{"id":235,"date":"2022-07-27T08:36:06","date_gmt":"2022-07-27T06:36:06","guid":{"rendered":"http:\/\/apitoxin.sk\/?p=235"},"modified":"2022-07-28T11:38:43","modified_gmt":"2022-07-28T09:38:43","slug":"vceli-jed-potencialny-kandidat-na-doplnkovu-medicinu-pre-infekcie-sars-cov-2","status":"publish","type":"post","link":"http:\/\/d.r5.wbsprt.com\/apitoxin.sk\/2022\/07\/27\/vceli-jed-potencialny-kandidat-na-doplnkovu-medicinu-pre-infekcie-sars-cov-2\/","title":{"rendered":"V\u010del\u00ed jed \u2013 potenci\u00e1lny kandid\u00e1t na doplnkov\u00fa medic\u00ednu pre infekcie SARS-CoV-2"},"content":{"rendered":"\n

<\/p>\n\n\n\n

1.Infection Medicine, Dekan\u00e1t biomedic\u00ednskych vied, College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh, Spojen\u00e9 kr\u00e1\u013eovstvo
2.School of Medicine, Univerzita Kabale, Kabale, Uganda
3.Katedra biosyst\u00e9mov\u00e9ho in\u017einierstva, Fakulta environment\u00e1lneho in\u017einierstva a strojn\u00e9ho in\u017einierstva, Pozna\u0148sk\u00e1 univerzita, Pozna\u0148, Po\u013esko
4.Katedra farmaceutickej ch\u00e9mie, College of Pharmacy, Univerzita Taif, Taif, Saudsk\u00e1 Ar\u00e1bia
5.Fakulta po\u013enohospod\u00e1rstva a \u017eivo\u010d\u00ed\u0161nych vied, Busitema University Arapai Campus, Soroti, Uganda
6.Fakulta biomedic\u00ednskych vied, Kampala International University Western Campus, Bushenyi, Uganda
7.Katedra klinickej farm\u00e1cie a farmaceutickej praxe, School of Pharmacy, Kampala International University Western Campus, Bushenyi, Uganda
8.Katedra lek\u00e1rskej mikrobiol\u00f3gie a imunol\u00f3gie, Lek\u00e1rska fakulta, Assiut University, Assiut, Egypt
9.Katedra z\u00e1kladn\u00fdch lek\u00e1rskych vied, Michael Chilufya Sata School of Medicine, Copperbelt University, Ndola, Zambia
10.Katedra farmakol\u00f3gie a terapie, Fakulta veterin\u00e1rneho lek\u00e1rstva, Univerzita Damanhour, Damanhour, Egypt
11.N\u00e1rodn\u00e9 v\u00fdskumn\u00e9 centrum pre choroby prvokov, Univerzita po\u013enohospod\u00e1rstva a veterin\u00e1rnej medic\u00edny Obihiro, Obihiro, Japonsko
12.Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Zhejiang University, Haining, \u010c\u00edna<\/p>\n\n\n\n

\u0164a\u017ek\u00fd ak\u00fatny respira\u010dn\u00fd syndr\u00f3m koronav\u00edrus 2 (SARS-CoV-2) je charakterizovan\u00fd syndr\u00f3mom z\u00e1va\u017enej cytok\u00ednovej b\u00farky po z\u00e1pale. SARS-CoV-2 priamo interaguje s receptormi angiotenz\u00edn-konvertuj\u00faceho enz\u00fdmu 2 (ACE-2) v \u013eudskom tele. Doplnkov\u00e9 terapie, ktor\u00e9 ovplyv\u0148uj\u00fa expresiu IgE a IgG protil\u00e1tok, vr\u00e1tane pod\u00e1vania v\u010delieho jedu (BV), s\u00fa \u00fa\u010dinn\u00e9 pri lie\u010dbe artrit\u00eddy a Parkinsonovej choroby. Ned\u00e1vna epidemiologick\u00e1 \u0161t\u00fadia v \u010c\u00edne uk\u00e1zala, \u017ee miestni v\u010del\u00e1ri maj\u00fa ur\u010dit\u00fa \u00farove\u0148 imunity proti SARS-CoV-2 s predch\u00e1dzaj\u00facim vystaven\u00edm v\u00edrusu aj bez neho. Protiz\u00e1palov\u00e9 vlastnosti BV s\u00fa spojen\u00e9 s melit\u00ednom a fosfolip\u00e1zou A2 (PLA2), pri\u010dom obe vykazuj\u00fa aktivitu proti obalen\u00fdm a neobalen\u00fdm v\u00edrusom, vr\u00e1tane H1N1 a HIV, s aktivitou sprostredkovanou antagonistickou aktivitou proti interleuk\u00ednu-6 (IL-6), IL-8, interfer\u00f3n-y (IFN-y) a tumor nekrotizuj\u00faci faktor-a (TNF-a). Melit\u00edn je spojen\u00fd s nedostato\u010dnou expresiou proz\u00e1palov\u00fdch cytok\u00ednov, vr\u00e1tane jadrov\u00e9ho faktora-kappa B (NF-KB), kin\u00e1z regulovan\u00fdch extracelul\u00e1rnym sign\u00e1lom (ERK1\/2) a prote\u00ednkin\u00e1zy Akt. BV terapia tie\u017e zah\u0155\u0148a sekre\u010dn\u00fa fosfolip\u00e1zu A2 skupiny III pri lie\u010dbe respira\u010dn\u00fdch a neurologick\u00fdch ochoren\u00ed. BV aktiv\u00e1cia bunkov\u00e9ho a humor\u00e1lneho imunitn\u00e9ho syst\u00e9mu by sa mala presk\u00fama\u0165 na aplik\u00e1ciu komplement\u00e1rnej medic\u00edny na zvl\u00e1danie infekci\u00ed SARS-CoV-2. BV \u201evakcin\u00e1cia\u201c sa pou\u017e\u00edva na imuniz\u00e1ciu proti cytomegalov\u00edrusu a m\u00f4\u017ee potla\u010di\u0165 metast\u00e1zy prostredn\u00edctvom PLA2 a fosfatidylinozitol-(3,4)-bisfosf\u00e1tov\u00fdch dr\u00e1h. To, \u017ee BV vykazuje \u00fa\u010dinnos\u0165 na HIV a H1NI, pon\u00faka pr\u00edle\u017eitos\u0165 ako kandid\u00e1ta na doplnkov\u00fa terapiu na ochranu pred SARS-CoV-2.<\/p>\n\n\n\n

\u00davod
\u0164a\u017ek\u00fd ak\u00fatny respira\u010dn\u00fd syndr\u00f3m koronav\u00edrus 2 (SARS-CoV-2) je p\u00f4vodcom koronav\u00edrusovej choroby 2019 (COVID-19), respira\u010dnej infekcie, ktor\u00e1 sa objavila v provincii Wuhan v \u010c\u00edne koncom roka 2019 (1, 2) a stala sa glob\u00e1lnou pand\u00e9miou v roku 2020. K 1. apr\u00edlu 2020 dosahovala celosvetov\u00e1 \u00famrtnos\u0165 5 % (3). V priebehu nieko\u013ek\u00fdch t\u00fd\u017ed\u0148ov sa celosvetov\u00e1 \u00famrtnos\u0165 zv\u00fd\u0161ila na 6,7 \u200b\u200b% (5 % v Afrike, 4,4 % v Amerike, 5 % v regi\u00f3ne v\u00fdchodn\u00e9ho Stredomoria, 4,4 % v juhov\u00fdchodnej \u00c1zii, 8,9 % v eur\u00f3pskom regi\u00f3ne, 4,4 % v z\u00e1padnej tichomorsk\u00e1 oblas\u0165) (4). V\u00fdzvy v oblasti verejn\u00e9ho zdravia sp\u00f4soben\u00e9 ochoren\u00edm COVID-19 s\u00fa obrovsk\u00e9, vr\u00e1tane zvl\u00e1dania vysok\u00e9ho po\u010dtu asymptomatick\u00fdch pr\u00edpadov (5). Choroba preh\u013abila existuj\u00face soci\u00e1lno-ekonomick\u00e9 rozdiely, najm\u00e4 v zranite\u013en\u00fdch komunit\u00e1ch v rozvojov\u00fdch krajin\u00e1ch vr\u00e1tane Afriky, ktor\u00e9 boli ne\u00famerne postihnut\u00e9 d\u00f4sledkami extr\u00e9mnych prevent\u00edvnych opatren\u00ed (6).<\/p>\n\n\n\n

