Polyphenols Targeting MAPK Mediated Oxidative Stress Thiab Inflammation hauv Rheumatoid Arthritis
Mar 16, 2022
Thov hu rauoscar.xiao@wecistanche.comyog xav paub ntxiv
Abstract:Rheumatoid mob caj dab (RA) yog ib qho mob ntev, kab mob, kab mob autoimmune, feem ntau sib luag, uas ua rau muaj kev sib koom ua ke, pob txha mos degeneration, thiab pob txha erosion, ua rau deformity thiab poob ntawm lub cev ua haujlwm. Txawm hais tias kev tswj hwm ntawm RA tau txhim kho tsis tu ncua, cov txheej txheem pathophysiological tsis ua tiav, thiab cov kev xaiv kho mob tseem txwv. Vim muaj qhov tsis zoo ntawm qhov ua tau zoo lossis kev nyab xeeb ntawm cov kev kho mob RA, cov kev kho mob tau raug txiav txim siab. Yog li ntawd, tej yam ntuj tso extracts uas muaj polyphenolic tebchaw tuaj yeem dhau los ua cov neeg ua haujlwm cog lus rau RA ntiaj teb kev tswj hwm, vim lawv cov tshuaj tiv thaiv antioxidant, tiv thaiv kab mob, thiab apoptotic zog. Polyphenols tuaj yeem tswj hwm txoj hauv kev hauv lub cev hauv RA thiab tuaj yeem tsim cov tshuaj tiv thaiv kab mob sib txawv los ntawm qee yam tseem ceeb (piv txwv li, MAPK, interleukins (ILs 1 thiab 6), qog necrosis factor (TNF), nuclear factor light k chain promoter of activated receptor (NF- KB), thiab c-Jun N-terminal kinases(JNK)). Lub luag haujlwm tseem ceeb ntawm Tol-like-receptor (TLR)-dependent mitogen-activating protein kinase (MAPK) taw qhia txoj hauv kev hauv kev kho cov kab mob pathogenic ntawm RA tau tham luv luv. Oxidative kev nyuaj siab tuaj yeem ua rau muaj kev hloov pauv hauv cov txheej txheem hloov pauv, uas ua rau muaj qhov sib txawv ntawm qee cov noob uas koom nrog hauv cov txheej txheem inflammatory. Qhov kev tshuaj xyuas no yog txhawm rau muab cov kev xav dav dav ntawm kev ua tau zoo ntawm polyphenols hauv kev txo qis RA los ntawm kev cuam tshuam cov kev taw qhia, qhia txog kev tshawb fawb yav tom ntej txhawm rau txheeb xyuas lawv cov kev siv.
Thov nias ntawm no kom paub ntxiv
Ntsiab lus:mob caj dab rheumatoid; TLR/MAPK; flavonoids; stilbenes; interleukin; TNF; oxidative
1. Taw qhia
Rheumatoid mob caj dab (RA) yog ib lub sij hawm ntev, autoimmune, thiab inflammatory kab mob uas feem ntau cuam tshuam rau cov pob qij txha synovial, uas ua rau cov pob txha thiab pob txha puas tsuaj raws li RA nce] 1]. Antibodies (xws li anti-citrullinated protein antibodies (ACPA) thiab rheumatoid factor (RF)) tau kuaj pom hauv ntau tus neeg mob RA. Nws txo cov neeg mob lub peev xwm ua haujlwm thaum nce kev tuag thiab kev mob morbidity piv [2]. Cov poj niam muaj kev cuam tshuam ntau dua li cov txiv neej. Kev tswj hwm tus nqi yog 1 feem pua ntawm cov pej xeem thoob ntiaj teb. Raws li ntawm 2015, nws kwv yees tias RA cuam tshuam txog 24.5 lab tus tib neeg. Tus lej no suav nrog 0.5 txog 1 feem pua ntawm cov neeg laus hauv lub ntiaj teb tsim, nrog 5 txog 50 rau 100,000 cov neeg mob tshiab tau ntxiv txhua xyoo [3,4]. Tus kab mob etiology thiab pathogenesis tseem tsis tau paub. Kev sib cuam tshuam ntawm ntau yam, suav nrog kev tsim los ntawm cov noob caj noob ces thiab lub ntuj tsim, ua rau muaj kev hloov pauv tsis raug ntawm lub cev tiv thaiv kab mob thiab cov txheej txheem o uas ua rau lub synovial membrane puas. Ntau qhov kev piav qhia tau raug npaj thaum tsis muaj kev nkag siab tiav ntawm cov txheej txheem pathophysiological hauv qab RA. Cov kab mob tiv thaiv kab mob tau pom tias tshwm sim ntau xyoo ua ntej qhov tshwm sim ntawm cov tsos mob thiab cov tsos mob, ib lub sij hawm hu ua pre-RA theem [5].
Kev sib cuam tshuam ntawm cov caj ces tseem ceeb (protein tyrosine phosphatase non-receptor type 22, interleukin -6 receptor, qog necrosis factor receptor-associated factor-1, signal transducer thiab activator of transcription 4, peptidyl arginine deiminase 4, CC chemokine ligand 21, DNA methylation hloov, Fc gamma receptor, loj histocompatibility complex cheeb tsam encoding tib neeg leukocyte antigen (HLA) proteins) thiab ib puag ncig yam (cua pa phem, ua hauj lwm plua plav, haus luam yeeb, plab microbiota, noj unbalanced noj, thiab lwm yam) tuaj yeem ua rau Hloov kho tus kheej-antigens los ntawm cov txheej txheem hu ua citrullination [6]. Tsis tas li ntawd, lub cev tiv thaiv kab mob tsis tuaj yeem paub txog citrullinated proteins li tus kheej cov qauv. Antigen-presenting cells raug txhawb los tsim cov tshuaj tiv thaiv kab mob thiab nqa cov hloov kho tus kheej-antigens rau hauv cov qog ntshav. Nyob rau theem no, kev ua kom cov T hlwb tshwm sim, uas yuav ua rau kom B hlwb los ntawm costimulation. Tom qab qee cov txheej txheem ntawm hypermutation thiab chav kawm-hloov recombination, B hlwb pib proliferate thiab sib txawv rau hauv plasma hlwb uas tsim autoantibodies (RF, ACPA, thiab lwm yam), nyob ntawm seb lub cellular precursors [5]. RF thiab ACPA yog cov proteins uas tsim los ntawm lub cev tiv thaiv kab mob uas tsis muaj peev xwm paub qhov txawv ntawm tus kheej thiab cov qauv tsis yog tus kheej, yog li qhov no cov ntaub so ntswg thiab lub cev tuaj yeem ua lub hom phiaj los ntawm kev sib tsoo [7].
