review article mitochondrion-permeable antioxidants to...

Review ArticleMitochondrion-Permeable Antioxidants toTreat ROS-Burst-Mediated Acute Diseases

Zhong-Wei Zhang1 Xiao-Chao Xu2 Ting Liu3 and Shu Yuan1

1College of Resources Science and Technology Sichuan Agricultural University Chengdu 611130 China2College of Bioindustry Chengdu University Chengdu 610106 China3Sichuan Kelun Pharmaceutical Co Ltd Chengdu 610071 China

Correspondence should be addressed to Shu Yuan roundtree318hotmailcom

Received 9 April 2015 Revised 9 July 2015 Accepted 14 July 2015

Academic Editor Luciano Saso

Copyright copy 2016 Zhong-Wei Zhang et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Reactive oxygen species (ROS) play a crucial role in the inflammatory response and cytokine outbreak such as during virusinfections diabetes cancer cardiovascular diseases and neurodegenerative diseases Therefore antioxidant is an importantmedicine to ROS-related diseases For example ascorbic acid (vitamin C VC) was suggested as the candidate antioxidant to treatmultiple diseases However long-term use of high-dose VC causes many side effects In this review we compare and analyzeall kinds of mitochondrion-permeable antioxidants including edaravone idebenone 120572-Lipoic acid carotenoids vitamin E andcoenzyme Q10 and mitochondria-targeted antioxidants MitoQ and SkQ and propose astaxanthin (a special carotenoid) to bethe best antioxidant for ROS-burst-mediated acute diseases like avian influenza infection and ischemia-reperfusion Neverthelessastaxanthins are so unstable thatmost of them are inactivated after oral administrationTherefore astaxanthin injection is suggestedhypothetically The drawbacks of the antioxidants are also reviewed which limit the use of antioxidants as coadjuvants in thetreatment of ROS-associated disorders

1 Introduction

Endogenous reactive oxygen species (ROS) were producedin cells over time causing oxidative-damage to nucleic acidsprotein lipids and other cellular components ROS are nowconsidered as signalling molecules to change the expressionof a large number of genes [1] The relationship betweensome diseases and oxidative-damage has been well studiedA large number of reports showed that oxidative stressis correlated with the pathogenesis of multiple age-relateddiseases like cancer and neurodegenerative diseases andseveral other common diseases such as ischemia-reperfusioninjury stroke hypertension heart failure atherosclerosisdiabetes rheumatic diseases and Alzheimer disease [2ndash10]Therefore a lot of antioxidants have been adopted to pre-vent and alleviate disease-accompanying oxidative-damageHowever some human clinical data of antioxidant thera-peutics indicated negative or ambiguous results or insignif-icant benefits Even some antioxidants showed apparent sideeffects [10 11] In this review we compare representative

mitochondrion-permeable antioxidants through analyzingtheir therapeutic mechanisms the application ranges andside effects

2 ROS-Burst-Mediated Acute Diseases

21 ROS Burst in Ischemia-Reperfusion When blood supplyor oxygen supply returns to the ischemic tissue the reperfu-sion injury occurs In this condition restoration of blood flowand oxygen supply does not restore cellular normal functionsbut induces inflammation and oxidative-damage [3 12]

Reperfusion of ischemic tissues is usually accompaniedwith microvascular damage which increases capillary andarteriole permeability and leads to fluid filtration and dif-fusion These damaged endothelial cells generate more ROSbut less nitric oxide after reperfusion and the disequilibriuminduces subsequently inflammatory responses [3 12 13]At the same time leukocytes circulated with the newlyreturning blood release interleukins free radicals and other

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2016 Article ID 6859523 10 pageshttpdxdoiorg10115520166859523

2 Oxidative Medicine and Cellular Longevity

inflammatory factors which damage the tissue further [312 13] The reintroduced oxygen damages nucleic acidsenzymes and the plasma membrane Oxidative-damagedcellular membrane may release more ROS in turn ThenROS may also trigger redox signalling indirectly and thesubsequent cell death or apoptosis Leukocytes may also bindto the small capillary endothelium causing more ischemia[3 12 13]

22 ROS Burst in Avian Influenza Infections The infection ofavian influenza virus (AIV) results in multiple complicationsto the patient causing multiorgan failures and may beassociated with the excessive immune responses which maybe the main reason for its high pathogenicity and mortality[2 10]TheAIV infection induces a cytokine storm includingchemokines interferon-inducible protein IP-10 interferon120573 and interleukin-6 (IL-6) and cell death presumably [14ndash17] Investigations suggested that healthy young people withstronger immune system may become a main target of AIVattacks [2]

In our previous review of the drugs to avian influenzainfection a large drug combination (including antioxi-dants protectant of mitochondrial membrane permeabilityimmunomodulators protease inhibitors and antiviral drugs)is proposed which mainly focuses on cytokine control andmay greatly reduce the mortality rate hypothetically [2] Forthe drug combination antioxidant is the most importantmedicine suggested because of the fact that ROS play acrucial role in the inflammatory response and cytokineoutbreak [18] Neutrophil aggregation and oxidative-damageto alveolar epithelial membrane result in acute respiratorydistress syndrome (ARDS) finally The activated neutrophilsinduce a ROS burst (more than ten times explosion)

There are many similarities between pulmonaryischemia-reperfusion and AIV infection-induced ARDSBoth of the oxidative injuries include the following (i) lipidperoxidation and oxidative-damage to cytomembrane andthe organelle-membrane (ii) enzyme activity inhibition(iii) lysosomal protease releasing and (iv) chemoattractantgeneration and aggregation ofmore neutrophils [19]Therebyfree radicals form a self-amplification feedback loop [18]

H1N1 infection also inhibits patientrsquos catalase expressiontherefore causing the hydrogen peroxide accumulation [20]while H5N1 triggers extracellular calcium influx whichinduces apoptosis [21]

Major inflammatory response is the mitochondrial dys-function AIV infection or ischemia-reperfusion inducescalcium overload and mitochondrial permeability transi-tion (mPT) Apoptosis indicator cytochrome c is releasedfrom mitochondria Cyclosporine A (CsA) can prevent thismitochondrial permeability transition and the subsequentapoptosis [22] CsA-treated cells are protected from ischemia-reperfusion injury but not from tumour necrosis factor 120572(TNF120572) or Bax (Bcl-2 associated X protein) induced celldeath [22] Both ROS-mediated apoptotic pathway and NF-120581B-mediated survival pathway are activated by the TNF120572ROS accumulation facilitates the cell-death pathway [23]Theratio of proapoptotic protein Bax to antiapoptotic proteinBcl-2 is also regulated by the ROS level Superoxide anion

induces the survival pathways while hydrogen peroxidetriggers the cell-death pathways [24] Thus antioxidants mayblock both TNF120572 and Bax-mediated apoptosis pathways [2]

23 Vitamin C May Be Potentially Used as the CandidateAntioxidant to Treat Avian Influenza Infections In view ofthe advantages such as relatively effective nontoxic and easyto be absorbed ascorbic acid (vitamin C VC) was suggestedas the candidate antioxidant for avian influenza infections[2] VC scavenges free radicals through a nonenzymaticprocess In the 19th century VC was used to cure cold(influenza infection) encephalitis hepatitis and some otherviral diseases for over a hundred years [25ndash27]

An investigation indicated that 50 of H5N1-infectedpatients in Vietnam did not die Ely [28] found that thesurvivals may take large amounts of VC from their foodswhich may alleviate the inflammatory responses

