El Paso, TX Uxinzelelo oluxhasayo kunye noKhuseleko lwe-Antioxidant

I-Chiropractor esekelwe kwiSayensi uDkt Alexander Jimenez ithatha ujongo uxinzelelo oluxhamlayo, yintoni na, indlela echaphazela ngayo umzimba kunye nokukhusela i-antioxidant ukulungisa imeko.

Esra Birben PhD,1 Umit Murat Sahiner MD,1 Cansin Sackesen MD,1 Serpil Erzurum MD,2 kunye no-Omer Kalayci, MD1

Ubungqina obucacileyo: Iintlobo zeoksijini esebenzayo (ROS) ziveliswa zizinto eziphilayo ngenxa yemetabolism eqhelekileyo yeselula kunye nezinto ezisingqongileyo, ezinje ngongcoliseko lomoya okanye umsi wecuba. I-ROS i-molecule esebenzayo kakhulu kwaye inokonakalisa izakhiwo zeeseli ezifana ne-carbohydrates, i-nucleic acids, i-lipids, kunye neeprotheni kwaye ziguqule imisebenzi yazo. Utshintsho kwibhalansi phakathi kwee-oxidants kunye ne-antioxidants ekuthandeni i-oxidants kuthiwa �i-oxidative stress. Izinto eziphilayo eziAerobic zidibanise iinkqubo zokulwa ne-antioxidant, ezibandakanya i-enzymatic kunye ne-non-enzymatic antioxidants ezihlala zisebenza ekuthinteleni iziphumo ezinobungozi ze-ROS. Nangona kunjalo, kwiimeko ze-pathological, iinkqubo ze-antioxidant zinokugqithiswa. Uxinzelelo lwe-oxidative lunegalelo kwiimeko ezininzi ze-pathological kunye nezifo, kubandakanya umhlaza, ukuphazamiseka kwemithambo-luvo, i-atherosclerosis, uxinzelelo lwegazi, ischemia / perfusion, isifo seswekile, isifo esinzima sokuphefumula, i-idiopathic pulmonary fibrosis, isifo esingapheliyo semiphunga, kunye ne-asthma. Kolu hlaziyo, sishwankathela iinkqubo ze-oxidant kunye ne-antioxidant kwaye sixoxe ngemiphumo yeselula kunye neendlela zoxinzelelo lwe-oxidative.

Amagama aPhambili: i-antioxidant, i-oxidant, uxinzelelo lwe-oxidative, iintlobo ze-oksijini ezisebenzayo, i-redox

(WAO Journal 2012; 5:9�19)

Iintlobo ze-oksijini ezisebenzayo (i-ROS) ziveliswa zizidalwa eziphilayo ngenxa ye-metabolism yeselula eqhelekileyo. Kwiindawo eziphantsi ukuya kwimodareyitha, zisebenza kwiinkqubo zeseli ye-physiological, kodwa ekugxininiseni okuphezulu, zivelisa ukuguqulwa okungalunganga kumacandelo eeseli, ezifana ne-lipids, iiprotheni, kunye ne-DNA. Kubizwa ngokuba luxinzelelo lwe-oxidative. � Uxinzelelo lwe-oxidative lunegalelo kwiimeko ezininzi ze-pathological, kubandakanya umhlaza, ukuphazamiseka kwemithambo-luvo, 1�6 i-atherosclerosis, uxinzelelo lwegazi, ischemia/perfusion,7�10 isifo seswekile, i-acute breathing distress syndrome, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease. ,11 kunye ne-asthma.14�15 Izinto eziphilayo ze-Aerobic zineenkqubo ezidibeneyo zokulwa ne-antioxidant,� ezibandakanya i-enzymatic kunye ne-nonenzymatic antioxidants ezidla ngokusebenzayo ekuthinteleni iziphumo ezinobungozi ze-ROS. Nangona kunjalo, kwiimeko ze-pathological, iinkqubo ze-antioxidant zinokugqithiswa. Kolu hlaziyo, sishwankathela iinkqubo ze-oxidant kunye ne-antioxidant kunye nokulawulwa kokunciphisa kunye ne-oxidizing (i-redox) kwimeko yempilo kunye nezifo.

IZIXHOBO

Imithombo ye-Endogenous ye-ROS

I-ROS iveliswa kwi-oksijeni ye-molekyuli ngenxa ye-metabolism eqhelekileyo yeselula. I-ROS inokwahlulwa ibe ngamaqela ama-2: i-radicals yamahhala kunye ne-nonradicals. Iimolekyuli eziqulethe i-electron enye okanye ezingaphezulu ezingasebenziyo kwaye ngaloo ndlela zinika i-reactivity kwi-molecule zibizwa ngokuba yi-radicals yamahhala. Xa ii-radicals ezi-2 zasimahla zabelana ngee-electron zazo ezingasebenziyo, iifom ze-nonradical ziyadalwa. I-ROS enkulu ye-3 ebalulekileyo ye-physiological i-superoxide anion (O22.), i-hydroxyl radical (OH), kunye ne-hydrogen peroxide (H2O2). I-ROS ishwankathelwa kwiThebhile 1.

