tshwm sim los ntawm cov tshuaj lom neeg muaj zog los ntawm ifosfamide, suav nrog mob hnyav.raum raug mob, interstitial nephritis, hemorrhagic cystitis, thiab Fanconi syndrome [3]. Hauv tsev kho mob, ntau yam kab mob toxicity tau tshaj tawm hauv cov neeg mob uas tau ntsib kev mob raum thaum ntxov thiab rov ua dua koob tshuaj ifosfamide-vim ib lub cev tsis ua haujlwm uas ua rau lub cev tsis ua haujlwm tom qab [4,5].

Cov tshuaj lom metabolite ntawm ifosfamide, acrolein, thiab chloroacetaldehyde, yog lub luag haujlwm tseem ceeb rau ifosfamide hauv nruab nrog cev toxicity. Cov kev tshawb fawb yav dhau los tau tsom mus rau cov xwm txheej cuam tshuam rau kev hloov pauv ntawm ifosfamide rau cov tshuaj lom metabolites, tshwj xeeb tshaj yog cytochrome P450 (CYP) [6]. Feem ntau CYP3A4 thiab CYP3A5 hauv lub raum ua rau muaj kev hloov pauv tshuaj lom hauv ifosfamide thiab induce nephrotoxicity [7]. Acrolein yog ib qho reactive aldehyde heev uas tuaj yeem ua rau cov kab mob hauv lub cev muaj zog oxidative txoj hauv kev thiab ua rau lub cev puas tsuaj. Chloroacetaldehyde tau tshaj tawm txog kev tawm tsam ntawm txoj haujlwm kuv ua kom nyob rau hauv mitochondrial respiratory saw uas yuav ua rau intracellular glutathione (GSH) depletion thiab cell tuag [8].

Kev tshawb fawb ntau yam kabmob toxicological muaj txiaj ntsig ntau dua rau kev nkag siab txog cov teebmeem ntawm cov tshuaj ntau dua li kev tsom mus rau cov kabmob tshwj xeeb rau kev tshawb fawb toxicity. Lub siab thiab ob lub raum yog cov kabmob tseem ceeb uas koom nrog hauv cov tshuaj metabolism thiab kev tso tawm, thiab cov kabmob loj no tau ua rau muaj kev phiv tshuaj tsis zoo; lub cev toxicity feem ntau ua raws li. Tsis tas li ntawd, kev ntsuas tshuaj lom neeg sib xyaw ua ke tuaj yeem nthuav qhia ntau yam pathological fifindings uas yuav pab kom nkag siab thiab kwv yees cov tshuaj toxicity hauv lub cev.

Ntau cov kev tshawb fawb tau siv cov noob qhia cov ntaub ntawv los kwv yees cov txiaj ntsig tsis zoo ntawm cov tshuaj. Txawm li cas los xij, feem ntau cov kev tshawb fawb ua ntej tau tsom mus rau kev ntsuam xyuas tib lub hom phiaj ntawm lub cev toxicity, tsuas yog cov tsos mob tsis tshua muaj tshwm sim [9]. Ntxiv mus, ua ke nrog microarray-based gene profiling, nws yuav tsim kom muaj kev nkag siab zoo ntawm cov kab mob toxicity uas tuaj yeem tiv thaiv cov tshuaj muaj feem cuam tshuam txog tshuaj lom [10]. Hauv qhov no, kev sib koom ua ke ntawm ntau yam kabmob toxicological txoj hauv kev nrog cov noob qhia profileing tau siv rau hauv kev tshawb fawb txog tshuaj lom neeg cov qauv kev tshawb fawb los kov yeej cov ntaub ntawv toxicity los ntawm ib qho kev ntsuam xyuas toxicity, uas tsis txaus los nkag siab txog cov tshuaj lom neeg hauv lub cev [11].

Nyob rau hauv txoj kev tshawb no, peb piav qhia txog cov tshuaj lom ntawm ifosfamide hauvraumthiabdaim siabTom qab mob hnyav thiab rov tshwm sim hauv Sprague-Dawley (SD) nas. Kev txhawb nqa gene qhia profileing kev soj ntsuam tau ua los qhia cov hom phiaj hom uas tau hloov pauv los ntawm ifosfamide hauv ob lub siab thiabraum, qhia txog kev pom rau kev sib xyaw ua ke ntawm ifosfamide toxicity.

2. Cov txiaj ntsig

2.1. Kev Tshawb Fawb Kev Toxicity Ib Leeg

Tsis muaj toxicity tau pom nyob rau hauv 12.5, 25, thiab 50 mg / kg ifosfamide pawg - tsis yog tuag, cov tsos mob lom, hloov lub cev hnyav, lossis kev tshawb nrhiav histopathological.

Lub caij no, nyob rau hauv txoj kev tshawb fawb hematology, cov txheeb ze suav ntawm reticulocytes (RET) thiab qhov tseeb suav ntawm neutrophils (NEUA) thiab lymphocytes (LYMA) tau txo qis hauv cov koob tshuaj.

