International Journal of Biological & Medical Research ...€¦ · Objective: Currently vaccination...

A R T I C L E I N F O A B S T R A C T

Keywords:

hepatitisBvirusmedicinalplantsHBsAghepatoprotectiveactivity

HEPATITISBTREATMENTINLIGHTOFNATURALSOURCES

Reviewarticle

Hepatitis B virus causes acute and chronic inflammation of liver which may leads to

hepatocellularcarcinoma,cirrhosisanddeath.ChronichepatitisBisusuallyaccompaniedby

thepresenceofdetectablehepatitisBsurfaceantigen(HBsAg)inthebloodforgreaterthan6

months.ThepresenceofhepatitisBenvelopeantigen(HBeAg)isrelatedtohigherratesofviral

replication leading to more infection. Objective: Currently vaccination for prevention of

hepatitis B is present and its treatment includes pegylated interferon α, lamivudine,

telbivudineandentecavir(nucleosideanalogues)andadefovir(nucleotideanalogues).This

treatmentispartiallyeffectiveandhassignificantdosedependentsideeffectsandresistance

afterlongtermuse.Hence,thereisaneedtodevelopnewmoresafeandpotentagentsagainst

hepatitisBfrommedicinalplants.Thisreviewillustratesthedescriptionofmedicinalplants,

family, their active ingredients, parts and extracts used to treat hepatitis B by their

mechanisms.Thepharmaceuticalcompaniesarestrivingtodiscoverappropriatealternative

and natural inhibitors of targeting different steps of HBV life cycle, because single plant

containsaninvaluablenumberofactiveingredientswhichcouldhelpinthemanufactureof

pharmaceutical grade proteins and has wide spectrum of antiviral activity. However,

informationofantiviralactivityofplantsisstillinadequate.

1.Introduction

Hepatitis B, a devastating ailment is distressing over 2

billionpopulationallovertheworld.Amongstthosemorethan

360millionpeoplesufferingfromchronichepatitisB(Lavanchy,

2004).Everyyear,thedeathrateis0.5-1.2millionpeopleowingto

chronichepatitis, cirrhosisaswell as liver canceraccording to

WHO.InPakistan,over15millionpeopleshavebeeninfectedwith

hepatitisBbecauseofignoranceofvaccinationwithcarrierrateof

3-5%(Ott,2012).HBVistransmittedviabloodtransfusion,useof

unhygienic tools for shaving, unsterilized instruments during

surgery as well as use of contaminated syringes. Hepatitis is

spreadviasexualmeansowingtoseveralsexualpartnersaswell

asviadiseasedmothertochildren(Enemuoretal.,2012).Patients

undergoingdialysisformorethantwoyearsareatgreaterriskfor

hepatitis(Wasleyetal.,2008).HBVhavingeightgenotypessuch

asAtoHarepredominantinnumerousareasglobally.GenotypeA

is prevalent globally;B alongwithC exists inAsia;D in South

Europe;EinAfricaaswellasFandGinUSA.Currently,inCentral

America genotype H has been invented. White patients with

genotypeAexhibit greater reductionofHBeAgaswell asHBV

DNAandunceasingremovalofHBeAgseroconversionascompare

topatientswithgenotypeD.PatientshavinggenotypeBinAsia,

hepatocellular carcinoma (Sumi et al., 2003). exhibit HBeAg

seroconversion in early age are at greater risk of developing

hepatitis and demonstrate superior response to interferon as

comparetopatientsofgenotypeC.PatientshavinggenotypeBare

differentfromthosewithgenotypeCindeveloping

Vaccination against hepatitis B is available but infection

remainsprominentinmanycountriessuchasIndia,easternAsia

and Pakistan (Chu et al., 2013). Currently several therapeutic

agents for instance pegylated interferon α, telbivudine,

lamivudine,adefovir(nucleotideanalogues)aswellasentecavir

(nucleosideanalogues)havebeenusedhoweverowingtotheir

adverseeffectsandresistance,medicinalplantshavebeenusedto

curehepatitisB(Papatheodoridisetal.,2008).Phytomedicines

derivedfromplantsareusedthroughouttheworldparticularlyin

developed countries such as in Europe and United States.