I-superoxide anion yenziwe ngokongezwa kwe-electron ye-1 kwi-oksijeni ye-molecular.22 Le nkqubo ixutywe yi-nicotine adenine dinucleotide phosphate [NAD (P)H] oxidase okanye i-xanthine oxidase okanye nge-mitochondrial electron trans-port system. Indawo enkulu yokuvelisa i-superoxide anion yi-mitochondria, oomatshini beseli ukuvelisa i-adenosine triphosphate. Ngokuqhelekileyo, ii-electron zihanjiswa ngekhonkco lothutho lwe-electron ye-mitochondrial ukuze kuncitshiswe ioksijini emanzini, kodwa malunga ne-1 ukuya kwi-3% yazo zonke ii-electron zivuza kwinkqubo kwaye zivelise i-superoxide. I-NAD (P) H oxidase ifumaneka kwi-polymorphonuclear leukocytes, i-monocytes, kunye ne-macrophages. Phezu kwe-phagocytosis, ezi seli zivelisa ukuqhuma kwe-superoxide ekhokelela kumsebenzi we-bactericidal. I-Superoxide iguqulwa ibe yi-hydrogen peroxide ngesenzo se-superoxide dismutases (i-SODs, i-EC 1.15.1.1). Ihydrogen peroxide isasazeke ngokulula kwi-plasma inwebu. I-hydrogen peroxide ikwaveliswa yi-xanthine oxidase, i-amino acid oxidase, kunye ne-NAD(P)H oxidase�23,24 nakwi-peroxisomes ngokusetyenziswa kwe-molecular oxygen reactions. Kulandelelwano lweempendulo ezibizwa ngokuba yi-Haber�Weiss kunye ne-Fenton reaction, i-H2O2 inokophuka iye kwi-OH2 xa kukho iintsimbi zothumelo ezifana ne-Fe21 okanye i-Cu21.25

Fe31 +�.O2�?Fe2 +�O2 Haber Weiss

Fe2 +�H2O2�?Fe3 +�OH�+ .OH Fenton reaction

I-O 2 yona ngokwayo ingasabela nge-H2 O2 kwaye ivelise i-OH�.26,27 I-Hydroxyl radical yeyona isebenzayo kwi-ROS kwaye inokonakalisa iiprotheni, i-lipids, kunye ne-carbohydrates kunye ne-DNA. Inokuthi iqalise i-lipid peroxidation ngokuthatha i-electron kwi-polyunsaturated fatty acids.

I-Granulocytic enzymes yandisa ngakumbi ukusebenza kwakhona kwe-H2O2 nge-eosinophil peroxidase kunye ne-myeloperoxidase (MPO). Kwi-neutrophils esebenzayo, i-H2O2 idliwe yi-MPO. Xa kukho i-chloride ion, i-H2O2 iguqulwa ibe yi-hypochlorous acid (HOCl). I-HOCl i-oxidative kakhulu kwaye idlala indima ebalulekileyo ekubulaleni iintsholongwane kwiindlela zomoya.28 Nangona kunjalo, i-HOCl inokuphinda isebenze kunye ne-DNA kwaye ifake i-DNA'intsebenziswano yeprotheni kwaye ivelise iimveliso ze-pyrimidine oxidation kunye nokongeza i-chloride kwiziseko ze-DNA.29,30 Eosinophil peroxidase kunye ne-MPO nayo inegalelo kuxinzelelo lwe-oxidative ngokuguqulwa kweeprotheni nge-halogenations, i-nitration, kunye ne-protein cross-links nge-tyrosyl radicals.31�33

Ezinye i-oxygen-derived free radicals yi-peroxyl radicals (ROO $). Eyona ndlela ilula yezi radicals yi-hydro-peroxyl radical (HOO $) kwaye inendima kwi-fatty acid peroxidation. Iiradicals zasimahla zinokubangela ukusabela kwetsheyina lelipid peroxidation ngokutsala iathomu yehidrojeni kwitsheyini esecaleni yemethylene carbon. I-lipid radical emva koko idibana neoksijini ukuvelisa i-peroxyl radical. I-Peroxyl radical iqala ukusabela kwekhonkco kwaye iguqule i-polyunsaturated fatty acids ibe yi-lipid hydroperoxides. I-Lipid hydroperoxides ayizinzile kwaye ibola ngokulula kwiimveliso zesibini, ezifana ne-aldehydes (ezifana ne-4-hydroxy-2,3-nonenal) kunye ne-malondialdehydes (MDAs). I-Isoprostanes yenye iqela leemveliso ze-lipid peroxidation eziveliswa nge-peroxidation ye-arachidonic acid kwaye zifunyenwe ziphakanyiswe kwi-plasma kunye nokuphefumula kwe-asthmatics. isakhiwo inwebu.

Ihydrogen peroxide, superoxide radical, oxidized glutathione (GSSG), MDAs, isoprostanes, carbonyls, kunye nenitrotyrosine zinokulinganiswa ngokulula kwiplasma, igazi, okanye ibronchoalveolar lavage iisampulu njenge biomarkers of oxidation ngovavanyo olusemgangathweni.

Umthombo wangaphandle weeOxidants

Umsi weCigarette

Umsi we-cigarette uqukethe i-oxidants kunye ne-radicals yamahhala kunye ne-organic compounds, njenge-superoxide kunye ne-nitric oxide.36 Ukongezelela, ukuphefumla umsi wecuba emphunga kuphinda kusebenze ezinye iindlela ezingapheliyo, ezifana nokuqokelela i-neutrophils kunye ne-macrophages, eyongeza ngakumbi ukwenzakala kwe-oxidant. .

Ukubonakaliswa kweOzone

Ukubonakaliswa kwe-ozone kunokubangela i-lipid peroxidation kwaye kubangele ukungena kwe-neutrophils kwi-epithelium yomoya. Ukutshatyalaliswa kwexesha elifutshane kwi-ozone kubangela ukukhululwa kwabalamli abavuthayo, njenge-MPO, i-eosinophil cationic proteins kunye ne-lactate dehydrogenase kunye ne-albumin.37 Nangona kwizifundo eziphilileyo, ukubonakaliswa kwe-ozone kubangela ukunciphisa imisebenzi ye-pulmonary.38 Cho et al39 baye babonisa ukuba i-particulate matter (umxube wamasuntswana aqinileyo kunye namathontsi angamalwelo axhonywe emoyeni) enza ukuba kucuthwe ioksijini.