2.2. Ib-lub lim tiam Repeated Dose Toxicity Study

Tag nrho lub cev qhov hnyav poob qis tom qab 1 lub lis piam ntawm kev tswj hwm ifosfamide, thiab qhov txiaj ntsig ntawm lub cev poob qis hauv 100 mg / kg pawg tau siab dua li ntawm 75 mg / kg pawg (Table 1). Lub caij no, tus txheeb ze lub cev hnyav tau maj mam nce hauv cov pab pawg kho mob ifosfamide (Table 2).

Ib lub lim tiam ntawm ifosfamide IP cov thawj coj sib law liag tau txwv cov hematology Performance index, suav nrog RBC, HGB, HCT, MCV, thiab PLT, nyob rau hauv ib koob tshuaj (Table 3). Ntxiv mus, BUN thiab CREA tau nce 1.2 npaug ntawm pawg tswj hwm thaum piv rau pawg ifosfamide (Table 4).Lub raumraug mobtau txhawb ntxiv los ntawm kev tshawb fawb histopathological.

Tsis muaj cov cim histopathological tau pom nyob rau hauv daim siab ntawm nas nyob rau hauv 75 thiab 100 mg / kg ifosfamide pawg (Daim duab 1A). Meanwhile, lublub raumlos ntawm 75 thiab 100 mg / kg pawg ifosfamide tau pom tias muaj tsawg kawg rau qib me ntsis ntawm kev hloov pauv pathologic, suav nrog tubular degeneration / dilatation (1 nruab nrab hauv 100 mg / kg pawg), ib leeg-cell necrosis, urothelium hyperplasia, thiab focal hemorrhage. / congestion (Table 5). Tsis tas li ntawd, qhov pom tseeb nce hauv KIM-1 kev qhia nyob rau hauv lub raum tubule cheeb tsam tau pom nyob rau hauvraumntawm 100 mg / kg pawg (Daim duab 1B).

2.3. Plaub-lub lim tiam Repeated Dose Toxicity Study

Kev tuag tau pom nyob rau hauv 50 (5/10) thiab 70 (10/10) mg / kg-kho pab pawg tom qab 21 thiab 10 hnub ntawm kev tswj hwm sib law liag, feem. Tsis tas li ntawd, qhov txo qis hauv lub cev nrog qhov hnyav ntawm lub cev,daim siab, thiabraum, hauv tag nrho cov pab pawg kho mob ifosfamide, txhawb nqa 4-lub lim tiam rov ua tshuaj toxicity.

Hematological thiab serum biochemical tsom xam tau ua rau cov neeg muaj sia nyob. Ntau qhov ntsuas ntshav, suav nrog RET, RBC, MONA, EOSA, thiab LUCA, tau poob qis heev tom qab 4 lub lis piam ntawm kev tswj hwm ifosfamide.

Piv nrog rau pawg tswj hwm, kev tshuaj xyuas biochemical pom qhov sib txawv ntawm qhov sib txawv tom qab 4 lub lis piam ntawm kev tswj hwm ifosfamide. Piv txwv li, cov qib AST thiab CK tau nce ntxiv, thiab qhov sib piv A / G, GLU, thiab GGT tau txo qis (p < 0.01)="" hauv="" pawg="" 50="" mg="" kg="" kho,="" thaum="" piv="" nrog="" kev="" tswj="" hwm.="" pab="">

2.4. Ifosfamide-Induced Gene Expression Analysis

Cov ifosfamide-induced DEGs tau txheeb xyuas hauv daim siab thiabraumcov ntaub so ntswg (Table 6). Rau lub siab, qhov sib txawv ntawm cov noob suav nrog 2672 cov noob ntawm 100 mg / kg BW / hnub, 1283 cov noob tau hloov kho, thiab 1389 cov noob tau raug txo qis. Hauv ob lub raum, 401 noob tau qhia txawv ntawm 100 mg / kg BW / hnub - 149 noob tau hloov kho, thiab 252 cov noob tau raug txo qis. Hauv ob lub siab thiab lub raum, tus naj npawb ntawm cov noob caj noob ces tau ntau dua li cov noob tau tswj hwm. Qhov no yuav qhia tau tias kev kho mob ifosfamide zoo li inhibit gene qhia.

Cov txiaj ntsig ntawm kev txheeb xyuas kev ua haujlwm lom neeg muaj npe nyob rau hauv Table 7. Lub lim tiam 1- kev tswj hwm ifosfamide tau pom los hloov cov noob ntsig txog kev loj hlob ntawm lub cev, feem ntau hauv daim siab. Hauvraum, nws tau lees paub tias cov noob muaj feem xyuam rau lub cev tiv thaiv kab mob hauv zos feem ntau cuam tshuam.

