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TRANSCRIPT
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
International Journal ofBIOLOGICAL AND MEDICAL RESEARCH
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
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
6760AishaShehzadetal./IntJBiolMedRes.10(2):6758-6772
6761AishaShehzadetal./IntJBiolMedRes.10(2):6758-6772
6762AishaShehzadetal./IntJBiolMedRes.10(2):6758-6772
6763AishaShehzadetal./IntJBiolMedRes.10(2):6758-6772
6764
AishaShehzadetal./IntJBiolMedRes.10(2):6758-6772
6765AishaShehzadetal./IntJBiolMedRes.10(2):6758-6772
6766AishaShehzadetal./IntJBiolMedRes.10(2):6758-6772
6767AishaShehzadetal./IntJBiolMedRes.10(2):6758-6772
6768AishaShehzadetal./IntJBiolMedRes.10(2):6758-6772
6769AishaShehzadetal./IntJBiolMedRes.10(2):6758-6772
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