Hyperoxia

I-Hyperoxia ibhekisa kwiimeko zamanqanaba aphezulu e-oksijini kunoxinzelelo oluqhelekileyo lweoksijini emiphungeni okanye kwezinye izicubu zomzimba. Ikhokelela kwimveliso enkulu ye-oksijeni esebenzayo kunye neentlobo ze-nitrogen.40,41

I-ionizing Radiation

I-ionizing radiation, phambi kwe-O2, iguqula i-hydroxyl radical, superoxide, kunye ne-organic radicals kwi-hydrogen peroxide kunye ne-organic hydroperoxides. Ezi ntlobo ze-hydroperoxide zisabela nge-redox yensimbi esebenzayo, njenge-Fe kunye ne-Cu, ngokuphendula kwe-Fenton kwaye ngaloo ndlela ibangele uxinzelelo lwe-oxidative. ukuveliswa nge-plasma membrane-eboshwe i-NADPH oxidase.42,43 Iimolekyuli zokutshintshwa kweSignali, ezifana ne-extracellular signal-regulated kinase 44 kunye ne-2 (ERK2 / 2), c-Jun N-terminal kinase (JNK), kunye ne-p2, kunye nezinto ezibhaliweyo, ezifana i-activator protein-44 (AP-1), i-nuclear factor-kB (NF-kB), kunye ne-p2, ziyasebenza, ezikhokelela ekubonakalisweni kwempendulo ye-radiation-related genes. ngokuvuswa kweefotosensitizers ezingapheliyo, ezifana ne-porphyrins, i-NADPH oxidase, kunye ne-riboflavins. I-1-Oxo-2- dihydroguanine (i-38-oxoGua) iyona nto iphambili ye-UVA-mediated DNA oxidation imveliso eyenziwa yi-oxidation ye-OH radical, i-1-electron oxidants, kunye ne-oksijini ye-singlett echaphazela kakhulu i-guanine.1 Ukubunjwa kwe-guanine i-radical cation kwi-DNA eyodwa ibonakaliswe ukuba yenzeke ngokufanelekileyo ngempembelelo echanekileyo ye-ionizing radiation.53 Emva kokuvezwa kwimitha ye-ionizing, i-intracellular level of glutathione (GSH) iyancipha ixesha elifutshane kodwa iphinda inyuke kwakhona.45

I-Ions zentsimbi enzima

I-ion zensimbi ezinzima, ezifana nentsimbi, ithusi, i-cadmium, i-mercury, i-nickel, i-lead, kunye ne-arsenic, inokubangela ukuveliswa kwee-radicals ezisebenzayo kwaye kubangele umonakalo weselula ngokunciphisa imisebenzi ye-enzyme ngokusebenzisa i-lipid peroxidation kunye nokuphendula ngeeprotheni zenyukliya kunye ne-DNA.55.

Enye yeendlela ezibaluleke kakhulu zesinyithi-mediated simahla iradical sizukulwana kukusebenzisa uhlobo lwe-Fenton reaction. I-ion ye-Superoxide kunye ne-hydrogen peroxide inokunxibelelana nesinyithi sokutshintsha, njengentsimbi kunye nobhedu, nge-metal catalyzed Haber'Weiss/Fenton reaction ukwenza i-OH radicals.

Metal31 1 $O2 /Metal21 1 O2 Haber Weiss Metal21 1 H2 O2 /Metal31 1 OH 2 1 $OH Fenton reaction

Ngaphandle kohlobo lwe-Fenton kunye neendlela zohlobo lwe-HaberWeiss, ii-ion ezithile zetsimbi zinokusabela ngokuthe ngqo kunye neemolekyuli zeselula ukuvelisa iiradicals zasimahla, ezinje nge-thiol radicals, okanye zenze iindlela zokubonisa iiseli. Ezi radicals zinokusabela kunye nezinye iimolekyuli ze-thiol ukuvelisa i-O22.. O22. iguqulwa ibe yi-H2O2, ebangela ukuveliswa kwe-oxygen eyongezelelweyo. Ezinye izinyithi, ezifana ne-arsenite, zenza i-ROS ibunjwe ngokungathanga ngqo ngokusebenza kweenkqubo zokuvelisa ngokugqithisileyo kwiiseli.56

I-Arsenic yinto enetyhefu kakhulu eyenza iindidi zeROS, kubandakanywa i-superoxide (O2 2), i-oxygen singlet (1O2), i-peroxyl radical (ROO), i-nitric oxide (NO), i-hydrogen peroxide (H2O2), kunye ne-dimethylarsinic peroxyl radicals [( CH3)2AsOO ].57�59 Arsenic (III) iikhompawundi zinokunqanda i-antioxidant enzymes, ngakumbi i-enzymes exhomekeke kwi-GSH, njenge-glutathione-S-transferases (GSTs), i-glutathione peroxidase (GSH-Px), kunye ne-GSH reductase, ngokubopha. - kumaqela abo e-sulfhydryl (�SH).60,61

Isikhokelo kwandisa i-lipid peroxidation.62 Ukuncipha okuphawulekayo kumsebenzi we-tissue SOD kunye nobuchopho be-GPx kuye kwabikwa emva kokuvezwa kwe-lead.63,64 Ukutshintshwa kwe-zinc, esebenza njenge-cofactor ye-enzymes ezininzi nge-lead, ikhokelela ekubeni i-enzyme ingasebenzi. Ukuvezwa kwelothe kunokubangela ukuvinjwa kwe-GST ngokuchaphazela i-thiols yezicubu.