Hauv kev tsom xam txoj hauv kev canonical ntawm DEGs, kev hloov pauv hauv cov roj cholesterol synthesis thiab antigen nthuav qhia txoj hauv kev ntsig txog cov noob tau tshwm sim hauvdaim siabthiabraumcov ntaub so ntswg, ntsig txog (Daim duab 2). Ntxiv mus, LXE / RXR thiab cov theem mob hnyav teb teeb liab yog qhov kev tswj hwm sab saum toj canonical txoj hauv kevdaim siabthiabraum, uas tau cuam tshuam rau hauv lipid homeostasis thiab inflammatory cytokine signaling, feem.

Hauv kev txheeb xyuas lub siab ua xua, cov cholesterol synthesis-hais txog cov noob feem ntau cuam tshuam, ua raws li cov theem zoo ntawm cov proteins thiab lub raum tsis ua haujlwm (Table 8). Tsis tas li ntawd, cov txiaj ntsig ntawm lub raum tau tshaj tawm tias lub raum tsis ua haujlwm ntawm cov noob caj ces feem ntau cuam tshuam los ntawm ifosfamide, suav nrog rov qab glomerulonephritis biomarkers thiab mob raum tsis ua haujlwm.

Raws li lub hauv paus kev paub txog IPA, ib qho kev tswj hwm cov dej ntws los tswj cov noob qhia hauv lub siab thiab lub raum tom qab kev kho mob ifosfamide (Daim duab 3). IRF7 yog lub luag haujlwm tseem ceeb uas hloov pauv hauv daim siab thiab lub raum thiab tau pom tias muaj kev cuam tshuam nrog lwm cov noob caj noob ces xws li USP18, RSAD2, thiab ISG15. Tsis tas li ntawd, kev tshawb xyuas RT-PCR tiag tiag tau lees paub qhov kev qhia ntawm IRF7, USP18, RSAD2, thiab ISG15. Txawm hais tias qhov kev hloov pauv ntawm txhua tus noob txawv ntawm daim siab thiab lub raum, kev qhia tau raug tshem tawm hauv ob lub siab thiab lub raum cov ntaub so ntswg tom qab 1 lub lis piam ntawm kev tswj hwm ifosfamide. RSAD2 thiab USP18 feem ntau hloov pauv cov noob los ntawm kev kho mob ifosfamide hauv daim siab thiab lub raum, feem.

3. Kev sib tham

Nyob rau hauv txoj kev tshawb no, tag nrho ifosfamide toxicity nyob rau hauv ntau lub cev tau tshawb fawb nrog ntau hom tshuaj thiab cov ntsiab lus raug los ntawm IP txoj hauv kev nas raws li GLP tus qauv. Hauv cov chaw kho mob, ifosfamide tuaj yeem siv tshuaj tua kab mob bimodal nrog cytotoxic thiab immunomodulatory teebmeem ua ke nrog kev siv tshuaj tiv thaiv kab mob [12]. Ifosfamide paub tias feem ntau raug tshem tawm los ntawm lub raum txoj kev thiab txog 80 feem pua ​​​​ntawm cov koob tshuaj yog nyob rau hauv daim ntawv tsis hloov pauv, nephrotoxicity yog ib qho kev mob tshwm sim feem ntau ntawm ifosfamide, thiab cov metabolites xws li chloroacetaldehyde thiab acrolein yog lub luag haujlwm rau kev siv tshuaj kho mob [13, 14] ib.

Hauv txoj kev tshawb fawb tam sim no, ib qho 1-ib lub lim tiam kev tshawb nrhiav tshuaj lom neeg rov qab tsim nyog rau kev tshawb nrhiav ifosfamide-derived organ toxicity. Ib lub lim tiam ntawm kev tswj hwm ifosfamide inhibited cov ntshav ntsuas nyob rau hauv koob tshuaj, uas tej zaum yuav muaj kev cuam tshuam ib txwm ifosfamide-derived myelosuppression. Nrog rau nephrotoxicity, ntau cov ntaub ntawv qhia tau hais tias myelosuppression yog ib qho ntawm cov tshuaj loj-txhim kho ifosfamide toxicities, thiab leukopenia feem ntau hnyav dua thrombocytopenia [15,16]. Ifosfamide nephrotoxicity tuaj yeem ua rau Fanconi syndrome, uas muaj qhov cuam tshuam ntawm kev ua haujlwm ntawm tubules uas ua rau muaj kev puas tsuaj tsis zoo, thiab cov tshuaj lom metabolite acrolein provokes urotoxicity nrog hemorrhagic cystitis [17]. Qhov no yog raws li cov txiaj ntsig ntawm kev tshawb fawb tam sim no. Hauv kev tshawb fawb histopathological, ob lub raum thiab lub siab tau raug tshuaj xyuas los tshawb txog ifosfamide-derived pathological hloov pauv. Hauv ob pawg 75 thiab 100 mg / kg ifosfamide-administered, thaj chaw loj ntawm tubular degeneration thiab dilation tau kuaj pom nrog urothelium hyperplasia hauv lub raum pelvis. Tsis tas li ntawd, qhov kev nthuav qhia ntawm KIM-1, lub raum proximal tubule raug mob molecule, txhawb nqa qhov muaj ntawm ifosfamide-related nephrotoxicity. Lub caij no, tsuas yog qhov tsawg kawg nkaus periportal vacuolation tau pom hauv daim siab. Ntxiv mus, txawm hais tias AST thiab ALT qhov tseem ceeb tau txo qis hauv kev siv tshuaj, qhov kev hloov pauv tau nyob hauv qhov kev siv ntau [18]. Cov laj thawj sib sib zog nqus kom txo qis siab enzyme yuav tsum tau kawm ntxiv. Nws feem ntau lees txais tias ifosfamide yog ib qho alkylating tus neeg sawv cev uas tsis tshua muaj feem cuam tshuam nrog hepatotoxicity, thiab tsuas yog ob peb kis tau raug tshaj tawm los ua rau lub siab raug mob, tshwj xeeb tshaj yog thaum ua ke nrog lwm cov tshuaj kho mob xws li doxorubicin [19].