Kev ua kom cov tsos mob RA tsis ua tiav, tab sis cov txheej txheem tiv thaiv kab mob tuaj yeem tshwm sim ob qho tib si hauv synovium thiab hauv cov kua dej synovial. Ib qho ntawm cov txheej txheem zoo tshaj plaws piav qhia hauv synovium yog cytokine tso tawm (I-1, IL-6, TNF- ) los ntawm macrophages thiab plasma hlwb uas tuaj yeem ua rau stimulation ntawm osteoclast kev ua thiab kev tsim cov matrix. metalloproteinase (MMP), cov txheej txheem uas tuaj yeem ua rau pob txha yaig thiab pob txha mos. Tsis tas li ntawd, neutrophils thiab lub cev tiv thaiv kab mob muaj nyob rau hauv cov kua dej synovial kuj yog lub luag haujlwm rau pob txha mos thiab pob txha puas tsuaj los ntawm kev ua ntawm MMP, ntxiv rau, thiab cov pa oxygen reactive (ROS) [5,8]. ROS tau suav hais tias yog tus neeg koom nrog tseem ceeb hauv cov txheej txheem no [9].
Feem ntau hom radical tsim los ntawm cov kab ke nyob yog ROS. Cov superoxide radical (O2), peroxyl radical (ROO), per hydroxyl radical (HO,), thiab hydroxyl radical (OH) yog oxygen-derived radicals, nrog rau hom tsis-dawb radicals xws li hydrogen peroxide (H2O2) thiab singlet. oxygen (O2). Peb qhov tseem ceeb tshaj plaws reactive nitrogen hom (RNS) yog nitric oxide (NO), nitrogen dioxide (NO2), thiab peroxy-nitrite (OONO) [10]. Atoms thiab cov ntsiab lus nrog ib los yog ntau dua unpaired electrons nyob rau hauv lub deb tshaj orbital plhaub yog hu ua dawb radicals [11].
Cistanche tuaj yeem txhim kho kev tiv thaiv
Lawv tsis khov kho, ua rau muaj kev cuam tshuam zoo, thiab kav ntev rau lub sijhawm txwv. Cov dawb radicals tuaj yeem rub cov electrons los ntawm cov khoom sib txawv kom tau txais kev cia siab; Raws li cov tshuaj tiv thaiv, cov atoms raug xaiv poob lawv cov electrons thiab dhau los ua dawb radicals, ua rau cov lus teb. ROS yog qhov tseem ceeb rau kev ua raws li cov cell 'redox tej yam kev mob thiab koom nrog cell flag-ging, sib cais, nthuav, kev loj hlob, demise, cytoskeletal tswj, thiab phagocytosis. Txawm li cas los xij, yog tias ROS fixations hla cov qib khoom, lawv tuaj yeem ua mob rau cov kab mob ntawm tes xws li fatty acids thiab phospholipids hauv cov cell membrane (chains ntawm amino acids thiab nucleic acids).Ntawm lub caij nyoog uas ib qho xwm txheej ua rau muaj qhov tsis sib xws ntawm oxidants thiab antioxidants, preferring oxidants, redox chij yog cuam tshuam, nqa txog kev hloov pauv raws li kev puas tsuaj rau sub-atomic. Lub xeev cellular hu ua oxidative kev nyuaj siab tuaj yeem tshwm sim los ntawm kev nplua nuj ntawm oxidants, tsis muaj antioxidants, lossis kev sib xyaw ntawm ob [12].
Antioxidants tiv thaiv kev puas tsuaj ntawm cov dawb radicals. Antioxidants yog ib qho molecules uas muaj peev xwm tshem tawm cov dawb radicals los yog cuam tshuam oxidation kev sib cuam tshuam hauv hlwb [13]. Superoxide dismutase-(SOD), catalase-(CAT), thiab glutathione (GSH)-hais txog cov tshuaj muaj feem xyuam rau cov kab mob enzymatic tswj kev mob qog noj ntshav, glutathione peroxidase (GPx), glutathione reductase (GR), thiab thioredoxin reductase ( TR). Qhov kev tiv thaiv tseem ceeb tshaj plaws rau cov lus teb tsis yog enzymatic cell antioxidant yog carotene, uas tseem yuav tsum tau kho tus kab mob, lossis tiv thaiv cov zaub mov (tooj liab, ferritin, zinc, manganese, thiab selenium), nrog rau L-glutamyl-cysteyl glycine |14 ].
Ib qho ntawm cov teeb meem uas ua rau oxidative kev nyuaj siab hauv RA. Ib qho kev nthuav dav tsib zaug hauv lub zog ntawm lub xov tooj ntawm tes ROS raug ntxias hauv cov neeg mob cov ntshav thiab cov monocytes, sib piv nrog kev noj qab haus huv, qhia tau hais tias oxidative siab yog ib qho kab mob ntawm cov kab mob. Raws li cov dawb radicals ua lub luag haujlwm tseem ceeb raws li cov tub txib theem nrab hauv kev txhawb nqa thiab cov lus teb ntawm lub cev tiv thaiv kab mob, lawv tau koom nrog kev sib koom ua ke [15]. T hlwb raug rau qib siab heev ntawm oxidative kev nyuaj siab dhau los ua rau ntau yam teeb meem, suav nrog cov uas tswj kev loj hlob thiab kev tuag, uas yuav pab tswj lub cev tsis muaj zog. Tib lub sijhawm, cov dawb radicals ncaj qha cuam tshuam rau pob txha mos los ntawm kev tsom nws cov proteoglycan thiab los ntawm kev txo thiab txo nws cov synthesis [16].
