Flavonoids As Promising Antiviral Agents Against SARS-CoV-2 Infection: A Mechanistic Review

Yog xav paub ntxiv. tiv taujtina.xiang@wecistanche.com

Abstract: Ib qho tshiab tau kuaj pom tus mob coronavirus hauv 2019 (COVID-19) tau cuam tshuam tag nrho tib neeg kev ua ub no txij li thaum nws nrhiav pom.Flavonoidsfeem ntau pom nyob rau hauv tib neeg noj cov zaub mov tau nyiam ntau xim vim lawv cov kev ua ub no zoo kawg li lom. Daim ntawv no muab kev tshuaj xyuas dav dav txog cov txiaj ntsig ntawm flavonoids hauv COVID-19 kab mob. Yav dhau los-tshaj tawm cov teebmeem ntawm flavonoids ntawm tsib tus kab mob RNA nrog cov tsos mob zoo sib xws thiab / lossis kev kho tshuaj, suav nrog mob khaub thuas, kab mob tib neeg tiv thaiv kab mob (HIV), mob hnyav ua pa nyuaj (SARS), Middle East ua pa syndrome (MERS), thiab Ebola, yog xav txog. Flavonoids ua haujlwm ncaj qhatshuaj tiv thaiv kab mobcov khoom, qhov twg lawv inhibit ntau theem ntawm tus kab mob kis kab mob thiab tsis ncaj qha cuam tshuam thaum lawv hloov kho cov lus teb rau tus kab mob thiab cov teeb meem tom qab. Flavonoids tau qhia txog kev tiv thaiv kab mob los ntawm inhibition ntawm tus kab mob protease, RNA polymerase, mRNA, tus kab mob replication, thiab kis kab mob. Cov tebchaw kuj tseem siv tau rau kev tswj hwm ntawm interferons, pro-inflammatory cytokines, thiab sub-cellular inflammatory pathways xws li nuclear factor-kB thiab Jun N-terminal kinases. Baicalin,quercetin, thiab nws cov derivatives, hesperidin, thiab catechins yog cov feem ntau kawm flavonoids nyob rau hauv no hais txog. Hauv kev xaus, kev noj haus flavonoids tau cog lus rau kev kho mob tiv thaiv COVID-19 kab mob; Txawm li cas los xij, kev tshawb nrhiav yav tom ntej raug pom zoo los ntsuas cov tshuaj tiv thaiv kab mob ntawm cov tshuaj tiv thaiv kab mob no.

Ntsiab lus: mob ntsws; oxidative kev puas tsuaj; tshuaj tiv thaiv kab mob; polyphenol

Nyem qhov no kom paub ntau yam khoom

1. Taw qhia

Thaum kawg ntawm xyoo 2019, cov kab mob ntsws txawv txawv tau raug tshaj tawm los ntawm Tuam Tshoj uas tau kuaj pom ntxiv tias yog tus kabmob tshiab (CoV) ua rau mob hnyav ua pa nyuaj (SARS) thiab hu ua COVID-19[1,2]. Tom qab ntawd, tus kab mob (SARS-CoV-2) kis mus rau lwm lub tebchaws thiab tau tshaj tawm tias muaj tus kabmob kis thoob ntiaj teb los ntawm WHO rau 11 Lub Peb Hlis 2020 [3]. Covkab mob vais lavFeem ntau kis tau los ntawm cov pa ua pa, thiab qhov hnyav yog nyob ntawm qhov mob me mus rau qhov mob hnyav. Cov mob asymptomatic nyob rau lub sijhawm incubation yog xav tias yog ib qho tseem ceeb ntawm kev sib kis [4]. Feem ntau, cov tsos mob me yuav siv sij hawm 1-2 lub lis piam los daws, qhov mob hnyav tuaj yeem ua rau tuag [5].

SARS-CoV-2 cuam tshuam rau txoj kev ua pa, ua npaws thiab hnoos qhuav [4]; Txawm li cas los xij, tus kab mob tuaj yeem ua rau lub cev tsis ua haujlwm, feem ntau hauv plawv thiab ob lub raum, nrog rau ua rau muaj cua daj cua dub cytokine, uas ua rau muaj kev tuag ntxiv. Viral lifecycle of SARS-CoV-2 suav nrog

Kev sib txuas, nkag mus, biosynthesis, maturation, thiab tso tawm. Tom qab kev sib txuas, tus kab mob RNA nkag mus rau hauv lub cell nucleus rau kev rov ua dua, thiab kab mob mRNA pib tsim cov kab mob kis kab mob, suav nrog cov kab mob (S), daim nyias nyias (M), lub hnab ntawv (E), thiab nucleocapsid (N) cov protein [6]. Lub angiotensin-hloov enzyme 2 (ACE2) receptor, uas tau hais tawm hauv lub ntsws, kuj tau pom tias ua tus co-receptor rau SARS-CoV [7].

SARS, MERS, and SARS-CoV-2 are all RNA CoVs. SARS-CoV-2 genome is 88% identical to bat-derived heavy acute respiratory syndromes(SARS)-like CoVs, 79% similar to SARS-CoV, and 50% similar to MERS-CoV [8,9]. SARS-CoV-2 proteins yog 90 feem pua ​​-100 feem pua ​​homologous to SARS-CoV; ho, orf10 and orf8 is different between SARS-CoV-2 and SARS-CoV.Orf8 is an accessory protein for CoVs. Nws tsim tau rau 6-strand alpha helix protein uas txhim kho tus kab mob muaj peev xwm kis tau.SARS-CoV-2 orfla/b, spike, lub hnab ntawv, daim nyias nyias, thiab nucleoprotein kuj zoo sib xws rau cov SARS-CoV [10] .

Txij li tsis muaj cov tshuaj tiv thaiv kab mob tshwj xeeb tiv thaiv SARS-CoV-2, tam sim no muaj tshuaj tiv thaiv kab mob raug txiav txim siab rau kev kho mob ntawm COVID-19. Remdesivir yog ib qho tshuaj tiv thaiv kab mob tshiab tshwj xeeb tshaj tawm rau tus kab mob Ebola xyoo 2015. Nws muaj kev cuam tshuam rau tus kab mob RNA polymerase thiab tsis ntev los no tau siv rau qee qhov kev sim rau COVID-19 kho [11]. Favipiravir muaj cov nyhuv inhibitory ntawm tus mob khaub thuas thiab tus kab mob Ebola nrog tib lub tswv yim thiab tseem raug soj ntsuam hauv SARS-CoV-2 [12-14]. Lopinavir yog tus kab mob protease inhibitor thiab tau tsim thawj zaug rau kev kho HV. Cov kev tshawb fawb hauv vitro tau pom tias muaj cov nyhuv inhibitory ntawm lopinavir hauv cov kab mob CoV [15,16]; Txawm li cas los xij, cov kev tshuaj xyuas tsis zoo ua tsis tau zoo los qhia txog cov txiaj ntsig zoo rau SARS-CoV-2 [17].