Tsis ntev los no, qhov tseem ceeb ntawm cov ntaub ntawv qhia txog noob hauv toxicology nrog cov thev naus laus zis siab dhau los tau ua rau muaj cov ntaub ntawv loj txaus hauv kev tshawb fawb toxicity, thiab ntau qhov kev sim tau ua los siv cov noob profile rau kev kwv yees tshuaj toxicity [10,20]. Hauv txoj kev tshawb no, kev tshuaj xyuas microarray tau ua los tshuaj xyuas cov lus teb ntawm cov lus teb cuam tshuam los ntawm kev tswj hwm ifosfamide, thiab DEGs nrog kev hloov pauv ntau dua lossis sib npaug li 1.5 tau raug xaiv los ua lub hom phiaj gene thiab kev ua haujlwm lom neeg, txoj hauv kev canonical, thiab kev txheeb xyuas Tox. kom nkag siab txog kev ua haujlwm ntawm ifosfamide-induced noob. Ib qho ntxiv kev tswj xyuas cov dej ntws tau ua tiav los ntsuas qhov muaj peev xwm ntawm ntau yam kabmob toxicity hauv daim siab thiab lub raum.

Hauv txoj kev tshawb no, DEGs tau hloov pauv 1.5-fold tau raug xaiv, thiab cov noob caj ces qis dua me ntsis ntau dua li cov noob uas tau tswj hwm hauv ob lub siab (52 feem pua) thiab lub raum (62 feem pua). Cov txiaj ntsig ntawm kev ua haujlwm lom neeg tau pom tias ifosfamide hloov pauv cov noob, nrog rau kev ua haujlwm lom neeg muaj feem cuam tshuam nrog kev loj hlob ntawm cov ntaub so ntswg uas feem ntau pom hauv daim siab thiab lub raum.

Kev kawm yav dhau los los ntawm Snouber et al. [21] qhia tias kev kho mob ifosfamide tau pom los txo qis- tswj Nrf-2 kho cov kev ntxhov siab oxidative teb txoj hauv kev hauv microfluidic kab lis kev cai [21]. Raws li cov kev tshawb fawb yav dhau los, NRF2-txoj kev kho oxidative kev nyuaj siab teb txoj hauv kev tau hloov kho los ntawm cov tes hauj lwm saum toj kawg nkaus, uas tau lees paub los ntawm ob qho tib si tam sim no txoj hauv kev canonical thiab kev txheeb xyuas cov tshuaj lom. Tam sim no hloov Nrf-2 kho kom haum xeeb oxidative teb txoj hauv kev tuaj yeem cuam tshuam nrog ifosfamide toxic metabolite. Ntau yam ifosfamide toxic metabolites tuaj yeem hnov ​​​​mob nrog GSH, muaj zog antioxidant, tsim kev sib txuas ntawm cov chaw sib txawv raws txoj kev, thiab qhov txo qis hauv GSH qib ua rau muaj tshuaj lom ntau ntxiv, uas qhia txog kev cuam tshuam ntawm oxidative kev nyuaj siab hauv ifosfamide organ toxicity [8,22 ]. Hauv qhov no, mesna thiab N-acetylcysteine ​​​​tau siv los txo cov kab mob hauv nruab nrog cev ifosfamide. Mesna ua hauj lwm raws li lub regional detoxifier los ntawm kev khi rau ifosfamide toxic metabolite, feem ntau tawm tsam acrolein, los ntawm ib tug Michael ntxiv rau tsim ib tug tsis tshua muaj teeb meem tshuaj [23]. Tsis tas li ntawd, N-acetylcysteine ​​​​tau tshaj tawm tias muaj kev ua haujlwm antioxidant thiab txhim kho GSH depletion nyob rau hauv oxidative kev nyuaj siab [24]. Cov kev tshawb fawb ntxiv yog xav tau los piav qhia qhov tseeb ntawm kev sib raug zoo ntawm ifosfamide antidote thiab txoj hauv kev tswj hwm nyob rau hauv cov mob nephrotoxic. Peb tuaj yeem xav tias ifosfamide toxicity amelioration los ntawm mesna lossis N-acetylcysteine ​​tuaj yeem ua raws los ntawm kev txhim kho Nrf-2-txoj kev sib haum xeeb ntawm kev ntxhov siab oxidative teb.