I-ROS eyenziwa yi-metal-catalyzed reactions inokuguqula iziseko ze-DNA. Ukutshintshwa kwesiseko ezintathu, i-G / C, i-G / T, kunye ne-C / T, inokuthi yenzeke ngenxa yomonakalo we-oxidative nge-ion zetsimbi, ezifana ne-Fe21, Cu21, kunye ne-Ni21. U-Reid et al65 ubonise ukuba i-G / C yaveliswa kakhulu yi-Fe21 ngelixa indawo ye-C / T yayiyi-Cu21 kunye ne-Ni21.

IZINTO EZOKUXHUMA

Umzimba womntu uxhotyiswe ngeendidi ze-antioxidants ezisebenza ukulungelelanisa umphumo wee-oxidants. Kuzo zonke iinjongo ezisebenzayo, ezi zinokwahlulwa zibe ziindidi ezi-2: i-enzymatic (iThebhile 2) kunye ne-nonenzymatic (iThebhile 3).

Ii-Antioxidants ze-Enzymatic

Ii-antioxidants ezinkulu ze-enzymatic zemiphunga zi-SOD (EC 1.15.1.11), i-catalase (EC 1.11.1.6), kunye ne-GSH-Px (EC 1.11.1.9). Ukongeza kwezi enzymes ezinkulu, ezinye i-antioxidants, ezibandakanya i-heme oxygenase-1 (EC 1.14.99.3), kunye neeprotheni ze-redox, ezifana ne-thioredoxins (TRXs, EC 1.8.4.10), i-peroxiredoxins (PRXs, EC 1.11.1.15), kunye ne-glutaredoxins, kunye ne-glutaredoxins , zikwafunyaniswa ukuba zidlala indima ebalulekileyo kukhuselo lwe-pulmonary antioxidant.

Ekubeni i-superoxide yi-ROS ephambili eveliswa kwimithombo eyahlukeneyo, ukuchithwa kwayo yi-SOD kubaluleke kakhulu kwiseli nganye. Zonke iifom ezi-3 ze-SOD, oko kukuthi, i-CuZn-SOD, i-Mn-SOD, kunye ne-EC-SOD, zibonakaliswa ngokubanzi kwimiphunga yomntu. I-Mn-SOD ibekwe kwindawo ye-mitochondria matrix. I-EC-SOD ngokuyinhloko ibekwe kwindawo ye-matrix engaphandle, ngokukodwa kwiindawo eziqulethe ixabiso eliphezulu lohlobo lwe-collagen fibers kunye ne-pulmonary and systemic vessels. Kwakhona kuye kwafunyanwa kwi-epithelium ye-bronchial, i-alveolar epithelium, kunye ne-alveolar macrophages. Inqanaba eliphezulu le-EC-SOD kwimiphunga kunye nokubopha ngokuthe ngqo kumacandelo e-matrix e-extracellular inokumela icandelo elisisiseko lokukhusela i-matrix ye-lung.66,67

I-H2O2 eveliswa yisenzo se-SOD okanye isenzo se-oxidases, njenge-xanthine oxidase, iyancitshiswa emanzini nge-catalase kunye ne-GSH-Px. ICatalase ikhona njengetetramer eyenziwe ngeemonomer ezi-4 ezifanayo, nganye kuzo ineqela le-heme kwindawo esebenzayo. Ukuthotywa kwe-H2O2 kufezekiswa ngoguqulo phakathi kwe-2 conformations ye-catalase-ferricatalase (intsimbi edityaniswe namanzi) kunye ne-compound I (intsimbi ehlanganiswe ne-athomu ye-oxygen). I-Catalase iphinda ibophe i-NADPH njengokunciphisa ukulinganisa ukuthintela ukungasebenzi kwe-oxidative ye-enzyme (ukwenziwa kwe-compound II) nge-H2O2 njengoko iyancipha emanzini.69

I-Enzymes kumjikelezo we-redox ojongene nokunciphisa i-H2O2 kunye ne-lipid hydroperoxides (eyenziwe ngenxa ye-membrane lipid peroxidation) iquka i-GSH-Pxs.70 I-GSH-Pxs yintsapho ye-tetrameric enzymes equkethe i-amino acid eyodwa selenocysteine ​​ngaphakathi iindawo ezisebenzayo kunye nokusebenzisa i-thiols ephantsi-molekyuli-ubunzima, njenge-GSH, ukunciphisa i-H2O2 kunye ne-lipid peroxides kwii-alcohols ezihambelanayo. I-GSH-Pxs ezine zichazwe, zifakwe kwii-genes ezahlukeneyo: I-GSH-Px-1 (i-cellular GSH-Px) iyindawo yonke kwaye iyanciphisa i-H2O2 kunye ne-peroxides ye-fatty acid, kodwa i-peroxyl lipids engabonakaliyo. -Px-71 (i-phospholipid hydroperoxide GSH-Px), enokusebenzisa i-thiols ezininzi ezahlukeneyo ezinobunzima obuphantsi bemolekyuli njengokunciphisa ukulingana. I-GSH-Px-4 (i-GSH-Px ye-gastrointestinal) ifumaneka kwiiseli ze-epithelial zesisu apho isebenza ukunciphisa i-peroxides yokutya. i-extracellular compartment kwaye kukholelwa ukuba yeyona enzyme ibalulekileyo kwi-antioxidant kwizilwanyana ezanyisayo. Kuzo, i-extracellular GSH-Px iphandwa kakhulu kwimiphunga yomntu.2

Ukongezelela, ukulahlwa kwe-H2O2 kuhambelana ngokusondeleyo kunye nee-enzyme ezininzi ezine-thiol, ezizezi, i-TRXs (TRX1 kunye ne-TRX2), i-thioredoxin reductases (EC 1.8.1.9) (TRRs), i-PRXs (eyi-thioredoxin peroxidases), kunye ne-glutaredoxin.