Cov nroj tsuag tshuaj tau muaj kev ntseeg siab ntawm cov tshuaj ntuj, suav nrog cov tshuaj tiv thaiv kab mob, txij li lub sijhawm qub. Cov tshuaj ib txwm siv thiab kev tshawb fawb ethnopharmacological ntawm ntau lub teb chaws thoob plaws ntiaj teb yeej ib txwm qhib txoj hauv kev tshiab rau kev tshawb nrhiav tshuaj [18-22]. Oseltamivir uas yog ib qho tshuaj tiv thaiv kab mob, yog ib qho derivative ntawm shikimic acid, ib tug thib ob metabolite ntawm lub hnub qub anise (Illicium verum Hook.f.). Nyob rau hauv cov ntaub ntawv ntawm SARS-CoV-2, nyob rau hauv silico kev tshawb fawb tau nthuav tawm cov khoom muaj peev xwm tiv thaiv kab mob ntawm cov khoom xyaw tshuaj ntsuab [23-25]. Flavonoids yog ib pawg loj ntawm phytochemicals uas feem ntau pom muaj nyob rau hauv ntau yam khoom noj thiab zaub hauv tib neeg noj zaub mov nrog ntau yam khoom muaj txiaj ntsig, suav nrog cov tshuaj tua kab mob. Nws tau pom tias cov tshuaj no tuaj yeem cuam tshuam cov kab mob kis tau los ntawm kev tsom mus rau theem tseem ceeb ntawm kab mob viral lub neej [26]. Quercetin, catechins, kaempferol, thiab baicalein yog cov piv txwv ntawm cov flavonoids tseem ceeb tshaj plaws uas nthuav tawm cov tshuaj tiv thaiv kab mob [18,27,28]. Txoj kev tshawb no tsom los tham txog cov pov thawj muaj tshuaj tiv thaiv kab mob ntawm flavonoids uas muaj peev xwm kho tau tawm tsam SARS-CoV-2 txiav txim siab txog qhov cuam tshuam yav dhau los ntawm cov tshuaj no ntawm tsib tus kab mob RNA nrog cov tsos mob zoo sib xws thiab / lossis kev kho tshuaj, suav nrog mob khaub thuas, human immunodeficiency virus (HIV), mob hnyav ua pa nyuaj (SARS), Middle East respiratory syndrome (MERS), thiab Ebola.

2. Cov txiaj ntsig

Antiviral kev ua haujlwmntawm flavonoids tuaj yeem muab faib ua cov tshuaj tiv thaiv kab mob ncaj qha uas tus kab mob cuam tshuam ncaj qha los ntawm flavonoid thiab tsis ncaj qha cuam tshuam qhov twg flavonoid txhim kho cov tswv cuab tiv thaiv kev tiv thaiv kab mob. Ntawm no, cov txheej txheem tiv thaiv kab mob hauv qab ntawm flavonoids tau tham nrog kev siv rau qhov tseem ceeb tshaj plaws flavonoids qhia txog cov txheej txheem no.

2.1.Direct Antiviral MechanismS

2.1.1. Inhibition ntawm Viral Protease

Viral proteases yog siv los ntxuav cov kab mob polyprotein precursors ntawm qee qhov chaw kom tso cov protein ua haujlwm. Cov tshuaj tiv thaiv kab mob tshwj xeeb kuj tau pom tias tshem tawm cov kab mob ntawm tes ntawm tes, suav nrog kev pib txhais lus (eF4 thiab elF3d) hauv HIV, txhawm rau tiv thaiv tus tswv tsev txhais lus protein [29,30]. Coronaviruses tsim peb hom kab mob proteases, suav nrog 3-chymotrypsin-zoo li cysteine ​​(3CLpro), papain-zoo li protease (PLpro), thiab lub ntsiab protease (M pro)[31].3CLpro yog qhov tseem ceeb rau SARS-CoV lub neej. lub voj voog, PLpro plays lub luag haujlwm hauv SARS-CoV-2 replication, thiab Mopar yog lub luag haujlwm rau kev loj hlob ntawm cov proteins ua haujlwm hauv SARS-CoV-2 [32,33]. Raws li qhov tshwm sim, cov molecules no yog lub hom phiaj tshuaj tsim nyog hauv kev tshawb fawb tshuaj tiv thaiv kab mob thiab tshuaj nrhiav pom [34].

Kaempferol uas yog ntau flavonoid nyob rau hauv ntau cov zaub mov txo CPE nyob rau hauv Vero E6 hlwb kis nrog soj ntsuam cais ntawm SARS-CoV-2 nrog ib ncig ntawm 88 feem pua ​​ntawm inhibition ntawm 125 μM concentration. Ib qho ua ke hauv kev tshawb nrhiav silico qhia tias inhibition ntawm SARS-CoV-2 3CLpro enzyme los ua lub luag haujlwm tseem ceeb ntawm kev ua [35]. Qhov sib ntxiv ntawm kaempferol rau 3CLpro thiab PLpro ntawm SARS-CoV thiab MERS-CoVexpressed nyob rau hauv E.coli ua rau cov tshuaj tua kab mob los ntawm inhibition ntawm cov enzymes [36]. Chaw ua si thiab cov neeg ua haujlwm ua haujlwm (2017) tau pom tias muaj cov pab pawg hydroxyl hauv kaempferol ua rau muaj zog tiv thaiv kab mob los ntawm inhibition ntawm 3CLpro thiab PLpro [37]. Epigallocatechin gallate (EGCG) yog ib qho flavonoid pom hauv tshuaj yej (Camellia sinensis L.) nrog cov tshuaj tua kab mob, tshuaj tua kab mob, thiab tshuaj tua kab mob [38.39]. Cov kev tshawb fawb tau qhia tias EGCG inhibits reverse transcriptase (RT) kev ua haujlwm, kev ua haujlwm protease, p24, kis kab mob, thiab kis kab mob hauv THP-1 thiab H9 hlwb kis tus kab mob HIV-1, thiab liposome hloov pauv ntawm EGCG amplified nws inhibitory. teebmeem. Cov kev tshawb fawb tsis muaj cell kuj pom tias muaj kev txo qis hauv protease kinetics tom qab kho nrog EGCG. Cov pab pawg galloyl hauv EGCG raug suav hais tias yog lub luag haujlwm rau nws cov tshuaj tua kab mob thiab tshuaj tua kab mob [40]. Isoliquiritigenin, chalcone, tuaj yeem siv los ua tus neeg sawv cev kho mob hauv cov kab mob thiab kis kab mob [41]. Qhov sib xyaw no tau pom tias muaj kev cuam tshuam rau SARS-CoV, thiab MERS-CoV 3CLpro thiab PLpro qhia hauv E.coli.Qhov muaj cov pab pawg ua haujlwm prenyl ntawm lub nplhaib resorcinol tso cai tsim cov kev sib cuam tshuam ntawm hydrophobic nrog proteases [37]. Theaflavins yog polyphenols pom nyob rau hauv ntau hom tshuaj yej [42]. Kev sim ntawm SARS-CoV recombinant protease pom qhov txo qis hauv 3CLpro kev ua haujlwm tom qab kho nrog theaflavin-3,3'-digallate nrog IC50 tus nqi ntawm 9.5 uM. Cov pab pawg neeg gallate txuas rau 3'txoj hauj lwm hauv qee qhov theaflavins yuav yog qhov tseem ceeb rau kev cuam tshuam nrog 3CL proactive site [43]. Prenylisoflavonoids muab rho tawm los ntawm Erythrina senegalensis DC. tau siv los soj ntsuam cov kev ua haujlwm tiv thaiv protease tiv thaiv cov kab mob HIV recombinant -1 protease. Cov txiaj ntsig tau pom tias cov tebchaw tuaj yeem cuam tshuam HIV-1 recombinant protease hauv vitro nrog 0.5 txog 30 μMIC50 qhov tseem ceeb. Hydroxy thiab prenyl pawg yuav ua lub luag haujlwm rau inhibition ntawm HIV protease [44]. Quercetin thiab quercetin- -galactoside downregulated PLpro, 3CLpro, deubiquitination, and DelSGylation activ in SARS-CoV, MERS-CoV, and HIV-1. Txoj hauj lwm ntawm cov pab pawg hydroxyl tej zaum yuav muaj txiaj ntsig zoo hauv kev ua haujlwm tiv thaiv protease. Quercetin nrog tsib pawg hydroxyl ntawm 3,5,7,3' thiab 4'txoj haujlwm tau nthuav tawm muaj zog inhibitory nyhuv ntawm cov kab mob proteases; Thaum lub xub ntiag ntawm glycosyl pawg ntawm txoj haujlwm 3,7A txo qis cov nyhuv inhibitory [37,45].