\u0164a\u017ek\u00e9 infekcie SARS-CoV-2 s\u00fa charakterizovan\u00e9 syndr\u00f3mom cytok\u00ednovej b\u00farky, hyperz\u00e1palom a multiorg\u00e1nov\u00fdm zlyhan\u00edm (2, 7). Hostite\u013esk\u00e9 bunky s\u00fa infikovan\u00e9 prostredn\u00edctvom receptora angiotenz\u00edn-konvertuj\u00faceho enz\u00fdmu 2 (ACE-2) (8, 9), ktor\u00fd je spojen\u00fd s vrodenou aj z\u00edskanou imunitou (10). Predpoklad\u00e1 sa, \u017ee ACE2 zvy\u0161uje replik\u00e1ciu v\u00edrusu a zosil\u0148uje inv\u00e1ziu hostite\u013esk\u00fdch buniek (10) a je hlavnou zlo\u017ekou syst\u00e9mu ren\u00edn-angiotenz\u00edn-aldoster\u00f3n (RAAS), ktor\u00fd interaguje s enz\u00fdmami CVS a kask\u00e1duje kardiovaskul\u00e1rne ochorenia (11, 12). ACE2 m\u00f4\u017ee by\u0165 d\u00f4vodom, pre\u010do pacienti so SARS-CoV-2 vy\u017eaduj\u00fa farmakologick\u00fa profylaxiu tromb\u00f3zy (13, 14); patogen\u00e9za SARS-CoV-2 zah\u0155\u0148a v\u00e4zbu v\u00edrusu na epitelov\u00e9 bunky a lok\u00e1lnu propag\u00e1ciu s minim\u00e1lnou vrodenou imunitnou odpove\u010fou (15). Druh\u00e9 \u0161t\u00e1dium infekcie vykazuje zv\u00fd\u0161en\u00e9 \u0161\u00edrenie v\u00edrusu, akt\u00edvnu imunitn\u00fa odpove\u010f, \u0161\u00edrenie v\u00edrusu do doln\u00e9ho d\u00fdchacieho syst\u00e9mu a m\u00f4\u017ee zah\u0155\u0148a\u0165 kardiovaskul\u00e1rny a tr\u00e1viaci syst\u00e9m (16). Tretie \u0161t\u00e1dium zah\u0155\u0148a hypoxiu, infiltr\u00e1ciu cel\u00e9ho d\u00fdchacieho syst\u00e9mu a nakoniec syndr\u00f3m ak\u00fatnej respira\u010dnej tiesne (ARDS), ktor\u00fd je potenci\u00e1lne smrte\u013en\u00fd (15). SARS-CoV-2 sa sp\u00e1ja s koagulopatiami, trombotick\u00fdmi pr\u00edhodami (17) a vy\u010derpan\u00edm lymfocytov (18).<\/p>\n\n\n\n

V s\u00fa\u010dasnosti neexistuje \u017eiadny celosvetovo uzn\u00e1van\u00fd protokol alternat\u00edvnej lie\u010dby SARS-CoV-2, hoci pod\u00e1vanie polyklon\u00e1lnych protil\u00e1tok je s\u013eubn\u00e9 (19). \u00da\u010dinnos\u0165 chloroch\u00ednu a jeho deriv\u00e1tov sa na\u010falej sk\u00fama pri prevencii COVID-19 (20, 21), ako aj famotid\u00ednu, protivredov\u00e9ho lieku, pod\u00e1van\u00e9ho vo vysok\u00fdch d\u00e1vkach (10\u00d7 norm\u00e1lne) po\u010das 14 dn\u00ed na kontrolu SARS-CoV- 2 infekcia (7). Remdesivir, ktor\u00fd sa predt\u00fdm pou\u017e\u00edval na zvl\u00e1dnutie bl\u00edzkov\u00fdchodn\u00e9ho respira\u010dn\u00e9ho syndr\u00f3mu-kronav\u00edrusu (MERS-CoV), bol sk\u00faman\u00fd ako kandid\u00e1tsky liek proti SARS-CoV-2 (22\u201324). Kombin\u00e1cie Lopinavir\/ritonavir, be\u017ene pou\u017e\u00edvan\u00e9 na prevenciu HIV\/AIDS, sa tie\u017e sk\u00famaj\u00fa z h\u013eadiska \u00fa\u010dinnosti proti SARS-CoV-2 (25, 26). Neutrofiln\u00e9 extracelul\u00e1rne pasce (NET), be\u017en\u00e9 u hadov, hmyzu, pav\u00fakovcov a myriapodov, sa tie\u017e zva\u017eovali pre SARS-CoV-2 (27, 28). V\u010del\u00ed jed (BV) m\u00f4\u017ee p\u00f4sobi\u0165 ako inhib\u00edtory ACE2 alebo blok\u00e1tory angiotenz\u00ednov\u00fdch receptorov (ARB), hoci \u0161t\u00fadie o BV a SARS-CoV-2 s\u00fa zriedkav\u00e9. Je zn\u00e1me, \u017ee had\u00ed jed p\u00f4sob\u00ed prostredn\u00edctvom fosfolip\u00e1zy A2 (PLA2) na produkciu kyseliny arachid\u00f3novej, ktor\u00e1 vyvol\u00e1va hypotenziu (29). U \u013eud\u00ed jed blanokr\u00eddlovcov zn\u00ed\u017eil k\u013e\u00fa\u010dov\u00e9 parametre v RAAS (30). Kombin\u00e1cia BV a propolisu bola spojen\u00e1 s hypotenziou u laborat\u00f3rnych zvierat prostredn\u00edctvom zn\u00ed\u017eenia hlad\u00edn angiotenz\u00ednu v s\u00e9re (31), \u010do dokazuje \u00fazky vz\u0165ah medzi BV a dr\u00e1hou ACE2.<\/p>\n\n\n\n

Terapia v\u010del\u00edm jedom
Terapia v\u010del\u00edm jedom (BV) sa datuje do \u00e9ry Hippokrata, kde bola nasaden\u00e1 na zmiernenie bolesti k\u013abov a artrit\u00eddy (32). V s\u00fa\u010dasnej medic\u00edne sa BV pou\u017e\u00edva na lie\u010dbu roztr\u00fasenej skler\u00f3zy (33), artrit\u00eddy a Parkinsonovej choroby (34). Aktivita je zalo\u017een\u00e1 na v\u00fdhod\u00e1ch anafylaktickej reakcie na metabolizmus a na organely, najm\u00e4 v d\u00fdchacom syst\u00e9me (35). Alerg\u00e9ny m\u00f4\u017eu pon\u00faka\u0165 v\u00fdhody proti COVID-19 (36, 37); BV m\u00f4\u017ee vyvola\u0165 zv\u00fd\u0161enie \u0161pecifick\u00fdch IgE a IgG protil\u00e1tok (38) a vedie k produkcii IgE protil\u00e1tok, ktor\u00e9 m\u00f4\u017eu reagova\u0165 na r\u00f4zne antig\u00e9ny (39) (tabu\u013eka 1). Hoci IgE s\u00fa zodpovedn\u00e9 za alergick\u00e9 vzplanutia, pon\u00fakaj\u00fa aj ochrann\u00fa \u00falohu hostite\u013ea v r\u00e1mci \u0161irok\u00e9ho spektra alerg\u00e9nov (39). BV m\u00f4\u017ee p\u00f4sobi\u0165 ako adjuvans, ke\u010f sa kombinuje s Toll-like receptormi (TLR) ligandami (40) a moduluje imunitn\u00fd syst\u00e9m, zvy\u0161uje diferenci\u00e1ciu buniek exprimuj\u00facich foxP3 a zvy\u0161uje cirkuluj\u00face regula\u010dn\u00e9 T bunky (41, 42). BV sp\u00fa\u0161\u0165a zv\u00fd\u0161enie CD25, CD4+ T buniek a foxP3 mRNA, \u010do vedie k posunu v BV-\u0161pecifickom pomere IgG4\/IgE (43). BV reguluje imunitn\u00fa odpove\u010f a fyziopatologick\u00e9 zmeny (44) a podporuje klinick\u00e9 pozorovania pri apiterapii, kde sa v\u010del\u00e1rom uk\u00e1zalo, \u017ee zvy\u0161uj\u00fa imunitu proti COVID-19 v provincii Wuhan, PR \u010c\u00edna (45).<\/p>\n\n\n\n