IiTRX ezimbini kunye ne-TRR zibonakaliswe kwiiseli zomntu, ezikhoyo kwi-cytosol kunye ne-mitochondria. Kwimiphunga, i-TRX kunye ne-TRR zibonakaliswa kwi-epithelium ye-bronchial kunye ne-alveolar kunye ne-macrophages. Ii-PRX ezintandathu ezahlukeneyo zifunyenwe kwiiseli zomntu, ezahlukileyo kwi-ultrastructural compartmentalization. Izifundo zovavanyo zibonakalise ukubaluleka kwe-PRX VI ekukhuseleni i-alveolar epithelium. Umphunga womntu uvakalisa zonke ii-PRXs kwi-epithelium ye-bronchial, i-alveolar epithelium, kunye ne-macrophages.75 I-PRX V isanda kufunyaniswa ukuba isebenze njenge-peroxynitrite reductase, i-76 ithetha ukuba inokusebenza njengento ekhuselekileyo yokukhusela ekuphuhlisweni kokulimala kwe-ROS-mediated lung .77

Okuqhelekileyo kwezi antioxidants yimfuneko ye-NADPH njengokunciphisa okufanayo. I-NADPH igcina i-catalase kwifom esebenzayo kwaye isetyenziswe njenge-cofactor nge-TRX kunye ne-GSH reductase (EC 1.6.4.2), eguqula i-GSSG kwi-GSH, i-co-substrate ye-GSH-Pxs. I-Intracellular NADPH, ngokuphindaphindiweyo, iveliswa ngokunciphisa i-NADP1 nge-glucose-6-phosphate dehydrogenase, i-enzyme yokuqala kunye ne-rate-limiting enzyme ye-pentose phosphate pathway, ngexesha lokuguqulwa kwe-glucose-6-phosphate kwi-6-phosphogluconolactone. Ngokuvelisa i-NADPH, i-glucose-6-phosphate dehydrogenase yinto ebalulekileyo yokumisela i-cytosolic GSH buffering capacity (GSH / GSSG) kwaye, ngoko ke, inokuthathwa njengento ebalulekileyo, elawula i-enzyme ye-antioxidant.78,79

I-GSTs (EC 2.5.1.18), enye intsapho ye-enzyme ye-antioxidant, yenza i-metabolites yesibini ingasebenzi, njenge-aldehydes engaxutywanga, i-epoxides, kunye ne-hydroperoxides. Iintsapho ezintathu ezinkulu ze-GST zichazwe: i-cytosolic GST, i-GST ye-mitochondrial, i-80,81 kunye ne-membrane ehambelana ne-microsomal GST enendima ye-eicosanoid kunye ne-GSH metabolism. I-Pi, i-Sigma, i-Theta, i-Omega, kunye ne-Zeta.82�83 Ngexesha leemeko ezingagxininiswanga, iklasi ye-Mu kunye ne-Pi GSTs isebenzisana ne-kinases Ask86 kunye ne-JNK, ngokulandelanayo, kwaye inhibit le kinases.1�87 Kuye kwaboniswa ukuba i-GSTP89 iyahlukana nayo I-JNK ekuphenduleni uxinzelelo lwe-oxidative.1 GSTP89 iphinda isebenze ngokomzimba kunye ne-PRX VI kwaye ikhokelela ekubuyiseleni umsebenzi we-enzyme ye-PRX nge-glutathionylation yeprotheni ene-oxidized.1

Nonenzymatic Antioxidants

I-Nonenzymatic antioxidants iquka iikhompawundi ezinobunzima obuphantsi be-molecular-weight, ezifana neevithamini (i-vitamin C kunye ne-E), i-b-carotene, i-uric acid, kunye ne-GSH, i-tripeptide (Lg-glutamyl-L-cysteynyl-L- glycine) equka i-thiol (i-thiol) sulfhydryl) iqela.

I-Vitamin C (i-Ascorbic Acid)

Ivithamin C enyibilikayo emanzini (i-ascorbic acid) ibonelela nge-intracellular kunye ne-extracellular aqueous-phase i-antioxidant umthamo we-antioxidant ngokuyinhloko ngokukhupha i-oxygen free radicals. Iguqula i-vitamin E ye-radicals yamahhala ibuyele kwi-vitamin E. Amanqanaba ayo e-plasma abonakaliswe ukuba ayancipha ngeminyaka.91,92

IVithamin E (a-Tocopherol)

I-Lipid-soluble vitamin E igxininiswe kwindawo yangaphakathi ye-hydrophobic ye-membrane yeseli kwaye iyona nto yokukhusela i-oxidant-induced membrane i-membrane. I-Vitamin E inikela nge-electron kwi-peroxyl radical, eveliswa ngexesha le-lipid peroxidation. I-a-Tocopherol yeyona ndlela isebenzayo ye-vitamin E kunye ne-membrane enkulu ebophe i-antioxidant kwiseli. I-Vitamin E ibangela i-apoptosis yeeseli zomhlaza kwaye inqanda ukubunjwa kwamahhala.93