Hauv txoj kev tshawb no, cov kab mob ntsig txog kev mob tshwm sim feem ntau tau kho nyob rau hauv ob lub siab thiab lub raum, uas tuaj yeem lees paub los ntawm cov theem mob hnyav hauv kev tsom xam txoj hauv kev canonical. Cov txiaj ntsig no tau qhia txog qhov cuam tshuam ntawm cov tshuaj tiv thaiv kab mob hauv cov kab mob pathophysiology ntawm ifosfamide organ toxicity nyob rau hauv ob qho tib si cov ntaub so ntswg, uas tau ntxiv kev txhawb nqa los ntawm kev soj ntsuam cov dej ntws. Hauv kev txheeb xyuas tus neeg saib xyuas sab saud, IRF7 thiab interferon (IFN) cov cim qhia txog cov noob, suav nrog USP18, RSAD2, thiab ISG15, tau raug xaiv los ua tus tswj hwm cov dej ntws hauv lub siab thiab lub raum. IRF7 yog ib qho lymphoid tshwj xeeb, uas tau tsim tawm hauv lub cev tiv thaiv kab mob cytoplasm, thiab tuaj yeem raug ntxias los ntawm hom I interferon, kab mob kis, thiab lwm yam stimuli hauv ntau lub hlwb [25]. Ib txoj kev tshawb fawb yav dhau los tau tshaj tawm txog kev tsis sib haum xeeb los yog cov khoom tiv thaiv oncogenic ntawm IRF7 hauv ntau hom qog nqaij hlav, thiab cov kev hloov hauv IRF7 qhia tau cuam tshuam nrog DNA puas [26–28].

Ntxiv rau nws lub luag haujlwm tseem ceeb hauv kev tswj hwm hauv hom I IFN rau kev ua haujlwm tiv thaiv kab mob, IRF7 tau tshaj tawm los tiv thaiv cov kab mob ua paug los ntawm TLR4 txoj kev taw qhia [29]. Ntxiv mus, Stout-Delgado et al. [30] qhia tias kev laus-induced oxidative increment impairs IRF7 kev ua, qhov txo qis ntawm kev ntxhov siab los ntawm cov neeg ua haujlwm antioxidant txhim kho IRF7 kev ua haujlwm. Hauv txoj kev tshawb no, kev tswj hwm ifosfamide tau txwv tsis pub qhia cov neeg tswj hwm cov dej ntws, thiab cov qauv qhia tau zoo ib yam hauv daim siab thiab lub raum. Cov kev hloov pauv tam sim no hauv IRF7 kev qhia yuav cuam tshuam rau cov tshuaj tiv thaiv kab mob thiab cytotoxic alkylating tus neeg sawv cev ntawm ifosfamide, uas yuav qhia tau tias IRF7 yog lub hom phiaj cog lus rau ifosfamide organ toxicity.

Nyob rau hauv txoj kev tshawb no, peb pom ib tug noob uas ib txwm inhibited nyob rau hauv ob lub siab thiab lub raum tom qab ifosfamide tswj, tab sis qhov kev txhais ntawm nws toxicological tseem ceeb yog tsom rau lub raum xwb, uas txwv qhov kev tshawb pom tam sim no. Tsis tas li ntawd, kev tshawb fawb ntxiv uas muaj feem cuam tshuam txog cov txiaj ntsig ntawm cov khoom lag luam muaj ifosfamide antidote ntawm cov noob hloov tam sim no tuaj yeem txhawb nqa qhov kev tshawb pom tam sim no.

Hauv kev xaus, ib qho kev tshawb nrhiav tshuaj lom neeg rov qab (1 lub lis piam) ntawm kev tswj hwm ifosfamide tau pom tias muaj kev cuam tshuam nephrotoxicity ntau dua li hepatotoxicity. Tsis tas li ntawd, cov txiaj ntsig tam sim no muab pov thawj rau ifosfamide-induced hepatotoxicity thiab nephrotoxicity mechanism uas cuam tshuam nrog IRF-7 inhibition. Cov kev tshawb fawb toxicogenomic ntxiv ntawm lub cev tiv thaiv kab mob yuav tsum tau ua kom paub meej txog cov txheej txheem toxicological ntawm ifosfamide, thiab txhawb kev sib raug zoo ntawm cov noob thiab cov kab mob toxicity.