Influenza patients need 44 g or higher levels of VC tocontrol the virus or alleviate the symptom [25ndash28] Howeverthe common oral dosage of VC tablets is 100ndash300mg a daymuch lower than the influenza treatment requires Oralintakes of VC that exceed 1 g may cause side effects likevomiting stomach cramps diarrhea and nausea [25ndash28]Therefore the VC injection should be used for AIV infectionsNevertheless high doses are still required Additionally long-term use of high level of VC (gt2-3 g a day) may result inscurvy after VC administration is stopped [25ndash27] Thesedrawbacks should be considered before the clinical therapies

24 Other ROS-Related Airway Disorders Chronic Obstruc-tive Pulmonary Disease for Example Chronic obstructivepulmonary disease (COPD) is a major and rapidly increas-ing health problem associated with a chronic inflamma-tory response predominantly in small airways and lungparenchyma Oxidative stress induced by reactive oxygenspecies and nitrogen species plays a central role in thepathophysiology of COPD [29] At the subcellular levelmitochondrial dysfunction (accompanied with a decreasedmitochondrial membrane potential) in patients with COPDis associated with excessive mitochondrial ROS levels whichcontribute to enhanced inflammation and cell hyperpro-liferation Thus targeting mitochondrial ROS represents apromising therapeutic approach in patients with COPD suchas the mitochondria-targeted antioxidant MitoQ (see laterdiscussion of MitoQ) [30]

3 Mitochondrion-Permeable Antioxidants

The most pivotal aspects of antioxidant therapies are thesite concentration effects Antioxidant efficiency is fullydependent on the locus concentration since as many otherpharmaceutical compounds antioxidants also have theirldquopharmacological windowsrdquo Therefore these scavengingquenching compounds should concentrate in the target-tissue (or subcellular site) in order to efficiently removeexceeding ROSwithout eliminating essential redox signallingmolecules such as nitric oxide hydrogen peroxide S-Ni-trosoglutathione (GSNO) and nitronitrosyl-lipid peroxides[24 31] It is well known that cellular redox status defines

Oxidative Medicine and Cellular Longevity 3

Table 1 Licensed antioxidants for alleviating disease-related oxidative-damage Their evidenced clinical uses drawbacks and possible sideeffects are summarized

Drugrsquos name Clinical uses Drawbacks Possible side effects

Edaravone Ischemic stroke Limited testing andsometimes ineffective Nephrotoxicity [95]

Idebenone Alzheimer disease Limited testing andsometimes ineffective

Gastrointestinal complaintsneurotoxicity and cardiotoxicity[95]

120572-Lipoic acid Diabetic neuropathy and eye-relateddisorders

Limited testing andsometimes ineffective

Headache tingling skin rash ormuscle cramps [95]

Carotenoids Inflammation cancer andcardiovascular diseases Sometimes ineffective

Damage to skeletal muscleintegrity (high-dose) [44]canthaxanthin retinopathy [102]and lung cancer in heavy smokers[103]

Vitamin E Inflammation cancer andcardiovascular diseases Sometimes ineffective Hemorrhage and vitamin K

deficiency (high-dose) [45]

Coenzyme Q10 Heart failure migraine hypertensionand neurodegenerative diseases

Limited testinginsoluble in watertherefore in lowbioavailability andsometimes ineffective

Largely gastrointestinal complaints(very high-dose) [50]

MitoQ

Alzheimerrsquos disease Parkinsonrsquosdisease hypertension diabetes heartattack sepsis alcohol-inducedsteatohepatitis and cocainecardiotoxicity

Sometimes ineffective inhuman bodies

No side effect observed (even aftera long-term oral administration)[56]

SkQ Age-related diseases Limited testing No side effect observed [59]

Astaxanthin

Atherosclerosis coronary heart diseaseand ischemic brain damageage-related macular degenerationacute pain inflammation cancer andcardiovascular diseases

Insoluble in water andsometimes ineffective No side effect observed [60ndash64]

the fate of one cell Depending on the redox status eukaryoticcells could proliferate keep it in steady state (G0 phase) orenter into cell death either by apoptosis (moderate oxidativecondition intrinsic mitochondrial pathway) or by necrosis(high oxidative insults) [24 31] More interestingly the redoxstatus sensibility varies obviously upon the cell type thathepatic cells aremore plastic thanneurons [32]Therefore thebiggest challenge researchers have nowadays on prescribingantioxidant therapies is how to reach the proper antioxidantconcentration in situ for a precise redox modulation againsta ROS-mediated pathology

As discussed above ROS-burst-mediated mitochondrialdysfunction andmitochondrial-derived apoptosis play a cru-cial role in the inflammatory response during avian influenzainfection or ischemia-reperfusionThus for these ROS-burst-mediated acute diseases mitochondrion-permeable antiox-idants should be much more effective than water-solubleantioxidants (like VC) Edaravone idebenone 120572-Lipoic acidcarotenoids (especially astaxanthin) vitamin E coenzymeQ10 and mitochondria-targeted antioxidants MitoQ andSkQ are summarized as follows (Table 1 and Figure 1) Inter-estingly most of them contain a six-membered carbon-ringwith a long alkyl side chain and multiple hydroxyl groupsand aldehyde groups (Figure 1) All of them are liposoluble

Therefore they could traverse across the cell membrane andthe mitochondrial membrane and accumulate in mitochon-dria On the contrary most water-soluble antioxidants aredistributed in the cytosol (Figure 1)

31 Representative Mitochondrion-Permeable AntioxidantsEdaravone (3-methyl-l-phenyl-pyrazoline-5-one) has beenapproved in Japan since 2001 Edaravone can reduceischemic-stroke-induced neuronal damage [33] Howeverthere are also studies that do not approve the effects Evensome cases of nephrotoxicity were reported for edaravone[34]

Idebenone (23-dimethoxy-5-methyl-6-(10-hydroxyde-cyl)-14-benzoquinonenoben) is a short chain benzoquinonestructurally similar to coenzymeQ10 Idebenone functions asan antioxidant and electron carrier [35] Although idebenonehas some effects on Alzheimerrsquos diseases [35 36] the solidclinical evidences are still missing Therefore its clinicalapplication is limited [37] The most common side effects aregastrointestinal complaints and some level of neurotoxicityor cardiotoxicity [38]120572-Lipoic acid (LA) is a unique lipid and water-soluble

antioxidant It is a naturally occurring dithiol compoundand essential for mitochondrial bioenergetic process [39]


N

N

O

O

O

O

S S

O

O

O

O

O

O

O

O

O

O

O

OO

Edaravone

Idebenone

120572-Lipoic acid

Coenzyme Q10

MitoQ

Vitamin E

120573-Carotene

Astaxanthin

OH

OH

H

HO

HO

HO

CH3

CH3

H3C

H3C

6ndash10

P+

Figure 1 Chemical structures of representative mitochondrion-permeable antioxidants (edaravone idebenone 120572-Lipoic acid coenzymeQ10 MitoQ vitamin E 120573-carotene and astaxanthin)


LA and its reduced-form dihydrolipoic acid are impor-tant mitochondrion-permeable antioxidants LA has beenapproved for diabetic neuropathy treatment [39 40]

Carotenoids consisting of over 600 lipid-soluble plantpigments and a few water-soluble carotenoids (such ascrocin) are present in many fruits and vegetables The com-mon carotenoids include 120572-carotene 120573-carotene lycopene120573-cryptoxanthin lutein and zeaxanthin [41] Among them120573-carotene the vitamin A precursor has been most wellstudied They neutralize free radicals effectively [42] How-ever there are inconsistent conclusions about the role of 120573-carotene in cardiovascular diseases (CVD) prevention [43]Moreover a study indicated that high intake of carotenoidsresulted in a faster skeletal muscle breakdown (skeletalmuscle integrity reducing) [44] Astaxanthin is a peculiarcarotenoid which will be discussed in detail later

