Цинк, медь, селен и витамин К
Oct. 19th, 2021 11:38 pm![[personal profile]](https://www.dreamwidth.org/img/silk/identity/user.png){kind=small}
chuka_lisРабота по анализу ассоциаций между уровнями "полезных" макроэлементов: цинка, меди, селена, и ваитмина К, в плазме и крови, и случаями заболевания ковидом, а так же госпитализациями и смертью от ковида показала, что надежды на то, что прием этих препаратов (и более высокие "защитные" уровни) может "облегчить" или предотвратить ковид- напрасны.
Corolla ry to drug repurposing efforts, the potential role o f micronutr ient s uppleme nta tion towards prev enting and all evia ting COVID-19 has been proposed(4,5). Suppl ements ha ve some unique advantages as they are inexpensiv e, widely ava ilable over-the -counter, eas ily distributed and s tored, genera lly well tolera ted a nd w ell characteris ed in t erms of s afety. Amongs t vitami ns and mineral s, good mechanistic reas ons for more res earch exis t for zinc, sel eni um, c opper and vitamin K1, chie fly due to the ir imp ortant roles in im mune a nd antiviral response(4). Zinc (Zn) is an ess entia l trace metal w ith s tructural roles in regulato ry prot eins, as enzy me cofactor, and as a s ignalling molecule . Of rel evance to COVID-19, zi nc deficiency can lead to dys functional immune response with reduc ed activity of innate i mmune c ells(6,7), lymphopenia(8) a nd a cti vation of N F-KB s ignalling inducing production of IL-6 and other cytokines involved in “ cytokine storm” , characteris tic of COVID-19(9–11). Furthermo re, zinc has manifold antivi ral properti es in v i tro and in v ivo(12,13). With respect to SARS-CoV, Zn combined with a ionophore was shown to inhibi t its RNA polymera se and block v irus replication in cell c ultur e(14). In S ARS-CoV-2, Zn2+ inhib its the main p roteas e (Mpro) whic h results in reduced viral replication in cell culture(15). Limit ed evidence fr om randomized tria ls on common cold suggests beneficial effect of zinc supplementation o n cold duration and les s concl us ively, incidence and severi ty(16), while adjuvant t rea tmen t in severe paediatri c pneumonia reduced hospital s tay (17). Selenium (Se) is a constituent of 25 sel enopro tei ns with func tions in re dox homeos tas is, endoplasmic reticulum stress and infla mmatory res pons e(18). Overall, Se can be a partial determinan t of v ira l v irul ence(19). S ub-optima lly low Se intake is combined with coxsacki evirus infection in aeti ol og y of Keshan diseas e(20). F urthermore, immunoc ompetence for infecti on c le ara nc e with other vi ral dise ases is decreas ed in Se deficiency (21) and marginal Se s tatus(22). In vitro, Se supplementati on was shown to inhibit replication of porcine c irc ov irus (23). Ebs elen, a sy nthetic organoselenium compound, was found to be one of the mos t ef fective SARS-CoV-2 main pro teas e (Mpro) i nh i b i t o r s b y forming a selenyl s ulphi de bond wi th the protease’s catalytic dy ad(24,25) which provides a potentia l mode o f antiv iral action for organic s elenium molec ules, s imi larly to ionic zinc. In addition, ebselen is func tionally relat ed to glutathi one perox idase 1, a major s elenoenz yme which has been also found to phy sical ly interac t wi th Mpro(26). Other mec hanis ms through which S e could help in COVID-19 management is through c ontrol of ROS-driv en endoth elial damage(18), reduced IL -6 pathway res pons e(27–29) and s timulation of inn ate immune system(30,31). Copper (Cu) is indis pensable for the p rocess es of respirati on, free rad ical defence and immune regulat ion due to its struc tural role in cuproenzymes(32,33). Similar to Zn, Cu pl ays an essential part in an tioxidan t response ac tiv ated during inf lammation. Copper defic iency can result in neutropenia and immun osuppression vi a reduced T-c ell prolif eration(34). Inactivation of vi ruses, i nc luding SARS-CoV-2(35) on c opper surfaces is widely exploited in clinic al practice(36), but Cu2+ w as also reported to decrease infec tiv i ty of HIV(37), influenza(38) virus and SARS-CoV-2(39) in mammal ia n cells. Copper can also exert ant ivi ral properti es potential ly by stimulating autophagy (40). Two vitamers of vitam in K exis t: K1 (phylloquinone) and K2 ( menaquinone)( 41). Vitamin K is necessary for a cti vation of pro - and a nti- cl ott ing factors in the live r and pe ripheral tissues , respectively. Moreover, v ita min K a cti vates Matrix G la protein (MGP) which i nhibits elastic fibre deg radati on and vas cular mi ner alis ati on. Ex trahepatic vitamin K de ficiency and low MGP activi ty hav e been found in hospitalis ed COVID-19 patients (42,43). Acc ording to Janss en et al (2021)(44), this could result from increased degradation of e l astic fibres by SARS-CoV-2 promot ing lung fibros is a nd c onc omitant with predic ted depl etion o f endotheli a l vita min K-depen dent anti -coagulant (protein S) l ead to coagulopathy. Therefore, vitamin K could prov ide adjunct thera py of thrombosis events which are characteristic of sev ere COVID-19(45). In the absence of well -powered ra nd omiz ed control trial s (RCT) testing the prophyl actic and therapeut ic potential of these mic ron utrients, w e decided to carry out a Mendelian Randomi zation (MR ) ass ess ment of their poten tial causal e ffects. MR is an established caus al inferenc e method which us es genetic v aria nts as ins trumental v aria ble s(46).