4. Cov ntaub ntawv thiab cov txheej txheem

4.1. Kev Kawm Tsiaj

Yim-lub lim tiam-laus txiv neej-cov kab mob tshwj xeeb-dawb Sprague-Dawley (SD) nas (n=140) tau txais los ntawm Orient Bio Inc. (Seongnam, Kauslim). Cov tsiaj tau raug tshuaj xyuas thiab ua kom haum rau qhov chaw kuaj ib puag ncig rau ib lub lis piam ua ntej qhov kev sim. Txhua tus tsiaj tau muab tso rau hauv lub tawb yas hauv kev tswj xyuas qhov chaw kuaj mob (kub, 23 ± 3 ◦C; av noo, 55 ± 10 feem pua; thiab 12/12-h lub teeb / tsaus nti) nrog rau chav kuaj chow thiab dej ad libitum. Txoj kev tshawb nrhiav tsiaj tau pom zoo los ntawm Pawg Saib Xyuas Tsiaj Tsiaj thiab Siv Khoom ntawm Kaus Lim Kauslim Lub Tsev Haujlwm Saib Xyuas Kev Noj Qab Haus Huv (Daejeon, Kaus Lim Qab Teb), thiab txhua tus txheej txheem tau ua raws li Kev Ntsuas Cov Lus Qhia rau Kev Ntsuam Xyuas Kev Nyab Xeeb ntawm Tshuaj los ntawm Kaus Lim Kauslim Food and Drug Administration. Kev tshawb fawb tsiaj tau muab faib ua peb ntu: ib koob tshuaj (mob hnyav) thiab rov ua dua (1 lub lis piam thiab 4 lub lis piam) sib law liag kev tshuaj xyuas tshuaj lom neeg. Plaub caug nas raug muab tso rau hauv plaub pawg (tswj, t1, t2, thiab t3) siv Path / Tox system (version. 4.2.2, Xybion Medical Systems Corporation, Lawrenceville, NJ, USA) hauv txhua txoj kev tshawb nrhiav toxicity.

4.2. Kev sim tshuaj toxicity

Txoj kev tshawb nrhiav tshuaj toxicity tau muab faib ua peb ntu: ib koob tshuaj (mob hnyav) thiab ob zaug rov ua dua (ib koob tshuaj sib law liag ntawm 1 lub lis piam lossis 4 lub lis piam) kev tshawb fawb toxicity. Rau txhua txoj kev tshawb fawb txog tshuaj lom, nas tau muab tso rau hauv cov pab pawg txaus (tswj, koob tshuaj 1, koob tshuaj 2, thiab koob tshuaj 3 rau ib zaug thiab 4-kev tshawb fawb tshuaj lom neeg lub lim tiam; tswj, koob tshuaj 1, thiab koob tshuaj 2 rau 1- lub limtiam kev kawm toxicity) los ntawm kev siv Path/Tox system (version. 4.2.2, Xybion Medical Systems Corporation, Lawrenceville, NJ, USA). Hauv txoj kev tshawb nrhiav tshuaj lom neeg, ifosfamide tau tswj hwm los ntawm txoj kev intraperitoneal (IP), thiab pawg tswj hwm tau txais cov dej distilled (DW). Cov koob tshuaj ifosfamide siv nyob rau hauv txoj kev tshawb nrhiav toxicity yog raws li hauv qab no: kev kawm tshuaj toxicity (12.5, 25, thiab 50 mg / kg), 1-kev kawm tshuaj toxicity (75 thiab 100 mg / kg BW / hnub), thiab {{19} }}txoj kev tshawb fawb tshuaj lom (25, 50, thiab 70 mg/kg BW/hnub). Cov tsiaj 'cov tsos mob dav dav, lub cev hnyav, thiab kev tuag tau sau tseg txhua hnub thaum lub sijhawm tswj hwm, thiab txhua tus tsiaj tau muab txi rau 24 teev tom qab kev tswj hwm ifosfamide kawg. Cov ntshav kuaj tau sau thiab muab tso rau hauv cov hlab microcentrifuge thiab EDTA-K2 hlab rau cov ntshav biochemistry thiab hematological tsom xam, feem. Lub siab thiab lub raum cov ntaub so ntswg tau kho nyob rau hauv formaldehyde thiab raug rau histopathological tsom xam. Ntxiv immunohistochemistry, microarray tsom xam, thiab real-time RT-PCR tau ua nyob rau hauv daim siab thiab lub raum cov ntaub so ntswg los ntawm subacute toxicity (100 mg / kg BW / hnub).