\"\"
TABU\u013dKA 1. Enz\u00fdmy a peptidy v\u010delieho jedu a ich funkcie v syst\u00e9moch cicavcov.<\/figcaption><\/figure>\n\n\n\n

bvPLA2 m\u00f4\u017ee spusti\u0165 dozrievanie \u017e\u00edrnych buniek (46), je d\u00f4le\u017eit\u00fd pri bunkovej signaliz\u00e1cii a pri produkcii k\u013e\u00fa\u010dov\u00fdch lipidov a m\u00f4\u017ee p\u00f4sobi\u0165 ako receptorov\u00fd ligand (47). PLA2 m\u00f4\u017ee inhibova\u0165 tok z\u00e1palov\u00fdch buniek k cie\u013eom (48). BV m\u00f4\u017eu vies\u0165 k trvalej indukovanej tolerancii na pr\u00edbuzn\u00e9 alerg\u00e9ny (49), ako funkcia zn\u00ed\u017eenia IgG4 a aktiv\u00e1cie IL-10, modul\u00e1cie imunitn\u00e9ho syst\u00e9mu a indukcie odch\u00fdlky od TH2 k TH1 (50\u201352). Melitt\u00edn (APi M 1) sa m\u00f4\u017ee pou\u017ei\u0165 na v\u00fdvoj mimotopov (49). APi M 10 (icarapin), zlo\u017eka BV, aktivuje efektorov\u00e9 bunky pacientov alergick\u00fdch na v\u010del\u00ed jed (53). Ke\u010f\u017ee IgE m\u00e1 epitop pre APi M 10, m\u00f4\u017ee to pon\u00faknu\u0165 pr\u00edle\u017eitos\u0165 na v\u00fdvoj adjuvans. Antig\u00e9ny BV mo\u017eno pou\u017ei\u0165 ako adjuvans pri lie\u010dbe bolesti (54) a p\u00f4sobenie melit\u00ednu na tvorbu p\u00f3rov bunkovej membr\u00e1ny (54, 55), \u010do vedie k apopt\u00f3ze, sl\u00fa\u017ei na posilnenie adjuvantn\u00fdch vlastnost\u00ed. BV m\u00e1 tie\u017e antiv\u00edrusov\u00e9 vlastnosti (56). BV m\u00f4\u017ee znecitlivie\u0165 \u017e\u00edrne bunky a bazofily (57) a potla\u010di\u0165 vroden\u00e9 lymfoidn\u00e9 bunky. Materi\u00e1ly BV m\u00f4\u017eu inhibova\u0165 synt\u00e9zu prote\u00ednov, indukova\u0165 angiogen\u00e9zu (58) a aktivova\u0165 kasp\u00e1zu-3-8-9 (59) (tabu\u013eka 1).<\/p>\n\n\n\n

Podmienky, ktor\u00e9 umo\u017e\u0148uj\u00fa pou\u017eitie v\u010delieho jedu napriek jeho toxicite
<\/strong>V\u010del\u00ed jed je vo vysok\u00fdch d\u00e1vkach cytotoxick\u00fd, av\u0161ak necytotoxick\u00e9 koncentr\u00e1cie BV sa pohybuj\u00fa od 1 do 3 \u03bcg\/ml a vykazuj\u00fa v\u00fdznamn\u00fd terapeutick\u00fd potenci\u00e1l (60). N\u00edzke d\u00e1vky, kontrolovan\u00e9 koncentr\u00e1cie a zrieden\u00e9 BV sp\u00fa\u0161\u0165aj\u00fa cel\u00fd rad protiz\u00e1palov\u00fdch reakci\u00ed (61, 62) a boli nasaden\u00e9 na lie\u010dbu cukrovky, reumatoidnej artrit\u00eddy (RA), srdcov\u00fdch chor\u00f4b, obezity, astmy, ko\u017en\u00fdch chor\u00f4b a centr\u00e1lnej choroby spojen\u00e9 s nervov\u00fdm syst\u00e9mom, ako je Alzheimerova choroba, Parkinsonova choroba a skler\u00f3za (61\u201364). V n\u00edzkych d\u00e1vkach m\u00f4\u017ee BV potla\u010di\u0165 z\u00e1palov\u00e9 cytok\u00edny, ako je interleuk\u00edn-6 (IL-6), IL-8, interfer\u00f3n-y (IFN-y) a tumor nekrotizuj\u00faci faktor-a (TNF-a). Zn\u00ed\u017eenie sign\u00e1lnych dr\u00e1h zodpovedn\u00fdch za aktiv\u00e1ciu z\u00e1palov\u00fdch cytok\u00ednov, ako je nukle\u00e1rny faktor-kappa B (NF-\u03baB), kin\u00e1zy regulovan\u00e9 extracelul\u00e1rnym sign\u00e1lom (ERK1\/2) a prote\u00ednkin\u00e1za Akt a lipopolysacharid porfyromonas gingivalis (PgLPS)- lie\u010den\u00fdch \u013eudsk\u00fdch keratinocytov bola spojen\u00e1 s lie\u010dbou zah\u0155\u0148aj\u00facou BV (65).<\/p>\n\n\n\n

BV sa pou\u017e\u00edva ako protiz\u00e1palov\u00e9 \u010dinidlo kombin\u00e1ciou zl\u00fa\u010den\u00edn v BV, t.j. sekre\u010dnej fosfolip\u00e1zy A2, s fosfatidylinozitol-(3,4)-bisfosf\u00e1tom alebo bunkami, najm\u00e4 dendritick\u00fdmi bunkami (DC), alebo kombin\u00e1ciou BV s DC (66) . Konjug\u00e1cia hormon\u00e1lnych receptorov a transport\u00e9rov g\u00e9novej terapie k BV peptidom ako u\u017eito\u010dn\u00e1 nov\u00e1 cielen\u00e1 terapia na pozit\u00edvnu modul\u00e1ciu imunitn\u00fdch odpoved\u00ed bola aplikovan\u00e1 v protirakovinovej a protiz\u00e1palovej terapii (67).<\/p>\n\n\n\n

Imunitn\u00e9 reakcie BV s\u00fa pri vysok\u00fdch d\u00e1vkach toxick\u00e9, ale ke\u010f s\u00fa kontrolovan\u00e9 alebo zrieden\u00e9 (kontrolovan\u00e9 koncentr\u00e1cie), tieto imunitn\u00e9 reakcie m\u00f4\u017eu sl\u00fa\u017ei\u0165 ako imunitn\u00e9 modul\u00e1tory. Kontrolovan\u00e1 alergick\u00e1 imunita m\u00f4\u017ee by\u0165 v\u00fdhodn\u00e1 pre obranu hostite\u013ea proti antig\u00e9nom a patog\u00e9nom vr\u00e1tane RNA v\u00edrusov. BV m\u00f4\u017ee stimulova\u0165 imunitn\u00e9 reakcie typu 2, imunita typu 2 je iniciovan\u00e1 protil\u00e1tkami T-buniek (T-pomocn\u00edk typu 2) a imunoglobul\u00ednov\u00fdch (Ig) protil\u00e1tok (IgE a IgG1) a p\u00f4soben\u00edm vroden\u00e9ho imunitn\u00e9ho syst\u00e9mu, ako je epitel a biela krviniek a sl\u00fa\u017ei ako bari\u00e9rov\u00e1 obrana na elimin\u00e1ciu antig\u00e9nov (68). BV skupina III sPLA2 vykazuje in vitro a in vivo \u00fa\u010dinky na imunitn\u00fd syst\u00e9m. Modulovan\u00e9 imunitn\u00e9 reakcie z BV m\u00f4\u017eu zmierni\u0165 imunologick\u00e9 ochorenia, ako je reumatoidn\u00e1 artrit\u00edda, z\u00e1palov\u00e9 ochorenia, astma a Parkinsonova choroba (69). Vroden\u00fd imunitn\u00fd syst\u00e9m indukuje obrann\u00fa imunitn\u00fa odpove\u010f proti antig\u00e9nom BV prostredn\u00edctvom receptorov rozpozn\u00e1vania vzorov (PRR), vr\u00e1tane receptorov podobn\u00fdch Toll, ktor\u00e9 sa nach\u00e1dzaj\u00fa na molekul\u00e1rnych vzoroch spojen\u00fdch s patog\u00e9nmi (PAMP) (70). BV pri terapeutickom ochoren\u00ed je protiz\u00e1palov\u00fd (44), zni\u017euje po\u010det infiltrovan\u00fdch z\u00e1palov\u00fdch buniek a expresiu tumor nekrotizuj\u00faceho faktora (TNF)-a, interleuk\u00ednu (IL)-1p, inhib\u00edciu Toll-like receptora (TLR)2 a CD14 . BV tie\u017e potl\u00e1\u010daj\u00fa v\u00e4zbov\u00fd potenci\u00e1l jadrov\u00e9ho faktora-\u03baB (NF-\u03baB) a aktiva\u010dn\u00e9ho prote\u00ednu (AP)-1 (71). \u013dudsk\u00fd receptor IL-1 (anakinra) tie\u017e vykazuje protiz\u00e1palov\u00fa aktivitu (72), av\u0161ak inform\u00e1cie sp\u00e1jaj\u00face tento receptor a v\u010del\u00ed jed s\u00fa riedke.<\/p>\n\n\n\n