We employed two-sample Mendelian Randomization (MR) analysis. Our genetic variants derived from European-ancestry GWAS reflected circulating levels of Zn, Cu, Se in red blood cells as well as Se and vitamin K1 in serum/plasma. For the COVID-19 outcome GWAS, we used infection, hospitalization or critical illness. Our inverse-variance weighted (IVW) MR analysis was complemented by sensitivity analyses: more liberal selection of variants at genome-wide subsignificant threshold, MR-Egger and weighted median/mode tests. Results: Circulating micronutrient levels show limited evidence of association with COVID-19 infection with odds ratio [OR] ranging from 0.97 (95% CI: 0.87-1.08, p-value=0.55) for zinc to 1.07 (95% CI: 1.00-1.14, p-value=0.06) - ie. no beneficial effect for copper, per 1 SD increase in exposure. Similarly minimal evidence was obtained for the hospitalization and critical illness outcomes with OR from 0.98 (95% CI: 0.87-1.09, p-value=0.66) for vitamin K1 to 1.07 (95% CI: 0.88-1.29, p-value=0.49) for copper, and from 0.93 (95% CI: 0.72-1.19, p-value=0.55) for vitamin K1 to 1.21 (95% CI: 0.79-1.86, p-value=0.39) for zinc, respectively. Our analys es attempted to e lucidate the poten tial o f zinc, s elenium, copper a nd v ita min K1 in prophyl axis and treatment of COVID-19 using MR techniques. However, we found little evidence of c ausal associa tion of genetically predicted micronutrien t concentration on COVID-19 outcomes. Conclusions: This study does not provide evidence that supplementation with zinc, selenium, copper or vitamin K1 can prevent SARS-CoV-2 infection, critical illness or hospitalization for COVID-19.
Corolla ry to drug repurposing efforts, the potential role o f micronutr ient s uppleme nta tion towards prev enting and all evia ting COVID-19 has been proposed(4,5). Suppl ements ha ve some unique advantages as they are inexpensiv e, widely ava ilable over-the -counter, eas ily distributed and s tored, genera lly well tolera ted a nd w ell characteris ed in t erms of s afety. Amongs t vitami ns and mineral s, good mechanistic reas ons for more res earch exis t for zinc, sel eni um, c opper and vitamin K1, chie fly due to the ir imp ortant roles in im mune a nd antiviral response(4). Zinc (Zn) is an ess entia l trace metal w ith s tructural roles in regulato ry prot eins, as enzy me cofactor, and as a s ignalling molecule . Of rel evance to COVID-19, zi nc deficiency can lead to dys functional immune response with reduc ed activity of innate i mmune c ells(6,7), lymphopenia(8) a nd a cti vation of N F-KB s ignalling inducing production of IL-6 and other cytokines involved in “ cytokine storm” , characteris tic of COVID-19(9–11). Furthermo re, zinc has manifold antivi ral properti es in v i tro and in v ivo(12,13). With respect to SARS-CoV, Zn combined with a ionophore was shown to inhibi t its RNA polymera se and block v irus replication in cell c ultur e(14). In S ARS-CoV-2, Zn2+ inhib its the main p roteas e (Mpro) whic h results in reduced viral replication in cell culture(15). Limit ed evidence fr om randomized tria ls on common cold suggests beneficial effect of zinc supplementation o n cold duration and les s concl us ively, incidence and severi ty(16), while adjuvant t rea tmen t in severe paediatri c pneumonia reduced hospital s tay (17). Selenium (Se) is a constituent of 25 sel enopro tei ns with func tions in re dox homeos tas is, endoplasmic reticulum stress and infla mmatory res pons e(18). Overall, Se can be a partial determinan t of v ira l v irul ence(19). S ub-optima lly low Se intake is combined with coxsacki evirus infection in aeti ol og y of Keshan diseas e(20). F urthermore, immunoc ompetence for infecti on c le ara nc e with other vi ral dise ases is decreas ed in Se deficiency (21) and marginal Se s tatus(22). In vitro, Se supplementati on was shown to inhibit replication of porcine c irc ov irus (23). Ebs elen, a sy nthetic organoselenium compound, was found to be one of the mos t ef fective SARS-CoV-2 main pro teas e (Mpro) i nh i b i t o r s b y forming a selenyl s ulphi de bond wi th the protease’s catalytic dy ad(24,25) which provides a potentia l mode o