4.3. Hematological thiab Serum Biochemical Analysis

Cov kev ntsuam xyuas hematological tau ua tiav siv ADVIA 120 hematology system (Bayer, Fernwald, Lub Tebchaws Yelemees). Cov ntsuas hauv qab no tau siv: Cov qe ntshav dawb suav (WBC), cov ntshav liab suav (RBC), hematocrit (HCT), hemoglobin concentration, txhais tau tias corpuscular volume (MCV), txhais tau tias corpuscular hemoglobin (MCH), platelet suav (PLT), lymphocyte (LYM), monocyte (MON), neutrophil (NEU), basophil (BAS), eosinophil (EOS), thiab loj unstained cells (LUC), thiab reticulocyte (RET) suav.

Kev ntsuam xyuas biochemistry tau ua los ntawm kev siv lub tshuab ntsuas tsis siv neeg (TBA 120FRNEO; Toshiba Corp., Tokyo, Nyiv) nrog centrifuged serum. Cov cim tseem ceeb ntawm biochemical yog alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), ntshav zis nitrogen (BUN), creatinine (CREA), qabzib (GLU), tag nrho cov cholesterol (TCHO), albumin / globulin ratio. (A/G), triglycerides (TG), tag nrho bilirubin (TB), gamma-glutamyl transferase (GGT), phospholipids (PL), calcium, chloride, inorganic sodium, phosphorus, thiab poov tshuaj.

4.4. Histopathological thiab Immunohistochemistry Examination

Paraffin-embedded ntaub so ntswg tau muab faib rau ntawm 5-µm thickness, stained nrog hematoxylin thiab eosin (H&E), thiab tshuaj xyuas microscopically.

Lub raum cov ntaub so ntswg tau raug rau immunohistochemistry. Cov seem deparaffinized thiab ntxuav tau preincubated nrog 10 feem pua ​​​​tshuaj ntshav los thaiv cov staining nonspecific. Tom qab ntawd cov slides tau incubated ib hmos nrog thawj anti-KIM1 antibody (1:750; Santa Cruz, CA, USA). Tom qab tshem tawm cov tshuaj tiv thaiv thawj zaug, cov seem tau ua tiav nrog VECTASTAIN Cov Neeg Tseem Ceeb ABC HRP Cov Khoom Siv (Vector Laboratories, Peterborough, UK), thiab KIM1expression tau tshuaj xyuas nyob rau hauv lub teeb pom kev zoo.

4.5. Microarray Analysis thiab Protein-Protein Interaction (PPI) Analysis

Lub siab thiab lub raum los ntawm 1-lub lim tiam (100 mg / kg) pawg tau homogenized, thiab tag nrho RNA raug rho tawm nrog RNase cov khoom siv mini (Qiagen). cDNA synthesis tau tiav siv cDNA Synthesis Kit (Affymetrix, Affymetrix, Santa Clara, CA, USA) thiab raug rau microarray thiab PPI analyses.

Kev tshuaj xyuas Microarray tau ua tiav siv Affymetrix GeneChip Rat {{0}}}0 nrog GeneChip Scanner 3000 (Affymetrix Santa Clara, CA, USA), thiab Cov txiaj ntsig tau ua tiav siv GeneSpring GX v13.0 tsom xam software (Agilent Technologies, Santa Clara, CA, USA). Cov noob sib txawv (DEGs), uas tau hloov ntau dua 1.5-fold tom qab kev tswj hwm ifosfamide, tau xaiv siv ib txoj kev tsom xam ntawm qhov sib txawv (ANOVA) nrog Tukey's post hoc test. Cov kev ua haujlwm lom neeg thiab cov txheej txheem canonical ntawm cov DEGs tau xaiv tau raug tshuaj xyuas siv Ingenuity Pathway Analysis software (IPA, ver. 9.0; Ingenuity Systems, Redwood City, CA, USA), thiab kev soj ntsuam txog kev tswj xyuas cov dej ntws los txheeb xyuas cov neeg tswj xyuas cov dej ntws uas yuav ua tau. ua lub luag haujlwm rau DEGs muab los ntawm ifosfamide toxicity. Ntxiv protein-protein interaction (PPI) network tsom xam ntawm DEGs tau ua siv STRING software (version 10), thiab kev sib cuam tshuam tau lees paub thaum qhov nruab nrab kev ntseeg siab tau dhau 0.4. Protein kev sib cuam tshuam yog kwv yees qhov tshwm sim uas qhov kev kwv yees txuas muaj nyob nruab nrab ntawm ob lub proteins hauv Kyoto Encyclopedia ntawm Genes thiab Genomes txoj hauv kev.

