1Faculty of Pharmaceutical Sciences, Government College University, Pakistan
2Department of Biochemistry, Hazara University, Pakistan
3Shifa College of Pharmaceutical Sciences, Shifa Tameer e Millat University, Pakistan
Submission: April 11, 2019; Published: May 10, 2019
*Corresponding author: Faiza Naseer, Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan
How to cite this article: Aisha Shehzad, Abida Hussain, Shifa Iman, Sohail Ahmed, Faiza Naseer. Hepatitis B Treatment in Light of Natural Sources. Adv
002 Res Gastroentero Hepatol. 2019; 13(1): 555852. DOI: 10.19080/ARGH.2019.13.555852.
Hepatitis B virus causes acute and chronic inflammation of liver which may leads to hepatocellular carcinoma, cirrhosis and death. Chronic hepatitis B is usually accompanied by the presence of detectable hepatitis B surface antigen (HBsAg) in the blood for greater than 6 months. The presence of hepatitis B envelope antigen (HBeAg) is related to higher rates of viral replication leading to more infection.
Objective: Currently vaccination for prevention of hepatitis B is present and its treatment includes pegylated interferon α, lamivudine, telbivudine and entecavir (nucleoside analogues) and adefovir (nucleotide analogues). This treatment is partially effective and has significant dose dependent side effects and resistance after long term use. Hence, there is a need to develop new more safe and potent agents against hepatitis B from medicinal plants.
This review illustrates the description of medicinal plants, family, their active ingredients, parts and extracts used to treat hepatitis B by their mechanisms. The pharmaceutical companies are striving to discover appropriate alternative and natural inhibitors of targeting different steps of HBV life cycle, because single plant contains an invaluable number of active ingredients which could help in the manufacture of pharmaceutical grade proteins and has wide spectrum of antiviral activity. However, information of antiviral activity of plants is still inadequate.
Hepatitis B, a devastating ailment is distressing over 2 billion population all over the world. Amongst those more than 360 million people suffering from chronic hepatitis B Lavanchy . Every year, the death rate is 0.5-1.2 million people owing to chronic hepatitis, cirrhosis as well as liver cancer according to WHO. In Pakistan, over 15 million peoples have been infected with hepatitis B because of ignorance of vaccination with carrier rate of 3-5% (Ott, 2012). HBV is transmitted via blood transfusion, use of unhygienic tools for shaving, unsterilized instruments during surgery as well as use of contaminated syringes .
Hepatitis is spread via sexual means owing to several sexual partners as well as via diseased mother to children Enemuor et al. . Patients undergoing dialysis for more than two years are at greater risk for hepatitis Wasley et al. . HBV having eight genotypes such as A to H are predominant in numerous areas
globally. Genotype A is prevalent globally; B along with C exists in Asia; D in South Europe; E in Africa as well as F and G in USA. Currently, in Central America genotype H has been invented. White patients with genotype A exhibit greater reduction of HBeAg as well as HBV DNA and unceasing removal of HBeAg seroconversion as compare to patients with genotype D. Patients having genotype B in Asia, exhibit HBeAg seroconversion in early age are at greater risk of developing hepatitis and demonstrate superior response to interferon as compare to patients of genotype C. Patients having genotype B are different from those with genotype C in developing hepatocellular carcinoma Saleem & Sumi et al. [4,5].
Vaccination against hepatitis B is available but infection remains prominent in many countries such as India, eastern Asia and Pakistan Chu et al. . Currently several therapeutic agents for instance pegylated interferon α, telbivudine, lamivudine,adefovir (nucleotide analogues) as well as entecavir (nucleoside
analogues) have been used however owing to their adverse effects
and resistance, medicinal plants have been used to cure hepatitis
B Papatheodoridis et al. . Phyto medicines derived from plants
are used throughout the world particularly in developed countries
such as in Europe and United States.
Pharmaceutical industries are more interested in phytomedicines
due to their importance and demand worldwide. The active
ingredients (e.g. terpenoids, lignans, phenolic compounds, polyphenols
and tannins etc.) obtained from plants are proved to be
effective against HBV Huang & Aftab et al. [9,10]. Therefore, this
review focuses on traditional plants used for treatment of HBV.