Nyob rau hauv RA, oxidative kev puas tsuaj rau hyaluronic corrosive thiab lipoperoxidation tshwm sim, oxidation ntawm low-thickness lipoprotein, thiab carbonyl expansion coj los ntawm protein oxidants, raws li zoo raws li DNA puas, tau tag nrho cov tau qhia. ROS-actuated genotoxic txheej xwm kuj tau txuam nrog kev hloov pauv ntawm p53 hauv RA-inferred fibroblast-zoo li synoviocytes[17I. Tsis tas li ntawd, cov txheej txheem ntawm tes txhawb zog, yog tias enzymatic, tau pom zoo kom muaj kev cuam tshuam hauv RA. Txo GR thiab SOD zog, nrog rau qis GSH tocopherols, beta-carotene, thiab retinol qib, tag nrho txuas nrog [18].
Qhov kev txhim kho hauv cov kab mob siab hauv RA pob qij txha tau xav tias yog qhov ua rau muaj kev pheej hmoo oxidative siab nyob rau hauv RA synovial daim nyias nyias vim nws nce ROS tiam nyob rau hauv cell oxidative phosphorylation thiab tsim tas li hypoxia / reoxygenation cycles. Hypoxia yog ib qho tshwm sim pom nyob rau hauv RA pob qij txha uas tau raug ntaus nqi rau cov tshuaj tiv thaiv kab mob ceev cell multiplication; nyob rau hauv txhua rooj plaub, xav txog cov ntaub ntawv cov ntaub ntawv, hypoxia tshwm sim ua ntej irritation, qhov tseem ceeb nyob rau hauv ib tug tsiaj arthritic qauv [19]. Cov tsos mob tshwm sim no tshwm sim hauv tib neeg mob, raws li "Risk Model", uas lub synoviocyte yog lub cell puas [20]. Thaum lub sij hawm oxidative tawg, enacted los ntawm phagocytic hlwb, oxidative kev nyuaj siab kuj yuav nce. Kev haus luam yeeb, tshuaj yeeb, thiab UV teeb tuaj yeem cuam tshuam tus kab mob. Cov oxidant sib txawv los yog kev tiv thaiv kab mob qog noj ntshav tau siv los tshawb txog kev koom tes ntawm oxidative stress thiab RA. Fatty acids, phospholipids, chains of amino acids, genomic alteration, and oxidation markers, as well as the step of enzyme action, cancer tiv thaiv kab mob, thiab kev kwv yees ncaj qha ntawm cov dawb radicals, yog cov piv txwv ntawm biomarkers [21].
Polyphenols yog tej yam ntuj tso extracts, pom nyob rau hauv tej qhov chaw ntawm cov nroj tsuag (txiv hmab txiv ntoo, cov hauv paus hniav, nplooj), nrog zoo-paub piv txwv yog txiv apples, berries, citrus txiv hmab txiv ntoo, broccoli, cocoa, tshuaj yej, thiab kas fes. Cov nroj tsuag-raws li cov tebchaw no muaj ntau yam kev ua ub no [22], nrog rau cov qauv tshuaj ntawm cov tebchaw no pom tseeb hais txog lawv cov dej num / kev ua, ob qho tib si hauv vitro thiab hauv vivo [23]. Tsis tas li ntawd, los ntawm kev ntsuam xyuas kev ua haujlwm lom neeg ntawm cov natural polyphenolic tebchaw, cov txiaj ntsig zoo tau pom nyob rau hauv kev tiv thaiv thiab kev kho mob ntawm hnub nyoog, kev puas tsuaj ntawm daim tawv nqaij, kab mob, malignancies, thiab kab mob plawv, tab sis lawv muaj peev xwm siv tau hauv kev tswj hwm ntawm RA yog. muab los ntawm lawv cov antioxidant thiab anti-inflammatory kev ua. Cov tshuaj tiv thaiv antioxidant ntawm polyphenols tau raug tshawb fawb ntau, suav nrog kev tshem tawm dawb radicals, txo qis hauv hydroperoxide ntau lawm, thiab kev tawm tsam ntawm lipid oxidation [24].
Ib txoj kev tshawb fawb hla dhau los ntsuas qhov muaj peev xwm antioxidant ntawm cov tshuaj yej ntsuab ntawm qhov sib txawv polyphenol ntau ntau thiab pom muaj kev sib raug zoo ntawm cov ntsiab lus antioxidant ntawm cov tshuaj yej ntsuab thiab cov antioxidant muaj peev xwm ntawm cov ntshav [25].
Kev tsim kho thev naus laus zis thiab kev kho mob tau muab kev nkag siab zoo dua ntawm kev sib cuam tshuam ntawm ntau yam polyphenols nrog rau txoj hauv kev ntawm inflammatory teb. Polyphenols muaj cov tshuaj tiv thaiv kab mob vim muaj ntau lub tswv yim, raws li hauv qab no: ● Kev tswj ntawm cyclooxygenase-2 kev ua;
Inhibition ntawm eicosanoid-generating enzymes (phospholipase A2 thiab cyclooxygenase);
● Kev txwv tsis pub tso tawm;
● Kev tswj ntawm cytokines;
● Inhibition ntawm NF-kB;
● Kev cai ntawm MAPK txoj kev [24].
Polyphenols tau muab faib ua plaub pawg zoo, raws li hauv qab no: phenolic acids, flavonoids, stilbenes, thiab lignans.
Txoj kev tshawb fawb tam sim no tsom rau kev soj ntsuam cov txiaj ntsig ntuj ntawm flavonoids, phenolic acids, stilbenes, thiab lwm yam phenolic tebchaw uas tau kawm txog lawv cov tshuaj tiv thaiv kab mob thiab antioxidant tiv thaiv RA. Oxidative stress thiab o nyob rau hauv cov ntaub so ntswg synovial yog txuam nrog kev loj hlob thiab mob hnyav ntawm tus kab mob no, kuj qhia los ntawm cov tsiaj qauv nrog osteoarthritis (OA). Cov ntaub ntawv tam sim no qhia tau hais tias polyphenols (xws li quercetin, rutin, morin, thiab lwm yam) qhia txog kev cuam tshuam ntawm cov hlwb uas cuam tshuam nrog kev mob, qhia lawv cov peev xwm siv hauv kev kho RA kev kho mob.