Glutathione

I-GSH ininzi kakhulu kuzo zonke iikhompatimenti zeeseli kwaye yeyona nto iphambili ekunyibilikeni kwe-antioxidant. Umlinganiselo we-GSH/GSSG sisona sigqibo siphambili soxinzelelo lwe-oxidative. I-GSH ibonisa imiphumo ye-antioxidant ngeendlela ezininzi.94 Ikhupha i-hydrogen peroxide kunye ne-lipid peroxides ngesenzo se-GSH-Px. I-GSH inika i-electron yayo kwi-H2O2 ukuyinciphisa ibe yi-H2O kunye ne-O2. I-GSSG iphinda ithotywe ibe yi-GSH nge-GSH reductase esebenzisa i-NAD(P)H njengomnikeli we-electron. Ii-GSH-Pxs zikwabalulekile ekukhuselweni kwenwebu yeseli kwi-lipid peroxidation. Ukunciphisa i-glutathione inika iiprotons kwi-membrane lipids kwaye ikhusela ekuhlaselweni kwe-oxidant.95

I-GSH yicofactor yee-enzyme ezininzi ezikhupha ubutyhefu, ezifana ne-GSH-Px kunye nokudluliselwa. Inendima ekuguquleni i-vitamin C kunye ne-E kwiifom zabo ezisebenzayo. I-GSH ikhusela iiseli ezichasene ne-apoptosis ngokusebenzisana neproapoptotic kunye ne-antiapoptotic indlela yokubonisa indlela.94 Ikwalawula kwaye isebenze izinto ezininzi zokubhala, ezifana ne-AP-1, NF-kB, kunye ne-Sp-1.

IiCarotenoids (b-Carotene)

I-Carotenoids zimibala yemibala efumaneka kwizityalo. Ngokuyintloko, i-b-carotene ifunyenwe ukuba iphendule nge-peroxyl (ROO), i-hydroxyl (OH), kunye ne-superoxide (O22.) i-radicals.96 I-Carotenoids ibonisa iziphumo zabo ze-antioxidant kwi-oxygen ephantsi yoxinzelelo oluyingxenye kodwa ingaba nemiphumo ye-pro-oxidant kwi-oxygen ephezulu. i-concentrations.97 Zombini i-carotenoids kunye ne-retinoic acids (i-RAs) ziyakwazi ukulawula izinto ezibhaliweyo.98 b-Carotene inqanda i-oxidant-induced NF-kB activation kunye ne-interleukin (IL) -6 kunye ne-tumor necrosis factor-a production. I-carotenoids nayo ichaphazela i-apoptosis yeeseli. Imiphumo ye-Antiproliferative ye-RA ibonakaliswe kwizifundo ezininzi. Esi siphumo se-RA sixutyushwa ikakhulu ngama-retinoic acid receptors kwaye ayahluka phakathi kweentlobo zeeseli. Kwiiseli ze-mammary carcinoma, i-retinoic acid receptor yaboniswa ukuba iqalise ukuvinjelwa kokukhula ngokubangela ukubanjwa komjikelezo weseli, i-apoptosis, okanye zombini.99,100

IZIPHUMO ZOXINEZELEKO LWE-OXIDATIVE: GENETIC, PHYSIOLOGICAL, & BIOCHEMICAL MECHANISMS

Uxinzelelo lwe-oxidative lwenzeka xa ibhalansi phakathi kwe-antioxidants kunye ne-ROS iphazamiseka ngenxa yokuncipha kwe-antioxidants okanye ukuqokelela kwe-ROS. Xa uxinzelelo lwe-oxidative lwenzeka, iiseli zizama ukuchasana nemiphumo ye-oxidant kunye nokubuyisela ibhalansi ye-redox ngokusebenza okanye ukuthuliswa kwejene-encoding enzymes ezikhuselayo, izinto ezibhaliweyo, kunye neeprotheni zesakhiwo.101,102 Umlinganiselo phakathi kwe-glutathione oxidized kunye nokunciphisa (2GSH / GSSG) enye izinto ezibalulekileyo zokumisela uxinzelelo lwe-oxidative emzimbeni. Ukuveliswa okuphezulu kwe-ROS emzimbeni kunokutshintsha isakhiwo se-DNA, kubangele ukuguqulwa kweeprotheni kunye ne-lipids, ukusetyenziswa kwezinto ezininzi ezibangelwa uxinzelelo, kunye nokuveliswa kwe-cytokines e-pro-inflammatory and anti-inflammatory.

Iziphumo zoxinzelelo lwe-Oxidative kwi-DNA

I-ROS inokukhokelela ekuguqulweni kwe-DNA ngeendlela ezininzi, ezibandakanya ukuthotywa kweziseko, i-DNA eyodwa okanye i-double-stranded breaks, i-purine, i-pyrimidine okanye i-sugar-bound modifications, ukuguqulwa, ukucinywa okanye ukuhanjiswa, kunye nokudibanisa kunye neeprotheni. Uninzi lwezi nguqulelo ze-DNA (umzobo 1) zibaluleke kakhulu kwi-carcinogenesis, ukuguga, kunye ne-neurodeergenerative, i-cardiovascular, kunye nezifo ezizimele. Umsi wecuba, isinyithi esine-redox, kunye neentsimbi ezi-nonredox, ezifana ne-iron, i-cadmium, i-chrome, kunye ne-arsenic, zikwabandakanyeka kwi-carcinogenesis kunye nokuguga ngokuvelisa ii-radicals zamahhala okanye ukubopha kunye namaqela e-thiol. Ukwenziwa kwe-8-OH-G ngowona monakalo waziwa kakhulu we-DNA owenzeka ngoxinzelelo lwe-oxidative kwaye yinto enokubakho i-biomarker ye-carcinogenesis.