Pharmaceuticalindustriesaremoreinterestedinphytomedicines

due to their importance and demand worldwide. The active

ingredients (e.g. terpenoids, lignans, phenolic compounds,

polyphenolsandtanninsetc.)obtainedfromplantsareprovedto

beeffectiveagainstHBV(Huangetal.,2014;Aftabetal.,2015).

Therefore, this review focuses on traditional plants used for

treatment of HBV. Numerous medicinal plants having active

ingredientsalongwithclassesforinstanceterpenoids,alkaloids,

lignans, flavonoids as well as polyphenols, have specific

mechanismofactionsonHBVlifecyclearedemonstratedinTable

1.

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InternationalJournalofBiological&MedicalResearch

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www.biomedscidirect.comInt J Biol Med ResVolume 10, Issue 2, April 2019

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a a a b a,cAishaShehzad ,AbidaHussain ,ShifaIman ,SohailAhmed FaizaNaseer *,aFacultyofPharmaceuticalSciences,GovernmentCollegeUniversity,Faisalabad,PakistanbDepartmentofBiochemistry,HazaraUniversity,Mansehra,KPK,PakistancShifaCollegeofPharmaceuticalSciences,ShifaTameereMillatUniversity,Islamabad,Pakistan

*CorrespondingAuthor: FaizaNaseer

c

[email protected]

Copyright2011.CurrentSciDirectPublications.IJBMR-Allrightsreserved.

PathogenesisofHepatitisBvirus(HBV)

HBV,amoderatelydoublestranded(ds)DNAvirushas

family of hepadnaviridae. This virus contains nucleocapsid

having DNA genome of 3.2 kb and DNA polymerase.

AssembledhepatitisBcoreantigenformnucleocapsidwhich

is protected by lipid envelope comprising of hepatitis B

envelope antigen (HBeAg) as well as hepatitis B surface

antigen (HBsAg) (Baumert et al., 2014). HBV replication

beginswhenvirusentershostcellandreleasesitsDNAinto

nucleus. First step is attachment of virus having pre S1

receptorsatitssurfaceandheparinsulfateproteoglycanson

livercells.Thenviruspenetrateshepatocytesviaendocytosis

or fusion which depends on host factors involving the

endosomesynthesis.Nucleocapsidofvirus,havingpartially

double stranded relaxed circular (rcDNA), is secreted into

cytoplasmpriortoreachingtonucleusofhepatocytes.Capsid

brings itsrcDNAtonucleusbynuclearporecomplex(NPC)

(Ezzikourietal.,2014)whichisduetoassociationbetween

nuclear localization signaling (NLS) in C-terminal of capsid

protein and nuclear import receptors (importin-α and β).

AfterthatrcDNAisconvertedintocovalentlyclosedcircleDNA

(cccDNA) via viral DNA polymerase. cccDNA is used as

template forsynthesizingofpregenomicRNAwhichat that

timeundergoassemblyofviralDNAaswellasmRNAresultsin

encoding entirely new viral proteins. During the reverse

transcriptionofpregenomicRNA intocomplementaryDNA,

thepregenomicRNAistainted.InitiallyHBVsurfaceproteins

are formed along with polymerized in rough endoplasmic

reticulum.TheproteinsaretransferredintoERandpregolgi

sectionsandgrowingofnucleocapsidisstarted.Consequently,

wholevirusisliberatedfromhostcellforstatingnewlifecycle

(LuandBlock,2004).