2.1.2. Inhibition ntawm Viral RNA Polymerase thiab Viral mRNA

RNA-dependent RNA polymerase (RdRp) yog ib qho tseem ceeb enzyme catalyzing replication ntawm RNA los ntawm RNA ib ntus [46]. Cov enzyme no tau encoded hauv tag nrho cov kab mob RNA, nrog rau qee cov eukaryotes [47]. Cov kab mob yog cov kab mob hauv lub cev, piv txwv li, lawv tsis tuaj yeem muaj sia nyob ntawm cov hlwb. Lawv yuav tsum siv cov cuab yeej txhais lus ntawm tes los txhais mRNAs rau kev tsim cov protein, uas yuav tsum tau ua kom rov ua dua. Yog li, ib qho kev cuam tshuam nrog mRNA kev txhais lus yuav cuam tshuam tus kab mob sib kis, kis, thiab hloov pauv [48].

Kev tshawb nrhiav tsis ntev los no los ntawm Zandi et al. tau nthuav tawm cov tshuaj tiv thaiv kab mob hauv vitro ntawm baicalin thiab baicalein tiv thaiv SARS-CoV-2 kab mob hauv Vero CCL-81 cell kab los ntawm inhibition ntawm RdRp, nrog lub zog ntau dua los ntawm baicalein. Ntxiv rau qhov kev ntsuam xyuas silico tau pom ob lub tebchaw no kom muaj kev sib raug zoo siab dua rau RdRp hauv kev sib piv rau kev xa rov qab: Qhov chaw txuas ntawm baicalin thiab baicalein kuj zoo li txawv ntawm remdesivir; Yog li, cov flavonoids tuaj yeem siv los ua kev kho mob ntxiv nrog rau remdesivir [49]. Cov teebmeem ntawm quercetin-7-O-glucoside(Q7G) tau raug soj ntsuam hauv kev tshawb fawb hauv vitro ntawm MDCK hlwb kis tus kab mob khaub thuas A thiab B piv rau tus qauv tshuaj tiv thaiv kab mob oseltamivir. Oseltamivir tau siv los ua cov tshuaj tswj hwm thiab pom cov tshuaj tiv thaiv kab mob nruab nrab nrog IC50 qhov tseem ceeb ntawm 25.4 txog 42.2 ug / mL; thaum Q7G inhibited kab mob khaub thuas A thiab B nrog IC50 qhov tseem ceeb ntawm 3.10ug / mL rau 8.19 ug / mL. Oseltamivir kuj pom tias muaj kev ua haujlwm tsis muaj zog tiv thaiv kab mob khaub thuas B dua li mob khaub thuas A; whereas Q7G pom muaj zog ua haujlwm tiv thaiv txhua tus kab mob khaub thuas. Tsis tas li ntawd, ntau qhov kev ntsuam xyuas PCR tau tshaj tawm tias qhov txo qis dua ntawm cov kab mob RNA synthesis tom qab Q7G kev kho mob piv nrog oseltamivir, qhia txog qhov inhibitory nyhuv ntawm Q7G ntawm tus kab mob RNA polymerase. Molecular docking tsom xam qhia qhov kev cuam tshuam no vim yog qhov txuas ntawm Q7G rau PB2 subunit ntawm tus kab mob RNA polymerase [50].

Oroxylin A(OA) yog ib qho flavonoid pom nyob rau hauv Oroxylum Indicum (L.)Kurz. Nws tau raug pom tias OA tuaj yeem cuam tshuam ntau hom kab mob khaub thuas A hauv MDCK hlwb hauv kev siv tshuaj ntau npaum li cas. Kev kho qhov ncauj ntawm cov nas uas kis tus kab mob khaub thuas H1N1 nrog OA kuj txo qis tus kab mob uas ua rau tuag, lub cev poob, thiab mob ntsws, nrog rau kev ciaj sia ntawm 60.0 feem pua ​​​​ntawm 100 mg / kg ib hnub. Cov teebmeem tshuaj tiv thaiv kab mob ntawm OA tau tshaj tawm tias yog vim kev txo qis ntawm H1N1 matrix1 (M1)mRNA transcription thiab protein synthesis (hauv li al. 2018). M1 protein yog ib qho protein nyob rau hauv lub hnab ntawv viral uas khi rau tus kab mob RNA thiab tuaj yeem kho qhov encapsidation ntawm RNA nucleoprotein cores rau hauv lub hnab ntawv membrane [51]. Txawm hais tias OA tuaj yeem cuam tshuam cov protein synthesis, nws tsis tuaj yeem thaiv cov kab mob nkag mus rau tus tswv tsev cell lossis nucleoprotein (NP) nkag mus rau tus tswv tsev cell nucleus [52]. Baicalin thiab biochanin A tuaj yeem tiv thaiv kab mob khaub thuas H5N1 hauv A549 hlwb nrog IC50 qhov tseem ceeb ntawm 18.79 thiab 8.92 μM raws li. Cov nyhuv no tau kho los ntawm kev tawm tsam nuclear viral ribonucleoprotein (RNP) xa tawm [53]. Lwm cov kev tshawb fawb kuj tau pom tias baicalin tuaj yeem txo qis kev mob khaub thuas M1 protein qhia [54,55].