2. Pathogenesis ntawm Rheumatoid Arthritis
Ntau qhov kev tshawb nrhiav tau qhia txog lub luag haujlwm ntawm ROS hauv kev loj hlob ntawm cov kab mob o nyob rau hauv lub sij hawm ntev arthropathies xws li RA9. Raws li qhov tshwm sim, tau txais kev paub zoo dua ntawm kev sib cuam tshuam nyuaj thoob plaws txoj hauv kev no tuaj yeem pab txhim kho kev kho RA tshiab thiab txoj hauv kev siv tshuaj.
RA tsim ROS los ntawm ob lub ntsiab mechanisms: active polymorphonuclear hlwb (PMNs) thiab cell-necrosis nyob rau hauv ib qho kev sib koom ua ke. Lipid peroxidation tshwm sim yog tias cov hom reactive no tsis khawb. Polyunsaturated thiab unsaturated fats tau oxidized thaum lub sij hawm lipid peroxidation kom zoo li lipid peroxyl revolutionaries, uas tom qab ntawd, nyob rau hauv tas li ntawd mus rau lub ntxiv oxidation ntawm polyunsaturated thiab unsaturated fats, tej zaum yuav ua rau kev puas tsuaj rau lub cell membrane. Lipoperoxidation cov khoom tau pom tias ua rau oxidative puas hauv RA synovial kua thiab cov ntaub so ntswg. Hauv plasma ntawm RA cov neeg mob tau tshawb pom qhov muaj txiaj ntsig zoo tshaj plaws ntawm superoxide anions revolutionaries thiab HO Extended SOD kev ua haujlwm zoo li yuav txiav txim siab superoxide anion revolutionaries hauv plasma los tsim hydrogen peroxide. Ntxiv mus, CAT lossis glutathione detoxification ntawm H2O2 tsis pom [26]. Kev nce ntshav lipid peroxidation hauv tib neeg tuaj yeem ua tiav los ntawm hydrogen peroxide hloov mus rau hydroxyl los ntawm hlau vim txo qis cov qib hloov pauv. Nyob rau hauv cov xwm txheej ib txwm muaj, nitric oxide (NO) tau qhia los hloov T cell kev ua ub no, thaum ntau dhau NO tiam yuav suav nrog T lymphocyte malfunction [27,28]. plasma NO qib hauv cov neeg mob RA tau sib txawv heev piv rau cov kev tswj hauv txoj kev tshawb fawb. Raws li tsis muaj, muaj cov khoom tsis zoo txuas nrog GSH, uas yuav tsum tau them nyiaj rau qhov cuam tshuam ntawm intracellular non-enzymatic antioxidative cycles vim lawv cov lus teb rau nce NO2 tiam [29].
Ob peb qhov kev ntsuam xyuas hauv cov neeg mob RA tau pom cov cim qhia ntawm kev sib txuas endogenous ntxiv, tawm tswv yim tias TSIS MUAJ ntau dhau tuaj yeem suav tias yog ib feem ntawm cov kab mob ntawm cov kab mob. Qhov chaw tseem ceeb ntawm NO hauv RA yog qhov sib koom ua ke [21]. Ntau tus kws tshawb fawb pom tau tias muaj kev sib koom ua ke ntawm cov ntsiab lus ntawm cov ntshav nitrite thiab RA kev mob nkeeg lossis kev puas tsuaj rau hluav taws xob, thaum lwm tus tsis ua. Hauv cov neeg uas muaj RA, kev sib txuas ntawm cov kab mob ua haujlwm thiab muaj cov oxidative kev nyuaj siab tau hais txog [30]. Cov kws tshuaj ntsuam sib txawv tau pom tias tsis muaj qhov cuam tshuam loj heev ntawm kev ua haujlwm ntawm tus kab mob thiab muaj oxidative siab hauv cov neeg mob RA. Txhawm rau tiv thaiv cov kab mob organic los ntawm oxidative raug mob, ntau yam kev tiv thaiv tau tshwm sim. Kev sib txuas ntawm erythrocyte SOD thiab RA tsis paub meej [21].
3. Polyphenols thiab Rheumatoid Arthritis
Polyphenols ua rau peb txoj hauv kev kom qeeb zog ntawm RA: txoj kev o, oxidative, thiab apoptotic pathways. Polyphenols muaj feem cuam tshuam rau cov kab mob o los ntawm MAPK taug qab thiab cov lus qhia ntawm NFATC1 zoo hauv osteoblasts. MAPK, ILs 1 thiab 6, TNF-, NF-kB, JNK, extracellular signal-directed kinase (ERK1/2), activator protein-1(AP-1), thiab COX-2 sawv cev ib feem ntawm cov khoom tseem ceeb cuam tshuam nrog cov txheej txheem no [31].
3.1. Phenolic Acids
Cov yam ntxwv phenolic acids yog hydroxybenzoic thiab hydroxycinnamic acids. Phenolic acids suav txog ze li ntawm 33 feem pua ntawm cov tshuaj polyphenolic hauv peb cov khoom noj thiab tuaj yeem pom muaj nyob rau hauv txhua yam-natural cog tshuaj; Txawm li cas los xij, lawv muaj ntau nyob rau hauv cov khoom muaj tshuaj lom. Ib txwm phenolic acids suav nrog caffeic corrosive, gallic corrosive, thiab corrosive. Phenolic acids muaj kev ua phem rau RA. Thaum cov nas monocytes thiab macrophage hlwb raug nthuav tawm ua ntej nees nkaum plaub teev rau ferulic corrosive, uas tau pom nyob rau hauv cov nplej thiab zaub, cov khoom ntuj, thiab txiv ntseej, lawv cuam tshuam cov yam ntxwv ntawm atomic activated T cell C1 (NFATc1), c-Fos. , NF-kB, Tartrate-safe corrosive phosphatase, network matrix metalloproteinases (MMP)-9, thiab cathepsins [32]. Hauv cov nas mob caj dab 'lub siab thiab cov hlwb poov xab yog N-feruloyl serotonin (Nf-5HT), lub ntuj polyphenol tau los ntawm Leuzea carthamoides, inhibited C-reactive proteins (CRP), 12/15-lipoxygenases (LOX ), TNF- , empirical NO synthase (iNOS), thiab IL-1. Txoj kev tshawb no ua haujlwm 3 mg / kg ntawm Nf-5HT thiab kav 28 hnub [33]. Chlorogenic acid los ntawm Gardenia jiasminoides inhibited p38, extracellular signals-directed kinase (ERK), thiab phosphorylation, thiab pib T cell yield ntawm mRNA yam ntxwv (NFATcl). Ib yam li ntawd, rau 4 hnub, thaum kaum, nees nkaum-tsib, lossis tsib caug g / mM ntawm CGA tau muab rau cov pob txha macrophages (BMMs), lipopolysaccharide-induced (LPS) pob txha tawg tau txais kev txhawb nqa hauv vivo [34].