Fosfolip\u00e1za 2 z v\u010delieho jedu (bvPLA2) je hlavn\u00fdm alerg\u00e9nom v BV a stimuluje vroden\u00fd imunitn\u00fd syst\u00e9m v\u00e4zbou na receptory rozpozn\u00e1vaj\u00face vzory (PRR), napr. 2 imunitn\u00e1 odpove\u010f. bvPLA2 indukuje reakcie typu T-helper buniek a vroden\u00e9 lymfoidn\u00e9 bunky skupiny 2 (ILC2) u\u013eah\u010den\u00e9 enz\u00fdmom podporovan\u00fdm \u0161tiepen\u00edm membr\u00e1nov\u00fdch fosfolipidov a sekr\u00e9ciou IL-33. bvPLA2 tie\u017e indukuje produkciu IgE, o ktorej sa uk\u00e1zalo, \u017ee m\u00e1 u my\u0161\u00ed ochranu pred bud\u00facimi alergick\u00fdmi\/imunologick\u00fdmi reakciami [v pr\u00edpade let\u00e1lnej d\u00e1vky BV (70)]. PLA2 hr\u00e1 d\u00f4le\u017eit\u00fa \u00falohu v obrane hostite\u013ea pri diferenci\u00e1cii Th2, aktiv\u00e1cii ILC2, produkcii imunoglobul\u00ednov, prestavbe membr\u00e1ny a protiz\u00e1palov\u00fdch reakci\u00e1ch (44, 70).<\/p>\n\n\n\n

BV vykazuje pozit\u00edvne imunomodula\u010dn\u00e9 \u00falohy; zn\u00ed\u017eenie progresie n\u00e1dorov a aktiv\u00e1cia imunitn\u00e9ho syst\u00e9mu kombin\u00e1ciou bvPLA2 s fosfatidylinozitol-(3,4)-bisfosf\u00e1tom alebo bunkami, najm\u00e4 dendritick\u00fdmi bunkami (DC) (66). DC pripraven\u00e9 s BV in vivo maj\u00fa protirakovinov\u00e9 aj antiv\u00edrusov\u00e9 vlastnosti. DC kombinovan\u00e9 s antig\u00e9nmi z n\u00e1doru alebo v\u00edrusu produkuj\u00fa peptidov\u00e9 epitopy hlavn\u00e9ho histokompatibiln\u00e9ho komplexu (MHC) triedy I a II pre CD8 a CD4 T lymfocyty (obr\u00e1zok 1).<\/p>\n\n\n\n

\"\"
OBR\u00c1ZOK 1. Bunkov\u00e9 a mikrobi\u00e1lne ciele relevantn\u00e9 pre zlo\u017eky v\u010delieho jedu a ciele pre bud\u00faci v\u00fdskum. V\u010del\u00ed jed p\u00f4sob\u00ed prostredn\u00edctvom dendritick\u00fdch buniek na stimul\u00e1ciu imunitn\u00e9ho syst\u00e9mu, prostredn\u00edctvom ktor\u00e9ho aktivuje bunkov\u00fa imunitu. Jeho antioxida\u010dn\u00e1 aktivita je spojen\u00e1 so zn\u00ed\u017een\u00edm reakt\u00edvnych foriem kysl\u00edka (ROS) a zv\u00fd\u0161en\u00edm antioxida\u010dn\u00fdch enz\u00fdmov (napr. GSH a PON1), \u010do vedie k ochrane pred bunkovou smr\u0165ou.<\/figcaption><\/figure>\n\n\n\n

PLA2 (bvPLA2-H34Q) sa via\u017ee na membr\u00e1nu a in vivo kombinuje antig\u00e9ny s membr\u00e1nou \u013eudsk\u00fdch DC buniek, \u010do sp\u00f4sobuje stimul\u00e1ciu CD8 T buniek a antiv\u00edrusov\u00e9 a protin\u00e1dorov\u00e9 vakc\u00edny (DC vakc\u00edna) mo\u017eno z\u00edska\u0165 od BV pomocou DC. Tieto antiv\u00edrusov\u00e9\/protin\u00e1dorov\u00e9 vakc\u00edny na b\u00e1ze buniek sa pou\u017e\u00edvaj\u00fa po\u010das imuniz\u00e1cie proti v\u00edrusom vr\u00e1tane cytomegalov\u00edrusu a na potla\u010denie n\u00e1dorov (73, 74). BV je zn\u00e1ma antimikrobi\u00e1lna a protin\u00e1dorov\u00e1 vakc\u00edna potencovan\u00e1 adjuvans. Melitt\u00edn, bvPLA2 a fosfatidylinozitol-(3,4)-bisfosf\u00e1t s\u00fa \u00fa\u010dinn\u00fdmi adjuvans pre vakc\u00edny proti leishm\u00e1nii, proti n\u00e1dorom a proti cytomegalov\u00edrusom (73\u201375). Konjug\u00e1cia BV peptidov s hormon\u00e1lnymi receptormi a g\u00e9nov\u00e1 terapia pon\u00fakaj\u00fa pozit\u00edvnu modul\u00e1ciu imunitn\u00fdch reakci\u00ed aplikovan\u00e9 pon\u00fakaj\u00fa cielen\u00e9 protirakovinov\u00e9 a protiz\u00e1palov\u00e9 terapie (67).<\/p>\n\n\n\n

BV sa m\u00f4\u017ee pou\u017ei\u0165 ako analgetikum v kontrolovan\u00fdch koncentr\u00e1ci\u00e1ch d\u00e1vky; inhib\u00edcia aktivity cyklooxygen\u00e1zy a blokovanie syst\u00e9mu prostagland\u00ednsyntet\u00e1zy, \u010do vedie k antipyretick\u00fdm, protiz\u00e1palov\u00fdm a antinocicept\u00edvnym\/analgetick\u00fdm kask\u00e1dam (76\u201378). V zriedenej forme m\u00f4\u017ee BV indukova\u0165 antinocicept\u00edvne \u00fa\u010dinky prostredn\u00edctvom \u03b1-adrenergn\u00e9ho receptora (aktiv\u00e1cia miechov\u00e9ho \u03b1-adrenergn\u00e9ho receptora) (61, 62). Konjug\u00e1cia BV peptidov s prote\u00ednov\u00fdmi receptormi, ako s\u00fa horm\u00f3ny a g\u00e9ny transportuj\u00face peptidy, poskytuje inovat\u00edvnu BV kontrolovan\u00fa protiz\u00e1palov\u00fa, antinocicept\u00edvnu a imunomodula\u010dn\u00fa terapiu (67).<\/p>\n\n\n\n

Farmakodynamika zlo\u017eiek v\u010delieho jedu
<\/strong>V\u010del\u00ed jed (BV) obsahuje enz\u00fdmy [fosfolip\u00e1za A2 (PLA2), fosfolip\u00e1za B, hyaluronid\u00e1zy, kysl\u00e9 fosfat\u00e1zy, kysl\u00e9 fosfomonester\u00e1zy, \u03b1-D-glukozid\u00e1zy a lyzofosfolip\u00e1zy]; peptidy lytick\u00fd peptid melit\u00edn, apam\u00edn, mastocyty (\u017e\u00edrne bunky) degranuluj\u00faci peptid, sekap\u00edn, pam\u00edn, minim\u00edn, procam\u00edn A, B, inhib\u00edtor prote\u00e1zy, tertiap\u00edn, kardiopep a adolap\u00edn; a aminokyseliny zah\u0155\u0148aj\u00fa kyselinu g-aminomaslov\u00fa a a-aminokyseliny. Nepeptidov\u00e9 zlo\u017eky zah\u0155\u0148aj\u00fa am\u00edny (dopam\u00edn, histam\u00edn, norepinefr\u00edn, neurotransmitery), sacharidy (gluk\u00f3za, frukt\u00f3za), ferom\u00f3ny (izo-pentylacet\u00e1t; n-butylacet\u00e1t; izo-pentanol; n-hexylacet\u00e1t; n-oktylacet\u00e1t; 2 -nonanol, n-decylacet\u00e1t, benzylacet\u00e1t, benzylalkohol a (2)-11-eikosen-1-ol) (79, 80) (tabu\u013eka 1).<\/p>\n\n\n\n

Uk\u00e1zalo sa, \u017ee BV m\u00e1 protiz\u00e1palov\u00e9, antinocicept\u00edvne, antioxida\u010dn\u00e9 a antiapoptotick\u00e9 vlastnosti a uk\u00e1zalo sa, \u017ee men\u00ed g\u00e9nov\u00fa expresiu a fibr\u00f3zu (81\u201384). Ved\u013eaj\u0161ie \u00fa\u010dinky zah\u0155\u0148aj\u00fa proz\u00e1paly [vy\u0161\u0161ie d\u00e1vky PLA2, peptidy degranuluj\u00face \u017e\u00edrne bunky, hemolytick\u00e9 zl\u00fa\u010deniny (melitt\u00edn)], alergick\u00e9 reakcie na inhib\u00edtory prote\u00e1zy a peptidy, anafylaktick\u00e9 reakcie a smr\u0165 (76).<\/p>\n\n\n\n