HepatitisBvirusandmedicinalplants

Boehmeria nivea (BN) is traditionally used for curing

hepatitis B. For screening of activity of ethanolic extract of

leavesofBNagainsthepatitisBvirusinvivo,viremiaHBVmice

modelswhichweregeneratedbysubcutaneousinoculationof

hepatomaGtumorcelllines(HepG22.2.15)forperiodof13

days,wereused.AresultexhibitedthatBNextractgivenorally

and intraperitoneally effectively inhibited the formation of

HBVDNAandHBsAg.Howeverintraperitonealadministration

suppressedserumHBVDNAlevelsmorethanoral(Changet

al., 2010). In earlier investigations, ethanolic extract of the

rootsofBNcoulddiminishthesupernatanthepatitisBvirus

(HBV)DNAinHBVproducingHepG22.2.15cells.Alsoethyl

acetateandchloroformfractionsofBNleavesinhibitedHBeAg

and HBsAg secretion in cells of HepG 2.2.15 without any

observed cytotoxic effects (Weil et al., 2014). Phyllanthus

amarus suppressed hepatitis B virus polymerase activity,

decreased episomal hepatitis B virus DNA content and

suppressedreleasingofvirusintocellsofHepG22.2.15.Asa

consequence it inhibited HBV replication. G26 hepatitis B

virus transgenic mice did not produce serum HBsAg but

neither HBcAg nor virion particles were used to study

transcriptional control mechanisms. The hepatic HBsAg

mRNA levels were decreased, indicating transcriptional or

post-transcriptionaldown-regulationofthetransgene(Leeet

al., 1996). Alternanthera philoxeroides have valuable

constituentssuchas flavones, triterpenoid,anthraquinones,

saponins,phytosterols,andorganicacids.Numerousoleanolic

acidanaloguesfromithavepotentialagainstHBV.Twonew6-

C-boivinopyranosyl flavones along with three known

analoguesseparatedfromplant,suppressedHBsAgsecretion

inHepG2.2.15cells(Lietal.,2001).

Oenanthejavanicahastraditionaluseinmanagementof

hepatitisinChina.Thereforeinvitromethodi.e.cultureofHep

G2.2.15cellsalongwithinvivoforinstanceduckhepatitisB

virus(DHBV)infectionmodelwereusedtoinvestigateanti-

HBVactivity.Resultsexhibitedthatphenoliccompoundsfrom

ethanolicextractoffruitofthisplantsignificantlyblockedHBV

replication,HBsAgandHBeAgsecretioninHepG2.2.15cells

line and suppressed DHBV replication in ducks in a dose

dependentmanner.TheconcentrationofHBsAgandHBeAgin

cellculturemediumwasmeasuredviauseofenzymeimmune-

assayafterbeingtreatedwithextractfor9days.DHBVDNAin

duck serum was analyzed by dot blot hybridization assay

(Huangetal.,2001). Methanolic extracts of leaves of

Enicostemma axillare and seeds of Terminalia bellerica,

blocked HBV DNA polymerase while methanolic extract of

leavesofHybanthusenneaspermusblockedHBsAgbindingin

plasmaofpatientsinvitrousingELISAkits(Anbalaganetal.,

2015). Alcoholic extract of leaves of Acanthus ilicifolius

decreasedtransaminaselevelssuchasALTandASTinduck

hepatitis B virus serum but did not significantly suppress

hepatitis B virus DNA in ducks. Thus, extract had

hepatoprotective effect against HBV induced liver damage

(Weietal.,2015).Gymnemasylvestredemonstratedantiviral

activityanditsactiveingredientsinhibitedHBsAgbindingand

HBV DNA polymerase (Subashini and Rajendran, 2015).

MethanolicextractofMimosapudicainhibitedHBsAgbinding

toitsreceptorat5mg/ml(invitro)whichindicatedthatithad

capabilitytoactasnovelentryinhibitorduringHBVinfection

by using hepatitis B positive blood (Rohan et al., 2014).

Medicinal plants have certain components that targets

differentstepsoflifecycleofHBVseeFigure1.

The compound LPRP-Et acquired from Liriope

platyphylla roots suppressed HBV bymeans ofmonitoring

gene expression besides DNA replication via viral proteins

which inhibited NF-kB (nuclear factor kappa B) pathway

(Huangetal.,2014).TraditionalChinesemedicinalplantssuch

asPhyllanthus,Salviamiltiorrhiza,RheumpalmatumL.and

Radix astragali and active ingredients such as oxymatrine,

artemisinin and artesunate and wogonin also are effective

against hepatitis B (Cui X et al., 2010). Active ingredients

obtainedfromplantsofdifferentclassessuchasterpenoids,

6759AishaShehzadetal./IntJBiolMedRes.10(2):6758-6772

alkaloids,polyphenols,flavonoidsandlignanshavespecificmechanismofactiontargetingatdifferentstepsoflifecycleofhepatitis

Basshowninfigure2,3,4and5.

Table2:Plantswiththeirclasses&activeingredientsusedintreatmentofHepatitis


6764

AishaShehzadetal./IntJBiolMedRes.10(2):6758-6772

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