TNF- x, IL-1, thiab IL-6 yog cov cytokines pro-inflammatory cytokines koom nrog kev tswj hwm lub cev tiv thaiv kab mob hauv RA thiab txuas rau cov txheej txheem inflammatory thiab txhawb kev ua haujlwm ntawm osteoclast. Mitogen-activated protein kinases (MAPK) muaj lub luag haujlwm tseem ceeb hauv kev tswj kev tsim cov cytokines pro-inflammatory, ua rau kev sib koom ua ke thiab kev puas tsuaj [35]. Vim lawv txoj kev koom tes hauv ntau yam txheej txheem pathophysiological, lawv tau dhau los ua lub hom phiaj kho mob rau kev kho mob ntawm RA. TNF- x (etanercept, infliximab, golimumab, adalimumab, certolizumab pegol), IL-1(anakinra, canakinumab, gevokizumab), thiab IL-6 inhibitors (tocilizumab, sarilumab, elotuzumab muaj nyob rau hauv biologically active tshuaj) lub khw muag tshuaj rau kev kho mob ntawm RA. Tsis tas li ntawd, p38 MAPKis lub hom phiaj zoo rau ntau tus neeg ua haujlwm kho mob uas nyob rau theem thib ob ntawm kev sim [36].
Lub receptor activator ntawm nuclear yam kappa-B-ligand (RANKL) thiab Thrombin receptor-activating peptide (TRAP) receptors txhawb cov inflammatory cytokines IL-1b, IL-6, IL-17, thiab cov iNOS(COX-2) txhawb cov synthesis ntawm cov tebchaw thiab NF-kB-p65, p-NF-kB-p65, NFATc-1, c-Fos, thiab NF-KB-p65, thiab NF-kB-NF-kB-p65 [37]. Cov qauv tshuaj ntawm ob peb phenolic acids tau nthuav tawm hauv daim duab 1.
3.2. Stilbenes
Cov stilbenes, 1, 2-diphenylethylene, tau faib ua ob hom: Trans isomers yog (E)-stilbenes, thaum cis isomers yog (Z)-stilbenes [38]. Stilbene yog ib qho polyphenol uas muaj kev tiv thaiv kab mob, cell ciaj sia, thiab antioxidant zog. Qhov tseem ceeb tshaj plaws ntawm saum toj no 400 ntuj stilbenes yog resveratrol (RSV). RSV tsis ntev los no tau raug txheeb xyuas tias yog ib qho kev xaiv kho mob tshiab rau kev tiv thaiv kab mob hauv tus nas qauv ntawm collagen-induced mob caj dab. Ntxiv mus, pib los ntawm cov txiaj ntsig no, kev sim tshuaj kho mob tau tsim los ua kom pom cov txiaj ntsig zoo ntawm RSV rau cov neeg mob RA.
Kev sim tshuaj ntsuam xyuas randomized suav nrog 100 tus neeg mob RA tau pom tias ntxiv RSV ua ib qho ntxiv rau cov tshuaj antirheumatic (leflunomide, hydroxychloroquine, sulfasalazine, methotrexate) tseem ceeb txhim kho cov txiaj ntsig ntawm kev kho mob (28 qhov sib koom ua ke) thiab biochemical markers. , TNF- , erythrocyte sedimentation tus nqi, IL-6), nrog rau cov qhab nia ntawm tus kab mob [39]. Qhov ua tau ntawm kev ua ntawm RSV muaj nyob rau hauv inhibition ntawm MAPK signaling txoj kev los ntawm kev txo ROS tsub zuj zuj, nrog rau kev txo qis ntawm hypoxia-inducible factor 1 (HIF-1)-mediated angiogenesis [40].
Fibroblast-zoo li synoviocytes (FLSs) yog cov hlwb tshwj xeeb nyob hauv cov synovium. Hauv cov ntsiab lus ntawm RA, FLSs tau qhib thiab tuaj yeem tsim MMP, tab sis kuj tuaj yeem txhawb nqa RANKL qhia, ua rau cov pob txha yaig thiab pob txha mos. Lub luag haujlwm tseem ceeb ntawm FLSs hauv cov kab mob ntawm RA thiab lawv cov kev cuam tshuam nrog lwm cov hlwb qhia tias cov cell hom tuaj yeem yog lub hom phiaj tshiab rau kev kho mob RA [41].
Glycolytic inhibitors tsis tsuas yog txo cov aggressive FLS phenotype tab sis kuj tiv thaiv cov ntaub so ntswg thiab pob txha mos nyob rau hauv ob peb qauv ntawm kev mob caj dab. Cov tshuaj tiv thaiv Beclin ib, LC3A / B, thiab manganese-subordinated superoxide dismutase (MnSOD), thiab txhawb MtROSs hauv FLSs ntawm reactive amyloids (AA) uas tau muab tshuaj ntawm tsib, kaum tsib, thiab plaub caug tsib mg / kg ntawm RSV. tshaj li ob lub lis piam [42].