Numerous medicinal plants having active ingredients along with
classes for instance terpenoids, alkaloids, lignans, flavonoids as
well as polyphenols, have specific mechanism of actions on HBV
life cycle are demonstrated in Table 1.
HBV, a moderately double stranded (ds) DNA virus has family
of hepadnaviridae. This virus contains nucleocapsid having DNA
genome of 3.2 kb and DNA polymerase. Assembled hepatitis
B core antigen form nucleocapsid which is protected by lipid
envelope comprising of hepatitis B envelope antigen (HBeAg) as
well as hepatitis B surface antigen (HBsAg) Baumert et al. .
HBV replication begins when virus enters host cell and releases its
DNA into nucleus. First step is attachment of virus having pre S1
receptors at its surface and heparin sulfate proteoglycans on liver
cells. Then virus penetrates hepatocytes via endocytosis or fusion
which depends on host factors involving the endosome synthesis.
Nucleocapsid of virus, having partially double stranded relaxed
circular (rcDNA), is secreted into cytoplasm prior to reaching to
nucleus of hepatocytes. Capsid brings its rcDNA to nucleus by
nuclear pore complex (NPC) which is due to association between
nuclear localization signaling (NLS) in C-terminal of capsid protein
and nuclear import receptors (importin-α and β).
After that rcDNA is converted into covalently closed circle DNA
(cccDNA) via viral DNA polymerase. ccc DNA is used as template
for synthesizing of pregenomic RNA which at that time undergo
assembly of viral DNA as well as mRNA results in encoding entirely
new viral proteins. During the reverse transcription of pregenomic
RNA into complementary DNA, the pregenomic RNA is tainted.
Initially HBV surface proteins are formed along with polymerized
in rough endoplasmic reticulum. The proteins are transferred into
ER and pre golgi sections and growing of nucleocapsid is started.
Consequently, whole virus is liberated from host cell for stating
new life cycle Lu & Block .
Boehmeria nivea (BN) is traditionally used for curing
hepatitis B. For screening of activity of ethanolic extract of
leaves of BN against hepatitis B virus in vivo, viremia HBV mice
models which were generated by subcutaneous inoculation of
hepatoma G tumor cell lines (HepG2 2.2.15) for period of 13 days,
were used. A result exhibited that BN extract given orally and
intraperitoneally effectively inhibited the formation of HBV DNA
and HBsAg. However intraperitoneal administration suppressed
serum HBV DNA levels more than oral Chang et al. . In earlier
investigations, ethanolic extract of the roots of BN could diminish
the supernatant hepatitis B virus (HBV) DNA in HBV producing
HepG2 2.2.15 cells.
Also, ethyl acetate and chloroform fractions of BN leaves
inhibited HBeAg and HBsAg secretion in cells of HepG 2.2.15
without any observed cytotoxic effects. Phyllanthus amarus
suppressed hepatitis B virus polymerase activity, decreased
episomal hepatitis B virus DNA content and suppressed releasing
of virus into cells of HepG 2 2.2.15. As a 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-transcriptional down-regulation of the transgene Saleem& Lee et al. [14,15]. Alternanthera philoxeroides have valuable
constituents such as flavones, triterpenoid, anthraquinones,
saponins, phytosterols, and organic acids. Numerous oleanolic
acid analogues from it have potential against HBV. Two new
6-C-boivinopyranosyl flavones along with three known analogues
separated from plant, suppressed HBsAg secretion in HepG 2.2.15
Oenanthe javanica has traditional use in management of
hepatitis in China. Therefore in vitro method i.e. culture of Hep G
2.2.15 cells along with in vivo for instance duck hepatitis B virus
(DHBV) infection model were used to investigate anti-HBV activity.
Results exhibited that phenolic compounds from ethanolic extract
of fruit of this plant significantly blocked HBV replication, HBsAg
and HBeAg secretion in Hep G2.2.15 cells line and suppressed
DHBV replication in ducks in a dose dependent manner. The
concentration of HBsAg and HBeAg in cell culture medium was
measured via use of enzyme immune assay after being treated
with extract for 9 days. DHBV DNA in duck serum was analyzed by
dot blot hybridization assay Huang et al. .