Tus tswv tsev cdc2-zoo li kinase 1(CLK1) muaj lub luag haujlwm tseem ceeb hauv kev sib txuas ntawm tus kab mob khaub thuas H1N1 M2 noob thiab yog lub hom phiaj tseem ceeb tiv thaiv kab mob khaub thuas. M2 yog proton channel nyob rau hauv lub hnab ntawv viral ntawm tus kab mob khaub thuas A [56,57]. Nws tau pom tias gallocatechin{10}}gallate cais los ntawm Pithecellobium clypearia yog ib qho inhibitor ntawm tus tswv cdc2-zoo li kinase 1 (CLK1), lub hom phiaj tiv thaiv kab mob khaub thuas vim nws lub luag haujlwm hauv viral M2 mRNA lwm txoj kev sib txuas. Kev tshawb fawb txog cov txiaj ntsig ntawm gallocatechin-7-gallate ntawm qhov koob tshuaj txhua hnub ntawm 30 mg / kg ntawm ICR nas uas kis tus kab mob H1N1 pom tias muaj sia nyob ntau dua mus txog 8 hnub. Nws kuj tseem tiv thaiv tus kab mob ua rau mob ntsws raug mob thiab poob phaus. Tsis tas li ntawd, kev ntsuam xyuas ntawm H1N1- kis A549 hlwb tau pom tias muaj kev txo qis ntawm cov kab mob NP thiab M2 mRNAs. Ntxiv mus, phosphorylation ntawm splicing yam SF2/ASF thiab SC35, yam tseem ceeb rau tus kab mob M2 noob lwm txoj kev splicing, tau txo qis heev tom qab kho nrog gallocatechin-7-gallate [58]. Cirsimaritin (CST), flavonoid los ntawm Artemisia scoparia Waldst. thiab Kitam tau raug soj ntsuam txog nws cov tshuaj tiv thaiv kab mob vitro rau MDCK thiab THP-1 cov hlwb uas muaj peb hom kab mob npaws uas pom IC50 qhov tseem ceeb ntawm 5.8 txog 11.1 ug/mL, piv nrog 3.4 txog 8.9 ug/mL rau ribavirin. Cov ntaub ntawv qhia tau hais tias CST tuaj yeem txo tus mob khaub thuas M2 thiab cov protein qhia nyob rau hauv koob tshuaj kom lub zog ntawm CST ntawm 20 ug / mL siab dua 10 uM ntawm tus qauv tshuaj tiv thaiv kab mob ribavirin [59]. Luteolin yog lwm flavonoid nrog inhibitory nyhuv ntawm M2mRNA qhia. Hauv MDCK cov hlwb uas muaj kab mob khaub thuas sib txawv, 15 μM ntawm luteolin tau zoo dua li 10 μM ntawm oseltamivir hauv H1N1 thiab H2N3 cov kab mob. Luteolin kuj txo qis tus kab mob khaub thuas khaub thuas lub tsho protein I (COPI) qhia, kho tus kab mob nkag mus thiab endocytic txoj hauv kev, hauv cov kab mob [60]. Santin yog ib qho flavonoid muab rho tawm los ntawm Artemisia rupestris L., uas kuj tau pom tias muaj kev tiv thaiv kab mob khaub thuas los ntawm kev tawm tsam ntawm M2 mRNA qhia nyob rau hauv ib koob tshuaj raws li [61].

Nws tau qhia tias quercetin tuaj yeem yog tus neeg sawv cev kho mob tiv thaiv kab mob khaub thuas thaum ntxov ntawm tus kab mob kom nws tuaj yeem siv rau kev tiv thaiv kab mob khaub thuas. Kev tshawb fawb txog qhov cuam tshuam ntawm quercetin ntawm MDCK thiab A549 hlwb kis tus kab mob khaub thuas A hom qhia tias nws tuaj yeem cuam tshuam tus kab mob NP mRNA raws li kev siv tshuaj, nrog rau kev ua haujlwm siab tshaj plaws ntawm 50 μM concentration 【62】.

Kev tshawb fawb tau pom tias tricin (4'5, 7-trihydroxy-3', 5'-dimethoxyflavone) nthuav tawm cov tshuaj tua kab mob tiv thaiv kab mob khaub thuas A thiab B. RT-PCR kev ntsuam xyuas tau qhia tias tricin tuaj yeem cuam tshuam M protein mRNA synthesis hauv MDCK hlwb kis tus kab mob khaub thuas; tsis muaj kev cuam tshuam tseem ceeb ntawm neuraminidase thiab hemagglutinin biosynthesis. Qhov 50 feem pua ​​​​kev siv tau zoo ntawm tricin, uas tuaj yeem tiv thaiv kab mob mRNA synthesis, yog 3.4-10 uM

rau tus kab mob npaws A thiab 4.9 μM rau tus kab mob npaws B. Hauv cov nas kis tus kab mob khaub thuas, tricin nrog koob tshuaj ntawm 20 ug / kg ameliorated lub cev hnyav thiab lub sijhawm ciaj sia [63].

2.1.3. Viral nkag, rov ua dua, thiab kis kab mob

Cov kab mob RNA encode cov proteins uas siv lub tshuab cellular rau lawv lub neej. Kev nkag siab txog cov tswv tsev tsim nyog ntawm tes tsis tsuas yog qhia peb txog txoj hauv kev molecular siv los ntawm tus kab mob tab sis kuj nthuav qhia ntxiv lub hom phiaj rau kev txhim kho tshuaj [64].