Among the vitamin E family 120572-tocopherol is the mostpredominant formThe hepatic120572-tocopherol transfer proteinbinds and carries 120572-tocopherol to all bodyrsquos cells [45] Most120572-tocopherol is associated with lipoproteins scavengingLCOO∙ results and inhibiting low-density lipoprotein (LDL)oxidation Thus 120572-tocopherol is thought to have a role inatherosclerosis prevention The uptake process of oxidizedLDL by the macrophage scavenger receptor and the foam cellformation are blocked by the 120572-tocopherol treatment [46]However some reports did not support the protective role ofvitamin E in prostate cancer [47 48]

CoenzymeQ10 (CoQ10) with its oxidized-form ubiquin-one and reduced-form ubiquinol is an endogenous lipidwhich participates in the mitochondrial electron transportin the respiratory chain [49] CoQ10 has been used totreat a variety of diseases such as cardiovascular diseases[50]migraine [51] hypertension [52] andneurodegenerativediseases [53] Although CoQ10 is considered a safe drugfurther large-scale studies are still needed to show its clinicalusefulness

MitoQ was designed in the late 1990s as a mitochondria-targeted antioxidant by Kelso et al [54] Both MitoQ andcoenzyme Q10 belong to the ubiquinone components Theubiquinone structure of MitoQ can be activated in themitochondrion (by the mitochondrial respiratory complexII) to form the ubiquinol antioxidant Thus MitoQ increasesthe mitochondrial antioxidant capacity in situ and therebydecreases mitochondrial oxidative-damage [54]

MitoQ is a lipophilic molecule bearing a cation moietywhich makes it pass directly through the mitochondrialmembrane because of the fact that the component is pos-itively charged (a hydrophobic structure) [55] ThereforeMitoQ is an effective mitochondria-targeted antioxidant

The ability of MitoQ and the mitochondrial oxidative-damage after the treatments (oral or intraperitoneal admin-istration) have been studied in the mouse model Thefollowing diseases have been studied Alzheimerrsquos diseasehypertension type I diabetes heart attack sepsis fatty liverdisease alcohol-induced steatohepatitis doxorubicin andcocaine cardiotoxicity [56 57] These findings are consistentwith the conclusion that mitochondrial oxidative-damageis the potential therapeutic target in multiple diseases andpathologies

However for Parkinsonrsquos disease trials MitoQ did notshow a benefit maybe because of the irreversible neuronaldamage in patientrsquos brain cells [58] Therefore more studiesof MitoQ in humans are much needed Moreover onlysuccessful phase II assessments of oral MitoQ tablets werereported It is not a FDA-approved drug so far

SkQ (10-(61015840-plastoquinonyl)decyltriphenyl-phosphoni-um) also is organic molecules composed of a large numberof organic cations attached with a plastoquinone SkQ trav-erses across the cellular membranes and accumulates inmitochondria The level of a penetrating cation in mito-chondria can be more than 1000-fold higher than itsextracellular level [59]Therefore it is anothermitochondria-targeted antioxidant

Several studies indicated that SkQ protects cells from age-related diseases efficiently including cataract retinopathyglaucoma balding canities osteoporosis hypothermia andtorpor [59] However its safety and the clinical usefulnessneed further investigations Like MitoQ SkQ is also not aFDA-approved drug so far

32 Astaxanthin Is a Promising Antioxidant Better thanabove antioxidants here we introduce another one astaxan-thin to be a candidate drug for AIV infection cure and someother diseases (Table 1) Astaxanthin a dietary carotenoidis present in algae shrimp lobster crab salmon and someother organisms [60ndash64] Its antioxidant activity is farexceeding the existing antioxidants The ROS-scavengingcapacity is 6000 times that of VC 800 times that of coenzymeQ10 550 times that of VE 200 times that of polyphenols 150times that of anthocyanins and 75 times that of 120572-Lipoic acid[65] Most importantly no apparent side effects or negativeresults have been reported for astaxanthin [60ndash62] In leuko-cyte cells half of the total astaxanthin is distributed in themitochondria Astaxanthin is also distributed in microsomesand nuclei [66] Therefore it is a mitochondrion-permeableantioxidant

Natural astaxanthin plays an important role in preventingatherosclerosis Low-density lipoprotein (LDL) oxidation isthe main reason of atherosclerosis Astaxanthin treatmentincreased high-density lipoprotein (HDL) significantly andreduced LDL effectively while 120573-carotene or canthaxanthinhas no such effect The main reason may be that onlyastaxanthin can reduce apolipoprotein oxidation thereforebeing important for preventing arteriosclerosis cardiovascu-lar diseases and ischemic brain damage [67 68]

Astaxanthin also maintains the eyes and central nervoussystem healthy Retina contains high levels of unsaturatedfatty acids and oxygen supplyThe singlet oxygen is generatedin the retina upon high-energy light illumination Howeverfor mammals carotenoids in diet are enough to maintain eyehealth and can quench these free radicals [69] Recent studyindicated that astaxanthin can pass through the blood-brainbarrier and prevent retina cell oxidation [70] Astaxanthinalso has a good effect on preventing and treating maculardegeneration [70]

Astaxanthin is an anti-inflammatory and pain relieverblocking different biochemical factors that cause ouch and


pain [71] More specifically astaxanthin inhibits cyclooxy-genase 2 (COX2) enzyme activities which are related withmany diseases such as osteoarthritis rheumatoid arthritisdysmenorrhea and acute pain [72] Astaxanthin and Cele-brex (another COX2 inhibitor) work cooperatively for somediseases which therefore were suggested to be taken bothtogether to alleviate oxidative-damage [72]

Astaxanthin affects not only theCOX2 signalling pathwaybut also multiple cytokines like nitric oxide interleukin 1-120573 prostaglandin E2 C-Reactive Protein (CRP) NF-120581B andTNF120572 [72] A study also showed that astaxanthin is a usefulantioxidant to treat insulin resistance by protecting cells fromTNF120572 and palmitate-induced oxidative-damage [73] Recentstudy suggested that astaxanthin also inhibits apoptosis inalveolar epithelial cells via mitochondrial ROS signallingpathways also indicating its mitochondrial location [74]

Astaxanthin also activates T-cell and inhibits autoim-mune reactions [75] The risk of many different types ofcancer can be significantly reduced by dietary intake of as-taxanthin alongwith other carotenoids [76ndash78] In themousebreast cancer model astaxanthin treatment caused higherlevels of apoptotic cancer cells and protective interferonsinhibiting tumor growth [79] (i) Astaxanthin prevents cancerinitiation by alleviating DNA oxidative-damage [80 81](ii) Astaxanthin promotes early check and elimination ofcells undergoing malignant transformation by activatingimmune surveillance [82] (iii) Astaxanthin prevents cancercell growth in cells by boosting immune detection [8384] (iv) Astaxanthin inhibits rapid tumor cell growth byblocking tumor cell reproductive cycle and inducing tumorcell apoptosis [85ndash87] (v) Astaxanthin prevents tumor cellspreading by decreasing tumor cellrsquos tissue-melting proteins[84]

McNulty et al [88] studied membrane structures ofcarotenoids and the relationship to their biological activitiesThey found that the vertical orientation of astaxanthin inmembranesmay be crucial for its high efficiency on removingaggressive free radicals from membranes especially in thepresence of water-soluble antioxidants such as glutathioneandor ascorbic acid [88]

4 Side Effects of Antioxidants

Most of the so-called antioxidant compounds also developprooxidant properties under specific conditions such asascorbic acid (gt1mM) that induces Fe(III) reduction to Fe(II)[89] Epigallocatechin 3-gallate (EGCG) produces hydrogenperoxide and hydroxyl radicals in the presence of Fe(III) [90]