f antiv iral action for organic s elenium molec ules, s imi larly to ionic zinc. In addition, ebselen is func tionally relat ed to glutathi one perox idase 1, a major s elenoenz yme which has been also found to phy sical ly interac t wi th Mpro(26). Other mec hanis ms through which S e could help in COVID-19 management is through c ontrol of ROS-driv en endoth elial damage(18), reduced IL -6 pathway res pons e(27–29) and s timulation of inn ate immune system(30,31). Copper (Cu) is indis pensable for the p rocess es of respirati on, free rad ical defence and immune regulat ion due to its struc tural role in cuproenzymes(32,33). Similar to Zn, Cu pl ays an essential part in an tioxidan t response ac tiv ated during inf lammation. Copper defic iency can result in neutropenia and immun osuppression vi a reduced T-c ell prolif eration(34). Inactivation of vi ruses, i nc luding SARS-CoV-2(35) on c opper surfaces is widely exploited in clinic al practice(36), but Cu2+ w as also reported to decrease infec tiv i ty of HIV(37), influenza(38) virus and SARS-CoV-2(39) in mammal ia n cells. Copper can also exert ant ivi ral properti es potential ly by stimulating autophagy (40). Two vitamers of vitam in K exis t: K1 (phylloquinone) and K2 ( menaquinone)( 41). Vitamin K is necessary for a cti vation of pro - and a nti- cl ott ing factors in the live r and pe ripheral tissues , respectively. Moreover, v ita min K a cti vates Matrix G la protein (MGP) which i nhibits elastic fibre deg radati on and vas cular mi ner alis ati on. Ex trahepatic vitamin K de ficiency and low MGP activi ty hav e been found in hospitalis ed COVID-19 patients (42,43). Acc ording to Janss en et al (2021)(44), this could result from increased degradation of e l astic fibres by SARS-CoV-2 promot ing lung fibros is a nd c onc omitant with predic ted depl etion o f endotheli a l vita min K-depen dent anti -coagulant (protein S) l ead to coagulopathy. Therefore, vitamin K could prov ide adjunct thera py of thrombosis events which are characteristic of sev ere COVID-19(45). In the absence of well -powered ra nd omiz ed control trial s (RCT) testing the prophyl actic and therapeut ic potential of these mic ron utrients, w e decided to carry out a Mendelian Randomi zation (MR ) ass ess ment of their poten tial causal e ffects. MR is an established caus al inferenc e method which us es genetic v aria nts as ins trumental v aria ble s(46).
We employed two-sample Mendelian Randomization (MR) analysis. Our genetic variants derived from European-ancestry GWAS reflected circulating levels of Zn, Cu, Se in red blood cells as well as Se and vitamin K1 in serum/plasma. For the COVID-19 outcome GWAS, we used infection, hospitalization or critical illness. Our inverse-variance weighted (IVW) MR analysis was complemented by sensitivity analyses: more liberal selection of variants at genome-wide subsignificant threshold, MR-Egger and weighted median/mode tests. Results: Circulating micronutrient levels show limited evidence of association with COVID-19 infection with odds ratio [OR] ranging from 0.97 (95% CI: 0.87-1.08, p-value=0.55) for zinc to 1.07 (95% CI: 1.00-1.14, p-value=0.06) - ie. no beneficial effect for copper, per 1 SD increase in exposure. Similarly minimal evidence was obtained for the hospitalization and critical illness outcomes with OR from 0.98 (95% CI: 0.87-1.09, p-value=0.66) for vitamin K1 to 1.07 (95% CI: 0.88-1.29, p-value=0.49) for copper, and from 0.93 (95% CI: 0.72-1.19, p-value=0.55) for vitamin K1 to 1.21 (95% CI: 0.79-1.86, p-value=0.39) for zinc, respectively. Our analys es attempted to e lucidate the poten tial o f zinc, s elenium, copper a nd v ita min K1 in prophyl axis and treatment of COVID-19 using MR techniques. However, we found little evidence of c ausal associa tion of genetically predicted micronutrien t concentration on COVID-19 outcomes. Conclusions: This study does not provide evidence that supplementation with zinc, selenium, copper or vitamin K1 can prevent SARS-CoV-2 infection, critical illness or hospitalization for COVID-19.
![[community profile]](https://www.dreamwidth.org/img/silk/identity/community.png){kind=small}