Kev tshawb fawb hauv vitro tau soj ntsuam cov txiaj ntsig ntawm quercetin thiab isorhamnetin ntawm SARS-CoV-2en-try to ACE2h cells. ACE2 qhia rau ntawm lub ntsws hlwb yog cov co-receptor ntawm cov kab mob sib kis kab mob protein thiab, yog li, yog lub hom phiaj tseem ceeb ntawm cov tshuaj tiv thaiv kab mob tiv thaiv SARS-CoV-2. Nws tau pom tias ob lub flavonoids no muaj kev sib raug zoo siab rau ACE2 thiab tom qab ntawd txo cov kab mob nkag los ntawm kev txwv tsis pub muaj cov protein ntau txuas rau cov receptor no [65]. Lwm txoj kev tshawb fawb tau soj ntsuam cov txiaj ntsig ntawm baicalein ntawm SARS-CoV{11}} kab mob hauv Vero E6 hlwb thiab hACE2 transgenic nas. Kev txo qis tseem ceeb tau pom nyob rau hauv vitro thiab hauv vivo viral replication, nrog rau lub cev poob thiab mob ntsws hauv cov tsiaj [66]. Dihydroxy-6'-methoxy-3',5'-dimethylchalcone, thiab myricetin-3'5'-dimethyl ether 3-O- -D-galactopyranoside yog flavonoids muab los ntawm Cleistocalyx operculate (Roxb.) Zoo siab. thiab LM Perry. Cytopathic effect (CPE) txo qhov kev soj ntsuam pom tias cov flavonoids inhibit viral replication ntawm tus kab mob khaub thuas H1N1 hauv MDCK hlwb. Structure-activity relationship (SAR) cov kev tshawb fawb qhia tias OH pawg ntawm C-7 thiab C-4, ob daim ntawv cog lus ntawm C-2 thiab C-3, thiab tshwj xeeb tshaj yog pawg carbonyl ntawm C-4 txoj haujlwm, yog pab pawg ua haujlwm tseem ceeb uas txhim kho cov tshuaj tiv thaiv kab mob ntawm flavonoids [67].3-deoxysappanchalcone (3DSC) cais los ntawm Caesalpinia sappan L.could inhibit influenza virus replication nyob rau hauv siab concentrations ntawm inhibition of viral NP expression in MDCK cells kis tus kab mob H1N1. Ntawm qhov sib npaug ntawm qhov sib npaug (30 uM), ob qho tib si ribavirin thiab 3DSC tau pom qhov cuam tshuam loj ntawm NP qhia, txawm hais tias ribavirin tau muaj zog dua [68]. Cov kev tshawb fawb tau pom tias biochanin A thiab baicalein inhibited caspase-3 ua kom, ib qho enzyme koom nrog hauv cov kab mob sib kis [53,69]. Cov tebchaw no tseem tuaj yeem cuam tshuam kev xa tawm nuclear ntawm cov kab mob RNP complexes, uas yog qhov tseem ceeb hauv kev sib kis kabmob [53]. Biochanin A tau pom tias muaj kev cuam tshuam inhibitory tiv thaiv, mitogen-activated p38 thiab NF-kB, uas tau pom tias muaj kev koom tes hauv cov kab mob sib kis. NF kB thiab p38 tau qhib ua haujlwm vim oxidative kev nyuaj siab thiab paub tias cuam tshuam rau tus kab mob khaub thuas A tus kab mob replication thiab pathology [53,70]. Kev tshawb xyuas ntawm cov kab lis kev cai ntawm MDCK hlwb thiab A549 hlwb uas kis tus kab mob npaws tau pom tias baicalein tuaj yeem cuam tshuam tus kab mob sib kis ntawm 20-80 ug/mL concentrations. Interestingly, baicalin pom zoo li cov tshuaj tiv thaiv kab mob rau ribavirin thiab oseltamivir ntawm qhov ntau ntawm 40 ug / mL thiab 60 ug / mL, feem. Baicalin kuj inhibited viral replication nyob rau hauv lub ntsws ntawm nas nyob rau hauv vivo [71]. CST tau pom tias txo qis NF-kB protein thiab NF-KB phosphorylation hauv cov nucleus [59]. Nws twb paub lawm tias NF-KB muaj lub luag haujlwm tseem ceeb hauvmob, oxidative kev nyuaj siab, thiab tus tswv tsev tiv thaiv kev tiv thaiv [72]. Kev txo qis ntawm NF-kB tseem txwv tsis pub rov ua dua hauv ntau hom kab mob, suav nrog tus kab mob khaub thuas [73].

Hauv Vero E6 hlwb kis nrog SARS-CoV-2, naringenin tuaj yeem cuam tshuam CPE nyob rau lub sijhawm-thiab qhov concentration-dependent yam. Cov nyhuv no tau kho los ntawm inhibition ntawm endo-lysosomal Ob-Pore Channels (TPCs), ib txoj hauv kev cuam tshuam nrog kev kis tus kab mob SARS-CoV-2, Ebola, thiab MERS los ntawm kev yooj yim kis kab mob [74]. EGCG tau pom tias muaj cov nyhuv inhibitory koob tshuaj (25,50 μM) ntawm HIV replication hauv T-cells; Txawm li cas los xij, inhibition ntawm viral replication tsis ncaj qha cuam tshuam los ntawm RT inhibition. Fassina et al.analyzed p24 enzyme, uas yog koom nrog hauv ntim cov kab mob. Cov txiaj ntsig tau pom qhov txo qis ntawm p24 concentration thiab RT kev ua haujlwm hauv HIV-infected T lymphoblasts. Raws li cov txiaj ntsig hauv qab no, nws tau sau tseg tias EGCGinhibited viral replication los ntawm kev txo qis ntawm kev kis kab mob. Tseem tsis tau muaj qhov tseeb txog qhov tseeb ntawm EGCGon tus kab mob kis tau tus mob [75]. gp120 signaling feem ntau cuam tshuam nrog kev nce HIV-1 rov ua dua tshiab hauv cov kab mob yav dhau los[75]. Cov kev tshawb fawb qhia cov nyhuv inhibitory ntawm genistein ntawm gp120 thiab, tom qab ntawd, HV-1 viral replication. Tsis muaj kev hloov pauv hauv viral replication tom qab admin-

istration ntawm genistein nrog ib tug concentration ntawm {{0}}.5 ug/mL, tab sis nyob rau hauv ib tug ntau ntawm 5-10 ug/mL, genistein tuaj yeem txwv tus kab mob replication [76]. Herbacitrin yog flavonoid muab los ntawm Drrosera peltata Thunb. thiab yav tas los hu ua tus neeg sawv cev antiviral. Nws tau pom tias herbacitrin inhibits RT thiab integrase hauv HIV-1 kab mob MT-4 thiab MT-2 cell kab lis kev cai, ua rau kis kab mob sib kis ntawm ntau theem. Ntawm qhov concentration ntawm 21.5 ug / M, herbacitrin tuaj yeem txo qis R kev ua haujlwm, thaum nws tuaj yeem cuam tshuam kev sib xyaw ua ke ntawm qhov qis dua, 2.15 uM [77]. Scutellarin purified los ntawm Erigeron breviscapus yog flavonoid nrog tiv thaiv HIV{13}} kev ua haujlwm. Qhov no flavonoid inhibited HIV-1 RT kev ua si thiab cell fusion raws li cov neeg koom nrog cov kab mob sib kis [Z8]. Hesperidin thiab linarin yog flavonoids nrog rutinose ntawm lub nplhaib A thiab methoxy (-OCH3) hloov ntawm lub nplhaib B. Isoquercetin tau pom tias inhibit influenza A thiab B virus replication nyob rau hauv cov kab mob MDCK hlwb. Kev sib xyaw ntawm isoquercetin nrog amantadine kuj tau pom muaj kev sib koom ua ke ntawm cov kab mob sib kis hauv MDCK cov hlwb uas kis tus kab mob khaub thuas A tus kab mob tsuas yog hauv cov koob tshuaj qis (0.5 uM rau isoquercetin thiab 1 uM rau amantadine). Tus kab mob titer qhov tseem ceeb tom qab kev tswj hwm ntawm isoquercetin thiab amantadine yog kwv yees li 7.5; nce isoquercetin thiab amantadine concentrations txo cov synergistic nyhuv ntawm tus kab mob titers rau tus nqi ntawm 5 [79].Q3R muab los ntawm Houttuynia cordata exerts anti-influenza virus teebmeem. Cov teebmeem ntawm Q3R ntawm MDCK hlwb kis tus kab mob npaws A tau muab piv rau oseltamivir. Pulmonary lesions thiab edema yog inhibited los ntawm Q3R ntau tshaj oseltamivir. Q3R kuj muaj qhov ua tau zoo dua piv rau oseltamivir. Cov nyhuv inhibitory ntawm Q3R ntawm tus kab mob khaub thuas replication yog indirect thiab los ntawm kev cuam tshuam nrog cov kab mob. Oseltamivir tau pom cov tshuaj tiv thaiv kab mob nruab nrab, kwv yees li 58 feem pua ​​​​ tiv thaiv kab mob khaub thuas A, thiab tsis muaj zog tiv thaiv kab mob tsawg dua 49 feem pua ​​​​ntawm cov koob tshuaj qis dua 10 ug / mL; thaum Q3R pom tias 86 feem pua ​​​​ntawm cov kab mob inhibition ntawm 100 ug / mL thiab 66 feem pua ​​inhibition hauv 10 ug / mL concentrations [80]. Quercetin 3- -OD-Glucoside (Q3G) tau pom tias tiv thaiv tus kab mob Ebola rov ua dua hauv vitro. Prophylactic kev tswj hwm ntawm Q3G 30 min ua ntej tus kab mob pom tias muaj kev tiv thaiv tseem ceeb ntawm tus kab mob Ebola. Q3G kuj tseem tuaj yeem cuam tshuam cov kab mob nkag mus thaum ntxov. Yog li O3G tuaj yeem yog flavonoid zoo rau Ebola tus kab mob tiv thaiv kab mob [81].