Clinical trials of some antioxidants in humans showednegative or ambiguous results or insignificant benefits [1011 91ndash95] The reasons may be as follows (i) Oxidative-damage is neither the primary cause nor the only causeof the disease (ii) Patients do not benefit from the sameantioxidant treatment equally (iii) Some antioxidants by oraladministration are of lower efficiencies (iv) Some antioxidantmolecules have toxic effects that mask their ROS-scavengingactivities (v) Certain antioxidants are not effective in well-nourished populations [11 95]

On the other hand ROS accumulation does not alwayscorrelate with disease onsets positively Watson [96] postu-lates that diabetes (especially the type 2 diabetes) dementiascardiovascular disease and some cancers may develop whenoxidative redox potential in the endoplasmic reticulum is toolow to form normal disulphide bonds [97ndash99] Maintaininga certain level of ROS may be necessary for correct proteinfolding with disulphide bonds which may be associatedwith type 2 diabetes and Alzheimerrsquos disease or some otherdiseases [96 100 101] Thus the antioxidants may producenegative or ineffective impacts on some diseases

Interactions of carotenoids (such as canthaxanthin) withthe lipid membranes and the aggregation of this pigmentmay be the factors enhancing canthaxanthin toxicity towardsthe macula vascular system which leads to the furtherdevelopment of canthaxanthin retinopathy [102] And highand long-term beta-carotene supplementation may increaselung tumor rates in heavy smokers [103]

5 Hypothesis of Astaxanthin Injection

Side effects of antioxidants (antioxidant-induced stress) onlypresent when antioxidants overwhelm the bodyrsquos free radicals[11] Thus antioxidants should be used carefully for chronicdiseases such as diabetes and Alzheimerrsquos disease whencellular ROS levels are not particularly high (no ROS burstsoccur) However for ROS-burst-mediated acute diseasessuch as avian influenza infection and ischemia-reperfusionantioxidants should be used as early as possible to avoidor retard excessive immune responses Mitochondrion-permeable or mitochondria-targeted antioxidants are pre-ferred

Astaxanthin is a good candidate drug for these acutediseases However so far astaxanthin is not a clinical drugbutmerely a health care productMost studies showed that itstreatment effects are not as good as people expect contrastingto its extraordinary high antioxidant activities [61] One ofthe reasons may be that astaxanthin is usually applied by oraladministration (such as astaxanthin soft capsule) All nour-ishments and oral drugs are digested in the gastrointestinaltract and then absorbed into gastric veins and intestinal veinsand transported to the liver through the portal vein Thenafter the liverrsquos process they are transported throughout thebody via heart and arteries Astaxanthin is easy to be oxidizedthat most of them are inactivated during the digestionabsorption and transportation After avian influenza virusinfection for instance severe oxidative-damage occurs at thelungs where neither oral VC tablets nor oral astaxanthincapsules could reach effectively For the same reason active(reduced) astaxanthin could not reach atherosclerosis sitesretina or brain arteries ideally too Therefore the injectionapproach of astaxanthin may be adopted to these patientsIt is well known that vitamin E injection (a mixture ofoil for injection and VE) is better absorbed by the bodysince it goes directly into the blood stream [60 62] Andrecent studies indicated that VC injections have stronganticancer effects especially when intravenous glutathione orvitamin K3 was applied synergistically [104 105] A similarastaxanthin injection could be easily developed For AIV


infections astaxanthin by injection can be quickly absorbedand go directly into the pulmonary alveoli where inflam-matory reactions occur through the bodyrsquos blood circulationsystem

It is well known that water- and lipid-soluble antioxidantsact in synergism to efficiently remove aggressive radicalsfrom hydrophobic compartments and thereby inhibit lipidperoxidation which is extremely harmful to most organelles[106] The collaborative mechanism involving 120572-tocopherolthrough tocopheryl formation and ascorbic acid has beenstudied since the middle of the 90s [106] In other words bycombining lipid-soluble antioxidants (such as astaxanthin)with water-soluble ones (such as ascorbic acid) in lowerconcentrations higher efficiency on ROS removal may beexpected However cellular ROS should not be removedentirely for retaining the essential redox signallingmoleculesThe precise dosages need further investigations

The astaxanthin injection might be suitable for otherkinds of disease-accompanying oxidative-damage and in-flammations However the astaxanthin injection must besubjected to clinical trials and FDA approval Neverthelessthey are time-consuming processes Before FDA approvaloral astaxanthin capsules are still suggested for AIV-infectedpatients Because when most patients are identified as havingavian influenza infections they have been sick for severaldays near or after the time pulmonary symptom developedTheir alveolar cells may become damaged Thus the risk todevelop acute respiratory distress syndrome (ARDS) is veryhigh So for the general public timely oral administrationof antioxidants before the diagnosis in the hospital is veryimportant [2 107] No matter if infected with avian influenzaor common influenza the patient is recommended to takeVC (800ndash1000mg a day presumably) orand astaxanthin (24ndash48mg a day presumably) before the hospital examination

6 Conclusions

Considering the adverse effects of antioxidants antioxidantdrugs should be used carefully for chronic diseases espe-cially for diabetes and Alzheimerrsquos disease when a certainlevel of ROS is required for normally cellular functionsHowever for ROS-burst-mediated acute diseases mitochon-drion-permeable antioxidants should be used in the earlystage

To treat ROS-accompanying diseases no matter chronicor acute antioxidants should be used combined with othertherapeutic drugs However drug combinations may haveadditive or possible antagonistic effects on the disease devel-opment And the dosage of the single compound should beadjusted according to the combination Thus carefully phar-maceutic studies should be done before certain antioxidant(eg astaxanthin injection) can really enter the clinical trialto oxidative-damage-related illnesses

Conflict of Interests

The authors confirm that this paper content has no conflict ofinterests

Authorsrsquo Contribution

Zhong-Wei Zhang and Xiao-Chao Xu contribute equally tothis work

Acknowledgments

This work was supported by the National Natural ScienceFoundation of China (31300207) the Funds from SichuanProvince Ministry of Education (13ZB0296 and 014z1700)and the Preeminent Youth Fund of Sichuan Province(2015JQO045)

References

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[2] S Yuan ldquoDrugs to cure avian influenza infectionmdashmultipleways to prevent cell deathrdquo Cell Death and Disease vol 4 no10 article e835 2013

[3] D L Carden and D N Granger ldquoPathophysiology of ischaemi-a-reperfusion injuryrdquo Journal of Pathology vol 190 no 3 pp255ndash266 2000

[4] R K Naviaux ldquoOxidative shielding or oxidative stressrdquo TheJournal of Pharmacology and Experimental Therapeutics vol342 no 3 pp 608ndash618 2012

[5] H Y Aboul-Enein P Berczynski and I Kruk ldquoPhenoliccompounds the role of redox regulation in neurodegenerativedisease and cancerrdquo Mini-Reviews in Medicinal Chemistry vol13 no 3 pp 385ndash398 2013

[6] C Gorrini I S Harris and TWMak ldquoModulation of oxidativestress as an anticancer strategyrdquoNature Reviews DrugDiscoveryvol 12 no 12 pp 931ndash947 2013

[7] B Jiang S Xiao M A Khan and M Xue ldquoDefective antioxi-dant systems in cervical cancerrdquo Tumor Biology vol 34 no 4pp 2003ndash2009 2013

[8] Y Kitagishi and S Matsuda ldquoRedox regulation of tumorsuppressor PTEN in cancer and aging (Review)rdquo InternationalJournal of Molecular Medicine vol 31 no 3 pp 511ndash515 2013

[9] M Majzunova I Dovinova M Barancik and J Y H ChanldquoRedox signaling in pathophysiology of hypertensionrdquo Journalof Biomedical Science vol 20 no 1 article 69 2013