Za alergick\u00fa reakciu s\u00fa zodpovedn\u00e9 viacer\u00e9 prote\u00ednov\u00e9 alerg\u00e9ny vo v\u010delom jede (85). Alergick\u00e9 reakcie sa m\u00f4\u017eu vyskytn\u00fa\u0165 v d\u00fdchacom syst\u00e9me, gastrointestin\u00e1lnom syst\u00e9me, kardiovaskul\u00e1rnom syst\u00e9me, ko\u017ei a bodnut\u00ed a m\u00f4\u017eu vy\u00fasti\u0165 do \u0165a\u017ek\u00e9ho anafylaktick\u00e9ho \u0161oku, niekedy ved\u00faceho k cerebr\u00e1lnej alebo myokardi\u00e1lnej isch\u00e9mii (86, 87). Imunitne nesprostredkovan\u00fd mechanizmus alergie na BV zah\u0155\u0148a produkciu medi\u00e1torov bradykin\u00ednu (BK), \u010do vedie k anafylaxii (88) z melit\u00ednovej aktiv\u00e1cie PLA2 (napodob\u0148ovanie BK).<\/p>\n\n\n\n

Biologick\u00e1 variabilita zlo\u017eenia v\u010delieho jedu medzi variantmi v\u010diel na pod\u00e1vanie biotox\u00ednov v komplement\u00e1rnej medic\u00edne
<\/strong>V\u010dely a osy patria do radu hmyzu Hymenoptera (89, 90). U v\u010diel je produkcia jedu najvy\u0161\u0161ia u v\u010del\u00edch kr\u00e1\u013eovien pri vzch\u00e1dzan\u00ed. Jed blanokr\u00eddlovcov sp\u00f4sobuje toxick\u00e9 alebo alergick\u00e9 reakcie v\u00e4\u010d\u0161inou sp\u00f4soben\u00e9 biochemick\u00fdmi zl\u00fa\u010deninami spojen\u00fdmi s lok\u00e1lnym z\u00e1palov\u00fdm p\u00f4soben\u00edm (91, 92). \u017dihadl\u00e1 br\u00e1nia kol\u00f3niu v\u0161etk\u00fdch druhov hmyzu radu Hymenoptera (93, 94). Melitt\u00edn je najv\u00fdznamnej\u0161ou zl\u00fa\u010deninou zodpovednou za tieto alergick\u00e9 reakcie (95, 96); hoci kombin\u00e1cia mastocytov s IgE vyvol\u00e1va aktivitu leukotri\u00e9nov, histam\u00ednov a faktorov aktivuj\u00facich krvn\u00e9 do\u0161ti\u010dky po\u010das alergick\u00fdch reakci\u00ed (93, 94, 97).<\/p>\n\n\n\n

Jedy blanokr\u00eddlovcov obsahuj\u00fa dopam\u00edn, adrenal\u00edn, hyaluronid\u00e1zu, noradrenal\u00edn, seroton\u00edn, histam\u00edn, fosfolip\u00e1zy A a B (85), ale iba BV obsahuje peptid degranuluj\u00faci \u017e\u00edrne bunky, melit\u00edn a apam\u00edn (57). R\u00f4zne druhy v\u010diel; Apis mellifera mellifera a Apis mellifera ligustica (v Eur\u00f3pe) a Apis mellifera scutellate (v Afrike) s\u00fa zodpovedn\u00e9 za \u013eudsk\u00e9 otravy (57). Stredn\u00e1 let\u00e1lna d\u00e1vka BV sa pohybuje od 2,8 do 3,5 mg\/kg telesnej hmotnosti a pri epiz\u00f3de bodnutia sa v priemere pod\u00e1 140\u2013150 \u03bcg BV (57). Pravdepodobnos\u0165 \u00famrtia len na nieko\u013eko bodnut\u00ed v\u010delou je u nealergick\u00fdch os\u00f4b minim\u00e1lna (98) a z\u00e1va\u017enos\u0165 otravy je n\u00e1le\u017eite ovplyvnen\u00e1 telesnou hmotnos\u0165ou, vekom a imunitn\u00fdm stavom obete (99, 100). \u010c\u00edslo bodnutia a ak\u00e1ko\u013evek predch\u00e1dzaj\u00faca senzibiliz\u00e1cia na BV ovplyv\u0148uje z\u00e1va\u017enos\u0165 otravy (99, 100).<\/p>\n\n\n\n

BV je \u010d\u00edra, bezfarebn\u00e1 vodnat\u00e1 kvapalina bez z\u00e1pachu s pH 4,5\u20135,5 s horkastou chu\u0165ou a v niektor\u00fdch pr\u00edpadoch s okrasn\u00fdm \u0161tip\u013eav\u00fdm z\u00e1pachom (101, 102). Zlo\u017eenie BV je ovplyvnen\u00e9 extrak\u010dn\u00fdmi met\u00f3dami kv\u00f4li jeho prchavosti (101). Jed Apis mellifera je pravdepodobne najlep\u0161ie charakterizovan\u00fdm jedom blanokr\u00eddlovcov (103). Jed zo v\u0161etk\u00fdch druhov Apis je podobn\u00fd zlo\u017een\u00edm a kvalitou. A. florea, v\u010dela medonosn\u00e1, je najmen\u0161ia vo svojej rodine, zatia\u013e \u010do A. dorsata je najv\u00e4\u010d\u0161ia (101). Apis cerana jed je dvakr\u00e1t tokick\u00fd ako jed Apis mellifera (104). V jedov\u00fdch \u017e\u013eaz\u00e1ch A. dorsata > A. cerana > A. mellifera > A. florea boli pozorovan\u00e9 rozdiely v zlo\u017een\u00ed sekr\u00e9cie jedovej \u017e\u013eazy a jedov\u00e9ho vaku a koncentr\u00e1cii lipidov, prote\u00ednov, aktivite kyslej fosfat\u00e1zy a hexokin\u00e1zy. Zistilo sa, \u017ee kompoz\u00edcie lipidov, prote\u00ednov, sacharidov a alkalickej fosfat\u00e1zy s\u00fa v porad\u00ed A. cerana > A. mellifera > A. florea. Glykog\u00e9n ch\u00fdbal v jedovej \u017e\u013eaze aj v jedovom vaku druhu Apis (101).<\/p>\n\n\n\n

Variabilita v zlo\u017een\u00ed v\u010delieho jedu s\u00favis\u00ed s druhom, vekom, geografickou lokaliz\u00e1ciou a soci\u00e1lnym stavom (96). Mlad\u00e9 v\u010dely robotnice maj\u00fa ni\u017e\u0161ie koncentr\u00e1cie melit\u00ednu a histam\u00ednu a vy\u0161\u0161ie koncentr\u00e1cie apam\u00ednu ako star\u0161ie v\u010dely robotnice (57). V\u010delie kr\u00e1\u013eovn\u00e9 maj\u00fa n\u00edzke koncentr\u00e1cie melit\u00ednu a apam\u00ednu a vysok\u00e9 koncentr\u00e1cie histam\u00ednu (57). APi M dosahuje svoj vrchol, ke\u010f m\u00e1 v\u010dela ~28 dn\u00ed a s vekom kles\u00e1 (105). Hladiny PLA2 dosahuj\u00fa maximum okolo 10. d\u0148a vyliahnutia (101). Africk\u00e9 v\u010dely uvo\u013e\u0148uj\u00fa mal\u00e9 mno\u017estv\u00e1 jedu pri bodnut\u00ed, s vysok\u00fdmi koncentr\u00e1ciami PLA2 a zn\u00ed\u017een\u00fdmi koncentr\u00e1ciami melit\u00ednu a hyaluronid\u00e1zy (57). Boli hl\u00e1sen\u00e9 sez\u00f3nne odch\u00fdlky v zlo\u017een\u00ed BV (106); napr\u00edklad po\u010das zimy sa produkcia APi M zvy\u0161uje, ale po\u010das leta kles\u00e1 (107, 108).<\/p>\n\n\n\n

S\u00fa\u010dasn\u00e9 terapeutick\u00e9 pokroky v\u010delieho jedu<\/strong><\/p>\n\n\n\n


Antiv\u00edrusov\u00e9 a antibakteri\u00e1lne vlastnosti
<\/strong>Melitt\u00edn a PLA2 vykazuj\u00fa antimikrobi\u00e1lne aktivity a boli pou\u017eit\u00e9 ako doplnkov\u00e9 antibakteri\u00e1lne \u010dinidl\u00e1 (103); vyvolanie tvorby p\u00f3rov a de\u0161trukcie bakt\u00e9ri\u00ed (109). APi M vykazuje antiv\u00edrusov\u00e9 vlastnosti proti niektor\u00fdm obalen\u00fdm v\u00edrusom a neobalen\u00fdm v\u00edrusom in vitro (110). Ochrana bola pozorovan\u00e1 u my\u0161\u00ed po expoz\u00edcii v\u00edrusu chr\u00edpky A H1N1, ale BV m\u00f4\u017ee tie\u017e interagova\u0165 priamo s v\u00edrusov\u00fdm povrchom (110) (obr\u00e1zok 2).<\/p>\n\n\n\n