2.2.Indirect Antiviral teebmeem

2.2.1. Kev cuam tshuam ntawm Interferons

Interferons (IFNs) suav nrog ib pawg ntawm cov protein uas tsim los ntawm ntau lub cev tiv thaiv kab mob hauv teb rau ntau yam kab mob xws li kab mob, kab mob, kab mob, thiab qog hlwb. Muaj peb chav kawm loj ntawm IFNs, suav nrog hom I lossis acid-stable interferons (IFN- subtypes, IFN-, IFN-K, IFN-e, IFN-w, thiab IFN-t), hom II (IFN-y), thiab hom III IFNs uas hu ua IFN-λ 【82-84】. Lawv qhia txog ntau yam kev ua ub no xws li kev ua kom lub cev tiv thaiv kab mob hauv lub cev, ua kom cov lus qhia ntawm cov tshuaj histocompatibility complex (MHC) molecules, suppressing angiogenesis. Lawv lub luag haujlwm tseem ceeb tshaj plaws yog cuam tshuam nrog kev kis kab mob [84,85].

Nyob rau theem pib ntawm kev kis tus kab mob, IFNs qhib lub cevtiv thaiv kab mob. Cov kev tshawb fawb tsis ntev los no tau tshaj tawm qhov txo qis hauv hom I thiab hom I IFN induction thiab teeb liab hauv COVID-19 cov neeg mob [86]. Cov hom IFN no tau pom cov tshuaj tiv thaiv kab mob los ntawm de-creasing neutrophils nkag teb chaws mus rau qhov chaw mob, ua kom muaj kev nthuav qhia antigen, suppressing mononuclear macrophage-mediated pro-inflammation, thiab ua kom muaj kev tiv thaiv kab mob rau kev nce qib ntawm antigen tshwj xeeb B thiab T cell teb [ 86-90]. Yog li, IFNs siv nyob rau theem pib ntawm tus kab mob tuaj yeem txo cov tsos mob ntawm COVID-19 los ntawm kev txo cov kab mob sib kis. Cov kws tshawb fawb kuj tau tshaj tawm tias IFN- qib tuaj yeem nce hauv COVID-19 cov neeg mob nrog ARDS. Kev nce nrawm hauv IFNs qib tuaj yeem caw cov cytokines rau hauv cov ntaub so ntswg alveolar thiab ua rau mob ntsws thiab mob ntsws [90,91]. Yog li ntawd, nws zoo nkaus li tias kev tswj hwm lossis kev tswj hwm ntawm IFNs thiab lwm cov lus teb rau cytokines lossis ob qho tib si tuaj yeem ua lub luag haujlwm tseem ceeb hauv kev nce qib thiab cov yam ntxwv ntawm SARS-CoV-2.

Cia al. tshawb xyuas cov tshuaj tiv thaiv kab mob khaub thuas ntawm baicalin, glycosyloxy flavone uas yog 7-O-glucuronide ntawm baicalein, hauv vitro thiab hauv vivo qauv ntawm tus kab mob khaub thuas A. TNF receptor-associated factor 6 (TRAF6) yog tus neeg kho kom haum xeeb zoo hauv IFN kev tsim cov teeb liab. Kev nthuav qhia ntau dhau ntawm TRAF6 ua rau muaj kev tsim ntau ntxiv ntawm hom I IFN [54]. MicroRNAs (miRNAs) yog cov molecules me me uas tswj cov gene regula-tion post-transcriptionally [92]. miR-146a tau pom tias muaj lub luag haujlwm tswj kev mob [93]. miR-146a tuaj yeem txhim kho qhov rov ua dua ntawm H1N1 thiab H3N2 los ntawm kev txo qis ntawm TRAF6. Baicalin (20 ug/mL) qhia txog kev txo qis hauv miR-146ib qho kev qhia, kab mob NP, Ml protein ntau, kab mob titer, thiab kuj nce cov nas ciaj sia [54]. Hauv lwm txoj kev tshawb fawb, Nayak thiab cov npoj yaig sawv cev rau tus kab mob khaub thuas tiv thaiv kab mob khaub thuas (H1N1-pdm09) kev ua ntawm baicalin los ntawm kev tswj hwm tus kab mob protein NS1, ua rau muaj kev tswj hwm ntawm interferon regulatory factor 3 (IRF-3), IFN -, thiab IFN-. Qhov no IFN up-regulation de-creased viral replication uas yuav txo tau tus kab mob transcripts thiab pro-inflammatory cytokines qhia, nrog rau IL-8 thiab TNF- x [55].

Ding et al. tsim ib txoj kev tshawb fawb los tshawb xyuas qhov cuam tshuam ntawm hesperidin, flavanone glycoside, hauv tus kab mob khaub thuas A (H1N1)-vim lub ntsws raug mob hauv cov txiv neej nas. Cov txiaj ntsig tau pom tias hesperidin txo qis kev raug mob ntawm lub ntsws los ntawm kev txo qis pro-inflammatory cytokine ntau lawm, suav nrog IFN- , TNF- x, thiab IL-6, los ntawm suppressing MAPK signaling pathways. Hesperidin kuj txo IFN- hauv H1N1 tus kab mob pulmonary microvascular endothelial hlwb [94]. Hauv lwm txoj kev tshawb fawb los ntawm Kim et al. isoquercetin tau txais txiaj ntsig zoo rau lub ntsws raug mob los ntawm tus kab mob H1N1 hauv cov nas los ntawm kev txo cov IFN- , iNOS, RANTES, tus kab mob titers, kab mob bronchitis, thiab bronchiolitis [79].

Oroxylin A (OA) los ntawm Oroxylum Indicum (L.)Kurz tiv thaiv lub ntsws raug mob los ntawm tus kab mob khaub thuas A H1NI hauv cov nas los ntawm kev tswj hwm ntawm IFN- thiab IFN- 【52】. Wogonin, lwm cov flavonoid cais los ntawm Scutellaria baicalensis Georgi, tau nthuav tawm cov haujlwm tseem ceeb los tiv thaiv kab mob khaub thuas los ntawm kev tswj hwm ntawm AMPKpathways. Wogonin kuj tau nce kev tswj hwm ntawm IFN- , IFN-λl, thiab IFN downstream molecules, suav nrog myxovirus resistance gene A (MxA) thiab 2-5' oligoadenylate synthetase (OAS), hauv MDCK thiab A549 cov kab mob kis [95].