[10] R Sgarbanti D Amatore I Celestino et al ldquoIntracellular redoxstate as target for anti-influenza therapy are antioxidants alwayseffectiverdquoCurrent Topics inMedicinal Chemistry vol 14 no 22pp 2529ndash2541 2014

[11] C Villanueva and R D Kross ldquoAntioxidant-induced stressrdquoInternational Journal of Molecular Sciences vol 13 no 2 pp2091ndash2109 2012

[12] C Nastos K Kalimeris N Papoutsidakis et al ldquoGlobalconsequences of liver ischemiareperfusion injuryrdquo OxidativeMedicine and Cellular Longevity vol 2014 Article ID 90696513 pages 2014

[13] Z-W Zhang J Cheng F Xu et al ldquoMammal cells double theirtotal RNAs against diabetes ischemia reperfusion and malaria-induced oxidative stressrdquo Molecular Medicine vol 17 no 5-6pp 533ndash541 2011

[14] M C W Chan C Y Cheung W H Chui et al ldquoProinflam-matory cytokine responses induced by influenza A (H5N1)


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[15] L A Perrone J K Plowden A Garcıa-Sastre J M Katz and TM Tumpey ldquoH5N1 and 1918 pandemic influenza virus infectionresults in early and excessive infiltration of macrophages andneutrophils in the lungs of micerdquo PLoS Pathogens vol 4 no 8Article ID e1000115 2008

[16] C Cilloniz M J Pantin-Jackwood C Ni et al ldquoLethal dissemi-nation of H5N1 influenza virus is associated with dysregulationof inflammation and lipoxin signaling in a mouse model ofinfectionrdquo Journal of Virology vol 84 no 15 pp 7613ndash76242010

[17] S Fukuyama and Y Kawaoka ldquoThe pathogenesis of influenzavirus infections the contributions of virus and host factorsrdquoCurrentOpinion in Immunology vol 23 no 4 pp 481ndash486 2011

[18] S Tasaka F Amaya S Hashimoto and A Ishizaka ldquoRolesof oxidants and redox signaling in the pathogenesis of acuterespiratory distress syndromerdquoAntioxidants amp Redox Signalingvol 10 no 4 pp 739ndash753 2008

[19] K R Short E J B V Kroeze R A M Fouchier and T KuikenldquoPathogenesis of influenza-induced acute respiratory distresssyndromerdquoThe Lancet Infectious Diseases vol 14 no 1 pp 57ndash69 2014

[20] Y Yamada G V Limmon D Zheng et al ldquoMajor shifts inthe Spatio-Temporal distribution of lung antioxidant enzymesduring influenza pneumoniardquo PLoS ONE vol 7 no 2 ArticleID e31494 2012

[21] M Ueda T Daidoji A Du et al ldquoHighly pathogenic H5N1avian influenza virus induces extracellular Ca2+ influx leadingto apoptosis in avian cellsrdquo Journal of Virology vol 84 no 6 pp3068ndash3078 2010

[22] C P Baines R A Kaiser NH Purcell et al ldquoLoss of cyclophilinD reveals a critical role for mitochondrial permeability transi-tion in cell deathrdquoNature vol 434 no 7033 pp 658ndash662 2005

[23] D Han M D Ybanez S Ahmadi K Yeh and N KaplowitzldquoRedox regulation of tumor necrosis factor signalingrdquo Antioxi-dants and Redox Signaling vol 11 no 9 pp 2245ndash2263 2009

[24] I C C Low J Kang and S Pervaiz ldquoBcl-2 a prime regulator ofmitochondrial redox metabolism in cancer cellsrdquo Antioxidantsamp Redox Signaling vol 15 no 12 pp 2975ndash2987 2011

[25] L Pauling Vitamin C and the Common Cold Freeman PressSan Francisco Calif USA 1970

[26] S LewinVitaminC ItsMolecular Biology andMedical PotentialAcademic Press New York NY USA 1976

[27] J S Bland Vitamin C The Future is Now (Keats Good HealthGuide) McGraw-Hill Press Columbus Ohio USA 1998

[28] J T A Ely ldquoAscorbic acid role in containment of theworld avianflu pandemicrdquo Experimental Biology and Medicine vol 232 no7 pp 847ndash851 2007

[29] B Antus and Z Kardos ldquoOxidative stress in COPD molecularbackground and clinical monitoringrdquoCurrentMedicinal Chem-istry vol 22 no 5 pp 627ndash650 2015

[30] C H Wiegman C Michaeloudes G Haji et al ldquoOxidativestressmdashinduced mitochondrial dysfunction drives inflamma-tion and airway smooth muscle remodeling in patients withchronic obstructive pulmonary diseaserdquo The Journal of Allergyand Clinical Immunology 2015

[31] F Q Schafer and G R Buettner ldquoRedox environment ofthe cell as viewed through the redox state of the glutathionedisulfideglutathione couplerdquo Free Radical Biology amp Medicinevol 30 no 11 pp 1191ndash1212 2001

[32] J M Mates C Perez-Gomez I N De Castro M Asenjo andJ Marquez ldquoGlutamine and its relationship with intracellularredox status oxidative stress and cell proliferationdeathrdquo Inter-national Journal of BiochemistryampCell Biology vol 34 no 5 pp439ndash458 2002

[33] T Watanabe M Tahara and S Todo ldquoThe novel antioxidantedaravone from bench to bedsiderdquo Cardiovascular Therapeu-tics vol 26 no 2 pp 101ndash114 2008

[34] A Hishida ldquoClinical analysis of 207 patients who developedrenal disorders during or after treatment with edaravonereported during post-marketing surveillancerdquo Clinical andExperimental Nephrology vol 11 no 4 pp 292ndash296 2007

[35] J B Schulz N A Di Prospero and K Fischbeck ldquoClinicalexperience with high-dose idebenone in Friedreich ataxiardquoJournal of Neurology vol 256 no 1 pp 42ndash46 2009

[36] H Gutzmann K-P Kuhl D Hadler and M A Rapp ldquoSafetyand efficacy of idebenone versus tacrine in patients withAlzheimerrsquos disease results of a randomized double-blindparallel-group multicenter studyrdquo Pharmacopsychiatry vol 35no 1 pp 12ndash18 2002

[37] L J Thal M Grundman J Berg et al ldquoIdebenone treatmentfails to slow cognitive decline in Alzheimerrsquos diseaserdquo Neurol-ogy vol 61 no 11 pp 1498ndash1502 2003

[38] T Meier and G Buyse ldquoIdebenone an emerging therapy forFriedreich ataxiardquo Journal of Neurology vol 256 supplement 1pp 25ndash30 2009

[39] U Singh and I Jialal ldquoAlpha-lipoic acid supplementation anddiabetesrdquo Nutrition Reviews vol 66 no 11 pp 646ndash657 2008

[40] S Tesfaye ldquoAdvances in the management of diabetic peripheralneuropathyrdquo Current Opinion in Supportive and Palliative Carevol 3 no 2 pp 136ndash143 2009

[41] S Voutilainen T Nurmi J Mursu and T H RissanenldquoCarotenoids and cardiovascular healthrdquoThe American Journalof Clinical Nutrition vol 83 no 6 pp 1265ndash1271 2006

[42] N I Krinsky and E J Johnson ldquoCarotenoid actions and theirrelation to health and diseaserdquo Molecular Aspects of Medicinevol 26 no 6 pp 459ndash516 2005

[43] S K Osganian M J Stampfer E Rimm D Spiegelman J EManson and W C Willett ldquoDietary carotenoids and risk ofcoronary artery disease in womenrdquo The American Journal ofClinical Nutrition vol 77 no 6 pp 1390ndash1399 2003