\"\"
OBR\u00c1ZOK 2. Antimikrobi\u00e1lne a imunomodula\u010dn\u00e9 \u00fa\u010dinky r\u00f4znych zlo\u017eiek v\u010delieho jedu. BV inhibuje bakteri\u00e1lny, antifung\u00e1lny a v\u00edrusov\u00fd rast a z\u00e1rove\u0148 stimuluje aktivitu dendritick\u00fdch buniek prostredn\u00edctvom hlavn\u00fdch protiz\u00e1palov\u00fdch cytok\u00ednov. To pon\u00faka zd\u00f4vodnenie jeho pou\u017eitia v komplement\u00e1rnej medic\u00edne na kontrolu pand\u00e9mie SARS-CoV-2.<\/figcaption><\/figure>\n\n\n\n

Mana\u017ement rakoviny
<\/strong>BV bol sk\u00faman\u00fd pri rakovine (111, 112); melit\u00edn sa pova\u017euje za cytolytick\u00fd, ale ne\u0161pecifick\u00fd. Melitt\u00edn m\u00f4\u017ee rozlo\u017ei\u0165 membr\u00e1nov\u00fa lipidov\u00fa dvojvrstvu a pri intraven\u00f3znej injekcii vykazuje toxicitu (113). APi M m\u00e1 schopnos\u0165 potla\u010di\u0165 rast n\u00e1dorov v bunk\u00e1ch rakoviny prsn\u00edka, pe\u010dene, prostaty a p\u013e\u00fac (111, 112). \u0160t\u00fadie in vitro a in vivo ukazuj\u00fa, \u017ee melit\u00edn m\u00f4\u017ee potla\u010di\u0165 rast rakovinov\u00fdch buniek inhib\u00edciou signaliz\u00e1cie NF-KB a aktiv\u00e1ciou dr\u00e1h kasp\u00e1zy 3 a 9. Inhib\u00edcia motility buniek hepatocelul\u00e1rneho karcin\u00f3mu sa pozorovala in vitro a in vivo potla\u010den\u00edm dr\u00e1h z\u00e1visl\u00fdch od Rac1 (114).<\/p>\n\n\n\n

Protiz\u00e1palov\u00fd potenci\u00e1l
<\/strong>N\u00edzke d\u00e1vky BV sp\u00fa\u0161\u0165aj\u00fa cel\u00fd rad protiz\u00e1palov\u00fdch reakci\u00ed, ktor\u00e9 sa sk\u00famali pri cukrovke, reumatoidnej artrit\u00edde (RA), srdcov\u00fdch ochoreniach, obezite, astme, ko\u017en\u00fdch ochoreniach a ochoreniach spojen\u00fdch s centr\u00e1lnym nervov\u00fdm syst\u00e9mom (Alzheimerova choroba, Parkinsonova choroba a amyotrofick\u00e1 later\u00e1lna skler\u00f3za) (63, 64). BV potl\u00e1\u010da z\u00e1palov\u00e9 cytok\u00edny, vr\u00e1tane interleuk\u00ednu-6 (IL-6), IL-8, interfer\u00f3nu-y (IFN-y) a tumor nekrotizuj\u00faceho faktora-a (TNF-a). Zn\u00ed\u017eenie sign\u00e1lnych dr\u00e1h zodpovedn\u00fdch za aktiv\u00e1ciu z\u00e1palov\u00fdch cytok\u00ednov, nukle\u00e1rneho faktora-kappa B (NF-KB), kin\u00e1z regulovan\u00fdch extracelul\u00e1rnym sign\u00e1lom (ERK1\/2) a prote\u00ednkin\u00e1zy Akt a lipopolysacharidu Porphyromonas gingivalis (PgLPS) lie\u010den\u00fdch \u013eud\u00ed keratinocyty s\u00fa spojen\u00e9 s lie\u010dbou melit\u00ednom(65) (obr\u00e1zok 2).<\/p>\n\n\n\n

Odpovede hostite\u013ea na v\u010del\u00ed jed \/BV\/<\/strong>
BV terapia m\u00f4\u017ee zmierni\u0165 ochorenia s\u00favisiace s imunitou. Sekre\u010dn\u00e1 fosfolip\u00e1za A2 skupiny III z BV (BV skupina III sPLA2) vykazuje in vitro a in vivo aktivitu na imunitn\u00fd syst\u00e9m a pou\u017e\u00edva sa na zvl\u00e1dnutie astmy, Parkinsonovej choroby a z\u00e1palu org\u00e1nov vyvolan\u00e9ho liekmi (69). BV imunitn\u00e9 reakcie m\u00f4\u017eu by\u0165 nebezpe\u010dn\u00e9, ke\u010f s\u00fa vysoko zv\u00fd\u0161en\u00e9, ale ke\u010f je kontrolovan\u00e1, alergick\u00e1 imunita m\u00f4\u017ee by\u0165 v\u00fdhodn\u00e1 pri obrane hostite\u013ea na stimul\u00e1ciu imunitn\u00fdch reakci\u00ed 2. typu. Imunita 2. typu je zalo\u017een\u00e1 najm\u00e4 na bari\u00e9rovej obrane a tieto reakcie s\u00fa iniciovan\u00e9 pomocn\u00fdmi T bunkami typu 2 (TH2), protil\u00e1tkami imunoglobul\u00ednov E a G1 (IgE a IgG1) a \u010fal\u0161\u00edmi zlo\u017ekami vroden\u00e9ho imunitn\u00e9ho syst\u00e9mu (epiteli\u00e1lne bari\u00e9ry, vroden\u00e9 lymfoidn\u00e9 bunky-ILC, eozinofily, \u017e\u00edrne bunky, bazofily a aktivovan\u00e9 makrof\u00e1gy) (68). Vroden\u00fd imunitn\u00fd syst\u00e9m vn\u00edma zlo\u017eky jedu a vyvol\u00e1va obrann\u00fa imunitn\u00fa odpove\u010f proti antig\u00e9nom prostredn\u00edctvom receptorov rozpozn\u00e1vania vzorov (PRR), napr. Toll-like receptorov, ktor\u00e9 sa nach\u00e1dzaj\u00fa na molekulov\u00fdch vzorcoch spojen\u00fdch s patog\u00e9nmi (PAMP) (70). Protiz\u00e1palov\u00e9 vlastnosti BV (44) m\u00f4\u017eu inhibova\u0165 aktivitu z\u00e1palov\u00fdch antig\u00e9nov, zn\u00ed\u017ei\u0165 po\u010det infiltrovan\u00fdch z\u00e1palov\u00fdch buniek a inhibova\u0165 expresiu (TNF)-\u03b1, IL-1\u03b2, Toll-like receptor (TLR)2 a CD14 potl\u00e1\u010daj\u00fac v\u00e4zbov\u00fa aktivitu jadrov\u00e9ho faktora-KB (NF-KB) a aktiva\u010dn\u00e9ho prote\u00ednu (AP)-1 (71). Hlavn\u00fd alerg\u00e9n Bet V 1, PLA2, stimuluje vroden\u00fd imunitn\u00fd syst\u00e9m, via\u017ee sa na PRR, napr. Toll-like receptory, ktor\u00e9 rozpozn\u00e1vaj\u00fa PAMP, \u010d\u00edm sp\u00fa\u0161\u0165a imunitn\u00fa odpove\u010f typu 2 u my\u0161\u00ed. PLA2 v BV indukuje reakcie typu T pomocn\u00fdch buniek typu 2 (Th2) a aktiv\u00e1ciu vroden\u00fdch lymfoidn\u00fdch buniek skupiny 2 (ILC2) prostredn\u00edctvom enzymatick\u00e9ho \u0161tiepenia membr\u00e1nov\u00fdch fosfolipidov a sekr\u00e9cie IL-33. PLA2 indukuje produkciu IgE, \u010d\u00edm chr\u00e1ni my\u0161i pred bud\u00facimi alergick\u00fdmi\/imunologick\u00fdmi reakciami v pr\u00edpade let\u00e1lnej d\u00e1vky BV (70); PLA2 hr\u00e1 rozhoduj\u00facu \u00falohu v obrane hostite\u013ea zlep\u0161en\u00edm diferenci\u00e1cie Th2, aktiv\u00e1cie ILC2, produkcie imunoglobul\u00ednov, prestavby membr\u00e1ny a protiz\u00e1palov\u00fdch reakci\u00ed (44, 70).<\/p>\n\n\n\n