2.2.2. Cov nyhuv ntawm Pro-Inflammatory Cytokines (TNF, IL, thiab MCP)

CoVs muaj qee qhov qhib kev nyeem ntawv uas encode ob peb cov khoom siv protein. Cov khoom siv ntxiv no tau pom tias yuav hloov kho txoj hauv kev xws li IFN signaling thiab pro-inflammatory cytokines [96]. Nws tau raug qhia meej tias qhov kev cia siab ntawm COVID-19 tuaj yeem ua rau tsis zoo los ntawm kev tso tawm ntawm cov cytokines pro-inflammatory, suav nrog interleukins, IFNy, thiab TNF- [97]. Blanco-Mello et al.indicated tias kev tiv thaiv kab mob tsis tsim nyog yuav pab tau tus kab mob rov ua dua thiab muaj teeb meem vim yog hom mob hnyav ntawm COVID-19 [98]. Ruan et al. kuj tau qhia tias qhov nce siab hauv cov kab mob cytokines xws li IL-6 cuam tshuam nrog ARDS, ua pa tsis ua haujlwm, thiab qhov tshwm sim tsis zoo rau kev kho mob [99]. Kev ua pa tsis ua haujlwm los ntawm lub ntsws puas yog tshwm sim los ntawm kev tsim tawm ntau dhau ntawm cov cytokines pro-inflammatory tom qab infiltration ntawm lub cev tiv thaiv kab mob rau hauv lub ntsws [100]. Cytokine cua daj cua dub yog ib qho kev mob tshwm sim uas cuam tshuam nrog ntau yam xws li kab mob thiab qee yam tshuaj. Ntau qhov kev tshawb fawb pom tias muaj kev sib txuas tseem ceeb ntawm cytokine cua daj cua dub, mob hnyav, thiab ntau lub cev tsis ua haujlwm hauv COVID{13}} cov neeg mob [101-103]. SARS-CoV-2 kev paub tus kab mob nrog lub cev tsis muaj zog thiab hloov kho lub cev tuaj yeem ua rau muaj kev ua kom thiab tsim cov cytokines inflammatory. Raws li kev tshawb fawb tsis ntev los no, qib plasma ntawm pro-inflammatory cytokines tau txhim kho hauv cov neeg mob COVID{18}}. Cov cytokines inflammatory xws li TNF-, IL6, IL 2, IL-1 , IL7, IL 10, thiab IL{25}}, as well as monocyte chemoattractant protein-1(MCP-1} ), muaj lub luag haujlwm tseem ceeb hauv kev txhim kho pathological thiab qhov hnyav ntawm COVID-19 los ntawm kev nce hauv cov kab mob kis, mob ntsws, mob ntsws, mob hlwb, thiab kev tuag [97,101].

Cov xwm txheej no tuaj yeem ua rau ntau lub cev tsis ua haujlwm thiab lub ntsws raug mob raws li qhov teeb meem tseem ceeb ntawm SARS-CoV-2; yog li ntawd, kev hloov kho ntawm cov cytokines uas muaj kev mob tshwm sim tuaj yeem suav tias yog lub hom phiaj kho mob tsim nyog hauv COVID-19. Tsis tas li ntawd, cov tshuaj tiv thaiv tseem ceeb ntawm flavonoids tau pom hauv ntau qhov kev tshawb fawb; yog li, lawv tuaj yeem cog lus cog lus sib txuas hauv kev tiv thaiv kev mob ntsig txog qhov mob ntawm COVID-19 [97].

Yang et al. ua pov thawj qhov kev tiv thaiv ntawm 3-deoxysappanchalcone (30 μM) nyob rau hauv vitro influenza H1N1 tus kab mob ua rau mob thiab apoptosis los ntawm kev txo qis IL-1 thiab IL-6 qib [68]. Baicalein, flavone, thiab biochanin A, O-methylated isoflavone, txo cov pro-inflammatory cytokine qhia hauv A549 hlwb thiab thawj tib neeg monocyte-derived macrophages (MDM) kis tus kab mob khaub thuas H5N1 kab mob, uas tuaj yeem tiv thaiv txoj kev ua kom muaj kab mob thiab cov ntaub so ntswg puas. [53]. Hauv kab mob khaub thuas A-kab mob A549 thiab MDCK hlwb, baicalin, glycosylated daim ntawv ntawm baicalein (baicalein-7-}glucuronide), tuaj yeem nce IFN qib, ua rau txo qis ntawm pro-inflammatory cytokines ntau lawm. Yog li, IL-8 thiab TNF- tau txo qis hauv baicalin-kho hlwb piv nrog cov hlwb tsis kho [55].

Ib qho kev tshawb fawb hauv vitro tau pom tias 2.5, 5, thiab 10 ug / mL concentrations ntawm CST, ib qho dimethoxyflavone, muaj kev cuam tshuam tseem ceeb rau kev txo qis ntawm NF-kB teeb liab hloov txoj hauv kev hauv THP-1 hlwb kis mob khaub thuas A. virus (H1N1). Ua raws li NF-kB inhibition, tsim cov pro-inflammatory cytokines nrog rau I-1 , IL-8, IL-10, thiab TNF-, nrog rau cov kab mob ntsig txog cov protein COX{{ 15}}, raug tshem tawm los ntawm CST nyob rau hauv ib qho kev noj tshuaj[59]. Hauv kev tshawb fawb hauv vitro los ntawm Yonekawa et al.on cov tshuaj tiv thaiv kab mob ntawm hesperidin thiab linarin, cov flavonoid glycosides inhibited R5-HIV-1-NL(AD8) viral replication hauv CD4 ntxiv rau NKT hlwb los ntawm kev ua kom ntau lawm. ntawm anti-inflammatory cytokines xws li IL-2, IL-5, thiab IL-13. Nws tau pom tias cov nyhuv stimulatory ntawm ob flavonoids no tseem ceeb heev nyob ntawm cov suab thaj moiety raws li aglycones (hesperetin thiab acacetin) ua tsis tau tej yam zoo li no. Tsis tas li ntawd, methoxy (-OCH3) hloov ntawm lub nplhaib B yog qhov tseem ceeb rau kev ua haujlwm ntawm hesperidin thiab linarin ntawm CD4 ntxiv rau NKT hlwb. Lawv kuj tuaj yeem ua rau RANTES, MIP-1 , thiab MIP{30}} tso tawm los ntawm V61 ntxiv rau kev nthuav qhia T cell receptors uas tom qab tua kab mob rov ua dua tshiab hauv CD4 ntxiv rau NKT hlwb[104]. Kang et al. tau tshaj tawm cov tshuaj tiv thaiv kab mob khaub thuas ntawm purified flavonoids los ntawm Pithecellobium clypearia Benth ntawm tus qauv in vitro ntawm tus kab mob khaub thuas A. Cov Purified flavonoids no txwv tsis pub tsim IL-6 thiab MCP-1 hauv H1N1- kis kab mob tib neeg A549 lub ntsws hlwb[105]. Mehrbod et al. tshawb xyuas cov tshuaj tiv thaiv kab mob ntawm quercetin-3-O- -L-rhamnopyranoside(Q3R), glycosylated flavone, ntawm MDCK hlwb kis tus kab mob npaws H1N1. Q3R ntawm 150 ug/mL concentration tau txo qis tus kab mob titer thiab nce IL-27 ntau lawm, uas tuaj yeem nce IL-10 tso tawm los ntawm CD4 ntxiv rau T hlwb thiab txhim kho lawv cov tshuaj tiv thaiv kab mob. Ntawm qhov tod tes, O3R suppressed TNF- ntau lawm ua ib qho tseem ceeb inflammatory mediators ua kub taub hau thiab ua rau NF-kB pro-inflammatory txoj kev, ntxiv zuj zus rau cov neeg mob [106]. Lub trimethoxy flavone Santin tau ua kom pom kev tiv thaiv kab mob khaub thuas hauv THP-1 thiab MDCK hlwb hauv 60 μM concentration. Influenza A(H3N2) virus induces pro-inflammatory cytokine production in THP-1 cells uas ua rau mob ntsws thiab raug mob [61]. Cov tshuaj tiv thaiv kab mob cytokines kuj tseem tuaj yeem hloov pauv thaum kis tus kab mob khaub thuas.IL-10 yog ib qho tshuaj tiv thaiv kab mob cytokine uas tuaj yeem tsim los ntawm tus kab mob khaub thuas. IL-10 inhibits invariant natural killer T hlwb los ntawm downregulating zus tau tej cov IL-12 pulmonary monocyte-derived dendritic hlwb[107]. Cov theem ntawm IL-6, IL-8, IL-10, IL-1 , thiab TNF- tau txo qis hauv pawg Santin-kho los ntawm kev txo qis ntawm MAPKs thiab NF- kB txoj kev taw qhia [61].