[44] K A Huggins K J Navara M T Mendonca and G E HillldquoDetrimental effects of carotenoid pigments the dark side ofbright colorationrdquo Naturwissenschaften vol 97 no 7 pp 637ndash644 2010

[45] M G Traber ldquoVitamin E regulatory mechanismsrdquo AnnualReview of Nutrition vol 27 no 1 pp 347ndash362 2007

[46] R Siekmeier C Steffen and W Marz ldquoRole of oxidants andantioxidants in atherosclerosis results of in vitro and in vivoinvestigationsrdquo Journal of Cardiovascular Pharmacology andTherapeutics vol 12 no 4 pp 265ndash282 2007

[47] V A Kirsh R B Hayes S T Mayne et al ldquoSupplemental anddietary vitamin E beta-carotene and vitamin C intakes andprostate cancer riskrdquo Journal of the National Cancer Institutevol 98 no 4 pp 245ndash254 2006

[48] S M Lippman E A Klein P J Goodman et al ldquoEffect ofselenium and vitamin E on risk of prostate cancer and othercancers the Selenium and Vitamin E Cancer Prevention Trial(SELECT)rdquo The Journal of the American Medical Associationvol 301 no 1 pp 39ndash51 2009


[49] G Dallner and P J Sindelar ldquoRegulation of ubiquinone metab-olismrdquo Free Radical Biology and Medicine vol 29 no 3-4 pp285ndash294 2000

[50] U Singh S Devaraj and I Jialal ldquoCoenzyme Q10 supplemen-tation and heart failurerdquo Nutrition Reviews vol 65 no 6 pp286ndash293 2007

[51] P S Sandor L Di Clemente G Coppola et al ldquoEfficacy of coen-zyme Q10 in migraine prophylaxis a randomized controlledtrialrdquo Neurology vol 64 no 4 pp 71ndash75 2005

[52] F L Rosenfeldt S J HaasH Krumet al ldquoCoenzymeQ10 in thetreatment of hypertension a meta-analysis of the clinical trialsrdquoJournal of HumanHypertension vol 21 no 4 pp 297ndash306 2007

[53] MMancuso D Orsucci L Volpi V Calsolaro andG SicilianoldquoCoenzyme Q10 in neuromuscular and neurodegenerative dis-ordersrdquo Current Drug Targets vol 11 no 1 pp 111ndash121 2010

[54] G F Kelso C M Porteous C V Coulter et al ldquoSelectivetargeting of a redox-active ubiquinone to mitochondria withincells antioxidant and antiapoptotic propertiesrdquo The Journal ofBiological Chemistry vol 276 no 7 pp 4588ndash4596 2001

[55] M F Ross G F Kelso F H Blaikie et al ldquoLipophilic triph-enylphosphonium cations as tools inmitochondrial bioenerget-ics and free radical biologyrdquoBiochemistry vol 70 no 2 pp 222ndash230 2005

[56] R A J Smith R C Hartley andM P Murphy ldquoMitochondria-targeted small molecule therapeutics and probesrdquo Antioxidantsamp Redox Signaling vol 15 no 12 pp 3021ndash3038 2011

[57] E J Gane F Weilert D W Orr et al ldquoThe mitochondria-targeted anti-oxidant mitoquinone decreases liver damage in aphase II study of hepatitis C patientsrdquo Liver International vol30 no 7 pp 1019ndash1026 2010

[58] B J Snow F L Rolfe M M Lockhart et al ldquoA double-blind placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy inParkinsonrsquos diseaserdquo Movement Disorders vol 25 no 11 pp1670ndash1674 2010

[59] V P Skulachev V N Anisimov Y N Antonenko et al ldquoAnattempt to prevent senescence a mitochondrial approachrdquoBiochimica et Biophysica Acta vol 1787 no 5 pp 437ndash461 2009

[60] B M Winklhofer-Roob E Rock J Ribalta D H Shmerlingand J M Roob ldquoEffects of vitamin E and carotenoid status onoxidative stress in health and disease Evidence obtained fromhuman intervention studiesrdquoMolecular Aspects ofMedicine vol24 no 6 pp 391ndash402 2003

[61] B Capelli and G Cysewski ASTAXANTHIN Natural Astaxan-thin King of the Carotenoids Cyanotech Corporation KailuaHawaii USA 2007

[62] P Cusack N McMeniman A Rabiee and I Lean ldquoAssessmentof the effects of supplementation with vitamin E on healthand production of feedlot cattle usingmeta-analysisrdquo PreventiveVeterinary Medicine vol 88 no 4 pp 229ndash246 2009

[63] M B Lu Y E Zhang C F Zhao P P Zhou and LJ Yu ldquoAnalysis and identification of astaxanthin and itscarotenoid precursors from Xanthophyllomyces dendrorhousby high-performance liquid chromatographyrdquo Zeitschrift furNaturforschung vol 65 no 7-8 pp 489ndash494 2010

[64] W Wu M B Lu and L J Yu ldquoExpression of carotenogenicgenes and astaxanthin production in Xanthophyllomyces den-drorhous as a function of oxygen tensionrdquo Zeitschrift furNaturforschung vol 66 no 5-6 pp 283ndash286 2011

[65] Y Nishida E Yamashita and W Miki ldquoQuenching activitiesof common hydrophilic and lipophilic antioxidants against

singlet oxygen using chemiluminescence detection systemrdquoCarotenoid Science vol 11 no 6 pp 16ndash20 2007

[66] J S Park HW Kim B D Mathison et al ldquoAstaxanthin uptakein domestic dogs and catsrdquo Nutrition amp Metabolism vol 7 no1 article 52 2010

[67] R G Fassett and J S Coombes ldquoAstaxanthin oxidative stressinflammation and cardiovascular diseaserdquo Future Cardiologyvol 5 no 4 pp 333ndash342 2009

[68] R G Fassett and J S Coombes ldquoAstaxanthin in cardiovascularhealth and diseaserdquo Molecules vol 17 no 2 pp 2030ndash20482012

[69] Y Nakajima Y Inokuchi M Shimazawa K Otsubo T Ishiba-shi and H Hara ldquoAstaxanthin a dietary carotenoid protectsretinal cells against oxidative stress in-vitro and inmice in-vivordquoThe Journal of Pharmacy and Pharmacology vol 60 no 10 pp1365ndash1374 2008

[70] S Piermarocchi S Saviano V Parisi et al ldquoCarotenoids in Age-related Maculopathy Italian Study (CARMIS) two-year resultsof a randomized studyrdquoEuropean Journal of Ophthalmology vol22 no 2 pp 216ndash225 2012

[71] N DrsquoOrazio M A Gammone E Gemello M De Girolamo SCusenza and G Riccioni ldquoMarine bioactives pharmacologicalproperties and potential applications against inflammatorydiseasesrdquoMarine Drugs vol 10 no 4 pp 812ndash833 2012

[72] S-J Lee S-K Bai K-S Lee et al ldquoAstaxanthin inhibitsnitric oxide production and inflammatory gene expression bysuppressing I120581Bkinase-dependentNF-120581BactivationrdquoMoleculesand Cells vol 16 no 1 pp 97ndash105 2003

[73] M Ishiki Y Nishida H Ishibashi et al ldquoImpact of diver-gent effects of astaxanthin on insulin signaling in L6 cellsrdquoEndocrinology vol 154 no 8 pp 2600ndash2612 2013

[74] X Song B Wang S Lin et al ldquoAstaxanthin inhibits apoptosisin alveolar epithelial cells type II in vivo and in vitro throughthe ROS-dependent mitochondrial signalling pathwayrdquo Journalof Cellular andMolecularMedicine vol 18 no 11 pp 2198ndash22122014