Imimandla yabakhuthazi bemizila yemfuza iqulathe ulandelelwano lwemvumelwano kwizinto ezikhutshelweyo. Ezi sayithi zibophelelayo ziqulathe ulandelelwano olutyebileyo lwe-GC olusesichengeni sohlaselo lwe-oxidant. Ukuqulunqwa kwe-8-OH-G DNA kwiindawo ezibophelelayo ze-transcription factor inokuguqula ukubophelela kwezinto ezibhaliweyo kwaye ngaloo ndlela iguqule ukubonakaliswa kweejene ezihambelanayo njengoko kuboniswe kwi-AP-1 kunye ne-Sp-1 yokulandelelana okujoliswe kuyo.103 Ngaphandle kwe-8-OH-G, I-8,59 -cyclo-29 -deoxyadenosine (i-cyclo-dA) nayo ibonakaliswe ukuba inqanda ukubhalwa kwi-generator gene kwi-cell system ukuba ifakwe kwibhokisi ye-TATA. . Ukubotshwa kweprotheni ye-TATA-ibophelelo kunokuphazamiseka ngenxa yobukho be-cyclo-dA.

Uxinzelelo lwe-oxidative lubangela ukungazinzi kwemimandla ye-microsatellite (i-tandem emfutshane ephindaphindayo). I-Redox yensimbi esebenzayo i-ion, i-hydroxyl radicals yandisa ukungazinzi kwe-microsatellite.105 Nangona i-DNA edibeneyo ikhefu ebangelwa ukulimala kwe-oxidant inokunyamezela ngokulula ngamaseli, i-DNA ephindwe kabini ikhefu eyenziwa yi-ionizing radiation ingaba yingozi enkulu kwi-cell survival.106

I-Methylation kwiziqithi ze-CpG kwi-DNA yindlela ebalulekileyo ye-epigenetic enokubangela ukuthuliswa kofuzo. I-Oxidation ye-5-MeCyt ukuya kwi-5-hydroxymethyl uracil (i-5-OHMeUra) ingenzeka ngokusebenzisa i-deamination / oxidation reactions ye-thymine okanye i-5-hydroxymethyl cytosine intermediates.107 Ukongeza kwi-modulating gene expression, i-DNA methylation ibonakala ichaphazela intlangano ye-chromatin.108 Iipateni ze-Aberrant DNA methylation ezibangelwa ukuhlaselwa kwe-oxidative nazo zichaphazela umsebenzi wokulungisa i-DNA.

Iziphumo zoxinzelelo lweOxidative kwiLipids

I-ROS inokubangela i-lipid peroxidation kwaye iphazamise ilungiselelo le-membrane ye-lipid bilayer enokuthi ingasebenzi i-membrane-bound bound receptors kunye ne-enzymes kunye nokwandisa i-tissue permeability. -linkages.109�110 I-112-Hydroxy-4-nonenal ibangela ukuchithwa kwe-GSH ye-intracellular kunye ne-induces yokuveliswa kwe-peroxide, i-2 isebenze i-epidermal growth factor receptor, i-113,114 kwaye ibangele ukuveliswa kwe-fibronectin.115 Imveliso ye-Lipid peroxidation, njenge-isoproactive substances kunye ne-asidi ye-isoprostabisturic , zisetyenziswe njenge-biomarkers ezingathanga ngqo zoxinzelelo lwe-oxidative, kunye namanqanaba okwandisa abonakaliswe kwi-exhaled breath condensate okanye i-bronchoalveolar lavage fluid okanye imiphunga yezigulane ezingapheliyo ze-pulmonary disease okanye ababhemayo.116�117

Iziphumo zoxinzelelo lwe-Oxidative kwiiProtheyini

I-ROS inokubangela ukuhlukana kwekhonkco le-peptide, ukuguqulwa kwentlawulo yombane yeeprotheni, ukudibanisa kweeprotheni, kunye ne-oxidation ye-amino acids ethile kwaye ngoko ke kukhokelela ekunyukeni kwe-proteolysis ngokuchithwa ngamaproteases athile. ngakumbi ichaphazeleka ngakumbi kwi-oxidation.120 I-Oxidation yamaqela e-sulfhydryl okanye iintsalela ze-methionine zeeprotheni zibangela utshintsho lwe-conformational, i-protein eqhubekayo, kunye nokuhla. Ukuguqulwa kwe-oxidative ye-enzymes kuboniswe ukuvimbela imisebenzi yabo.121

Kwezinye iimeko, i-oxidation ethile yeeprotheni inokuthi yenzeke. Ngokomzekelo, i-methionine ingaba yi-oxidized methionine sulfoxide126 kunye ne-phenylalanine kwi-o-tyrosine127; Amaqela e-sulfhydryl anokuthi afakwe i-oxidized ukuze enze iibhondi ze-disulfide;I-128 kunye namaqela e-carbonyl anokuthi afakwe kumatyathanga asecaleni amaprotheni. Imitha ye-Gamma, i-metal-catalyzed oxidation, i-HOCl, kunye ne-ozone inokubangela ukubunjwa kwamaqela e-carbonyl.129