Ntxiv rau qhov saum toj no, gallocatechin-7-gallate, genistein thiab theaflavins yog lwm cov flavonoids uas muaj kev cuam tshuam los ntawm kev tsim cov pro-inflammatory cytokines [58,76,108]; Yog li, cov molecules zoo li muaj qhov xav tau los tiv thaiv kab mob, pab tswj kev kis kab mob ntsig txog kev mob.

2.2.3.Effect on Sub-Cellular Inflammatory Pathways (NF-kB, PI3K/Akt, and MAPK/JNK)

Thaum tus kab mob nkag mus rau hauv lub xov tooj ntawm tes, tus tswv tsev cell lees paub nws qhov kev rov ua dua los ntawm tus qauv lees paub receptors (PRRs) [109]. Tus kab mob RNA tus qauv yog koom nrog hauv oligomerization ntawm PRRs thiab ua kom cov dej ntws qis, tshwj xeeb, interferon regulatory factor (IRF) thiab NF-kB. Kev ua kom NF-kB thiab IRFs ua rau muaj kev koom tes ntawm cellular antiviral tiv thaiv los ntawm induction ntawm hom I thiab kuv interferons thiab chemokine secretion [110].

Chiou et al.investigated cov teebmeem ntawm 8-prenylkaempferol(8-PK) nyob rau hauv A549 hlwb kis tus kab mob npaws A (H1N1). Cov txiaj ntsig tau pom tias cuam tshuam nrog PI3K-Akt txoj hauv kev yog lub hauv paus ntsiab lus ntawm 8-PK ua rau muaj kev tiv thaiv los ntawm tus kab mob khaub thuas A. 8-PK txo NF-kB thiab IRF-3 nuclear translocation Los ntawm attenuation ntawm Akt phosphorylation thiab PI3K kev ua. Thaum kawg, nrog kev txo qis ntawm kev tswj hwm kev ua haujlwm, ib txwm T hlwb qhia thiab zais (RANTES) los ntawm H1N1- kis A549 hlwb [111]. Zhu et al. sawv cev tias tus kab mob khaub thuas A (H3N2) virus-induced autophagy nyob rau hauv A549 thiab Ana{20}} cov kab mob kis los ntawm suppressing mTOR signaling txoj kev. Baicalin tuaj yeem nce mTOR phosphorylation thiab cawm H3N2 tus kab mob cuam tshuam rau hauv koob tshuaj [112]. Hauv lwm txoj kev tshawb fawb, baicalin tau pom los ua haujlwm tiv thaiv kab mob khaub thuas (H1N1-pdm09) kev ua haujlwm los ntawm kev txo qis ntawm PI3k/Akt txoj hauv kev tshwm sim los ntawm kev hloov pauv cov kab mob sib kis NS1 qhia 55]. Tsis tas li ntawd, biochanin A, ib qho O-methylated isoflavone, qhia txog kev tiv thaiv ntawm H5N1 kab mob khaub thuas A cov kab mob khaub thuas los ntawm kev txo qis AKT, ERK1/2, JNK, thiab p38 phosphorylation. Nws kuj tseem tuaj yeem hloov kho cov kev taw qhia ntawm tes, txo IL-6, IL-8, CXCL10(IP-10), TNF- , thiab txhim kho IkB qib [53].

CST sawv cev cuam tshuam txog kev cuam tshuam ntawm tus qauv hauv vitro ntawm tus kab mob khaub thuas A tus kab mob los ntawm inhibition ntawm NF-kB / p65 teeb liab txoj hauv kev, ua rau txo qis ntawm pro-inflammatory cytokines. CST kuj txo qis phospho-p38 MAPK thiab phospho-JNK qib [59]. Hauv lwm txoj kev tshawb fawb los ntawm Ding li al., kev tswj hwm ntawm hesperidin ntawm cov koob tshuaj txhua hnub ntawm 200 thiab 500 mg / kg rau tsib hnub tuaj yeem tiv thaiv kev mob ntsws ntsws ntawm tus kab mob khaub thuas A (H1N1)-vim lub ntsws raug mob hauv nas. Cov nyhuv no tau kho los ntawm kev txo qis kev tsim cov cytokine, suav nrog IL-6 thiab TNF- . Hesperidin kuj de-creased IL-6 thiab TNF- qhia hauv H1N1 tus kab mob pulmonary microvascular endothelial hlwb los ntawm inhibition ntawm MAPK signaling pathways [94]. Ntxiv mus, cov kev tshawb fawb qhia ERK signaling txoj hauv kev raws li lub ntsiab modulator ntawm MAPK signaling pathway. Isorham-netin (50 μM), monomethoxy flavone, txo ERK phosphorylation hauv MDCK hlwb tom qab mob khaub thuas A(H1N1) tus kab mob [113]. Jeong thiab cov npoj yaig tau tshawb xyuas cov teebmeem cytotoxic ntawm pyroxylin A thiab tectorigenin hauv CHME5 hlwb thiab thawj tus tib neeg macrophages kis HIV-1-D3. Cov flavonoids no siv lawv cov teebmeem los ntawm kev txo cov phosphorylation ntawm PI3K, Akt, mTOR, PDK1, GSK-3 , thiab Phem hauv lipopolysaccharide/cycloheximide kho hlwb Santin suppressed influenza A tus kab mob replication hauv MDCK thiab THP-1 mob hlwb [114]. Ntawm qhov concentration ntawm 60 uM, Santin attenuated phosphorylation ntawm p38 MAPK, ERK, JNK / SAPK, thiab NF-kB [61].