[75] A P Bolin R C Macedo D P Marin M P Barros and ROtton ldquoAstaxanthin prevents in vitro auto-oxidative injury inhuman lymphocytesrdquo Cell Biology and Toxicology vol 26 no 5pp 457ndash467 2010

[76] T Tanaka H Makita M Ohnishi H Mori K Satoh and AHara ldquoChemoprevention of rat oral carcinogenesis by naturallyoccurring xanthophylls astaxanthin and canthaxanthinrdquo Can-cer Research vol 55 no 18 pp 4059ndash4064 1995

[77] Y YasuiMHosokawaNMikami KMiyashita andT TanakaldquoDietary astaxanthin inhibits colitis and colitis-associated coloncarcinogenesis in mice via modulation of the inflammatorycytokinesrdquo Chemico-Biological Interactions vol 193 no 1 pp79ndash87 2011

[78] T Tanaka M Shnimizu and H Moriwaki ldquoCancer chemopre-vention by carotenoidsrdquoMolecules vol 17 no 3 pp 3202ndash32422012

[79] R Nakao O L Nelson J S Park B D Mathison P AThompson and B P Chew ldquoEffect of dietary astaxanthin atdifferent stages of mammary tumor initiation in BALBc micerdquoAnticancer Research vol 30 no 6 pp 2171ndash2175 2010

[80] N M Lyons and N M OrsquoBrien ldquoModulatory effects of analgal extract containing astaxanthin on UVA-irradiated cells inculturerdquo Journal of Dermatological Science vol 30 no 1 pp 73ndash84 2002


[81] M Santocono M Zurria M Berrettini D Fedeli and GFalcioni ldquoLutein zeaxanthin and astaxanthin protect againstDNA damage in SK-N-SH human neuroblastoma cells inducedby reactive nitrogen speciesrdquo Journal of Photochemistry andPhotobiology B Biology vol 88 no 1 pp 1ndash10 2007

[82] J-P Yuan J Peng K Yin and J-H Wang ldquoPotential health-promoting effects of astaxanthin a high-value carotenoidmostly frommicroalgaerdquoMolecular Nutrition amp Food Researchvol 55 no 1 pp 150ndash165 2011

[83] P Kidd ldquoAstaxanthin cell membrane nutrient with diverseclinical benefits and anti-aging potentialrdquo Alternative MedicineReview vol 16 no 4 pp 355ndash364 2011

[84] P Nagendraprabhu and G Sudhandiran ldquoAstaxanthin inhibitstumor invasion by decreasing extracellular matrix productionand induces apoptosis in experimental rat colon carcinogenesisby modulating the expressions of ERK-2 NFkB and COX-2rdquoInvestigational New Drugs vol 29 no 2 pp 207ndash224 2011

[85] P Palozza C Torelli A Boninsegna et al ldquoGrowth-inhibitoryeffects of the astaxanthin-rich alga Haematococcus pluvialis inhuman colon cancer cellsrdquo Cancer Letters vol 283 no 1 pp108ndash117 2009

[86] X-D Song J-J Zhang M-R Wang W-B Liu X-B Guand C-J Lv ldquoAstaxanthin induces mitochondria-mediatedapoptosis in rat hepatocellular carcinoma CBRH-7919 cellsrdquoBiological amp Pharmaceutical Bulletin vol 34 no 6 pp 839ndash8442011

[87] X Song M Wang L Zhang et al ldquoChanges in cell ultra-structure and inhibition of JAK1STAT3 signaling pathway inCBRH-7919 cells with astaxanthinrdquo ToxicologyMechanisms andMethods vol 22 no 9 pp 679ndash686 2012

[88] H McNulty R F Jacob and R P Mason ldquoBiologic activityof carotenoids related to distinct membrane physicochemicalinteractionsrdquo The American Journal of Cardiology vol 101 no10 pp S20ndashS29 2008

[89] A V Kozlov D I Egorov I A Vladimirov and O AAzizova ldquoFormation of iron complexes with ascorbic acid inphysiological conditions in vitro and in tissue in vivordquoBiofizikavol 35 no 3 pp 513ndash517 1990

[90] H-S Kim M J Quon and J-A Kim ldquoNew insights intothe mechanisms of polyphenols beyond antioxidant propertieslessons from the green tea polyphenol epigallocatechin 3-gallaterdquo Redox Biology vol 2 no 1 pp 187ndash195 2014

[91] J Choi ldquoOxidative stress endogenous antioxidants alcoholand hepatitis C pathogenic interactions and therapeutic con-siderationsrdquo Free Radical Biology and Medicine vol 52 no 7pp 1135ndash1150 2012

[92] D P Vivekananthan M S Penn S K Sapp A Hsu and EJ Topol ldquoUse of antioxidant vitamins for the prevention ofcardiovascular disease meta-analysis of randomised trialsrdquoTheLancet vol 361 no 9374 pp 2017ndash2023 2003

[93] A Shuaib K R Lees P Lyden et al ldquoNXY-059 for the treatmentof acute ischemic strokerdquoTheNew England Journal of Medicinevol 357 no 6 pp 562ndash571 2007

[94] H M Cocheme and M P Murphy ldquoCan antioxidants be effec-tive therapeuticsrdquo Current Opinion in Investigational Drugsvol 11 no 4 pp 426ndash431 2010

[95] O Firuzi R Miri M Tavakkoli and L Saso ldquoAntioxidanttherapy current status and future prospectsrdquoCurrentMedicinalChemistry vol 18 no 25 pp 3871ndash3888 2011

[96] J D Watson ldquoType 2 diabetes as a redox diseaserdquo The Lancetvol 383 no 9919 pp 841ndash843 2014

[97] S K Powers and M J Jackson ldquoExercise-induced oxidativestress cellularmechanisms and impact onmuscle force produc-tionrdquo Physiological Reviews vol 88 no 4 pp 1243ndash1276 2008

[98] M Ristow K Zarse A Oberbach et al ldquoAntioxidants preventhealth-promoting effects of physical exercise in humansrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 106 no 21 pp 8665ndash8670 2009

[99] A Martin-Montalvo E M Mercken S J Mitchell et alldquoMetformin improves health span and lifespan in micerdquoNatureCommunications vol 4 no 1 p 2192 2013

[100] G Nardai K Stadler E Papp T Korcsmaros J Jakus and PCsermely ldquoDiabetic changes in the redox status of the micro-somal protein folding machineryrdquo Biochemical and BiophysicalResearch Communications vol 334 no 3 pp 787ndash795 2005

[101] J C Smith K A Nielson P Antuono et al ldquoSemantic memoryfunctional mri and cognitive function after exercise inter-vention in mild cognitive impairmentrdquo Journal of AlzheimerrsquosDisease vol 37 no 1 pp 197ndash215 2013

[102] A Sujak ldquoInteractions between canthaxanthin and lipidmembranesmdashpossible mechanisms of canthaxanthin toxicityrdquoCellular and Molecular Biology Letters vol 14 no 3 pp 395ndash410 2009

[103] R Goralczyk ldquoBeta-carotene and lung cancer in smokersreview of hypotheses and status of researchrdquo Nutrition andCancer vol 61 no 6 pp 767ndash774 2009

[104] M-F Chen C-M Yang C-M Su J-W Liao and M-L HuldquoInhibitory effect of vitamin C in combination with vitaminK3 on tumor growth and metastasis of Lewis lung carcinomaxenografted in C57BL6 micerdquo Nutrition and Cancer vol 63no 7 pp 1036ndash1043 2011

[105] P Chen J Stone G Sullivan J A Drisko and Q Chen ldquoAnti-cancer effect of pharmacologic ascorbate and its interactionwith supplementary parenteral glutathione in preclinical cancermodelsrdquo Free Radical Biology and Medicine vol 51 no 3 pp681ndash687 2011