Vakc\u00edny <\/strong>
BV m\u00f4\u017ee potla\u010di\u0165 progresiu n\u00e1dorov a aktivova\u0165 imunitn\u00fd syst\u00e9m kombin\u00e1ciou sekre\u010dnej fosfolip\u00e1zy A2 v BV so zl\u00fa\u010deninami vr\u00e1tane fosfatidylinozitol-(3,4)-bisfosf\u00e1tu alebo dendritick\u00fdch buniek (DC) (66). DC o\u0161etren\u00e9 BV in vivo vykazuj\u00fa protirakovinov\u00e9 a antiv\u00edrusov\u00e9 vlastnosti. DC kombinovan\u00e9 s antig\u00e9nmi z n\u00e1doru alebo v\u00edrusu m\u00f4\u017eu produkova\u0165 peptidov\u00e9 epitopy hlavn\u00e9ho histokompatibiln\u00e9ho komplexu (MHC) triedy I a triedy II pre CD8 a CD4 T lymfocyty, \u010do vedie k s\u00e9rii imunitn\u00fdch reakci\u00ed v reakcii na antig\u00e9ny. BV fosfolip\u00e1za A2 (bvPLA2-H34Q) sa via\u017ee na membr\u00e1nu a sp\u00e1ja antig\u00e9ny v bunkovej membr\u00e1ne \u013eudsk\u00fdch DC in vivo. To indukuje rozpozn\u00e1vanie a aktiv\u00e1ciu CD8 T buniek s t\u00fdm, \u017ee antiv\u00edrusov\u00e9 a protin\u00e1dorov\u00e9 vakc\u00edny m\u00f4\u017eu by\u0165 odvoden\u00e9 z BV (DC vakc\u00edna). Vakc\u00edny od BV a DC (bunkov\u00e9 antiv\u00edrusov\u00e9\/protin\u00e1dorov\u00e9 vakc\u00edny) sa pou\u017e\u00edvaj\u00fa na imuniz\u00e1ciu proti v\u00edrusom, ako je cytomegalov\u00edrus, a na potla\u010denie n\u00e1dorov (73, 74). BV mo\u017eno pou\u017ei\u0165 ako siln\u00fa antimikrobi\u00e1lnu a protin\u00e1dorov\u00fa vakc\u00ednu zosilnen\u00fa adjuvans a vykazuje potenci\u00e1l vo vakc\u00ednach obsahuj\u00facich melit\u00edn. sPLA2 a fosfatidylinozitol-(3,4)-bisfosf\u00e1t s\u00fa \u00fa\u010dinn\u00fdmi adjuvans (proti leishm\u00e1nii, protin\u00e1dorov\u00fdm a anticytomegalov\u00edrusov\u00fdm vakc\u00ednam) (73\u201375).<\/p>\n\n\n\n

Ved\u00facim adjuvantom terapi\u00ed SARS-CoV-2, ktor\u00e9 sa v s\u00fa\u010dasnosti podporuje, je hydroxid hlinit\u00fd kv\u00f4li jeho pomal\u00e9mu uvo\u013e\u0148ovaniu a zv\u00fd\u0161enej interakcii s bunkami prezentuj\u00facimi antig\u00e9n (115). V\u010del\u00ed jed pon\u00faka kandid\u00e1ta na kontrolu infekci\u00ed SARS-CoV-2 a mohol by pon\u00faknu\u0165 v\u00fdhody proti COVID-19. PLA2 bola spojen\u00e1 s \u00farov\u0148ou \u00faspechu proti infekci\u00e1m SARS-CoV-2 (116, 117). Konjug\u00e1cia BV peptidov by mohla pon\u00faknu\u0165 nov\u00fd pr\u00edstup vo v\u00fdvoji BV vakc\u00edny.<\/p>\n\n\n\n

Potenci\u00e1lny vz\u0165ah medzi prote\u00ednmi v\u010delieho jedu a prote\u00ednmi COVID-19
<\/strong>SARS-CoV-2 patr\u00ed do rodu \u03b2-koronav\u00edrusov. SARS-CoV-2 m\u00e1 \u0161tyri zrejm\u00e9 \u0161truktur\u00e1lne prote\u00edny: membr\u00e1nov\u00fd, hrotov\u00fd, nukleokapsidov\u00fd prote\u00edn a obal. \u0160truktur\u00e1lna integrita v\u00edrusu SARS-CoV-2 je udr\u017eiavan\u00e1 \u0161truktur\u00e1lnymi prote\u00ednmi a vytv\u00e1ra ochrann\u00fd obal okolo jeho RNA. Membr\u00e1na koronav\u00edrusu obsahuje 3 alebo 4 v\u00edrusov\u00e9 prote\u00edny (118, 119), membr\u00e1nov\u00fd glykoprote\u00edn je najhojnej\u0161\u00edm \u0161truktur\u00e1lnym prote\u00ednom a trikr\u00e1t pokr\u00fdva membr\u00e1nov\u00fa dvojvrstvu, s dlh\u00fdm COOH koncom vo viri\u00f3ne a kr\u00e1tkou NH2-koncovou dom\u00e9nou mimo v\u00edrusu (120). Gen\u00f3m SARS-CoV-2 k\u00f3duje nieko\u013eko \u010d\u00edtac\u00edch r\u00e1mcov (ORF); ORF1a\/b k\u00f3duje 16 ne\u0161truktur\u00e1lnych prote\u00ednov a preklad\u00e1 dva polyprote\u00edny (pp1a a pp1ab), ktor\u00e9 tvoria a\u017e 2\/3 v\u00edrusovej RNA. Zvy\u0161n\u00e9 ORF k\u00f3duj\u00fa \u0161truktur\u00e1lne prote\u00edny (\u0161pi\u010dkov\u00fd glykoprote\u00edn, matricov\u00fd prote\u00edn, nukleokapsidov\u00fd prote\u00edn a mal\u00fd obalov\u00fd prote\u00edn) (118, 119). SARS-CoV-2 m\u00e1 doplnkov\u00e9 prote\u00edny, ktor\u00e9 interferuj\u00fa s vrodenou imunitnou odpove\u010fou hostite\u013ea (118).<\/p>\n\n\n\n

\u0160pi\u010dkov\u00fd prote\u00edn je zvy\u010dajne membr\u00e1nov\u00fd glykoprote\u00edn typu I a tvor\u00ed peplom\u00e9ry, o ktor\u00fdch je zn\u00e1me, \u017ee sa podie\u013eaj\u00fa na interakcii protil\u00e1tky. Membr\u00e1na hr\u00e1 v\u00fdznamn\u00fa \u00falohu pri intracelul\u00e1rnej tvorbe v\u00edrusov\u00fdch \u010dast\u00edc nez\u00e1visle od v\u00edrusovej \u0161pi\u010dky. Koronav\u00edrusy rast\u00fa a produkuj\u00fa formy bez hrotov v pr\u00edtomnosti tunicamyc\u00ednu, \u010do vedie k produkcii neinfek\u010dn\u00fdch viri\u00f3nov, ktor\u00e9 obsahuj\u00fa membr\u00e1ny, ale bez hrotov (118).<\/p>\n\n\n\n

Melitt\u00edn m\u00f4\u017ee prepichn\u00fa\u0165 ochrann\u00e9 membr\u00e1nov\u00e9 obaly obklopuj\u00face v\u00edrusy vr\u00e1tane v\u00edrusu \u013eudskej imunodeficiencie (HIV) (119). Mnoh\u00e9 v\u00edrusy, vr\u00e1tane SARS-CoV-2, sa spoliehaj\u00fa na svoj ochrann\u00fd obal a m\u00f4\u017eu by\u0165 zranite\u013en\u00e9 pri terapii v\u010del\u00edm jedom veden\u00fdm melit\u00ednom (tabu\u013eka 1).<\/p>\n\n\n\n

Zlo\u017eky fosfolip\u00e1zy A2 v\u010delieho jedu maj\u00fa potenci\u00e1l pre antiv\u00edrusov\u00e9 aktivity (121). Nano\u010dastice naplnen\u00e9 melitt\u00ednom dod\u00e1vali zna\u010dn\u00e9 mno\u017estvo melit\u00ednu intraven\u00f3zne, pri\u010dom sa zameriavali a zab\u00edjali prekancer\u00f3zne l\u00e9zie u my\u0161\u00ed K14-HPV16 so skvam\u00f3znou dyspl\u00e1ziou a karcin\u00f3mom obsahuj\u00facim transg\u00e9nne prvky \u013eudsk\u00e9ho papilomav\u00edrusu (HPV) (onkog\u00e9ny E6 a E7) (122, 123).<\/p>\n\n\n\n

V provincii Chu-pej, epicentre prepuknutia SARS-CoV-2 v \u010c\u00edne, vykonalo miestne zdru\u017eenie v\u010del\u00e1rov medzi 23. febru\u00e1rom a 8. marcom prieskum medzi 5 115 v\u010del\u00e1rmi (vr\u00e1tane 723 vo Wu-chane) a uk\u00e1zalo sa, \u017ee u \u017eiadneho sa u pacientov s COVID-19 nerozvinuli \u017eiadne pr\u00edznaky ( 124). Op\u00fdtan\u00fdch bolo p\u00e4\u0165 apiterapeutov vo Wu-chane a 121 ich pacientov, ktor\u00ed absolvovali apiterapiu v obdob\u00ed od okt\u00f3bra do decembra 2019; dvaja apiterapeuti boli vystaven\u00ed podozriv\u00fdm a\/alebo potvrden\u00fdm obetiam COVID-19 bez ochrany. U \u017eiadneho z apiterapeutov sa nerozvinuli sympt\u00f3my s\u00favisiace so SARS-CoV-2 a \u017eiadny z ich 121 pacientov sa nenakazil COVID 19, napriek tomu, \u017ee 3 boli vystaven\u00ed pr\u00edbuzn\u00fdm infikovan\u00fdm SARS-CoV-2 (124).<\/p>\n\n\n\n