Akt, p38 MAPK, ERK1/2, COX-2, prostaglandin E2 (PGE2), nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (ROS) [43], thiab NF-kB tau tag nrho suppressed hauv FLSs hauv tib neeg tom qab ib tug noj 50 g rau 24 teev. Hauv kev sim siv resveratrol ntawm koob tshuaj 6.25, 12.5, 25, thiab 50 μM ntawm tib neeg cov ntaub so ntswg, resveratrol tau zoo ib yam los ntawm kev hloov pauv IL-1, MMP-3, p-Akt, thiab PI3K - Kev [39]. Cov ntaub ntawv cov ntaub ntawv qhia tau hais tias qhov kev sim tshuaj ntsuam xyuas peb lub hlis twg tau ua nyob rau hauv uas tsib caug tus neeg mob tau muab 1 g RSV capsules. Kev kho RSV tau txais txiaj ntsig zoo hauv RA, raws li txoj kev tshawb no [39]. Swollen 28-joint suav (SJC-28), Kev sib tw 28-joint suav (TJC-28), CRP, erythrocyte sedimentation rate (ESR), uncarboxylated osteocalcin (UCOC), MMP -3, TNF, IL-6, thiab DAS28-ESR(Cov Kab Mob Kev Ua Si -28 rau Rheumatoid Arthritis nrog ESR) qib kuj txo qis [44].
Ntxiv mus, ntawm 20 mg / kg koob, RSV eased RA indications los ntawm downregulating immunoglobulins G (lgG1, IgG2a). Cov outflows ntawm I-17 thiab interferon (IFN)- tau txo qis tom qab kho nas cov qog ntshav qog ntshav (DLN) thiab Th cells nrog plaub caug M RSV rau 3 hnub. Infusions ntawm 30 M los yog 50 M rau 3 hnub stifled TH-17 thiab IL{10}} nyob rau hauv ib tug zoo xws li cell kab. Cov qauv tshuaj ntawm 1,2-diphenylmethane thiab resveratrol tau nthuav tawm hauv daim duab 2.
3.3. Flavonoids
Flavonoids yog ib hom polyphenol tsim los ntawm ob lub nplhaib phenyl koom ua ke rau hauv 15- cov qauv carbon. Tej zaum qhov tseem ceeb tshaj plaws flavonoids yog quercetin thiab epigallocatechin-3-gallate (EGCG), flavonoid pom intea. Cov qauv ntawm quercetin thiab epigallocatechin-3-gallate yog sawv cev hauv daim duab 3.
Cov tebchaw ntuj no muaj cov tshuaj tiv thaiv kab mob thiab ua siab phem rau cholinesterase thiab yog li siv los kho ntau yam kab mob. Kev noj zaub mov nplua nuj flavonoid, piv txwv li, tau txuas nrog kev pheej hmoo tsawg ntawm cov kab mob plawv [45]. Citrus flavonoids tuaj yeem cuam tshuam lipid metabolism thiab tuaj yeem siv los kho cov kab mob metabolic. Flavonoids'anti-inflammatory zog yog siv los txo cov yam ntxwv ntawm RA [46]. Thaum 3 mg rau 0.3 mL ntawm -glucosyl hesperidin tau muab peb zaug hauv ib lub lis piam rau 31 hnub rau collagen-induced mob caj dab (CIA) nas qauv, nws pom cov teebmeem los tiv thaiv RA los ntawm kev tswj cov qog necrosis ( TXF)[47,48]. EGCG, lub zog muaj zog los ntawm Camellia sinensis, muaj cov khoom tiv thaiv RA rau tib neeg rheumatoid pob qij txha mob aggravating synovial fibroblasts (RASF), thaum noj rau 12 h, los ntawm kev txo qis epithelial neutrophil-pib peptide (ENA)-78, Regulated raws li Kev ua kom muaj zog, Ib txwm T Cell nthuav tawm thiab xav tias zais zais (RANTES), thiab kev loj hlob-tswj oncogene (GRO)-IL-1-impelled MMP-2 [49]. Hauv tib neeg RA synovial fibroblasts (RASFs), EGCG ntau npaum li cas ntawm 125,250, thiab 500nM rau 24h inhibited cov synthesis ntawm MAPK, MMP-1, MMP-3, p-extracellular regulated kinases (ERK) 1/2, p-JNK, p-p38, thiab AP-1 (RASFs) [50].
Thaum CIA nas raug kho nrog 10 mg koob tshuaj rau txhua kg ntawm lub cev hnyav rau peb lub lis piam, IL-6, TNF, thiab interferon (IFN)- tau txwv, thaum tiv thaiv hom II collagen (CII) qhia meej IgG1 cov tshuaj tiv thaiv. tau qhib [51]. Kev txwv ntawm myeloperoxidase los ntawm EGCG ntawm kaum mg / kg rau tsib hnub tau pom cov antagonist ntawm RA cov txiaj ntsig hauv pristane-induced arthritis (PIA), myeloperoxidase (MPO) [52], CTR, carbonic anhydrase II, cathepsins K, alpha- thiab beta -integrins, thiab NF-ATcl tag nrho cov teb tsis zoo hauv tib neeg osteoclasts thiab nas tom qab 15 hnub ntawm kev kho mob ntawm 20 thiab 50 M [53].
3.4.Lwm cov khoom xyaw
Cov polyphenols sib txawv tau raug tshuaj xyuas zoo ib yam vim lawv cov khoom sib txawv ntawm RA. Ntxiv virgin txiv roj roj (EVOO) polyphenol, uas tau muab rho tawm los ntawm cov roj nkauj xwb, inhibit RA hauv cov nas uas muaj collagen-induced mob caj dab (CIA). EVOOpolyphenols
tau induced li 2 lub lis piam los ntawm downregulating TNF-, IL-1, IL-6, pEG2. P38, INK, thiab P65[54,55]. Lwm lub tswv yim los nthuav CA bioavailability yog los ntawm kev tsim CM-stacked Ns (CM-Ns). Lawv kuj tau siv peb pawg tshawb nrhiav sib txawv thiab ib pab pawg ntsuas los npaj rau lawv qhov kev sim siab. Txawm li cas los xij, tsis muaj kev ntsuam xyuas ntawm cov khoom siv hauv qab atomic ntawm CM-N antagonist ntawm RA teebmeem [56]. Lwm txoj kev tshawb fawb tau tshuaj xyuas seb emodin cuam tshuam li cas rau txoj hauv kev apoptotic, tsom mus rau B-cell lymphoma protein 2 (Bcl-2)-koom nrog X (Bax) irregularity thiab caspase 3 thiab caspase 9 pib [57].