4.6. Quantitative Real-Time RT-PCR Kev Kawm

Cov kev qhia ntawm cov noob caj noob ces nyob rau hauv txoj kev tshawb fawb microarray tau lees paub tias siv ntau npaum li cas ntawm RT-PCR. Gene-specific primers tau txais los ntawm Bioneer (Daejeon, Kauslim). Cov txheej txheem primer tau raws li hauv qab no: interferon regulatory factor 7 (IRF7): pem hauv ntej, 5-TGCTTGTCTAGCACCAATAG-3 thiab thim rov qab, 5-CACAAGGTCCACTAGAGATG-3; ubiquitin tshwj xeeb peptidase 18 (USP18): rau pem hauv ntej, 5-CTGTAGTTTTGCTCCCAACA-3 thiab thim rov qab 5-GAACTGATTACCTCCCACTG-3; radical S-adenosyl methionine domain muaj 2(RSAD2): pem hauv ntej, 5-ACCAATCATCAGAGGTTGAC-3 thiab thim rov qab, 5-CTGCATGATTGTTCTTGGAC-3; interferon-stimulated gene 15 (ISG15): rau pem hauv ntej, 5-AAGTCTCCCAAGACCAATTC-3thiab rov qab, 5-CTACATGGCTCTGGATAGG-30.

Tag nrho RNA tau thim rov qab rau cDNA siv SuperScript II (Invitrogen, Carls phem, CA, USA) thiab oligo-dT primers, raws li cov chaw tsim khoom cov lus qhia. mRNA qhia theem ntawm kev tswj hwm cov noob caj noob ces tau txheeb xyuas los ntawm StepOnePlus Real-Time PCR System (Applied Biosystems, Carlsbad, CA, USA) nrog anSYBR Green master mix (Applied Biosystems), raws li cov chaw tsim khoom raws tu qauv. 18S ribosomal RNA primer tau siv los ua kev tswj hwm sab hauv, thiab cov txiaj ntsig tau qhia tias hloov pauv hloov mus rau pawg tswj hwm ib txwm muaj.

4.7. Kev txheeb cais

Cov ntaub ntawv tau txheeb xyuas los ntawm ntau txoj kev sib piv. ThaumBartlett qhov kev ntsuam xyuas pom tias tsis muaj qhov sib txawv ntawm qhov sib txawv ntawm qhov sib txawv, kev tsom xam ntawm qhov sib txawv (ANOVA) tau siv los txiav txim seb ib pab pawg twg txhais tau tias txawv ntawm qhov tseem ceeb ntawm p < {{0}}.05.="" tsis="" tas="" li="" ntawd,="" dunnett="" qhov="" kev="" sim="" tau="" siv="" los="" txiav="" txim="" siab="" qhov="" sib="" txawv="" ntawm="" cov="" ntaub="" ntawv="" ntawm="" pawg="" tswj="" hwm="" thiab="" kev="" kho="" mob="" thaum="" cov="" ntaub="" ntawv="" tau="" pom="" tias="" muaj="" qhov="" tseem="" ceeb="" los="" ntawm="" kev="" xeem="" anova.="" tsis="" tas="" li="" ntawd,="" thaum="" muaj="" qhov="" sib="" txawv="" tseem="" ceeb="" ntawm="" qhov="" sib="" txawv="" ntawm="" qhov="" sib="" txawv="" tau="" pom="" los="" ntawm="" bartlett="" qhov="" kev="" sim,="" qhov="" kev="" ntsuas="" tsis="" sib="" piv,="" kruskal-wallis="" (h)="" test,="" tau="" ua="" los="" txiav="" txim="" seb="" ib="" pab="" pawg="" twg="" txhais="" tau="" tias="" txawv="" ntawm="" p=""><0.05. thaum="" pom="" qhov="" sib="" txawv="" tseem="" ceeb="" hauv="" kruskal–wallis="" (h)="" kev="" xeem,="" dunn's="" rank="" subtest="" tau="" ua="" los="" txheeb="" xyuas="" cov="" khub="" tshwj="" xeeb="" ntawm="" pab="" pawg="" cov="" ntaub="" ntawv="" uas="" txawv="" ntawm="" qhov="" nruab="" nrab.="" fisher="" qhov="" kev="" ntsuas="" tseeb="" tau="" ua="" los="" sib="" piv="" cov="" ntaub="" ntawv="" (nrog="" rau="" qhov="" ntau="" thiab="" feem="" pua).="" qib="" ntawm="" qhov="" yuav="" tshwm="" sim="" tau="" teem="" rau="" 1="" lossis="" 5="" feem="" pua.="" kev="" txheeb="" xyuas="" txheeb="" cais="" tau="" ua="" los="" ntawm="" kev="" sib="" piv="" cov="" ntaub="" ntawv="" los="" ntawm="" cov="" pab="" pawg="" kho="" mob="" sib="" txawv="" nrog="" cov="" pab="" pawg="" tswj="" hwm="" siv="" path/tox="" (version.="" 4.2.2,="" xybion="" medical="" systems="" corporation,="" lawrenceville,="" nj,="">

Cov ntaub ntawv muaj nyob:

Cov ntaub ntawv muaj nyob rau hauv tsab xov xwm lossis Cov Khoom Siv Ntxiv.

Kev tsis sib haum xeeb ntawm kev txaus siab:

Cov kws sau ntawv tshaj tawm tias lawv tsis muaj kev sib tw nyiam.

Cov ntaub ntawv

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