Apiterapia vyu\u017e\u00edva v\u010dely medonosn\u00e9 a ich produkty (BV, med, matersk\u00e1 ka\u0161i\u010dka, pe\u013e, propolis, v\u010del\u00ed vosk). BV terapia vyu\u017e\u00edva jed na modul\u00e1ciu imunitn\u00e9ho syst\u00e9mu tela a zlep\u0161enie\/u\u013eah\u010denie hojenia a zah\u0155\u0148a bu\u010f pou\u017eitie \u017eiv\u00fdch v\u010del\u00edch bodnut\u00ed alebo injek\u010dn\u00e9ho jedu na lie\u010dbu artrit\u00eddy, reumatoidnej artrit\u00eddy, roztr\u00fasenej skler\u00f3zy (MS), lupusu, ischias, bolesti kr\u00ed\u017eov, a tenisov\u00fd lake\u0165 (125, 126). Produkty blanokr\u00eddlovcov s\u00fa siln\u00fdmi ur\u00fdch\u013eova\u010dmi hojenia r\u00e1n (127). Hmyz\u00ed jed je v porovnan\u00ed s had\u00edm jedom menej zlo\u017eit\u00fd a menej variabiln\u00fd v zlo\u017een\u00ed a fyziologickej aktivite (125, 126). BV sa m\u00f4\u017ee pod\u00e1va\u0165 na vyvolanie alergick\u00fdch imunitn\u00fdch reakci\u00ed stimuluj\u00facich vroden\u00fd imunitn\u00fd syst\u00e9m hostite\u013ea (68) v d\u00f4sledku pr\u00edtomnosti alerg\u00e9nov, ktor\u00e9 podporuj\u00fa imunitn\u00e9 reakcie typu 2 (44, 68\u201371). Protiv\u00edrusov\u00fd a protin\u00e1dorov\u00fd \u00fa\u010dinok BV, ke\u010f sa BV sekre\u010dn\u00e1 fosfolip\u00e1za A2 zmie\u0161a s in\u00fdmi zl\u00fa\u010deninami, ako je fosfatidylinozitol-(3,4)-bisfosf\u00e1t alebo dendritick\u00e9 bunky a\/alebo v\u010delie prote\u00edny, ako je melit\u00edn, je v\u00fdhodn\u00fd (66) a pou\u017e\u00edva sa v produkcia bunkov\u00fdch antiv\u00edrusov\u00fdch\/protin\u00e1dorov\u00fdch vakc\u00edn (73\u201375). Imunologick\u00e9 vlastnosti BV sa nach\u00e1dzaj\u00fa aj v pr\u00edrodn\u00fdch produktoch, ktor\u00e9 napodob\u0148uj\u00fa v\u010del\u00ed jed (127, 128), a \u010fal\u0161\u00edch \u0161t\u00fadi\u00e1ch t\u00fdkaj\u00facich sa \u00falohy v\u010delieho jedu ako potenci\u00e1lneho kandid\u00e1ta na pou\u017eitie v komplement\u00e1rnej medic\u00edne pri lie\u010dbe v\u00edrusov, ako je SARS-CoV- 2 mohli zv\u00e1\u017ei\u0165 in\u00e9 pr\u00edrodn\u00e9 produkty, ktor\u00e9 napodob\u0148uj\u00fa aktivitu BV.<\/p>\n\n\n\n

Bud\u00faci v\u00fdskum v\u010delieho jedu
<\/strong>V\u00fdvoj adjuvantn\u00fdch terapi\u00ed (pomocou APi M a PLA2) na pou\u017eitie proti infekci\u00e1m SARS-CoV-2 pon\u00faka jedine\u010dn\u00fd pr\u00edstup k v\u00edrusovej terapii. V\u00fdvoj vakc\u00edny proti v\u010del\u00edmu jedu pomocou DC s pou\u017eit\u00edm APi M a bvPLA2 pon\u00faka nov\u00fa pr\u00edle\u017eitos\u0165 na doplnkov\u00e9 medic\u00ednske z\u00e1sahy proti infekci\u00e1m SARS-CoV-2. \u0160t\u00fadie na sk\u00famanie bunkovej signaliz\u00e1cie medzi prote\u00ednmi BV, Janus kin\u00e1zou (JAK) a aktiv\u00e1torom transkripcie (JAK-STAT) by pomohli posilni\u0165 jej prijatie v komplement\u00e1rnej medic\u00edne proti SARS-CoV-2. Inhib\u00edtory JAK s\u00fa spojen\u00e9 so zlep\u0161enou progn\u00f3zou u pacientov s COVID-19 (72, 129), ale na objasnenie bunkov\u00fdch mechanizmov s\u00fa potrebn\u00e9 \u0161t\u00fadie. Synergick\u00e1 aktivita prostredn\u00edctvom kombin\u00e1ci\u00ed v alternat\u00edvnej a komplement\u00e1rnej medic\u00edne by pomohla bojova\u0165 proti ved\u013eaj\u0161\u00edm \u00fa\u010dinkom spojen\u00fdm so s\u00fa\u010dasn\u00fdmi monoterapiami na zvl\u00e1danie infekci\u00ed SARS-CoV-2. SARS-CoV-2 je nov\u00fd v\u00edrus a m\u00f4\u017eu by\u0165 potrebn\u00e9 nov\u00e9 terapie na podporu mana\u017ementu v priebehu \u010dasu a m\u00f4\u017eu by\u0165 cenn\u00e9 pri podpore imunitnej odpovede u pacientov trpiacich takzvan\u00fdm dlhotrvaj\u00facim COVID.<\/p>\n\n\n\n

Z\u00e1ver<\/strong>
\u00da\u010dinky SARS-CoV-2 na receptory ACE2 s\u00fa spojen\u00e9 so z\u00e1va\u017enou z\u00e1palovou aktivitou a zlou progn\u00f3zou v z\u00e1vislosti od sprievodn\u00fdch ochoren\u00ed pacienta a in\u00fdch s\u00favisiacich rizikov\u00fdch faktorov. Aj ke\u010f sa pacient zotav\u00ed z po\u010diato\u010dnej infekcie, m\u00f4\u017ee by\u0165 konfrontovan\u00fd s dlhou a komplikovanou rekonvalescenciou a\/alebo takzvan\u00fdm dlhodob\u00fdm ochoren\u00edm COVID. Je nepravdepodobn\u00e9, \u017ee \u010doskoro bude k dispoz\u00edcii magick\u00e1 terapia COVID-19 a mali by sa presk\u00fama\u0165 doplnkov\u00e9 terapie, ktor\u00e9 dop\u013a\u0148aj\u00fa konven\u010dn\u00fa terapiu a podporuj\u00fa zdrav\u00e9 zotavenie. BV melit\u00edn a aktivita fosfolip\u00e1zy A2 maj\u00fa siln\u00fd protiz\u00e1palov\u00fd \u00fa\u010dinok a mohli by sa pou\u017ei\u0165 na podporu zotavenia. To, \u017ee sa BV \u00faspe\u0161ne pou\u017e\u00edva na zvl\u00e1danie neurologick\u00fdch a imunologick\u00fdch ochoren\u00ed, posil\u0148uje d\u00f4vod na sk\u00famanie jeho pou\u017eitia v doplnkovej medic\u00edne pri infekci\u00e1ch SARS-CoV-2. BV je potenci\u00e1lnym adjuvans proti COVID-19, ktor\u00fd by sa mal prida\u0165 do zoznamu hlavn\u00fdch terapi\u00ed.<\/p>\n\n\n\n

Autorsk\u00e9 pr\u00edspevky
V\u0161etci uveden\u00ed autori v\u00fdznamne, priamo a intelektu\u00e1lne prispeli k dielu a schv\u00e1lili ho na zverejnenie.<\/p>\n\n\n\n

Financovanie
T\u00fato pr\u00e1cu podporil Fond pre n\u00fadzov\u00fd v\u00fdskum nad\u00e1cie Zhejiang University Education Foundation (SCW); Global Challenges Research Fund a University of Edinburgh.<\/p>\n\n\n\n

Konflikt z\u00e1ujmov
Autori vyhlasuj\u00fa, \u017ee v\u00fdskum bol vykonan\u00fd bez ak\u00fdchko\u013evek obchodn\u00fdch alebo finan\u010dn\u00fdch vz\u0165ahov, ktor\u00e9 by mohli by\u0165 ch\u00e1pan\u00e9 ako potenci\u00e1lny konflikt z\u00e1ujmov.<\/p>\n\n\n\n

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Zdroj: https:\/\/www.frontiersin.org\/articles\/10.3389\/fpubh.2020.594458\/full#F1<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"

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