Polyphenols ua lub luag haujlwm tseem ceeb hauv kev txo cov tsos mob RA. Txawm li cas los xij, oxidative, thiab apoptotic systems tsis tau tham ntau hauv kev tshawb fawb. Polyphenols 'cov khoom tiv thaiv RA feem ntau tau kawm txog cov kab mob inflammatory. Ob peb txoj kev tshawb fawb tsom mus rau polyphenols 'cov tshuaj tiv thaiv oxidative thiab apoptotic, uas txo cov tsos mob RA, tab sis lawv muaj tsawg. Kev tshawb nrhiav ntxiv yuav tsum nkag siab txog cov kab ke atomic ntawm polyphenols antioxidative thiab apoptotic kev ua ub no hauv RA pathogenic pathways [58]. 4. Cog Polyphenols Targeting Oxidative Stress thiab Inflammation
Polyphenols yog cov metabolites tsim los ntawm cov nroj tsuag, nrog rau cov khoom organic, nplooj, thiab tawv ntoo. Polyphenols muaj ntau nyob rau hauv ntau yam khoom ntuj tsim (txiv hmab txiv ntoo, cherries, txiv apples, pomegranates, thiab txiv kab ntxwv) [59], spices, thiab flavors. Anti-inflammatory thiab antioxidant teebmeem, nrog rau kev tiv thaiv tus neeg sawv cev cuam tshuam, yog siv los ntawm cov tshuaj no. Polyphenols 'cov khoom antioxidant yog nyob ntawm lub peev xwm txhawm rau txhawm rau ROS molecules, suppress prooxidant gene qhia hauv articulation, thiab ua ntej cov lus ntawm cov noob caj noob ces antioxidant xws li SODs thiab catalases [60,61].
Lawv kuj pom cov khoom tiv thaiv kab mob uas yog nyob ntawm lawv lub peev xwm los tiv thaiv cov kab mob tiv thaiv kab mob xws li (MAPK), AP-1, thiab NF-kB. Ntau qhov kev sim tau pom tias cov tshuaj polyphenolic, feem ntau paub txog lawv cov tshuaj tiv thaiv kab mob antioxidant thiab tiv thaiv kab mob, tuaj yeem pab tiv thaiv OA [61-63]. Ntau cov polyphenols tau kawm hauv vitro thiab hauv vivo qauv ntawm OA, suav nrog pomegranate extracts, Butlin, ntsuab tshuaj yej polyphenol, EGCG, resveratrol, wogonin, quercetin, harpagoside, curcumin, morin, thiab lwm yam Nws tsis ntev los no pom tau tias Butein, chalcone- nplua nuj concentrate ntawm Butea monosperma blossoms, ib yam li unadulterated Butein, muaj cov yam ntxwv tseem ceeb ntawm kev tiv thaiv kabmob kheesxaws thiab ua rau muaj kev tsim txom ntawm IL-rau thiab metalloproteases hauv chondrocytes los ntawm kev nthuav dav autophagy los ntawm kev ua kom muaj protein ntau kinase (AMPK) / mTOR signaling pathway [62]. Butein enacts AMPK los ntawm kev nthuav cov phosphorylation ntawm AMPKThr172 thiab cuam tshuam mTOR txav los ntawm kev txo cov phosphorylation ntawm MTORSer-2448 [63].
Tsis tas li ntawd, nws tau pom tias kev sib sau ua ke ntawm Scutellaria baicalensis nrog cov ntshiab wogonins txwv kev tawm ntawm IL-6, COX-2, iNOS, thiab metalloproteases teem tawm los ntawm IL-1, nrog rau kev txhim kho ntawm PGE2 thiab NO. Hauv cov tib neeg tseem ceeb chondrocytes, wogonins pab lub zog ntawm Nrf2, tus kws tshaj lij cov ntaub ntawv tswj hwm ntawm cov tshuaj tiv thaiv antioxidant, vim tias kev tsim HO1 muaj kev tiv thaiv los ntawm IL-1-induced oxidative stress [64]. Harpagoside, ib qho iridoid, cem IL-1, induced tsim MMP-13 thiab ib tug loj tus naj npawb ntawm pro-inflammatory cytokines thiab chemokines, nrog rau IL-6, nyob rau hauv lub tseem ceeb tib neeg OA chondrocytes los ntawm kev txwv. lub cFos/AP-1 txoj kev taw qhia, uas tsis pub dawb ntawm c-Jun thiab NF-kB txoj hauv kev [65]. Harpagoside, thaum ua ke nrog glucosamine hydrochloride, chondroitin sulfate, methyl sulfonyl methane, thiab bromelain extracts, suppressed zus tau tej cov IL-1 thiab TNF-a nyob rau hauv ib tug formalin-induced nas OA qauv]66).
Curcumin, ib qho phenylpropanoid thiab lub ntsiab tseem ceeb ntawm turmeric, muaj ib qho qab ntxiag tsw, nrog rau cov yam ntxwv los tiv thaiv kab mob uas tau piav qhia. Curcumin thiab resveratrol yog qee cov npe nrov tshaj plaws uas paub txog lawv cov tshuaj tiv thaiv kab mob thiab tshuaj kho mob, kuj qhia txog ntau yam kev taw qhia molecule lub hom phiaj ua haujlwm ntawm qib cellular uas txhawb OA thiab RA pathogeneses. TNF- yog lub luag haujlwm tseem ceeb hauv OA thiab RA thiab cov nyhuv no tau tswj hwm los ntawm kev ua kom NF-kB. Txawm hais tias, TNF- paub tias yog lub zog tseem ceeb NF-kB activator [67-69]. Curcumin's chondroprotective txav tau raug qhia nyob rau hauv ntau yam hauv vitro thiab hauv vivo kev tshuaj xyuas siv chondrocytes, pob txha pob txha, thiab ntau hom tsiaj qauv [70-72]. Kev tswj hwm qhov ncauj ntawm curcumin thiab tetrahydro-curcumin txo qis kev tsim tawm ntawm IL-1, IL-rau, thiab metalloprotease hauv nas thiab nas qauv ntawm kev sim OA, thaum tseem txo qhov mob thiab pob txha mos degeneration [71]. Enzymatically altered curcumin txo qhov mob thiab ua rau lub sijhawm OA nyob rau hauv ib qho kev sib hloov ntawm lub cev (ACLT)-induced OA hauv cov qauv luav [73]. Ferulic acid (FA) [74], curcumin derivative pom nyob rau hauv lub cell faib ntawm cov nroj tsuag sib txawv, uas muaj xws li oats, mov, thiab txiv kab ntxwv thiab txiv apple noob, muaj anti-inflammatory thiab antioxidant yam ntxwv thiab tau pom tias inhibit TNF thiab IL{ {16}} qhia thaum raug H2O2[75]. Resveratrol tau pom tias txo qis cov kab mob [76].