[106] M G Traber and J F Stevens ldquoVitamins C and E beneficialeffects fromamechanistic perspectiverdquoFree Radical Biology andMedicine vol 51 no 5 pp 1000ndash1013 2011

[107] N J White R G Webster E A Govorkova and T M UyekildquoWhat is the optimal therapy for patients withH5N1 influenzardquoPLoS Medicine vol 6 no 6 Article ID e1000091 2009

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


inflammatory factors which damage the tissue further [312 13] The reintroduced oxygen damages nucleic acidsenzymes and the plasma membrane Oxidative-damagedcellular membrane may release more ROS in turn ThenROS may also trigger redox signalling indirectly and thesubsequent cell death or apoptosis Leukocytes may also bindto the small capillary endothelium causing more ischemia[3 12 13]

22 ROS Burst in Avian Influenza Infections The infection ofavian influenza virus (AIV) results in multiple complicationsto the patient causing multiorgan failures and may beassociated with the excessive immune responses which maybe the main reason for its high pathogenicity and mortality[2 10]TheAIV infection induces a cytokine storm includingchemokines interferon-inducible protein IP-10 interferon120573 and interleukin-6 (IL-6) and cell death presumably [14ndash17] Investigations suggested that healthy young people withstronger immune system may become a main target of AIVattacks [2]

In our previous review of the drugs to avian influenzainfection a large drug combination (including antioxi-dants protectant of mitochondrial membrane permeabilityimmunomodulators protease inhibitors and antiviral drugs)is proposed which mainly focuses on cytokine control andmay greatly reduce the mortality rate hypothetically [2] Forthe drug combination antioxidant is the most importantmedicine suggested because of the fact that ROS play acrucial role in the inflammatory response and cytokineoutbreak [18] Neutrophil aggregation and oxidative-damageto alveolar epithelial membrane result in acute respiratorydistress syndrome (ARDS) finally The activated neutrophilsinduce a ROS burst (more than ten times explosion)

There are many similarities between pulmonaryischemia-reperfusion and AIV infection-induced ARDSBoth of the oxidative injuries include the following (i) lipidperoxidation and oxidative-damage to cytomembrane andthe organelle-membrane (ii) enzyme activity inhibition(iii) lysosomal protease releasing and (iv) chemoattractantgeneration and aggregation ofmore neutrophils [19]Therebyfree radicals form a self-amplification feedback loop [18]

H1N1 infection also inhibits patientrsquos catalase expressiontherefore causing the hydrogen peroxide accumulation [20]while H5N1 triggers extracellular calcium influx whichinduces apoptosis [21]

Major inflammatory response is the mitochondrial dys-function AIV infection or ischemia-reperfusion inducescalcium overload and mitochondrial permeability transi-tion (mPT) Apoptosis indicator cytochrome c is releasedfrom mitochondria Cyclosporine A (CsA) can prevent thismitochondrial permeability transition and the subsequentapoptosis [22] CsA-treated cells are protected from ischemia-reperfusion injury but not from tumour necrosis factor 120572(TNF120572) or Bax (Bcl-2 associated X protein) induced celldeath [22] Both ROS-mediated apoptotic pathway and NF-120581B-mediated survival pathway are activated by the TNF120572ROS accumulation facilitates the cell-death pathway [23]Theratio of proapoptotic protein Bax to antiapoptotic proteinBcl-2 is also regulated by the ROS level Superoxide anion

induces the survival pathways while hydrogen peroxidetriggers the cell-death pathways [24] Thus antioxidants mayblock both TNF120572 and Bax-mediated apoptosis pathways [2]

23 Vitamin C May Be Potentially Used as the CandidateAntioxidant to Treat Avian Influenza Infections In view ofthe advantages such as relatively effective nontoxic and easyto be absorbed ascorbic acid (vitamin C VC) was suggestedas the candidate antioxidant for avian influenza infections[2] VC scavenges free radicals through a nonenzymaticprocess In the 19th century VC was used to cure cold(influenza infection) encephalitis hepatitis and some otherviral diseases for over a hundred years [25ndash27]

An investigation indicated that 50 of H5N1-infectedpatients in Vietnam did not die Ely [28] found that thesurvivals may take large amounts of VC from their foodswhich may alleviate the inflammatory responses

Influenza patients need 44 g or higher levels of VC tocontrol the virus or alleviate the symptom [25ndash28] Howeverthe common oral dosage of VC tablets is 100ndash300mg a daymuch lower than the influenza treatment requires Oralintakes of VC that exceed 1 g may cause side effects likevomiting stomach cramps diarrhea and nausea [25ndash28]Therefore the VC injection should be used for AIV infectionsNevertheless high doses are still required Additionally long-term use of high level of VC (gt2-3 g a day) may result inscurvy after VC administration is stopped [25ndash27] Thesedrawbacks should be considered before the clinical therapies

24 Other ROS-Related Airway Disorders Chronic Obstruc-tive Pulmonary Disease for Example Chronic obstructivepulmonary disease (COPD) is a major and rapidly increas-ing health problem associated with a chronic inflamma-tory response predominantly in small airways and lungparenchyma Oxidative stress induced by reactive oxygenspecies and nitrogen species plays a central role in thepathophysiology of COPD [29] At the subcellular levelmitochondrial dysfunction (accompanied with a decreasedmitochondrial membrane potential) in patients with COPDis associated with excessive mitochondrial ROS levels whichcontribute to enhanced inflammation and cell hyperpro-liferation Thus targeting mitochondrial ROS represents apromising therapeutic approach in patients with COPD suchas the mitochondria-targeted antioxidant MitoQ (see laterdiscussion of MitoQ) [30]

3 Mitochondrion-Permeable Antioxidants

The most pivotal aspects of antioxidant therapies are thesite concentration effects Antioxidant efficiency is fullydependent on the locus concentration since as many otherpharmaceutical compounds antioxidants also have theirldquopharmacological windowsrdquo Therefore these scavengingquenching compounds should concentrate in the target-tissue (or subcellular site) in order to efficiently removeexceeding ROSwithout eliminating essential redox signallingmolecules such as nitric oxide hydrogen peroxide S-Ni-trosoglutathione (GSNO) and nitronitrosyl-lipid peroxides[24 31] It is well known that cellular redox status defines

















MitoQ





Astaxanthin










N

N

O

O

O

O

S S

O

O

O

O

O

O

O

O

O

O

O

OO

Edaravone

Idebenone

120572-Lipoic acid

Coenzyme Q10

MitoQ

Vitamin E

120573-Carotene

Astaxanthin

OH

OH

H

HO

HO

HO

CH3

CH3

H3C

H3C

6ndash10

P+


































6 Conclusions







Acknowledgments


References






















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
































MitoQ





Astaxanthin










N

N

O

O

O

O

S S

O

O

O

O

O

O

O

O

O

O

O

OO

Edaravone

Idebenone

120572-Lipoic acid

Coenzyme Q10

MitoQ

Vitamin E

120573-Carotene

Astaxanthin

OH

OH

H

HO

HO

HO

CH3

CH3

H3C

H3C

6ndash10

P+


































6 Conclusions







Acknowledgments


References






















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















N

N

O

O

O

O

S S

O

O

O

O

O

O

O

O

O

O

O

OO

Edaravone

Idebenone

120572-Lipoic acid

Coenzyme Q10

MitoQ

Vitamin E

120573-Carotene

Astaxanthin

OH

OH

H

HO

HO

HO

CH3

CH3

H3C

H3C

6ndash10

P+


































6 Conclusions







Acknowledgments


References






















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















































6 Conclusions







Acknowledgments


References






















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article mitochondrion-permeable antioxidants to...

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