Methanolic extracts of leaves of Enicostemma axillare and
seeds of Terminalia bellerica, blocked HBV DNA polymerase
while methanolic extract of leaves of Hybanthus enneaspermus
blocked HBs Ag binding in plasma of patients in vitro using ELISA
kits Anbalagan et al. . Alcoholic extract of leaves of Acanthus
ilicifolius decreased transaminase levels such as ALT and AST in
duck 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 Naseer & Wei et al.
[18,19]. Gymnema sylvestre demonstrated antiviral activity and
its active ingredients inhibited HBsAg binding and HBV DNA
polymerase Subashini & Rajendran . Methanolic extract of
Mimosa pudica inhibited HBs Ag binding to its receptor at 5mg/ml
(in vitro) which indicated that it had capability to act as novel entry
inhibitor during HBV infection by using hepatitis B positive blood
Rohan et al. . Medicinal plants have certain components that
targets different steps of life cycle of HBV see Figure 1.
The compound LPRP-Et acquired from Liriope platyphylla
roots suppressed HBV by means of monitoring gene expression
besides DNA replication via viral proteins which inhibited NF-kB
(nuclear factor kappa B) pathway Saleem & Huang et al. [22,23].
Traditional Chinese medicinal plants such as Phyllanthus, Salvia
miltiorrhiza, Rheum palmatum L. and Radix astragali and active
ingredients such as oxymatrine, artemisinin and artesunate
and wogonin also are effective against hepatitis B Cui et al. .
Active ingredients obtained from plants of different classes such
as terpenoids, alkaloids, polyphenols, flavonoids and lignans have
specific mechanism of action targeting at different steps of life
cycle of hepatitis B as shown in Figure 2-5 & Table 1 [25-88].
Although there are many drugs available for treatment of
hepatitis B and vaccination is also effective against virus but due
to side effects and resistance associated with these drugs, there is
need to explore safer and most potent drugs. Natural products are
considered good candidates with strong anti-hepatitis B activity.
This review illustrates the description of medicinal plants used
to treat hepatitis B. Forthcoming energies should be dedicated to
enhancing and progress these principal complexes into effective
anti HBV agents for experimental claims. There is limited data
available illustrating mechanism of action of medicinal plants
with anti-hepatitis B activity. Thus, mechanisms of function and
safety of herbs remain incomprehensive and even controversial.
The toxicological data for screening the safety of medicinal plants
is not discussed and people have blind faith in herbal treatment.
For determination of activity of medicinal plants against hepatitis
B, various HBV animal models for instance HBV transgenic mice
and duck model have been used thus, are very expensive but these
representations can only describe a portion of the mechanism
of anti-hepatitis B medicines. In several findings, cell lines such
as HepG 2 2.2.15 within mice were recognized to mimic the
occurrence of HBV viremia, for the reason that viruses produced
from HepG 2 2.2.15 cells have been defined to be transmittable.
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Huang ZM, Yang XB, Cao WB (2001) Effects of Qin ling ke li in the treatment of 90 patients with chronic hepatitis B. Pharm J Chinese People’s Lib Army 17: 41-44.
Anbalagan S, M Sankareswaran, P Rajendran, M Karthikeyan, K Priyadharshini (2015) In vitro screening of anti-HBV properties of selected indian medicinal plants from Kolli hills, Namakkal district of Tamilnadu, India. World J of Pharm and Pharmaceut Sci 4(10): 909-915.
Naseer F, Ahmad S, Ahmad T, Ashraf MZ (2015) Antioxidant Potential of Leaves of Opuntia monacantha Ethanol Extract and Various Fractions: An in vitro 2015. Global Journal of Pharmacology 9(2): 144-149.
Subashini MS, Rajendran P (2015) In vitro screening of anti HBV and anti-HIV properties of Gymnema sylvestre Br leaves from Kolli Hills, Tamilnadu, India. Int J Curr Microbiol Appl Sci 4: 542-547.
Rohan N, Durgadevi P, Mythily VB, Elanchezhiyan M (2014) Prevention of hepatitis b virus (hbv) replication by extracts of Mimosa pudica, a unique Indian medicinal plant. Bio Info Drug Targets 2(1): 20-23.