Resveratrol (trans-3,4',5-trihydroxystilbene) feem ntau pom muaj nyob rau hauv daim tawv nqaij thiab cawv txiv hmab, txiv laum huab xeeb, pistachios, blueberries, mulberries, cocoa thiab chocolate, soy, thiab lwm yam. Cov lus qhia ntawm iNOS thiab TSIS MUAJ. nyob rau hauv Artesunate attenuates (ACLT) OA bunnies tau ploj zuj zus los ntawm intra-articular resveratrol infusions [77]. Hauv cov nas nrog kev sim OA, resveratrol txo qis kev qhia ntawm IL-1, TNF- , thiab IL6. Resveratrol repressed NF-kB thiab AP1 signaling pathways [78], uas txo AGE-instigated creation ntawm iNOS, COX-2, thiab MMP-13 hauv chondrocytes [79]. Resveratrol enacted SIRT1 nyob rau hauv chondrocytes repressed NF-kB pib thiab txo qis IL-1-activated iNOS creation nyob rau hauv tib neeg chondrocytes [80]. Cov roj txiv roj muaj ntau hauv polyphenols thiab tau noj tsis tu ncua hauv Mediterranean noj [81,82]. Cov roj txiv roj tau pom tias ua haujlwm ntawm kev noj qab haus huv sib koom ua ke thiab muaj peev xwm hauv ob peb hauv vitro thiab hauv vivo kuaj. Cov polyphenol hydroxytyrosol nyob rau hauv cov roj txiv roj activates autophagy thiab nres chondrocyte mortality [83].Nyob rau hauv ib tug nas qauv ntawm ACLT-prompted OA, lub qhov ncauj nkag ntawm ib tug nkauj xwb txiv roj roj nplua nuj noj regimen muaj mitigating cuam tshuam, txo qis IL-6 articulation , thiab nthuav lubricin articulation [84,85]. Txoj kev tshawb fawb tam sim no thiab lwm yam kev tshawb fawb rov qab siv cov txiv ntseej roj nplua nuj noj zaub mov raws li kev xaiv siv tau los tswj kev noj qab haus huv sib koom ua haujlwm [83-85].
Ntxiv nrog rau cov nroj tsuag rho tawm cov ntsiab lus tau tham saum toj no, ob peb ntxiv polyphenols tau pom tias txo qis oxidative siab thiab ua rau hnyav dua hauv chondrocytes, ib yam li hauv OA pathogenesis. Imperatorin (ib qho metabolite thib ob pom hauv Apiaceae thiab Rutaceae tsev neeg cov nroj tsuag) tau pom tias txwv iNOS articulation thiab TSIS muaj hnub nyoog los ntawm kev txwv ERK1/2-AP1(cFos/cJun) txoj kev[86l; nws txuas rau iNOS thiab inhibits nws qhov kev ua, raws li kev tshawb fawb tshawb pom [87].
Genistein, ib qho isoflavone, txo COX-2, iNOS, thiab tsis muaj tiam hauv chondrocytes tom qab kis LPS thiab IL-1 hauv kev tshawb nrhiav hauv vitro. Hauv monosodium iodoacetate (MIA)-induced OA nyob rau hauv nas, ib qho aqueous extract ntawm Java tshuaj yej (Orthsiphonstamineus) txo o thiab txo qhov hnyav ntawm OA hauv pob txha explants [88,89].
Txiv roj roj thiab txiv hmab txiv ntoo extracts siab nyob rau hauv hydroxytyrosol thiab procyanidins (HT / PCy) inhibited zus tau tej cov iNOS, COX-2, thiab metalloproteases nyob rau hauv chondrocytes triggered nrog IL-1 thiab tso tawm chondroprotective teebmeem nyob rau hauv post-traumatic OA qauv nyob rau hauv nas thiab luav [90] Hauv vivo kev tshawb fawb pom tau tias kev noj zaub mov oleuropein-enriched zoo txo cov kab mob synovial thiab cov ntshav ntawm PGE2 hauv tus qauv npua guinea ntawm spontaneous OA. Hauv tib neeg chondrocytes, chlorogenic acid kho tau txo qis kev sib txuas ntawm PGE2 thiab TSIS TAU thiab inhibited qhov kev qhia ntawm iNOS thiab COX-2 tsim los ntawm IL-1 [91].
Yog li ntawd, polyphenols tau pom los txhawm rau txhawm rau ROS, ua kom lub cev tiv thaiv kab mob antioxidant hauv chondrocytes, thiab thaiv cov kab mob pro-inflammatory, uas txo qhov mob. Kev tshawb fawb yav tom ntej yuav tsum tsom mus rau kev xa cov tshuaj kho cov tshuaj polyphenolic rau cov pob qij txha puas, uas yog ib qho kev txwv ntawm kev kho OA. Qhov no yuav txhim kho kev siv tshuaj thiab kev noj qab haus huv thiab kev ua haujlwm. Hauv kev xaus, cov tshuaj polyphenolic muaj peev xwm los tsim kho tau zoo rau OA, raws li kev tshawb fawb tsis ntev los no.
Kab lus no yog muab rho tawm los ntawm Molecules 2021, 26, 6570. https://doi.org/10.3390/molecules26216570 https://www.mdpi.com/journal/molecules