Iziphumo zoxinzelelo lwe-Oxidative kuTshintsho lweSignali

I-ROS inokubangela ukubonakaliswa kweentlobo ezininzi zofuzo ezibandakanyekayo kwi-transduction ye-signal.1,130 Umlinganiselo ophezulu we-GSH / GSSG ubalulekile ekukhuselweni kweseli kumonakalo we-oxidative. Ukuphazamiseka kwesi silinganiselo kubangela ukusetyenziswa kwezinto ezithintekayo ze-redox, ezifana ne-NF-kB, i-AP-1, i-nuclear factor ye-activated T cells kunye ne-hypoxia-inducible factor 1, ezibandakanyekayo kwimpendulo yokuvuvukala. Ukusetyenziswa kwezinto ezikhutshelweyo nge-ROS kuphunyezwa ngokugqithiswa komqondiso we-cascades ohambisa ulwazi ukusuka ngaphandle ukuya ngaphakathi kwiseli. I-Tyrosine kinase i-receptors, ininzi ye-receptors factor receptor, njenge-epidermal growth factor receptor, i-vascular endothelial growth factor receptor, kunye ne-receptor ye-platelet-derived factor factor, i-protein tyrosine phosphatases, kunye ne-serine / threonine kinases ziithagethi ze-ROS.131�133 I-extra-cellular signal-regulated kinases, i-JNK, kunye ne-p38, engamalungu e-mitogen-activated protein kinase family kwaye abandakanyeka kwiinkqubo ezininzi kwiseli kuquka ukwanda, ukuhlukana, kunye ne-apoptosis, nayo inokulawulwa yi-oxidants.

Ngaphantsi kweemeko zokuxinzezeleka kwe-oxidative, i-cysteine ​​​​intsalela kwindawo ye-DNA-binding ye-c-Jun, ezinye i-AP-1 subunits, kunye ne-inhibitory kB kinase i-S-glutathiolation eguqulwayo. I-Glutaredoxin kunye ne-TRX ziye zabikwa ukuba zidlala indima ebalulekileyo ekulawuleni iindlela zokubonisa i-redox-sensitive, ezifana ne-NF-kB kunye ne-AP-1, i-p38 mitogen-activated protein kinase, kunye ne-JNK.134�137

I-NF-kB inokuthi isebenze ekuphenduleni iimeko zokuxinzezeleka kwe-oxidative, njenge-ROS, i-radicals yamahhala, kunye ne-UV irradiation.138 I-Phosphorylation ye-IkB ikhulula i-NF-kB kwaye ivumela ukuba ingene kwi-nucleus ukuze isebenze i-gene transcription.139 Inani le-kinases kuxelwe kwi-phosphorylate IkBs kwiintsalela ze-serine. Ezi kinases zijoliswe kwiimpawu ze-oxidative ukuze kusebenze i-NF-kB.140 ii-agent zokunciphisa ziphucula i-NF-kB DNA yokubopha, ngelixa i-oxidizing agents zivimbela i-DNA yokubopha i-NF-kB. I-TRX inokusebenzisa izenzo ezi-2 ezichaseneyo kulawulo lwe-NF-kB: kwi-cytoplasm, ivimba ukuthotywa kwe-IkB kwaye inqanda ukusebenza kwe-NF-kB kodwa iphucula i-NF-kB DNA ebophelelayo kwi-nucleus.141 Ukusetyenziswa kwe-NF-kB ngokuchithwa kwe-oxidation-related degradation. ye-IkB iphumela ekubeni kusebenze iijini ezininzi ezinxulumene nokhuselo lwe-antioxidant. I-NF-kB ilawula ukubonakaliswa kwezakhi zofuzo ezininzi ezithatha inxaxheba ekuphenduleni komzimba, njenge-IL-1b, i-IL-6, i-tumor necrosis factor-a, i-IL-8, kunye neemolekyuli ezininzi zokubambelela. ukwahlukana kweeseli.

I-AP-1 nayo ilawulwa yi-redox state. Phambi kwe-H2O2, ezinye ii-ion zetsimbi zingenza ukuba kusebenze i-AP-1. Ukonyuka komlinganiselo we-GSH/GSSG kuphucula ukubophelela kwe-AP-1 ngelixa i-GSSG inqanda ukubophelela kwe-DNA ye-AP-1.144 DNA yokubopha i-Fos/Jun heterodimer yonyuka ngokunciphisa i-cysteine ​​eyodwa egciniweyo kwi-domain ebopha i-DNA nganye iiprotheyini, i-145 ngelixa i-DNA ibophelela i-AP-1 inokuvinjelwa yi-GSSG kwiintlobo ezininzi zeeseli, ebonisa ukuba ukubunjwa kwebhondi ye-disulphide ngama-cysteine ​​​​i-residues inqanda i-AP-1 DNA yokubopha.146,147 Ukutshintshwa kweSignali ngokusebenzisa uxinzelelo lwe-oxidative lushwankathelwe kwi-Figure 2.

 

IMISEBENZI

Uxinzelelo lwe-oxidative lunokuvela kwimveliso egqithisileyo ye-ROS ngokuphendula kwemetabolism esebenzisa ioksijini kunye nokutshintsha ibhalansi phakathi i-oxidant/antioxidant iimeko ezixhasa i-oxidants. I-ROS iveliswa yimisebenzi ye-metabolic yeselula kunye nezinto ezisingqongileyo, ezinje ngongcoliseko lomoya okanye umsi wecuba. I-ROS ziamolekyu ezisebenzayo kakhulu ngenxa yee-electron ezingasebenziyo kwisakhiwo sazo kwaye zisabela kunye ne-biological macromolecules ezininzi kwiseli, njenge-carbohydrates, i-nucleic acids, i-lipids, kunye neeprotheni, kwaye ziguqule imisebenzi yazo. I-ROS ikwachaphazela ukubonakaliswa kofuzo oluninzi ngokunyusa izinto ezikhutshelweyo ezibuthathaka kwi-redox kunye nohlengahlengiso lwechromatin ngotshintsho kwi-histone acetylation/deacetylation. Ukulawulwa kwemeko ye-redox ibalulekile ekusebenzeni kweeseli, ukusebenza, ukwanda, kunye nokusebenza kwamalungu.

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